bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2024‒09‒22
twenty papers selected by
Brett Chrest, Wake Forest University
  1. Ketone Body Metabolism is Not Required for Improvement of Heart Failure by Ketogenic Diet in Mice.
  2. Technologies for Decoding Cancer Metabolism with Spatial Resolution.
  3. Dietary Interventions for Cancer Prevention: An Update to ACS International Guidelines.
  4. mLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer.
  5. Effects of Different Exercises Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis.
  6. Glutaminase 2 as a therapeutic target in glioblastoma.
  7. Understanding the Warburg Effect in Cancer.
  8. Keep It Moving: Physical Activity in the Prevention of Obesity-Driven Pancreatic Cancer.
  9. Phosphoproteomics predict response to midostaurin plus chemotherapy in independent cohorts of FLT3-mutated acute myeloid leukaemia.
  10. Nutrient Levels and Nutrient Sources in Pancreatic Tumors.
  11. Mitochondrial dynamics as a potential therapeutic target in acute myeloid leukemia.
  12. Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
  13. Nutrient analysis of three low-carbohydrate diets differing in carbohydrate content.
  14. Cancer Metabolism: Aspirations for the Coming Decade.
  15. Current status and research directions in acute myeloid leukemia.
  16. Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
  17. Optimal fasting duration for mice as assessed by metabolic status.
  18. Oxidized polyunsaturated fatty acid promotes colitis and colitis-associated tumorigenesis in mice.
  19. Exercise training and changes in skeletal muscle mitochondrial proteins: from blots to "omics".
  20. Non-Specific Elevated Serum Free Fatty Acids in Lung Cancer Patients: Nutritional or Pathological?
  1. bioRxiv. 2024 Sep 02. pii: 2024.08.30.610511. [Epub ahead of print]
    Ketone Body Metabolism is Not Required for Improvement of Heart Failure by Ketogenic Diet in Mice.
    Zachary Foulks, Carla J Weinheimer, Attila Kovacs, Jessica Michael, Kelly D Pyles, Thiago N Menezes, Kevin Cho, Gary J Patti, Kyle S McCommis.
      Failing hearts increasingly metabolize ketone bodies, and enhancing ketosis improves heart failure (HF) remodeling. Circulating ketones are elevated by fasting/starvation, which is mimicked with a high-fat, low-carbohydrate "ketogenic diet" (KD). While speculated that KD improves HF through increased ketone oxidation, some evidence suggests KD paradoxically downregulates cardiac ketone oxidation despite increased ketone delivery. We sought to clarify the significance of cardiac ketone metabolism during KD in HF. Mice were subjected to transverse aortic constriction with apical myocardial infarction (TAC-MI) and fed either low-fat (LF) control or KD. Cardiac-specific mitochondrial pyruvate carrier 2 (csMPC2-/-) mice were used as a second model of heart failure. In both mice, feeding a KD improved HF, determined by echocardiography, heart weights, and gene expression analyses. Although KD increases plasma ketone bodies, gene expression for ketone metabolic genes is decreased in the hearts of KD-fed mice. Cardiac-specific β-hydroxybutyrate dehydrogenase 1 (csBDH1-/-), the first enzyme in ketone catabolism, mice were also studied and crossed with the csMPC2-/- mice to create double knockout (DKO) mice. These mice were aged to 16 weeks and switched to LF or KD, and KD was able to completely normalize the hearts of both csMPC2-/- and DKO mice, suggesting that ketone metabolism is unnecessary for improving heart failure with ketogenic diet. These studies were then repeated, and mice injected with U-13C-β-hydroxybutyrate to evaluate ketone metabolism. KD feeding significantly decreased the enrichment of the TCA cycle from ketone body carbons, as did the BDH1-deletion in DKO mice. Gene expression and respirometry suggests that KD instead increases cardiac fat oxidation. In conclusion, these results suggest that ketogenic diet decreases cardiac ketone metabolism and does not require ketone metabolism to improve heart failure.
    DOI:  https://doi.org/10.1101/2024.08.30.610511
  2. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041553. [Epub ahead of print]
    Technologies for Decoding Cancer Metabolism with Spatial Resolution.
    Walter W Chen, Michael E Pacold, David M Sabatini, Naama Kanarek.
      It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.
    DOI:  https://doi.org/10.1101/cshperspect.a041553
  3. Nutrients. 2024 Aug 29. pii: 2897. [Epub ahead of print]16(17):
    Dietary Interventions for Cancer Prevention: An Update to ACS International Guidelines.
    Álvaro Torres, Francisca Quintanilla, Esteban Barnafi, César Sánchez, Francisco Acevedo, Benjamín Walbaum, Tomás Merino.
      Cancer, the second leading cause of death worldwide, demands the identification of modifiable risk factors to optimize its prevention. Diet has emerged as a pivotal focus in current research efforts. This literature review aims to enhance the ACS guidelines on diet and cancer by integrating the latest findings and addressing unresolved questions. The methodology involved an advanced PubMed search with specific filters relevant to the research topic. Topics covered include time-restricted diet, diet quality, acid load, counseling, exercise and diet combination, Mediterranean diet, vegetarian and pescetarian diets, weight loss, dairy consumption, coffee and tea, iron, carbohydrates, meat, fruits and vegetables, heavy metals, micronutrients, and phytoestrogens. The review highlights the benefits of the Mediterranean diet in reducing cancer risk. Adherence to overnight fasting or carbohydrate consumption may contribute to cancer prevention, but excessive fasting may harm patients' quality of life. A vegetarian/pescetarian diet is associated with lower risks of general and colorectal cancer compared to a carnivorous diet. High heme and total iron intake are linked to increased lung cancer risk, while phytoestrogen intake is associated with reduced risk. Coffee and tea have a neutral impact on cancer risk. Finally, the roles of several preventive micronutrients and carcinogenic heavy metals are discussed.
    Keywords:  Mediterranean diet; cancer; carbohydrates; dairy; diet; diet quality; nutrition; prevention; risk; vitamin D
    DOI:  https://doi.org/10.3390/nu16172897
  4. Cancer Res. 2024 Sep 17.
    mLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer.
    Kai Chen, Patrick Ernst, Anusua Sarkar, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D Ringel, Xiaoguang Liu, Lufang Zhou.
      Mitochondria are important in various aspects of cancer development and progression. Targeting mitochondria in cancer cells holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we developed mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. The therapeutic approach included synthesis of a blue light-gated cationic channelrhodopsin (CoChR) in the IMM and co-expression of a blue bioluminescence-emitting nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes were selectively delivered to cancer cells in vivo by an adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV (mAb-Exo-AAV). Induction with NLuc luciferin elicited robust endogenous bioluminescence, which activated CoChR, triggering cancer cell mitochondrial depolarization and subsequent cell death. Importantly, mLumiOpto demonstrated remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma and triple-negative breast cancer xenograft mouse models. Furthermore, the approach induced an anti-tumor immune response, increasing infiltration of dendritic cells and CD8+ T cells in the tumor microenvironment. These findings establish mLumiOpto as a promising therapeutic strategy by targeting cancer cell mitochondria in vivo.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0984
  5. Nutrients. 2024 Sep 05. pii: 3007. [Epub ahead of print]16(17):
    Effects of Different Exercises Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis.
    Yongchao Xie, Yu Gu, Zhen Li, Bingchen He, Lei Zhang.
      BACKGROUND: Exercise and dietary interventions are essential for maintaining weight and reducing fat accumulation. With the growing popularity of various dietary strategies, evidence suggests that combining exercise with dietary interventions offers greater benefits than either approach alone. Consequently, this combined strategy has become a preferred method for many individuals aiming to maintain health. Calorie restriction, 5/2 intermittent fasting, time-restricted feeding, and the ketogenic diet are among the most popular dietary interventions today. Aerobic exercise, resistance training, and mixed exercise are the most widely practiced forms of physical activity. Exploring the best combinations of these approaches to determine which yields the most effective results is both meaningful and valuable. Despite this trend, a comparative analysis of the effects of different exercise and diet combinations is lacking. This study uses network meta-analysis to evaluate the impact of various combined interventions on body composition and to compare their efficacy.METHODS: We systematically reviewed literature from database inception through May 2024, searching PubMed, Web of Science, Embase, and the Cochrane Library. The study was registered in PROSPERO under the title: "Effects of Exercise Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis" (identifier: CRD42024542184). Studies were meticulously selected based on specific inclusion and exclusion criteria (The included studies must be randomized controlled trials involving healthy adults aged 18 to 65 years. Articles were rigorously screened according to the specified inclusion and exclusion criteria.), and their risk of bias was assessed using the Cochrane risk of bias tool. Data were aggregated and analyzed using network meta-analysis, with intervention efficacy ranked by Surface Under the Cumulative Ranking (SUCRA) curves.
    RESULTS: The network meta-analysis included 78 randomized controlled trials with 5219 participants, comparing the effects of four combined interventions: exercise with calorie restriction (CR+EX), exercise with time-restricted eating (TRF+EX), exercise with 5/2 intermittent fasting (5/2F+EX), and exercise with a ketogenic diet (KD+EX) on body composition. Intervention efficacy ranking was as follows: (1) Weight Reduction: CR+EX > KD+EX > TRF+EX > 5/2F+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 2.94 (-3.64, 9.52); 2.37 (-0.40, 5.15); 1.80 (-1.75, 5.34)). (2) BMI: CR+EX > KD+EX > 5/2F+EX > TRF+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 1.95 (-0.49, 4.39); 2.20 (1.08, 3.32); 1.23 (-0.26, 2.71)). (3) Body Fat Percentage: CR+EX > 5/2F+EX > TRF+EX > KD+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 2.66 (-1.56, 6.89); 2.84 (0.56, 5.13); 3.14 (0.52, 5.75).). (4) Lean Body Mass in Male: CR+EX > TRF+EX > KD+EX (Relative to CR+EX, the effect sizes of TRF+EX and KD+EX are -1.60 (-6.98, 3.78); -2.76 (-7.93, 2.40)). (5) Lean Body Mass in Female: TRF+EX > CR+EX > 5/2F+EX > KD+EX (Relative to TRF+EX, the effect sizes of CR+EX, 5/2F+EX and KD+EX are -0.52 (-2.58, 1.55); -1.83 (-4.71, 1.04); -2.46 (-5.69,0.76).).
    CONCLUSION: Calorie restriction combined with exercise emerged as the most effective strategy for reducing weight and fat percentage while maintaining lean body mass. For women, combining exercise with time-restricted eating proved optimal for preserving muscle mass. While combining exercise with a ketogenic diet effectively reduces weight, it is comparatively less effective at decreasing fat percentage and preserving lean body mass. Hence, the ketogenic diet combined with exercise is considered suboptimal.
    Keywords:  BMI; aerobic exercise; body fat percentage; caloric restriction; intermittent fasting; ketogenic diet; lean body mass; resistance exercise; weight
    DOI:  https://doi.org/10.3390/nu16173007
  6. Biochim Biophys Acta Rev Cancer. 2024 Sep 16. pii: S0304-419X(24)00113-6. [Epub ahead of print]1879(6): 189182
    Glutaminase 2 as a therapeutic target in glioblastoma.
    Rithvik K Veeramachaneni, Robert K Suter, Emma Rowland, Anna Jermakowicz, Nagi G Ayad.
      Glioblastoma (GBM) is the most common malignant primary adult brain tumor. Despite standard-of-care treatment, which consists of surgical resection, temozolomide (TMZ) treatment, and radiotherapy, the prognosis for GBM patients remains poor with a five-year survival rate of 5 %. With treatment, the median survival time is 14 months, suggesting the dire need for new, more effective therapies. Glutaminolysis, the metabolic pathway by which cells can convert glutamine to ATP, is essential for the survival of GBM cells and represents a putative target for treatment. Glutamine replenishes tricarboxylic acid (TCA) cycle intermediates through glutaminolysis. The first step of glutaminolysis, the deamination of glutamine, can be carried out by either glutaminase 1 (GLS) or glutaminase 2 (GLS2). However, it is becoming increasingly clear that these enzymes have opposing functions in GBM; GLS induces deamination of glutamine, thereby acting in an oncogenic fashion, while GLS2 has non-enzymatic, tumor-suppressive functions that are repressed in GBM. In this review, we explore the important role of glutaminolysis and the opposing roles of GLS and GLS2 in GBM. Further, we provide a detailed discussion of GLS2's newly discovered non-enzymatic functions that can be targeted in GBM. We conclude by considering therapeutic approaches that have emerged from the understanding of GLS and GLS2's opposing roles in GBM.
    Keywords:  Glioblastoma; Glutaminase; Glutaminolysis; Tumor suppression; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189182
  7. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041532. [Epub ahead of print]
    Understanding the Warburg Effect in Cancer.
    Zhaoqi Li, Muhammad Bin Munim, Daniel A Sharygin, Brooke J Bevis, Matthew G Vander Heiden.
      Rapidly proliferating cells, including cancer cells, adapt metabolism to meet the increased energetic and biosynthetic demands of cell growth and division. Many rapidly proliferating cells exhibit increased glucose consumption and fermentation regardless of oxygen availability, a phenotype termed aerobic glycolysis or the Warburg effect in cancer. Several explanations for why cells engage in aerobic glycolysis and how it supports proliferation have been proposed, but none can fully explain all conditions and data where aerobic glycolysis is observed. Nevertheless, there is convincing evidence that the Warburg effect is important for the proliferation of many cancers, and that inhibiting either glucose uptake or fermentation can impair tumor growth. Here, we discuss what is known about metabolism associated with aerobic glycolysis and the evidence supporting various explanations for why aerobic glycolysis may be important in cancer and other contexts.
    DOI:  https://doi.org/10.1101/cshperspect.a041532
  8. Cancer Res. 2024 Sep 16. 84(18): 2935-2937
    Keep It Moving: Physical Activity in the Prevention of Obesity-Driven Pancreatic Cancer.
    Akin Sogunro, Mandar D Muzumdar.
      Despite the already dire impact of pancreatic cancer, a growing subset of patients with obesity exhibits an amplified risk of disease and worse outcomes. Mouse models have revealed that obesity is distinctly pathogenic, accelerating pancreatic ductal adenocarcinoma (PDAC) progression and inducing increased desmoplasia and myeloid cell infiltration in the tumor microenvironment. However, whether and how obesity-countering interventions, such as exercise, reverse the protumorigenic effects of obesity is incompletely understood. In this issue of Cancer Research, Pita-Grisanti and colleagues investigate the impact of physical activity (PA) in disrupting obesity-driven PDAC. Employing a variety of sophisticated models, including autochthonous genetically engineered mice, orthotopic syngeneic allografts, high-fat diet-induced obesity, and PA interventions in mice and humans, the authors found that PA impedes PDAC development in obese mice but does not impact the growth of advanced tumors. These antitumor effects correlated with reduced inflammation and fibrosis in the tumor microenvironment, a decline in high-fat diet-induced circulating inflammatory cytokines, and an increase in the IL15 signaling axis in white adipose tissue. Although adipose-targeted IL15 therapy was effective in suppressing advanced tumor growth in lean mice, obese mice were resistant to its therapeutic benefits. Together, the findings argue that PA delays obesity-driven early PDAC progression, implicating the preferential benefit of exercise as a preventative strategy. They further identify changes in obesity-associated local and systemic cytokine production as a possible mechanism for the antitumor effects of PA and help define context-specific determinants of response for emerging IL15-based immunotherapies. See related article by Pita-Grisanti et al., p. 3058.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1474
  9. EBioMedicine. 2024 Sep 17. pii: S2352-3964(24)00352-9. [Epub ahead of print]108 105316
    Phosphoproteomics predict response to midostaurin plus chemotherapy in independent cohorts of FLT3-mutated acute myeloid leukaemia.
    Weronika E Borek, Luis Nobre, S Federico Pedicona, Amy E Campbell, Josie A Christopher, Nazrath Nawaz, David N Perkins, Pedro Moreno-Cardoso, Janet Kelsall, Harriet R Ferguson, Bela Patel, Paolo Gallipoli, Andrea Arruda, Alex J Ambinder, Andrew Thompson, Andrew Williamson, Gabriel Ghiaur, Mark D Minden, John G Gribben, David J Britton, Pedro R Cutillas, Arran D Dokal.
      BACKGROUND: Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients.METHODS: We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n = 20).
    FINDINGS: We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n = 20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p < 7∗10-5, HR = 0.005 [95% CI: 0-0.31]).
    INTERPRETATION: In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology.
    FUNDING: This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd.
    Keywords:  Acute myeloid leukaemia; Drug response prediction; Machine learning; Midostaurin plus chemotherapy; Phosphoproteomics; Precision medicine
    DOI:  https://doi.org/10.1016/j.ebiom.2024.105316
  10. Cancer Res. 2024 Sep 16. 84(18): 2947-2949
    Nutrient Levels and Nutrient Sources in Pancreatic Tumors.
    Sven Groessl, Wilhelm Palm.
      It has been known that poor tumor perfusion and dysregulated cancer cell metabolism give rise to tumor microenvironments with unphysiologic nutrient levels, but the precise alterations in metabolite abundance are not well defined. In a 2015 study in Cancer Research, Kamphorst and colleagues published a detailed comparison of the metabolome from human pancreatic tumors and benign tissues. Tumors were depleted in glucose and various nonessential amino acids but, surprisingly, enriched in essential amino acids. The authors attributed these nutrient imbalances to macropinocytosis of extracellular proteins, a RAS-driven amino acid acquisition pathway that was found to be increased in human tumors and supports pancreatic cancer cell growth during amino acid starvation. These findings substantially contributed to the understanding of altered nutrient levels in tumors and extracellular proteins as noncanonical nutrients. Intratumoral nutrient levels in different cancer contexts and signaling pathways that regulate nutrient acquisition by cancer cells remain a focus of current research. See related article by Kamphorst and colleagues, Cancer Res 2015;75:544-53.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2447
  11. Int J Hematol. 2024 Sep 16.
    Mitochondrial dynamics as a potential therapeutic target in acute myeloid leukemia.
    Mariko Kinoshita, Yusuke Saito, Kento Otani, Yuya Uehara, Shun Nagasawa, Midori Nakagawa, Ai Yamada, Sachiyo Kamimura, Hiroshi Moritake.
      Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation and the mitochondrial dynamics regulated by fusion-related genes MFN1, MFN2, and OPA1 and fission-related genes DNM1L and MFF. An analysis of previously published gene expression datasets showed that high expression of MFF was significantly associated with poor prognosis in patients with AML. Based on this finding, we investigated the impact of mitochondrial dynamics in AML. Transduction of shRNA against fission-related genes, DNM1L and MFF, inhibited growth and increased the mitochondrial area in AML cell lines. Extracellular flux analysis showed that deletion of mitochondrial dynamic regulators reduced mitochondrial respiration without significantly affecting glycolysis, except in shDNM1L-transfected cells. Immunodeficient NOG mice transplanted with DNM1L- or MFF-knockdown AML cells survived significantly longer than controls. Treatment of AML cell lines with Mdivi-1, which inhibits the DRP1 encoded by DNM1L, inhibited cell proliferation and oxidative phosphorylation. Our results show that mitochondrial dynamics play an important role in AML, and provide novel biological insights. The inhibition of mitochondrial dynamics induces unique mitochondrial alterations, which may be explored as a potential therapeutic target in AML.
    Keywords:  AML; DNM1L; MFF; Mdivi-1; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s12185-024-03843-8
  12. Dis Model Mech. 2024 Sep 01. pii: dmm050814. [Epub ahead of print]17(9):
    Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
    Patrick B Jonker, Alexander Muir.
      Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.
    Keywords:  Acidosis; Diet; Hypoxia; Lipid metabolism; Nutrient deprivation; Tumor microenvironment
    DOI:  https://doi.org/10.1242/dmm.050814
  13. Front Nutr. 2024 ;11 1449109
    Nutrient analysis of three low-carbohydrate diets differing in carbohydrate content.
    Lani Banner, Beth H Rice Bradley, Jonathan Clinthorne.
      Introduction: Low-carbohydrate diets are increasing in popularity. Despite clinical evidence demonstrating their safety and efficacy, concerns regarding the nutrient adequacy of low-carbohydrate diets persist. The aims of this study were to assess the nutrient adequacy of three 7-day meal plans that delivered 20 (VLCD20), 40 (VLCD40), and 100 (LCD100) grams of net carbohydrate per day respectively.Methods: Nutrient analyses were conducted using USDA Food Data Central.
    Results: All three low-carbohydrate meal plans exceeded recommendations for vitamins A, C, D, E, K, thiamin, riboflavin, niacin, B6, folate and B12 in males and females 31-70 years and exceeded calcium recommendations for adults 31-50 years but remained below the Tolerable Upper Intake Level. VLCD40 and LCD100 met or exceeded fiber recommendations for females ages 31-70 years and were adequate for males 51-70 years. None of the meal plans contributed meaningful amounts of added sugar. The plans exceeded the Recommended Dietary Allowance for protein for adults ages 31-70 years of age but were within the Acceptable Macronutrient Distribution Range of 10-35% of energy. The plans slightly exceeded recommendations for saturated fat and sodium but were lower in these nutrients than the average American diet and had more favorable omega-6 to omega-3 and sodium to potassium ratios than is typical. All three meals plans met or exceeded the Estimated Average Requirement for micronutrients in females ages 31-50 years, the population group most likely to consume low-carbohydrate diets.
    Discussion: Well-constructed low-carbohydrate meal plans can be nutritionally adequate in adults.
    Keywords:  diet; ketogenic diet; low-carbohydrate; low-carbohydrate diet; micronutrients; nutrient adequacy
    DOI:  https://doi.org/10.3389/fnut.2024.1449109
  14. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041555. [Epub ahead of print]
    Cancer Metabolism: Aspirations for the Coming Decade.
    Ralph J DeBerardinis, Karen H Vousden, Navdeep S Chandel.
      Fueled by technological and conceptual advancements over the past two decades, research in cancer metabolism has begun to answer questions dating back to the time of Otto Warburg. But, as with most fields, new discoveries lead to new questions. This review outlines the emerging challenges that we predict will drive the next few decades of cancer metabolism research. These include developing a more realistic understanding of how metabolic activities are compartmentalized within cells, tissues, and organs; how metabolic preferences in tumors evolve during cancer progression from nascent, premalignant lesions to advanced, metastatic disease; and, most importantly, how we can best translate basic observations from preclinical models into novel therapies that benefit patients with cancer. With modern tools and an incredible amount of talent focusing on these problems, the upcoming decades should bring transformative discoveries.
    DOI:  https://doi.org/10.1101/cshperspect.a041555
  15. Blood Cancer J. 2024 Sep 19. 14(1): 163
    Current status and research directions in acute myeloid leukemia.
    Hagop Kantarjian, Gautam Borthakur, Naval Daver, Courtney D DiNardo, Ghayas Issa, Elias Jabbour, Tapan Kadia, Koji Sasaki, Nicholas J Short, Musa Yilmaz, Farhad Ravandi.
      The understanding of the molecular pathobiology of acute myeloid leukemia (AML) has spurred the identification of therapeutic targets and the development of corresponding novel targeted therapies. Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in AML]); and CPX-351 (encapsulated liposomal 5:1 molar ratio of cytarabine and daunorubicin), and glasdegib (hedgehog inhibitor). Other targeted therapies (menin inhibitors, CD123 antibody-drug conjugates) are showing promising results. To achieve optimal results in such a rare and heterogeneous entity as AML requires expertise, familiarity with this rare cancer, and the access to, and delivery of disparate therapies under rigorous supportive care conditions. In this review, we update the standard-of-care and investigational therapies and outline promising current and future research directions.
    DOI:  https://doi.org/10.1038/s41408-024-01143-2
  16. Nat Cardiovasc Res. 2024 Sep 18.
    Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
    Khanh V Doan, Timothy S Luongo, Thato T Ts'olo, Won Dong Lee, David W Frederick, Sarmistha Mukherjee, Gabriel K Adzika, Caroline E Perry, Ryan B Gaspar, Nicole Walker, Megan C Blair, Nicole Bye, James G Davis, Corey D Holman, Qingwei Chu, Lin Wang, Joshua D Rabinowitz, Daniel P Kelly, Thomas P Cappola, Kenneth B Margulies, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.
    DOI:  https://doi.org/10.1038/s44161-024-00542-9
  17. Sci Rep. 2024 09 14. 14(1): 21509
    Optimal fasting duration for mice as assessed by metabolic status.
    Jian Fu, Sha Liu, Mengyao Li, Fangrui Guo, Xiaoran Wu, Jiahao Hu, Lixin Wen, Ji Wang, Xiaowen Li.
      In the study of obesity and diabetes, mice are widely used for experimental research, and fasting is a common procedure used to reset metabolism in mouse models. The fasting duration for experimental mice varies greatly in nutritional and metabolic studies, ranging from 2 to 48 h. This study aims to assess the optimal fasting duration for mice fed low- and high-fat diets over a short period of time. C57BL/6J mice were fed a low-fat diet (LFD) or high-fat diet (HFD) and fasted for 4, 6, 8, 10, 12, or 24 h. The effects of different conditions after fasting on the metabolic level of mice were explored, and the data were collected for analysis. Our data indicate that fasting has inconsistent effects on mice fed a low-fat or high-fat diet. To compare the metabolic differences between mice in different dietary levels and thereby secure better scientific data, mice should fast for 6 h in animal experiments. Fasting for 6 h is also recommended when comparing glucose tolerance with insulin tolerance.
    Keywords:  Fasting duration; High-fat diet; Metabolic research; Mouse model; Nutritional research
    DOI:  https://doi.org/10.1038/s41598-024-72695-3
  18. J Crohns Colitis. 2024 Sep 16. pii: jjae148. [Epub ahead of print]
    Oxidized polyunsaturated fatty acid promotes colitis and colitis-associated tumorigenesis in mice.
    Weicang Wang, Yuxin Wang, Katherine Z Sanidad, Yige Wang, Jianan Zhang, Wenqi Yang, Quancai Sun, Ipek Bayram, Renhua Song, Haixia Yang, David Johnson, Heather L Sherman, Daeyoung Kim, Lisa M Minter, Justin J-L Wong, Melody Y Zeng, Eric A Decker, Guodong Zhang.
      BACKGROUND AND AIMS: Human studies suggest that a high intake of polyunsaturated fatty acid (PUFA) is associated with an increased risk of inflammatory bowel disease (IBD). PUFA is highly prone to oxidation. To date, it is unclear whether unoxidized or oxidized PUFA is involved in the development of IBD. Here, we aim to compare the effects of unoxidized PUFA vs. oxidized PUFA on the development of IBD and associated colorectal cancer.METHODS: We evaluated the effects of unoxidized and oxidized PUFA on dextran sodium sulfate (DSS)- and IL-10 knockout-induced colitis, and azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice. Additionally, we studied the roles of gut microbiota and Toll-like receptor 4 (TLR4) signaling involved.
    RESULTS: Administration of a diet containing oxidized PUFA, at human consumption-relevant levels, increases the severity of colitis and exacerbates the development of colitis-associated colon tumorigenesis in mice. Conversely, a diet rich in unoxidized PUFA doesn't promote colitis. Furthermore, oxidized PUFA worsens colitis-associated intestinal barrier dysfunction and leads to increased bacterial translocation, and it fails to promote colitis in Toll-like receptor 4 (TLR4) knockout mice. Finally, oxidized PUFA alters the diversity and composition of gut microbiota, and it fails to promote colitis in mice lacking the microbiota.
    CONCLUSIONS: These results support that oxidized PUFA promotes the development of colitis and associated tumorigenesis in mouse models via TLR4- and gut microbiota-dependent mechanisms. Our findings highlight the potential need to update regulation policies and industrial standards for oxidized PUFA levels in food.
    Keywords:  Colitis; Colitis-Associated Tumorigenesis; Lipid Oxidation; Polyunsaturated Fatty Acid
    DOI:  https://doi.org/10.1093/ecco-jcc/jjae148
  19. Crit Rev Biochem Mol Biol. 2024 Sep 17. 1-23
    Exercise training and changes in skeletal muscle mitochondrial proteins: from blots to "omics".
    Elizabeth G Reisman, Nikeisha J Caruana, David J Bishop.
      Mitochondria are essential, membrane-enclosed organelles that consist of ∼1100 different proteins, which allow for many diverse functions critical to maintaining metabolism. Highly metabolic tissues, such as skeletal muscle, have a high mitochondrial content that increases with exercise training. The classic western blot technique has revealed training-induced increases in the relatively small number of individual mitochondrial proteins studied (∼5% of the >1100 proteins in MitoCarta), with some of these changes dependent on the training stimulus. Proteomic approaches have identified hundreds of additional mitochondrial proteins that respond to exercise training. There is, however, surprisingly little crossover in the mitochondrial proteins identified in the published human training studies. This suggests that to better understand the link between training-induced changes in mitochondrial proteins and metabolism, future studies need to move beyond maximizing protein detection to adopting methods that will increase the reliability of the changes in protein abundance observed.
    Keywords:  Mitochondria; fiber type; proteins; proteomics; skeletal muscle; training
    DOI:  https://doi.org/10.1080/10409238.2024.2383408
  20. Nutrients. 2024 Aug 28. pii: 2884. [Epub ahead of print]16(17):
    Non-Specific Elevated Serum Free Fatty Acids in Lung Cancer Patients: Nutritional or Pathological?
    Yelin Shao, Sicong Wang, Xiaohang Xu, Ce Sun, Fei Cai, Qian Guo, Ming Wu, Min Yang, Xifeng Wu.
      IMPORTANCE: The reprogramming of lipid metabolism is a significant feature of tumors, yet the circulating levels of fatty acids in lung cancer patients remain to be explored. Moreover, the association between fatty acid levels and related factors, including nutritional intake, tumor metabolism, and tumor immunity, has been rarely discussed.OBJECTIVES: To explore the differences in serum free fatty acids between lung cancer patients and healthy controls, and investigate the factors associated with this phenomenon.
    DESIGN AND PARTICIPANTS: A case-control study enrolled 430 primary lung cancer patients and 430 healthy controls. The whole population had a medium [Q1, Q3] age of 48.0 [37.0, 58.9] years, with females comprising 56% of the participants. The absolute quantification of 27 serum free fatty acids (FFAs) was measured using a liquid chromatography-mass spectrometry (LC-MS/MS) detection. Data, including dietary intake, blood indicators, and gene expression of lung tissues, were obtained from questionnaires, blood tests, and RNA-sequencing. Statistical differences in FFA levels between lung cancer patients and healthy controls were investigated, and related contributing factors were explored.
    RESULTS: Levels of 22 FFAs were significantly higher in lung cancer patients compared to those in healthy controls, with fold changes ranging from 1.14 to 1.69. Lung cancer diagnosis models built with clinical and FFA features yielded an area under the receiver operating characteristic curve (AUROC) of 0.830 (0.780-0.880). Total fatty acids (TFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) showed no significant dietary-serum associations, indicating that the elevations might not be attributed to an excessive intake of relevant fatty acids from the diet. For RNA-sequencing of lung tissues, among the 68 lipid metabolism genes, 26 genes showed significant upregulation (FDR < 0.05), while 33 genes exhibited significant downregulation, indicating the involvement of the fatty acids in the tumor metabolism. Through joint analysis with immune cells and inflammatory factors in the blood, fatty acids might exert suppressing effects on tumor immunity.
    CONCLUSIONS: Lung cancer patients had elevated levels of serum free fatty acids compared to healthy individuals. The elevations might not be attributed to an excessive intake of relevant fatty acids from the diet but related to pathological factors of tumor metabolism and immunity. These findings will complement research on fatty acid metabolism of lung cancer and provide insights into potential intervention targets.
    Keywords:  LC-MS/MS; immunity; lung cancer; nutrition; serum free fatty acids; tumor metabolism
    DOI:  https://doi.org/10.3390/nu16172884
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