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Amino Acid Metabolism in Human Health and Disease

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutrition and Metabolism".

Deadline for manuscript submissions: closed (20 January 2023) | Viewed by 42773

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Dr. Evasio Pasini

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1. Department of Clinical and Experimental Sciences, University of Brescia, 25100 Brescia, Italy
2. Italian Association of Functional Medicine, 20855 Lesmo, MB, Italy
Interests: metabolism; amino acid; sarcopenia; chronic diseases
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Prof. Dr. Francesco S. Dioguardi

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Department of Internal Medicine, University of Cagliari, Cagliari, Italy
Interests: internal medicine; clinical nutrition; molecular biology
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Prof. Dr. Giovanni Corsetti

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Division of Human Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25023 Brescia, Italy
Interests: cell metabolism; amino acids; immunohistochemistry; electron microscopy
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Special Issue Information

Dear Colleagues,

As we known, amino acids (AAs) are the molecular constituents of structural, globular and enzymatic proteins, which are fundamental molecules of cell life.

Recent data show that AAs and protein metabolisms are markedly altered in both acute and chronic diseases influencing the functions of many organs and/or systems.

The purpose of this Special Issue is to review and update our knowledge on the effects of AA metabolisms in both health and diseases.

Dr. Evasio Pasini
Prof. Dr. Francesco S. Dioguardi
Prof. Dr. Giovanni Corsetti
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

amino acid
nutrition
metabolism
inflammation
fat tissue
connective tissue
hemoglobin
albunine
sarcopenia
chemotherapies
cancer
COVID-19
exercise
aging

Published Papers (13 papers)

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Editorial

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3 pages, 197 KiB

Open AccessEditorial

Behind Protein Synthesis: Amino Acids—Metabokine Regulators of Both Systemic and Cellular Metabolism

by Evasio Pasini, Giovanni Corsetti and Francesco S. Dioguardi

Nutrients 2023, 15(13), 2892; https://doi.org/10.3390/nu15132892 - 26 Jun 2023

Viewed by 987

Abstract

Recent scientific research suggests that amino acids (AA) are not only the “building bricks” of protein synthesis but may also be considered “metabokines” [...] Full article

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

Research

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17 pages, 5493 KiB

Open AccessArticle

Essential Amino Acids-Rich Diet Increases Cardiomyocytes Protection in Doxorubicin-Treated Mice

by Giovanni Corsetti, Claudia Romano, Evasio Pasini, Tiziano Scarabelli, Carol Chen-Scarabelli and Francesco S. Dioguardi

Nutrients 2023, 15(10), 2287; https://doi.org/10.3390/nu15102287 - 12 May 2023

Cited by 2 | Viewed by 2048

Abstract

Background: Doxorubicin (Doxo) is a widely prescribed drug against many malignant cancers. Unfortunately, its utility is limited by its toxicity, in particular a progressive induction of congestive heart failure. Doxo acts primarily as a mitochondrial toxin, with consequent increased production of reactive oxygen species (ROS) and attendant oxidative stress, which drives cardiac dysfunction and cell death. A diet containing a special mixture of all essential amino acids (EAAs) has been shown to increase mitochondriogenesis, and reduce oxidative stress both in skeletal muscle and heart. So, we hypothesized that such a diet could play a favorable role in preventing Doxo-induced cardiomyocyte damage. Methods: Using transmission electron microscopy, we evaluated cells’ morphology and mitochondria parameters in adult mice. In addition, by immunohistochemistry, we evaluated the expression of pro-survival marker Klotho, as well as markers of necroptosis (RIP1/3), inflammation (TNFα, IL1, NFkB), and defense against oxidative stress (SOD1, glutathione peroxidase, citrate synthase). Results: Diets with excess essential amino acids (EAAs) increased the expression of Klotho and enhanced anti-oxidative and anti-inflammatory responses, thereby promoting cell survival. Conclusion: Our results further extend the current knowledge about the cardioprotective role of EAAs and provide a novel theoretical basis for their preemptive administration to cancer patients undergoing chemotherapy to alleviate the development and severity of Doxo-induced cardiomyopathy. Full article

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

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25 pages, 1392 KiB

Open AccessArticle

Pretreatment Glasgow Prognostic Score Correlated with Serum Histidine Level and Three-Year Mortality of Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma and Optimal Performance Status

by Kun-Yun Yeh, Chao-Hung Wang, Hang Huong Ling, Chia-Lin Peng, Zih-Syuan Chen and Simon Hsia

Nutrients 2022, 14(17), 3475; https://doi.org/10.3390/nu14173475 - 24 Aug 2022

Cited by 5 | Viewed by 1854

Abstract

Few prospective cohort trials have investigted the effect of pretreatment nutritional and inflammatory status on the clinical outcome of patients with cancer and optimal performance status and assessed the interplay between nutrition, inflammation, body composition, and circulating metabolites before treatment. Here, 50 patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were prospectively recruited along with 43 healthy participants. Before concurrent chemoradiotherapy, compared with healthy controls, the cancer group showed lower levels of histidine, leucine, and phenylalanine and had low values in anthropometric and body composition measurements; however, the group displayed higher ornithine levels, more malnutrition, and severe inflammation. Pretreatment advanced Glasgow prognostic score (1 and 2) status was the sole prognostic factor for 3-year mortality rate and was associated with age and serum histidine levels in patients with cancer. Thus, even at the same tumor stage and ECOG PS, patients with LAHNSCC, poor nutrition, and high inflammation severity at baseline may have inferior survival outcomes than those with adequate nutrition and low inflammation severity. Assessment of pretreatment nutritional and inflammatory status should be included in the enrollment criteria in future studies. Full article

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

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19 pages, 2915 KiB

Open AccessArticle

Artificial Diets Based on Selective Amino Acid Restriction versus Capecitabine in Mice with Metastatic Colon Cancer

by Julio José Jiménez-Alonso, Emilio Guillén-Mancina, José Manuel Calderón-Montaño, Víctor Jiménez-González, Patricia Díaz-Ortega, Estefanía Burgos-Morón and Miguel López-Lázaro

Nutrients 2022, 14(16), 3378; https://doi.org/10.3390/nu14163378 - 17 Aug 2022

Cited by 5 | Viewed by 2366

Abstract

New therapies are needed to improve the low survival rates of patients with metastatic colon cancer. Evidence suggests that amino acid (AA) restriction can be used to target the altered metabolism of cancer cells. In this work, we evaluated the therapeutic potential of selective AA restriction in colon cancer. After observing anticancer activity in vitro, we prepared several artificial diets and evaluated their anticancer activity in two challenging animal models of metastatic colon cancer. These models were established by injecting CT26.WT murine colon cancer cells in the peritoneum (peritoneal dissemination) or in the tail vein (pulmonary metastases) of immunocompetent BALB/cAnNRj mice. Capecitabine, which is a first-line treatment for patients with metastatic colon cancer, was also evaluated in these models. Mice fed diet TC1 (a diet lacking 10 AAs) and diet TC5 (a diet with 6% casein, 5% glutamine, and 2.5% leucine) lived longer than untreated mice in both models; several mice survived the treatment. Diet TC5 was better than several cycles of capecitabine in both cancer models. Cysteine supplementation blocked the activity of diets TC1 and TC5, but cysteine restriction was not sufficient for activity. Our results indicated that artificial diets based on selective AA restriction have therapeutic potential for colon cancer. Full article

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

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13 pages, 6831 KiB

Open AccessArticle

Effects of Amino Acids Supplementation on Lipid and Glucose Metabolism in HepG2 Cells

by Shuang Wang, Soohan Jung and Kwang Suk Ko

Nutrients 2022, 14(15), 3050; https://doi.org/10.3390/nu14153050 - 25 Jul 2022

Cited by 7 | Viewed by 2838

Abstract

Non-alcoholic fatty liver disease and type 2 diabetes are representing symptoms of metabolic syndrome, which is often accompanied with hepatic fat accumulation and insulin resistance. Since liver is the major site of glucose and lipid metabolism, this study aimed to understand the effects of SCAAs and BCAAs supplementations on glucose and lipid metabolism in HepG2 cells. These cells were pretreated with SAMe, betaine, taurine, and BCAA for 24 h, followed by treatments of a high concentration of glucose (50 mM) or palmitic acid (PA, 0.5 mM) for 48 h to simulate high-glucose and high-fat environments. Pretreatment of BCAA and SCAAs inhibited the fat accumulation. At the transcriptional level, glucose and PA treatment led to significant increase of mRNA gluconeogenic enzyme. The mRNA expression level of GLUT2 was decreased by 20% in the SAMe-treated group and inhibited glucose synthesis by reducing the level of gluconeogenic enzyme. After SAMe or BCAA pretreatment, the mRNA expression of lipogenic enzymes was decreased. The PPAR-γ expression was increased after BCAA pretreatment, but SAMe not only downregulated the expression of PPAR-γ, but also inhibited the expression of ChREBP approximately 20% and SREBP-1c decreased by about 15%. Taken together, the effect of SAMe on glucose and lipid metabolism is significant especially on inhibiting hepatic lipogenesis and gluconeogenesis under the metabolic syndrome environment. Full article

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

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17 pages, 3736 KiB

Open AccessArticle

Essential Amino Acids-Rich Diet Decreased Adipose Tissue Storage in Adult Mice: A Preliminary Histopathological Study

by Giovanni Corsetti, Claudia Romano, Silvia Codenotti, Evasio Pasini, Alessandro Fanzani and Francesco S. Dioguardi

Nutrients 2022, 14(14), 2915; https://doi.org/10.3390/nu14142915 - 15 Jul 2022

Cited by 3 | Viewed by 2217

Abstract

Background: Excess body adipose tissue accumulation is a common and growing health problem caused by an unbalanced diet and/or junk food. Although the effects of dietary fat and glucose on lipid metabolism regulation are well known, those of essential amino acids (EAAs) have been poorly investigated. Our aim was to study the influence of a special diet containing all EAAs on retroperitoneal white adipose tissue (rpWAT) and interscapular brown adipose tissue (BAT) of mice. Methods: Two groups of male Balb/C mice were used. The first was fed with a standard diet. The second was fed with an EAAs-rich diet (EAARD). After 3 weeks, rpWAT and BAT were removed and prepared for subsequent immunohistochemical analysis. Results: EAARD, although consumed significantly less, moderately reduced body weight and BAT, but caused a massive reduction in rpWAT. Conversely, the triceps muscle increased in mass. In rpWAT, the size of adipocytes was very small, with increases in leptin, adiponectin and IL-6 immunostaining. In BAT, there was a reduction in lipid droplet size and a simultaneous increase in UCP-1 and SIRT-3. Conclusions: A diet containing a balanced mixture of free EAA may modulate body adiposity in mice, promoting increased thermogenesis. Full article

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

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17 pages, 860 KiB

Open AccessArticle

Exploring the Barriers and Motivators to Dietary Adherence among Caregivers of Children with Disorders of Amino Acid Metabolism (AAMDs): A Qualitative Study

by Jing Ying Lim, Roslee Rajikan, Noh Amit, Nazlena Mohamad Ali, Haslina Abdul Hamid, Huey Yin Leong, Maslina Mohamad, Bi Qi Koh and Aini Musa

Nutrients 2022, 14(12), 2535; https://doi.org/10.3390/nu14122535 - 18 Jun 2022

Cited by 3 | Viewed by 2695

Abstract

Dietary intervention is generally accepted as the mainstay of treatment for patients with disorders of amino acid metabolism (AAMDs). However, dietary adherence to a low-protein diet is always reported as a common challenge among these patients. This study explored the perception of barriers and motivators to dietary adherence among caregivers of AAMD patients in Malaysia. Twenty caregivers of children with AAMDs receiving ongoing treatment at the genetic clinic participated in an online focus group discussion from November to December 2021. Findings showed a total of five interrelated main themes identified from focus group discussion (FGD) exploring parents’ experiences related to the management of their child’s daily diet. The barriers to dietary adherence were burden of dietary treatment, diet and dietary behavior, parenting challenges, limited knowledge related to dietary treatment, and challenges in healthcare system delivery. Key factors facilitating good dietary adherence include good knowledge of dietary treatment, parental coping strategies, social coping, and dietary behavior. In conclusion, despite the existence of several barriers to the implementation of dietary treatment, caregivers managed to use a wide range of coping strategies to overcome some, if not all, of the challenges. The important next step is to develop, in conjunction with multidisciplinary healthcare professionals, feasible implementation strategies that could address these barriers and at the same time improve the quality of life of caregivers. Full article

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

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Review

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30 pages, 1620 KiB

Open AccessReview

Extensive Summary of the Important Roles of Indole Propionic Acid, a Gut Microbial Metabolite in Host Health and Disease

by Hui Jiang, Congying Chen and Jun Gao

Nutrients 2023, 15(1), 151; https://doi.org/10.3390/nu15010151 - 28 Dec 2022

Cited by 22 | Viewed by 4514

Abstract

Increasing evidence suggests that metabolites produced by the gut microbiota play a crucial role in host–microbe interactions. Dietary tryptophan ingested by the host enters the gut, where indole-like metabolites such as indole propionic acid (IPA) are produced under deamination by commensal bacteria. Here, we summarize the IPA-producing bacteria, dietary patterns on IPA content, and functional roles of IPA in various diseases. IPA can not only stimulate the expression of tight junction (TJ) proteins to enhance gut barrier function and inhibit the penetration of toxic factors, but also modulate the immune system to exert anti-inflammatory and antioxidant effects to synergistically regulate body physiology. Moreover, IPA can act on target organs through blood circulation to form the gut–organ axis, which helps maintain systemic homeostasis. IPA shows great potential for the diagnosis and treatment of various clinical diseases, such as NAFLD, Alzheimer’s disease, and breast cancer. However, the therapeutic effect of IPA depends on dose, target organ, or time. In future studies, further work should be performed to explore the effects and mechanisms of IPA on host health and disease to further improve the existing treatment program. Full article

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

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23 pages, 2322 KiB

Open AccessReview

The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia

by Regina F. Nasyrova, Aiperi K. Khasanova, Kuanysh S. Altynbekov, Azat R. Asadullin, Ekaterina A. Markina, Arseny J. Gayduk, German A. Shipulin, Marina M. Petrova and Natalia A. Shnayder

Nutrients 2022, 14(23), 5142; https://doi.org/10.3390/nu14235142 - 2 Dec 2022

Cited by 7 | Viewed by 3736

Abstract

Schizophrenia (Sch) is a severe and widespread mental disorder. Antipsychotics (APs) of the first and new generations as the first-line treatment of Sch are not effective in about a third of cases and are also unable to treat negative symptoms and cognitive deficits of schizophrenics. This explains the search for new therapeutic strategies for a disease-modifying therapy for treatment-resistant Sch (TRS). Biological compounds are of great interest to researchers and clinicians, among which D-Serine (D-Ser) and D-Aspartate (D-Asp) are among the promising ones. The Sch glutamate theory suggests that neurotransmission dysfunction caused by glutamate N-methyl-D-aspartate receptors (NMDARs) may represent a primary deficiency in this mental disorder and play an important role in the development of TRS. D-Ser and D-Asp are direct NMDAR agonists and may be involved in modulating the functional activity of dopaminergic neurons. This narrative review demonstrates both the biological role of D-Ser and D-Asp in the normal functioning of the central nervous system (CNS) and in the pathogenesis of Sch and TRS. Particular attention is paid to D-Ser and D-Asp as promising components of a nutritive disease-modifying therapy for TRS. Full article

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

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15 pages, 626 KiB

Open AccessReview

Leucine Supplementation in Cancer Cachexia: Mechanisms and a Review of the Pre-Clinical Literature

by Anna G. Beaudry and Michelle L. Law

Nutrients 2022, 14(14), 2824; https://doi.org/10.3390/nu14142824 - 9 Jul 2022

Cited by 18 | Viewed by 3511

Abstract

Cancer cachexia (CC) is a complex syndrome of bodily wasting and progressive functional decline. Unlike starvation, cachexia cannot be reversed by increased energy intake alone. Nonetheless, targeted nutritional support is a necessary component in multimodal syndrome management. Due to the highly catabolic nature of cancer cachexia, amino acid supplementation has been proposed. Interestingly, leucine has been found to increase protein synthesis and decrease protein degradation via mTORC1 pathway activation. Multiple pre-clinical studies have explored the impact of leucine supplementation in cachectic tumor-bearing hosts. Here, we provide an overview of leucine’s proposed modes of action to preserve lean mass in cachexia and review the current pre-clinical literature related to leucine supplementation during CC. Current research indicates that a leucine-rich diet may attenuate CC symptomology; however, these works are difficult to compare due to methodological differences. There is need for further pre-clinical work exploring leucine’s potential ability to modulate protein turnover and immune response during CC, as well as the impact of additive leucine on tumor growth. Full article

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

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11 pages, 514 KiB

Open AccessReview

Recommendations for the Diagnosis and Therapeutic Management of Hyperammonaemia in Paediatric and Adult Patients

by Amaya Bélanger-Quintana, Francisco Arrieta Blanco, Delia Barrio-Carreras, Ana Bergua Martínez, Elvira Cañedo Villarroya, María Teresa García-Silva, Rosa Lama More, Elena Martín-Hernández, Ana Moráis López, Montserrat Morales-Conejo, Consuelo Pedrón-Giner, Pilar Quijada-Fraile, Sinziana Stanescu and Mercedes Martínez-Pardo Casanova

Nutrients 2022, 14(13), 2755; https://doi.org/10.3390/nu14132755 - 2 Jul 2022

Cited by 12 | Viewed by 3762

Abstract

Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating the prognosis of its triggering disease. In small children it is a rare condition usually associated to inborn errors of the metabolism. As age rises, and especially in adults, it may be precipitated by heterogeneous causes such as liver disease, drugs, urinary infections, shock, or dehydration. In older patients, it is often overlooked, or its danger minimized. This protocol was drafted to provide an outline of the clinical measures required to normalise ammonia levels in patients of all ages, aiming to assist clinicians with no previous experience in its treatment. It is an updated protocol developed by a panel of experts after a review of recent publications. We point out the importance of frequent monitoring to assess the response to treatment, the nutritional measures that ensure not only protein restriction but adequate caloric intake and the need to avoid delays in the use of specific pharmacological therapies and, especially, extrarenal clearance measures. In this regard, we propose initiating haemodialysis when ammonia levels are >200–350 µmol/L in children up to 18 months of age and >150–200 µmol/L after that age. Full article

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

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19 pages, 544 KiB

Open AccessEditor’s ChoiceReview

The Potential of L-Arginine in Prevention and Treatment of Disturbed Carbohydrate and Lipid Metabolism—A Review

by Aleksandra Szlas, Jakub Michał Kurek and Zbigniew Krejpcio

Nutrients 2022, 14(5), 961; https://doi.org/10.3390/nu14050961 - 24 Feb 2022

Cited by 32 | Viewed by 8346

Abstract

L-arginine, an endogenous amino acid, is a safe substance that can be found in food. The compound is involved in synthesis of various products responsible for regulatory functions in the body. Particularly noteworthy is, among others, nitric oxide, a signaling molecule regulating carbohydrate and lipid metabolism. The increasing experimental and clinical data indicate that L-arginine supplementation may be helpful in managing disturbed metabolism in obesity, regulate arterial blood pressure or alleviate type 2 diabetes symptoms, but the mechanisms underlying these effects have not been sufficiently elucidated. This review aims to present the up-to-date information regarding the current uses and health-promoting potential of L-arginine, its effects on nitric oxide, carbohydrate and lipid metabolisms, based on the results of in vivo, in vitro studies, and clinical human trials. Available literature suggests that L-arginine may have beneficial effects on human health. However, some studies found that higher dietary L-arginine is associated with worsening of an existing disease or may be potential risk factor for development of some diseases. The mechanisms of regulatory effects of L-arginine on carbohydrate and lipid metabolism have not been fully understood and are currently under investigation. Full article

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

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Other

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16 pages, 3173 KiB

Open AccessBrief Report

Nutritional Niches of Cancer Therapy-Induced Senescent Cells

by Àngela Llop-Hernández, Sara Verdura, Elisabet Cuyàs and Javier A. Menendez

Nutrients 2022, 14(17), 3636; https://doi.org/10.3390/nu14173636 - 2 Sep 2022

Cited by 6 | Viewed by 2445

Abstract

Therapy-induced senescence (TIS) is a state of stable proliferative arrest of both normal and neoplastic cells that is triggered by exposure to anticancer treatments. TIS cells acquire a senescence-associated secretory phenotype (SASP), which is pro-inflammatory and actively promotes tumor relapse and adverse side-effects in patients. Here, we hypothesized that TIS cells adapt their scavenging and catabolic ability to overcome the nutritional constraints in their microenvironmental niches. We used a panel of mechanistically-diverse TIS triggers (i.e., bleomycin, doxorubicin, alisertib, and palbociclib) and Biolog Phenotype MicroArrays to identify (among 190 different carbon and nitrogen sources) candidate metabolites that support the survival of TIS cells in limiting nutrient conditions. We provide evidence of distinguishable TIS-associated nutrient consumption profiles involving a core set of shared (e.g., glutamine) and unique (e.g., glucose-1-phosphate, inosine, and uridine) nutritional sources after diverse senescence-inducing interventions. We also observed a trend for an inverse correlation between the intensity of the pro-inflammatory SASP provoked by different TIS agents and diversity of compensatory nutritional niches utilizable by senescent cells. These findings support the detailed exploration of the nutritional niche as a new metabolic dimension to understand and target TIS in cancer. Full article

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

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