bims-medica 2024-05-12 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–05–12
twenty-six papers selected by
Brett Chrest, East Carolina University

Reprogrammed mitochondria: a central hub of cancer cell metabolism.
Acetoacetate and D- and L-β-hydroxybutyrate have distinct effects on basal and insulin-stimulated glucose uptake in L6 skeletal muscle cells.
Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
Fructose-induced metabolic reprogramming of cancer cells.
Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use.
Nutritional status, body composition and diet quality in children with cancer.
Tryptophan deficiency induced by indoleamine 2,3-dioxygenase 1 results in glucose transporter 1-dependent promotion of aerobic glycolysis in pancreatic cancer.
Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition.
The glucose transporter GLUT12, a new actor in obesity and cancer.
Unveiling the altered metabolic pathways induced by nivolumab in non-small cell lung cancer via GC-MS metabolomics approach coupled with multivariate analysis.
The Warburg Effect Reinterpreted 100 yr on: A First-Principles Stoichiometric Analysis and Interpretation from the Perspective of ATP Metabolism in Cancer Cells.
Measuring single-cell density with high throughput enables dynamic profiling of immune cell and drug response from patient samples.
Time-dependent proteomics and drug response in expanding cancer cells.
Effectiveness of dietetic care for cancer survivors in the primary care setting: A systematic review and meta-analysis of randomized controlled trials.
MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions.
Acute Pancreatitis Associated With Ketogenic Diet: A Case Report.
Characterizing human postprandial metabolic response using multiway data analysis.
Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy.
Short-term high-calorie high-fat feeding induces hyperinsulinemia and blunts skeletal muscle microvascular blood flow in healthy humans.
BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine.
High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.
Cell competition promotes metastatic intestinal cancer through a multistage process.
Exercise-induced changes in myocardial glucose utilization during periods of active cardiac growth.
Measuring response to therapy in AML: Difference from normal flow cytometry vs RQ-PCR.
A Review of Plant-Based Diets for Obesity Management.
The Significant Impact of High-Fat, Low-Carbohydrate Ketogenic Diet on Serum Lipid Profile and Atherosclerotic Cardiovascular Disease Risk in Overweight and Obese Adults.

Biochem Soc Trans. 2024 May 08. pii: BST20231090. [Epub ahead of print]

Reprogrammed mitochondria: a central hub of cancer cell metabolism.

Fabio Ciccarone, Maria Rosa Ciriolo.

  Mitochondria represent the metabolic hub of normal cells and play this role also in cancer but with different functional purposes. While cells in differentiated tissues have the prerogative of maintaining basal metabolism and support the biosynthesis of specialized products, cancer cells have to rewire the metabolic constraints imposed by the differentiation process. They need to balance the bioenergetic supply with the anabolic requirements that entail the intense proliferation rate, including nucleotide and membrane lipid biosynthesis. For this aim, mitochondrial metabolism is reprogrammed following the activation of specific oncogenic pathways or due to specific mutations of mitochondrial proteins. The main process leading to mitochondrial metabolic rewiring is the alteration of the tricarboxylic acid cycle favoring the appropriate orchestration of anaplerotic and cataplerotic reactions. According to the tumor type or the microenvironmental conditions, mitochondria may decouple glucose catabolism from mitochondrial oxidation in favor of glutaminolysis or disable oxidative phosphorylation for avoiding harmful production of free radicals. These and other metabolic settings can be also determined by the neo-production of oncometabolites that are not specific for the tissue of origin or the accumulation of metabolic intermediates able to boost pro-proliferative metabolism also impacting epigenetic/transcriptional programs. The full characterization of tumor-specific mitochondrial signatures may provide the identification of new biomarkers and therapeutic opportunities based on metabolic approaches.

Keywords:  TCA cycle; metabolic disorders; mitochondrial dysfunction

DOI:  https://doi.org/10.1042/BST20231090
Am J Physiol Cell Physiol. 2024 May 06.

Acetoacetate and D- and L-β-hydroxybutyrate have distinct effects on basal and insulin-stimulated glucose uptake in L6 skeletal muscle cells.

Hannah Khouri, Mathilde Roberge, John R Ussher, Céline Aguer.

  Ketone bodies (acetoacetate and β-hydroxybutyrate) are oxidized in skeletal muscle mainly during fasting as an alternative source of energy to glucose. Prior studies suggest that there is a negative relationship between increased muscle ketolysis and muscle glucose metabolism in mice with obesity and/or type 2 diabetes. Therefore, we investigated the connection between increased ketone body exposure and muscle glucose metabolism by measuring the effect of a 3-hour exposure to ketone bodies on glucose uptake in differentiated L6 myotubes. We showed that exposure to acetoacetate at a typical concentration (0.2 mM) resulted in increased basal glucose uptake in L6 myotubes, which was dependent on increased membrane GLUT4 translocation. Basal and insulin-stimulated glucose uptake was also increased with a concentration of acetoacetate reflective of diabetic ketoacidosis or a ketogenic diet (1 mM). We found that β-hydroxybutyrate had a variable effect on basal glucose uptake, in that a racemic mixture of the two β-hydroxybutyrate enantiomers (D and L) appeared to decrease basal glucose uptake, while 3 mM D-β-hydroxybutyrate alone increased basal glucose uptake. However, the effects of the ketone bodies individually were not observed when acetoacetate was present in combination with β-hydroxybutyrate. These results provide insight that will help elucidate the effect of ketone bodies in the context of specific metabolic diseases and nutritional states (e.g., type 2 diabetes and ketogenic diets).

Keywords:  acetoacetate; glucose uptake; ketone bodies; skeletal muscle; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00718.2023
bioRxiv. 2024 Apr 28. pii: 2024.04.25.591150. [Epub ahead of print]

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.

David R Ziehr, Fei Li, K Mark Parnell, Nathan M Krah, Kevin J Leahy, Christelle Guillermier, Jack Varon, Rebecca M Baron, Bradley A Maron, Nancy J Philp, Lida P Hariri, Edy Y Kim, Matthew L Steinhauser, Rachel S Knipe, Jared Rutter, William M Oldham.

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo . Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.
SUMMARY: Small molecule inhibitors of lactate transporters, including the novel MCT4 inhibitor VB253, reprogram fibroblast metabolism to prevent myofibroblast differentiation and decrease bleomycin-induced pulmonary fibrosis.

DOI: https://doi.org/10.1101/2024.04.25.591150
Front Immunol. 2024 ;15 1375461

Fructose-induced metabolic reprogramming of cancer cells.

Kenneth K Y Ting.

  Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.

Keywords:  GLUT5; cancer; fructose; glycolysis; ketohexokinase (KHK); metabolic reprogramming; metabolism; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2024.1375461
Cells. 2024 May 04. pii: 784. [Epub ahead of print]13(9):

Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use.

Filippo Annoni, Elisa Gouvea Bogossian, Lorenzo Peluso, Fuhong Su, Anthony Moreau, Leda Nobile, Stefano Giuseppe Casu, Elda Diletta Sterchele, Lorenzo Calabro, Michele Salvagno, Mauro Oddo, Fabio Silvio Taccone.

  Cardiac arrest survivors suffer the repercussions of anoxic brain injury, a critical factor influencing long-term prognosis. This injury is characterised by profound and enduring metabolic impairment. Ketone bodies, an alternative energetic resource in physiological states such as exercise, fasting, and extended starvation, are avidly taken up and used by the brain. Both the ketogenic diet and exogenous ketone supplementation have been associated with neuroprotective effects across a spectrum of conditions. These include refractory epilepsy, neurodegenerative disorders, cognitive impairment, focal cerebral ischemia, and traumatic brain injuries. Beyond this, ketone bodies possess a plethora of attributes that appear to be particularly favourable after cardiac arrest. These encompass anti-inflammatory effects, the attenuation of oxidative stress, the improvement of mitochondrial function, a glucose-sparing effect, and the enhancement of cardiac function. The aim of this manuscript is to appraise pertinent scientific literature on the topic through a narrative review. We aim to encapsulate the existing evidence and underscore the potential therapeutic value of ketone bodies in the context of cardiac arrest to provide a rationale for their use in forthcoming translational research efforts.

Keywords:  anoxic brain injury; cerebral metabolism; heart arrest; ischemia–reperfusion; ketone bodies

DOI:  https://doi.org/10.3390/cells13090784
Front Oncol. 2024 ;14 1389657

Nutritional status, body composition and diet quality in children with cancer.

Magdalena Schab, Szymon Skoczen.

  During cancer treatment, nutritional status disorders such as malnutrition or obesity affect the tolerance of cancer treatment, quality of life, but also the pharmacokinetics of drugs. It is hypothesized that changes in fat and lean body mass can modify chemotherapy volume distribution, metabolism and clearance. In children with cancer, lean body mass decreases or remains low during treatment and fat mass increases. Body composition is influenced by the cancer itself, aggressive multimodal-therapies, changes in metabolism, unbalanced diet and reduced physical activity. Due to the side effects of treatment, including changes in the sense of taste and smell, nausea, vomiting, diarrhea, and stress, eating according to recommendation for macronutrients and micronutrients is difficult. Research indicates that throughout cancer treatment, the consumption of fruits, vegetables, and dairy products tends to be insufficient, whereas there is an elevated intake of sugar and unhealthy snacks. Children exhibit a preference for high-carbohydrate, salty, and strongly flavored products. This review revealed the importance of body composition and its changes during cancer treatment in children, as well as eating habits and diet quality.

Keywords:  body composition; childhood cancer; diet quality; dietary habits; nutritional status

DOI:  https://doi.org/10.3389/fonc.2024.1389657
MedComm (2020). 2024 May;5(5): e555

Tryptophan deficiency induced by indoleamine 2,3-dioxygenase 1 results in glucose transporter 1-dependent promotion of aerobic glycolysis in pancreatic cancer.

Heng Liang, Jiani Zhan, Yunqiu Chen, Zikang Xing, Zhen Ning Tony He, Yuying Liu, Xuewen Li, Yijia Chen, Zhiyao Li, Chunxiang Kuang, Dan Yang, Qing Yang.

  Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2), pyruvate kinase (PK), lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1-glycolysis-apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.

Keywords:  Indoleamine 2,3‐dioxygenase 1 (IDO1); aerobic glycolysis; apoptosis; glucose transporter 1 (GLUT1); pancreatic cancer

DOI:  https://doi.org/10.1002/mco2.555
J Transl Med. 2024 May 07. 22(1): 431

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition.

Erwan Beauchamp, Jay M Gamma, Christopher R Cromwell, Eman W Moussa, Rony Pain, Morris A Kostiuk, Claudia Acevedo-Morantes, Aishwarya Iyer, Megan Yap, Krista M Vincent, Lynne M Postovit, Olivier Julien, Basil P Hubbard, John R Mackey, Luc G Berthiaume.

   BACKGROUND: In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs.
METHODS AND RESULTS: Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes.
CONCLUSIONS: Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.

Keywords:  Cancer; Complex I; N-myristoylation; N-myristoyltransferase; NDUFAF4; NMT inhibitor (NMTI); Oxidative phosphorylation; PCLX-001 (zelenirstat); Respiration

DOI:  https://doi.org/10.1186/s12967-024-05150-6
J Physiol Biochem. 2024 May 10.

The glucose transporter GLUT12, a new actor in obesity and cancer.

Miguel Burgos, Eva Gil-Iturbe, Adrián Idoate-Bayón, Rosa Castilla-Madrigal, Maria J Moreno-Aliaga, M Pilar Lostao.

  Obesity constitutes a global health epidemic which worsens the main leading death causes such as type 2 diabetes, cardiovascular diseases, and cancer. Changes in the metabolism in patients with obesity frequently lead to insulin resistance, along with hyperglycemia, dyslipidemia and low-grade inflammation, favoring a more aggressive tumor microenvironment. One of the hallmarks of cancer is the reprogramming of the energy metabolism, in which tumor cells change oxidative phosphorylation to aerobic glycolysis or "Warburg effect". Aerobic glycolysis is faster than oxidative phosphorylation, but less efficient in terms of ATP production. To obtain sufficient ATP, tumor cells increase glucose uptake by the glucose transporters of the GLUT/SLC2 family. The human glucose transporter GLUT12 was isolated from the breast cancer cell line MCF7. It is expressed in adipose tissue, skeletal muscle and small intestine, where insulin promotes its translocation to the plasma membrane. Moreover, GLUT12 over-expression in mice increases the whole-body insulin sensitivity. Thus, GLUT12 has been proposed as a second insulin-responsive glucose transporter. In obesity, GLUT12 is downregulated and does not respond to insulin. In contrast, GLUT12 is overexpressed in human solid tumors such as breast, prostate, gastric, liver and colon. High glucose concentration, insulin, and hypoxia upregulate GLUT12 both in adipocytes and tumor cells. Inhibition of GLUT12 mediated Warburg effect suppresses proliferation, migration, and invasion of cancer cells and xenografted tumors. This review summarizes the up-to-date information about GLUT12 physiological role and its implication in obesity and cancer, opening new perspectives to consider this transporter as a therapeutic target.

Keywords:  Cancer; GLUT12; Obesity; Warburg effect

DOI:  https://doi.org/10.1007/s13105-024-01028-9
J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Apr 30. pii: S1570-0232(24)00152-1. [Epub ahead of print]1240 124144

Unveiling the altered metabolic pathways induced by nivolumab in non-small cell lung cancer via GC-MS metabolomics approach coupled with multivariate analysis.

Manal E Alosaimi, Badriyah S Alotaibi, Maram H Abduljabbar, Reem M Alnemari, Atiah H Almalki, Ahmed Serag.

  This research investigates the effects of the immunotherapeutic agent nivolumab on the metabolism of lung cancer cells (NCI-H1975) using GC-MS metabolomic profiling. Multivariate analysis such as unsupervised PCA and supervised OPLS-DA along with univariate analysis and pathway analysis were employed to explore the metabolomic data and identify altered metabolic pathways induced by nivolumab treatment. The study revealed distinct metabolic alterations in cancer cells, linked to proliferative and survival advantages, such as enhanced glycolysis, increased glutaminolysis, and modified amino acid metabolism. Key findings indicate elevated levels of glycolysis-related metabolites (glycine, alanine, pyruvate, and lactate) and TCA cycle intermediates (succinate, fumarate, malate) in cancer cells, with a significant decrease following nivolumab treatment. Additionally, lower levels of aspartic acid and citrate in cancer cells imply altered nucleotide synthesis and fatty acid production essential for tumor growth. Treatment with nivolumab also reduced oleic acid levels, indicative of its effect on disrupted lipid metabolism. Our research shows nivolumab's potential to modify metabolic pathways involved in lung cancer progression, suggesting its dual role in cancer therapy: as an immune response modulator and a metabolic pathway disruptor.

Keywords:  GC–MS; Immune Checkpoint Inhibitors; Lung Cancer Treatment; Metabolic Reprogramming; Metabolomics; Nivolumab

DOI:  https://doi.org/10.1016/j.jchromb.2024.124144
Function (Oxf). 2024 ;5(3): zqae008

The Warburg Effect Reinterpreted 100 yr on: A First-Principles Stoichiometric Analysis and Interpretation from the Perspective of ATP Metabolism in Cancer Cells.

Sunil Nath, Rudi Balling.

  The Warburg Effect is a longstanding enigma in cancer biology. Despite the passage of 100 yr since its discovery, and the accumulation of a vast body of research on the subject, no convincing biochemical explanation has been given for the original observations of aerobic glycolysis in cancer cell metabolism. Here, we have worked out a first-principles quantitative analysis of the problem from the principles of stoichiometry and available electron balance. The results have been interpreted using Nath's unified theory of energy coupling and adenosine triphosphate (ATP) synthesis, and the original data of Warburg and colleagues have been analyzed from this new perspective. Use of the biomass yield based on ATP per unit substrate consumed, [Formula: see text], or the Nath-Warburg number, NaWa has been shown to excellently model the original data on the Warburg Effect with very small standard deviation values, and without employing additional fitted or adjustable parameters. Based on the results of the quantitative analysis, a novel conservative mechanism of synthesis, utilization, and recycling of ATP and other key metabolites (eg, lactate) is proposed. The mechanism offers fresh insights into metabolic symbiosis and coupling within and/or among proliferating cells. The fundamental understanding gained using our approach should help in catalyzing the development of more efficient metabolism-targeting anticancer drugs.

Keywords:  Nath’s two-ion theory of energy coupling and torsional mechanism of ATP synthesis; Nath’s unified theory of ATP synthesis/hydrolysis; Warburg-Nath ratio; Nath-Warburg number, NaWa; metabolic regulation based on ATP demand and supply; aerobic glycolysis and the Warburg Effect; biomass yield coefficients based on ATP; cancer, malignancy, and heterogeneity; lactate and lactic acid; mathematical model; metabolic coupling and symbiosis; oxidative phosphorylation (OXPHOS) and F0F1-ATP synthase; stoichiometry and available electron balance

DOI:  https://doi.org/10.1093/function/zqae008
bioRxiv. 2024 Apr 28. pii: 2024.04.25.591092. [Epub ahead of print]

Measuring single-cell density with high throughput enables dynamic profiling of immune cell and drug response from patient samples.

Weida Wu, Sarah H Ishamuddin, Thomas W Quinn, Smitha Yerrum, Ye Zhang, Lydie L Debaize, Pei-Lun Kao, Sarah Marie Duquette, Mark A Murakami, Morvarid Mohseni, Kin-Hoe Chow, Teemu P Miettinen, Keith L Ligon, Scott R Manalis.

Cell density, the ratio of cell mass to volume, is an indicator of molecular crowding and therefore a fundamental determinant of cell state and function. However, existing density measurements lack the precision or throughput to quantify subtle differences in cell states, particularly in primary samples. Here we present an approach for measuring the density of 30,000 single cells per hour with a precision of 0.03% (0.0003 g/mL) by integrating fluorescence exclusion microscopy with a suspended microchannel resonator. Applying this approach to human lymphocytes, we discovered that cell density and its variation decrease as cells transition from quiescence to a proliferative state, suggesting that the level of molecular crowding decreases and becomes more regulated upon entry into the cell cycle. Using a pancreatic cancer patient-derived xenograft model, we found that the ex vivo density response of primary tumor cells to drug treatment can predict in vivo tumor growth response. Our method reveals unexpected behavior in molecular crowding during cell state transitions and suggests density as a new biomarker for functional precision medicine.

DOI: https://doi.org/10.1101/2024.04.25.591092
Pharmacol Res. 2024 May 08. pii: S1043-6618(24)00152-X. [Epub ahead of print] 107208

Time-dependent proteomics and drug response in expanding cancer cells.

Yuting Pan, Ying Xuan, Piliang Hao, Xianzhi Chen, Rong Yan, Chengqian Zhang, Xisong Ke, Yi Qu, Xue Zhang.

  Cancer cell line is commonly used for discovery and development of anti-cancer drugs. It is generally considered that drug response remains constant for a certain cell line due to the identity of genetics thus protein patterns. Here, we demonstrated that cancer cells continued dividing even after reaching confluence, in that the proteomics was changed continuously and dramatically with strong relevance to cell division, cell adhesion and cell metabolism, indicating time-dependent intrinsically reprogramming of cells during expansion. Of note, the inhibition effect of most anti-cancer drugs was strikingly attenuated in culture cells along with cell expansion, with the strongest change at the third day when cells were still expanding. Profiling of an FDA-approved drug library revealed that attenuation of response with cell expansion is common for most drugs, an exception was TAK165 that was a selective inhibitor of mitochondrial respiratory chain complex I. Finally, we screened a panel of natural products and identified four pentacyclic triterpenes as selective inhibitors of cancer cells under prolonged growth. Taken together, our findings underscore that caution should be taken in evaluation of anti-cancer drugs using culture cells, and provide agents selectively targeting overgrowth cancer cells.

Keywords:  Anti-cancer agents; Cell expansion; Cell metabolism; Drug tolerance; Pentacyclic triterpenoids; Time-dependent proteomics

DOI:  https://doi.org/10.1016/j.phrs.2024.107208
J Cancer Surviv. 2024 May 06.

Effectiveness of dietetic care for cancer survivors in the primary care setting: A systematic review and meta-analysis of randomized controlled trials.

Henriette G Ryding, Lana J Mitchell, Roshan R Rigby, Lauren Ball, Julie Hobby, Lauren T Williams.

   PURPOSE: Nutrition plays an important role in cancer survivorship. This systematic review and meta-analysis aim to critically assess and quantify the effectiveness of nutrition care interventions provided by dietitians to survivors who have completed treatment for cancer.
METHODS: A systematic review of randomized controlled trials (RCTs) published from January 2004 to November 2023 reporting the effectiveness of primary care dietetic interventions with adult cancer survivors was conducted. PubMed, Scopus, CINAHL, Embase, ProQuest and PsycINFO databases were searched for key terms. Meta-analyses were conducted where there were sufficient studies of the same cancer type and outcomes.
RESULTS: Twelve RCTs representing 1138 cancer survivors (519 breast cancer; 75 prostate cancer; 544 colorectal cancer) were included. Primary outcome measures included weight loss (n = 6), quality of life (n = 2), reducing lymphedema-related arm volume (n = 2), nutritional status (n = 1) and increasing fruit and vegetable intake (n = 1). Weight loss was observed in studies where this was the primary outcome. Results for quality of life varied. Meta-analyses of RCTs with breast cancer survivors showed that dietitian intervention achieved a mean of 3.7 kg greater intentional weight loss and 2.3% greater body fat decrease than control (p < 0.0001).
CONCLUSIONS: This study provides evidence for the effectiveness of primary care dietetic interventions by dietitians with cancer survivors, particularly with respect to intentional weight and fat loss in breast cancer survivors.
IMPLICATIONS FOR CANCER SURVIVORS: Dietitians can play a key role in managing weight and improving long term health outcomes and prognosis for cancer survivors beyond the acute care setting.

Keywords:  Cancer; Cancer survivorship; Dietetic consultation; Dietitian; Nutritional care; Primary health care

DOI:  https://doi.org/10.1007/s11764-024-01583-6
Redox Rep. 2024 Dec;29(1): 2345455

MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions.

Hai-Yu Mo, Ruo-Bing Wang, Meng-Yao Ma, Yi Zhang, Xin-Yu Li, Wang-Rong Wen, Yi Han, Tian Tian.

   OBJECTIVES: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress.
METHODS: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo.
RESULTS: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models.
DISCUSSION: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

Keywords:  Gastric cancer; NADPH; methylene tetrahydrofolate dehydrogenase 2 (MTHFD2); reactive oxygen species (ROS); redox metabolism

DOI:  https://doi.org/10.1080/13510002.2024.2345455
Cureus. 2024 Apr;16(4): e57547

Acute Pancreatitis Associated With Ketogenic Diet: A Case Report.

Ibrahim Shanti, Malik Samardali, Leena Alhusari.

  This case study explores the relationship between acute pancreatitis and the ketogenic diet, a dietary approach characterized by low carbohydrate and high fat intake. The report details the experience of a 47-year-old woman who developed intense abdominal pain and vomiting following her self-prescribed ketogenic diet for weight loss. The patient had a medical history of hypertension, depression, and hypothyroidism. Laboratory findings indicated elevated levels of lipase and amylase, confirming the diagnosis of acute pancreatitis. Imaging procedures, including CT scans, further substantiated the diagnosis. The case underscores the potential association between the ketogenic diet and the onset of acute pancreatitis, emphasizing the necessity for healthcare professionals to consider dietary elements in the assessment and treatment of such cases. Additionally, the discussion explores the mechanisms, causes, and complications of acute pancreatitis, shedding light on the increasing interest in the ketogenic diet for weight management and its potential implications for pancreatic health. The study advocates for heightened awareness among healthcare practitioners concerning the risks linked to low-carbohydrate, high-fat diets, urging careful consideration and supervision for individuals contemplating their adoption.

Keywords:  abdominal pain; acute pancreatitis; dietary influence; elevated serum amylase and lipase; ketogenic diet

DOI:  https://doi.org/10.7759/cureus.57547
Metabolomics. 2024 May 09. 20(3): 50

Characterizing human postprandial metabolic response using multiway data analysis.

Shi Yan, Lu Li, David Horner, Parvaneh Ebrahimi, Bo Chawes, Lars O Dragsted, Morten A Rasmussen, Age K Smilde, Evrim Acar.

   INTRODUCTION: Analysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial responses of individuals. Traditional data analysis methods often rely on data summaries or univariate approaches focusing on one metabolite at a time.
OBJECTIVES: Our goal is to provide a comprehensive picture in terms of the changes in the human metabolism in response to a meal challenge test, by revealing static and dynamic markers of phenotypes, i.e., subject stratifications, related clusters of metabolites, and their temporal profiles.
METHODS: We analyze Nuclear Magnetic Resonance (NMR) spectroscopy measurements of plasma samples collected during a meal challenge test from 299 individuals from the COPSAC2000 cohort using a Nightingale NMR panel at the fasting and postprandial states (15, 30, 60, 90, 120, 150, 240 min). We investigate the postprandial dynamics of the metabolism as reflected in the dynamic behaviour of the measured metabolites. The data is arranged as a three-way array: subjects by metabolites by time. We analyze the fasting state data to reveal static patterns of subject group differences using principal component analysis (PCA), and fasting state-corrected postprandial data using the CANDECOMP/PARAFAC (CP) tensor factorization to reveal dynamic markers of group differences.
RESULTS: Our analysis reveals dynamic markers consisting of certain metabolite groups and their temporal profiles showing differences among males according to their body mass index (BMI) in response to the meal challenge. We also show that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state. Furthermore, while similar dynamic patterns are observed in males and females, the BMI-related group difference is observed only in males in the dynamic state.
CONCLUSION: The CP model is an effective approach to analyze time-resolved postprandial metabolomics data, and provides a compact but a comprehensive summary of the postprandial data revealing replicable and interpretable dynamic markers crucial to advance our understanding of changes in the metabolism in response to a meal challenge.

Keywords:  CANDECOMP/PARAFAC; Challenge tests; Dynamic metabolomics data; Tensor factorizations

DOI:  https://doi.org/10.1007/s11306-024-02109-y
Mol Metab. 2024 May 03. pii: S2212-8778(24)00083-8. [Epub ahead of print] 101952

Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy.

Kiavash Hushmandi, Behzad Einollahi, Seyed Hassan Saadat, E Hui Clarissa Lee, Marzieh Ramezani Farani, Elena Okina, Yun Suk Huh, Noushin Nabavi, Shokooh Salimimoghadam, Alan Prem Kumar.

  Solute carrier (SLC), a diverse family of membrane proteins, are instrumental in orchestrating the intake and efflux of nutrients including amino acids, vitamins, ions, nutrients, etc, across cell membranes. This dynamic process is critical for sustaining the metabolic demands of cancer cells, promoting their survival, proliferation, and adaptation to the tumor microenvironment. Amino acids are fundamental building blocks of cells, playing essential roles not only in protein synthesis but also in nutrient sensing, and in signaling pathways that can promote tumorigenesis. As key transporters of amino acids, SLCs have emerged as crucial players in maintaining cellular amino acid homeostasis, and their dysregulation is implicated in various cancer types. Thus, understanding the intricate connections between amino acids, SLCs, and cancer is pivotal for unraveling novel therapeutic targets and strategies. Amino acid uptake by SLCs positively affects tumor progression. However, some studies revealed the tumor suppressor function of SLCs. Although a body of studies evaluated the function of SLC7A11 and SLC1A5, some of the SLC proteins are not studied sufficiently in cancer. In this review, we delve into the significant impact of amino acid carriers of the SLCs family on the growth and progression of cancer and explore the current state of knowledge in this field, shedding light on the molecular mechanisms that underlie these relationships and highlighting potential avenues for future research and clinical interventions. This comprehensive review provides insights into a rapidly evolving area of cancer biology by focusing on amino acids, as one of the most important materials that cancer cells need, and their transporters within the SLC superfamily.

Keywords:  Amino acid; Cancer; Cancer metabolism; Nutrient sensing; SLC

DOI:  https://doi.org/10.1016/j.molmet.2024.101952
Am J Physiol Endocrinol Metab. 2024 May 08.

Short-term high-calorie high-fat feeding induces hyperinsulinemia and blunts skeletal muscle microvascular blood flow in healthy humans.

Barbara Brayner, Michelle A Keske, Katherine M Roberts-Thomson, Lewan Parker, Andrew C Betik, Hannah J Thomas, Shaun Mason, Kimberley L Way, Katherine M Livingstone, D Lee Hamilton, Gunveen Kaur.

  Skeletal muscle microvascular blood flow (MBF) plays an important role in glucose disposal in muscle. Impairments in muscle MBF contribute to insulin resistance and pre-diabetes. Animal studies show that short-term (3 day) high-fat feeding blunts skeletal muscle MBF prior to impairing insulin-stimulated glucose disposal. It is not known if this occurs in humans. We investigated the temporal impact of a 7-day high-calorie high-fat (HCHF) diet intervention (+52% kJ; 41% fat) on fasting and postprandial cardiometabolic outcomes in 14 healthy adults (18-37 years). Metabolic health and vascular responses to a mixed meal challenge (MMC) were measured at pre- (day 0), mid- (day 4) and post-intervention (day 8). There were no significant differences in body weight, body fat %, fasting blood glucose, and fasting plasma insulin concentrations at pre-, mid- and post-intervention. Compared to pre-intervention there was a significant increase in insulin (but not glucose) total area under the curve, in response to the MMC at mid-intervention (p=0.041) and at post-intervention (p=0.028). Unlike at pre- and mid-intervention, at post-intervention muscle MBF decreased at 60 min (p=0.024) and 120 min (p=0.023) following the MMC. However, macrovascular blood flow was significantly increased from 0 to 60 mins (p<0.001) and 120 mins (p<0.001) following the MMC at pre-, mid- and post-intervention. Therefore, short-term HCHF feeding in healthy individuals leads to elevated postprandial insulin but not glucose levels and a blunting of meal-induced skeletal muscle MBF responses but not macrovascular blood flow responses.

Keywords:  Microvascular blood flow; high-calorie high-fat diet; insulin resistance; overfeeding; skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00070.2024
Cancer Lett. 2024 May 03. pii: S0304-3835(24)00312-4. [Epub ahead of print]592 216919

BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine.

Aubrey L Miller, Samuel C Fehling, Rebecca B Vance, Dongquan Chen, Eric Josh Brown, M Iqbal Hossain, Eric O Heard, Shaida A Andrabi, Hengbin Wang, Eddy S Yang, Donald J Buchsbaum, Robert C A M van Waardenburg, Susan L Bellis, Karina J Yoon.

  Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an enzyme involved in cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models. Mechanistic data demonstrate the novel findings that HMGCS2 contributes to gemR and confers metastatic properties in PDAC models, and that HMGCS2 is BRD4 dependent. Further, BET inhibitor JQ1 decreases levels of HMGCS2, sensitizes PDAC cells to gemcitabine, and a combination of gemcitabine and JQ1 induced regressions of gemR tumors in vivo. Our data suggest that decreasing HMGCS2 may reverse gemR, and that HMGCS2 represents a useful therapeutic target for treating gemcitabine resistant PDAC.

Keywords:  BET bromodomain inhibitor (BETi); Gemcitabine resistance (gemR); HMG-CoA synthase 2 (HMGCS2); Pancreatic cancer; Patient-derived xenograft (PDX) models

DOI:  https://doi.org/10.1016/j.canlet.2024.216919
EMBO Mol Med. 2024 May 09.

High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.

Nneka Southwell, Onorina Manzo, Sandra Bacman, Dazhi Zhao, Nicole M Sayles, Jalia Dash, Keigo Fujita, Marilena D'Aurelio, Annarita Di Lorenzo, Giovanni Manfredi, Hibiki Kawamata.

  Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high-fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.

Keywords:  CHCHD10; High-Fat Diet; Mitochondrial Cardiomyopathy; Mitophagy

DOI:  https://doi.org/10.1038/s44321-024-00067-5
iScience. 2024 May 17. 27(5): 109718

Cell competition promotes metastatic intestinal cancer through a multistage process.

Ana Krotenberg Garcia, Mario Ledesma-Terrón, Maria Lamprou, Joyce Vriend, Merel Elise van Luyk, Saskia Jacoba Elisabeth Suijkerbuijk.

  Cell competition plays an instrumental role in quality control during tissue development and homeostasis. Nevertheless, cancer cells can exploit this process for their own proliferative advantage. In our study, we generated mixed murine organoids and microtissues to explore the impact of cell competition on liver metastasis. Unlike competition at the primary site, the initial effect on liver progenitor cells does not involve the induction of apoptosis. Instead, metastatic competition manifests as a multistage process. Initially, liver progenitors undergo compaction, which is followed by cell-cycle arrest, ultimately forcing differentiation. Subsequently, the newly differentiated liver cells exhibit reduced cellular fitness, rendering them more susceptible to outcompetition by intestinal cancer cells. Notably, cancer cells leverage different interactions with different epithelial populations in the liver, using them as scaffolds to facilitate their growth. Consequently, tissue-specific mechanisms of cell competition are fundamental in driving metastatic intestinal cancer.

Keywords:  Cancer; Cell biology; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2024.109718
J Mol Cell Cardiol. 2024 May 03. pii: S0022-2828(24)00064-6. [Epub ahead of print]191 50-62

Exercise-induced changes in myocardial glucose utilization during periods of active cardiac growth.

Kyle L Fulghum, Helen E Collins, Pawel K Lorkiewicz, Teresa A Cassel, Teresa W M Fan, Bradford G Hill.

Exercise training can promote physiological cardiac growth, which has been suggested to involve changes in glucose metabolism to facilitate hypertrophy of cardiomyocytes. In this study, we used a dietary, in vivo isotope labeling approach to examine how exercise training influences the metabolic fate of carbon derived from dietary glucose in the heart during acute, active, and established phases of exercise-induced cardiac growth. Male and female FVB/NJ mice were subjected to treadmill running for up to 4 weeks and cardiac growth was assessed by gravimetry. Cardiac metabolic responses to exercise were assessed via in vivo tracing of [13C6]-glucose via mass spectrometry and nuclear magnetic resonance. We found that the half-maximal cardiac growth response was achieved by approximately 1 week of daily exercise training, with near maximal growth observed in male mice with 2 weeks of training; however, female mice were recalcitrant to exercise-induced cardiac growth and required a higher daily intensity of exercise training to achieve significant, albeit modest, increases in cardiac mass. We also found that increases in the energy charge of adenylate and guanylate nucleotide pools precede exercise-induced changes in cardiac size and were associated with higher glucose tracer enrichment in the TCA pool and in amino acids (aspartate, glutamate) sourced by TCA intermediates. Our data also indicate that the activity of collateral biosynthetic pathways of glucose metabolism may not be markedly altered by exercise. Overall, this study provides evidence that metabolic remodeling in the form of heightened energy charge and increased TCA cycle activity and cataplerosis precedes cardiac growth caused by exercise training in male mice.

DOI: https://doi.org/10.1016/j.yjmcc.2024.04.014
Methods Cell Biol. 2024 ;pii: S0091-679X(24)00050-5. [Epub ahead of print]186 233-247

Measuring response to therapy in AML: Difference from normal flow cytometry vs RQ-PCR.

Michael R Loken, Chad A Hudson.

  Multiple technologies have been used to monitor response to therapy in acute myeloid leukemia (AML) to improve detection of leukemia over the standard of practice, morphologic counting of blasts. The two techniques most frequently used in a routine clinical setting, flow cytometry and RQ-PCR, differ in their targets, sensitivity, and ability to detect residual disease. Both flow cytometry and RQ-PCR detect the expression of abnormal gene products, at the protein level or RNA level, respectively. Flow cytometry can be applied to a broad range of AML cases while RQ-PCR is limited to specific genetic abnormalities identified in subsets of AML. This article compares the results when both techniques were used in a reference laboratory to monitor AML over the course of treatment, comparing quantitative and qualitative results.

Keywords:  Acute myeloid leukemia; Flow cytometry; Measurable residual disease; RQ-PCR

DOI:  https://doi.org/10.1016/bs.mcb.2024.02.019
Endocr Pract. 2024 May 08. pii: S1530-891X(24)00513-5. [Epub ahead of print]

A Review of Plant-Based Diets for Obesity Management.

Sandhya Rao Bassin, Julia Ferreira De Carvalho, Mahima Gulati.

OBJECTIVE: Obesity is the most prevalent chronic disease in the United States with over 70% of the American population suffering from overweight/obesity. Recently, the popularity of plant-based diets has grown, with individuals adopting these diets for ethical, health and environmental reasons. Our aim is to evaluate the effect of a plant-based diet (PBD) on weight loss among patients who are overweight or obese.
METHODS: A literature review of PBDs for the treatment of obesity was conducted using PubMed and Scopus. Our search yielded 27 intervention trials (3361 participants) and six metanalyses (9168 participants, 61 trials).
RESULTS: Among the intervention trials evaluated, 75% showed a significant decrease in weight loss in the intervention group, on average -5.0kg (range -1.8 to -12.1kg). Other outcomes included energy intake (-420 Kcal/day), systolic blood pressure (-3.78 mmHg), fasting plasma glucose (-2.0 mmol/L), HbA1c (-0.5%, -3.4 mmol/L), total cholesterol (-0.40 mmol/L), low-density lipoprotein (-0.38 mmol/L), triglyceride levels (+0.13 mmol/L), and fiber intake (+10.8 g/day). The six meta-analyses showed weight loss (average -2.9 kg , range -2.02 kg to -4.1 kg), BMI reduction, and improvements in HbA1c, LDL, and total cholesterol.
CONCLUSION: PBDs result in significant weight loss and improve metabolic outcomes. PBDs offer a sustainable approach to long-term weight loss maintenance. Healthcare providers should encourage open discussions with their patients regarding their dietary habits to assist them in setting feasible lifestyle goals and consider shared medical appointments to support patients in transitioning to PBDs.

DOI: https://doi.org/10.1016/j.eprac.2024.04.020
Cureus. 2024 Apr;16(4): e57920

The Significant Impact of High-Fat, Low-Carbohydrate Ketogenic Diet on Serum Lipid Profile and Atherosclerotic Cardiovascular Disease Risk in Overweight and Obese Adults.

Shadan Khdher, Salm Mohammed, Kwestan Muhammed, Abdulrahman Ismael.

  Background and objectives Overweight and obesity are becoming more commonplace globally. The ketogenic diet (KD), also known as the high-fat, low-carbohydrate diet, has become increasingly popular in recent years as a means to lose weight quickly. This present study aims to examine the clinical effects of ketogenic diets in individuals who are obese or overweight by evaluating or assessing variations in metabolic parameters associated with lipid control, the risk of atherosclerotic cardiovascular disease, and other kidney risk indicators. Methods and subjects This observational case-control research involved 250 individuals in total and was conducted from May 2023 to January 2024. Of these, 158 were on a ketogenic diet, and 92 adults not following any type of diet were chosen to serve as controls. The biochemistry parameters of the kidney function test and lipid profile were measured for the two comparing groups. Data were analyzed for statistical significance using the Student t-test, Mann-Whitney U test, and one-way analysis of variance (ANOVA), followed by a post hoc test (least significant difference (LSD)). Chi-square tests were employed in the analysis to compare proportions. Results Out of 250 participants, there was a 20-80 age range, with their median age being 40 years old. The two comparing groups' lipid profiles were very different from one another; the cardiovascular risk (triglyceride (TG)/high-density lipoprotein (HDL)), total cholesterol, low-density lipoprotein (LDL), and triglyceride levels were all greater in the KD group when compared to the non-KD group. The mean LDL cholesterol (LDL-C) of the normal-weight participants was 56 mg/dL (p=0.079). Thereafter, it experienced a significant rise to 97.58 mg/dL and 108.2 mg/dL in those individuals who were overweight and obese, respectively (p<0.020). Conclusions As obesity rates in the populace keep rising, dietary fads such as the ketogenic diet are gaining traction. Although they could help with weight loss, this study had a notable observation of severe hypercholesterolemia and increased risk of atherosclerotic cardiovascular disease among the ketogenic diet participants. Additional research is necessary to ascertain if a ketogenic diet can be sustained over the long term and how it affects endpoints that are more clinically significant, such as morbidity and mortality due to obesity.

Keywords:  body mass index; cardiovascular risk; ketogenic diet; lipid profile; obesity; overweight

DOI:  https://doi.org/10.7759/cureus.57920