bims-medica 2024-06-02 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–06–02
twenty papers selected by
Brett Chrest, East Carolina University

Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells.
13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.
Sex-dependent adipose glucose partitioning by the mitochondrial pyruvate carrier.
Reciprocal Regulation of Cardiac β-Oxidation and Pyruvate Dehydrogenase by Insulin.
Oleic acid stimulates proliferation of RMG-1 ovarian cancer cells by activating the pentose phosphate pathway and glutamine metabolism.
Reduced beta-hydroxybutyrate disposal after ketogenic diet feeding in mice.
Exploring the mystery of tumor metabolism: Warburg effect and mitochondrial metabolism fighting side by side.
AspSnFR: A genetically encoded biosensor for real-time monitoring of aspartate in live cells.
Insights into the regulation of malate dehydrogenase: inhibitors, activators, and allosteric modulation by small molecules.
Review of Nutrition Guidelines and Evidence on Diet and Survival Outcomes for Cancer Survivors: Call for Integrating Nutrition into Oncology Care.
Redistribution of defective mitochondria-mediated dihydroorotate dehydrogenase imparts 5-fluorouracil resistance in colorectal cancer.
The Future of Obesity Management through Precision Nutrition: Putting the Individual at the Center.
Diabetes Risk Reduction Diet (DRRD) and Breast Cancer Risk: A Review.
The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival.
Role of dietary nutrients and metabolism in colorectal cancer.
Nutritional Considerations During Major Weight Loss Therapy: Focus on Optimal Protein and a Low-Carbohydrate Dietary Pattern.
Redox modulator iron complexes trigger intrinsic apoptosis pathway in cancer cells.
Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women.
Multifaceted mitochondria in innate immunity.
Potential roles of sex-linked differences in obesity and cancer immunotherapy: revisiting the obesity paradox.

Cancer Metab. 2024 May 29. 12(1): 16

Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells.

Hadas Fulman-Levy, Raichel Cohen-Harazi, Bar Levi, Lital Argaev-Frenkel, Ifat Abramovich, Eyal Gottlieb, Sarah Hofmann, Igor Koman, Elimelech Nesher.

   BACKGROUND: The ketogenic diet (KD), based on high fat (over 70% of daily calories), low carbohydrate, and adequate protein intake, has become popular due to its potential therapeutic benefits for several diseases including cancer. Under KD and starvation conditions, the lack of carbohydrates promotes the production of ketone bodies (KB) from fats by the liver as an alternative source of metabolic energy. KD and starvation may affect the metabolism in cancer cells, as well as tumor characteristics. The aim of this study is to evaluate the effect of KD conditions on a wide variety of aspects of breast cancer cells in vitro.
METHODS: Using two cancer and one non-cancer breast cell line, we evaluate the effect of β-hydroxybutyrate (βHb) treatment on cell growth, survival, proliferation, colony formation, and migration. We also assess the effect of KB on metabolic profile of the cells. Using RNAseq analysis, we elucidate the effect of βHb on the gene expression profile.
RESULTS: Significant effects were observed following treatment by βHb which include effects on viability, proliferation, and colony formation of MCF7 cells, and different effects on colony formation of MDA-MB-231 cells, with no such effects on non-cancer HB2 cells. We found no changes in glucose intake or lactate output following βHb treatment as measured by LC-MS, but an increase in reactive oxygen species (ROS) level was detected. RNAseq analysis demonstrated significant changes in genes involved in lipid metabolism, cancer, and oxidative phosphorylation.
CONCLUSIONS: Based on our results, we conclude that differential response of cancer cell lines to βHb treatment, as alternative energy source or signal to alter lipid metabolism and oncogenicity, supports the need for a personalized approach to breast cancer patient treatment.

Keywords:  Beta-hydroxybutyrate; Breast cancer; Ketone bodies; MCF7; βHb

DOI:  https://doi.org/10.1186/s40170-024-00339-1
Sci Adv. 2024 May 31. 10(22): eadj1431

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.

Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Brandon M Oswald, Joseph Longo, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Lauren R Duimstra, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.

DOI: https://doi.org/10.1126/sciadv.adj1431
bioRxiv. 2024 May 14. pii: 2024.05.11.593540. [Epub ahead of print]

Sex-dependent adipose glucose partitioning by the mitochondrial pyruvate carrier.

Christopher E Shannon, Terry Bakewell, Marcel J Fourcaudot, Iriscilla Ayala, Giovanna Romero, Mara Asmis, Leandro C Freitas Lima, Martina Wallace, Luke Norton.

Objective: The mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice.
Methods: The impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 ( Mpc1 AD-/- ) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.
Results: Treatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants from Mpc1 AD-/- mice were intrinsically incapable of incorporating pyruvate into triglycerides. In vivo , MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved in Mpc1 AD-/- mice regardless of sex, even under conditions of zero dietary fat.
Conclusion: These findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.

DOI: https://doi.org/10.1101/2024.05.11.593540
J Biol Chem. 2024 May 23. pii: S0021-9258(24)01913-6. [Epub ahead of print] 107412

Reciprocal Regulation of Cardiac β-Oxidation and Pyruvate Dehydrogenase by Insulin.

Abdallah Elnwasany, Heba A Ewida, Ivan Menendez-Montes, Monika Mizerska, Xiaorong Fu, Chai-Wan Kim, Jay D Horton, Shawn C Burgess, Beverly A Rothermel, Pamela A Szweda, Luke I Szweda.

  The heart alters the rate and relative oxidation of fatty acids and glucose based on availability and energetic demand. Insulin plays a crucial role in this process diminishing fatty acid and increasing glucose oxidation when glucose availability increases. Loss of insulin sensitivity and metabolic flexibility can result in cardiovascular disease. It is therefore important to identify mechanisms by which insulin regulates substrate utilization in the heart. Mitochondrial pyruvate dehydrogenase (PDH) is the key regulatory site for the oxidation of glucose for ATP production. Nevertheless, the impact of insulin on PDH activity has not been fully delineated, particularly in the heart. We sought in vivo evidence that insulin stimulates cardiac PDH and that this process is driven by inhibition of fatty acid oxidation. Mice injected with insulin exhibited dephosphorylation and activation of cardiac PDH. This was accompanied by an increase in the content of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 (CPT1) and, thus, mitochondrial import of fatty acids. Administration of the CPT1 inhibitor oxfenicine was sufficient to activate PDH. Malonyl-CoA is produced by acetyl-CoA carboxylase (ACC). Pharmacologic inhibition or knockout of cardiac ACC diminished insulin-dependent production of malonyl-CoA and activation of PDH. Finally, circulating insulin and cardiac glucose utilization exhibit daily rhythms reflective of nutritional status. We demonstrate that time of day-dependent changes in PDH activity are mediated, in part, by ACC-dependent production of malonyl-CoA. Thus, by inhibiting fatty acid oxidation, insulin reciprocally activates PDH. These studies identify potential molecular targets to promote cardiac glucose oxidation and treat heart disease.

Keywords:  Acetyl-CoA Carboxylase; Heart; Insulin; Malonyl-CoA; Mitochondria; Pyruvate Dehydrogenase; β-Oxidation

DOI:  https://doi.org/10.1016/j.jbc.2024.107412
Biochem Biophys Res Commun. 2024 May 24. pii: S0006-291X(24)00698-3. [Epub ahead of print]722 150162

Oleic acid stimulates proliferation of RMG-1 ovarian cancer cells by activating the pentose phosphate pathway and glutamine metabolism.

Takeru Tamaki, Nobuyuki Fukushima.

  Extracellular fatty acids (FAs) play an important role in regulating cellular functions such as cell proliferation, survival, and migration. The effects of oleic acid (OA) on cancer cells vary depending on the cell type. Our prior study showed that two distinct ovarian cancer cell lines, RMG-1 and HNOA, proliferate in response to OA, but they differ with respect to glucose utilization. Here, we aimed to elucidate the mechanism(s) by which OA stimulates proliferation of RMG-1 cells. We found that OA stimulates RMG-1 proliferation by activating the FA transporter CD36. OA also increases uptake of glucose and glutamine, which subsequently activate the pentose phosphate pathway (PPP) and glutamine metabolism, respectively. Given that ribose 5-phosphate derived from the PPP is utilized for glutamine metabolism and the subsequent de novo nucleotide synthesis, our findings suggest that OA affects the PPP associated with Gln metabolism, rather than glycolysis associated with glutaminolysis; this leads ultimately to activation of DNA synthesis, which is required for cell proliferation. This selective activation by OA contrasts with the mechanisms observed in HNOA cells, in which OA-induced cell proliferation is driven by transcriptional regulation of the GLUT gene. The diverse responses of cancer cells to OA may be attributed to distinct mechanisms of OA reception and/or different metabolic pathways activated by OA.

Keywords:  CD36; Glutamine metabolism; Oleic acid; Ovarian cancer cell; Pentose phosphate pathway; de novo nucleotide synthesis

DOI:  https://doi.org/10.1016/j.bbrc.2024.150162
bioRxiv. 2024 May 18. pii: 2024.05.16.594369. [Epub ahead of print]

Reduced beta-hydroxybutyrate disposal after ketogenic diet feeding in mice.

Cody M Cousineau, Detrick Snyder, JeAnna R Redd, Sophia Turner, Treyton Carr, Dave Bridges.

The ketogenic diet (KD) has garnered considerable attention due to its potential benefits in weight loss, health improvement, and performance enhancement. However, the phenotypic responses to KD vary widely between individuals. Skeletal muscle is a major contributor to ketone body (KB) catabolism, however, the regulation of ketolysis is not well understood. In this study, we evaluated how mTORC1 activation and a ketogenic diet modify ketone body disposal in muscle Tsc1 knockout (KO) mice, inbred A/J mice, and Diversity Outbred (DO) mice. Muscle Tsc1 KO mice demonstrated enhanced ketone body clearance. Contrary to expectations, KD feeding in A/J mice did not improve KB disposal, and in most strains disposal was reduced. Transcriptional analysis revealed reduced expression of important ketolytic genes in KD-fed A/J mice, suggesting impaired KB catabolism. Diversity Outbred (DO) mice displayed variable responses to KD, with most mice showing worsened KB disposal. Exploratory analysis on these data suggest potential correlations between KB disposal and cholesterol levels as well as weight gain on a KD. Our findings suggest that ketone body disposal may be regulated by both nutritional and genetic factors and these relationships may help explain interindividual variability in responses to ketogenic diets.

DOI: https://doi.org/10.1101/2024.05.16.594369
Cell Signal. 2024 May 28. pii: S0898-6568(24)00207-9. [Epub ahead of print] 111239

Exploring the mystery of tumor metabolism: Warburg effect and mitochondrial metabolism fighting side by side.

Yongxin Yu, Yulang Jiang, Christian Glandorff, Mingyu Sun.

  The metabolic reconfiguration of tumor cells constitutes a pivotal aspect of tumor proliferation and advancement. This study delves into two primary facets of tumor metabolism: the Warburg effect and mitochondrial metabolism, elucidating their contributions to tumor dominance. The Warburg effect facilitates efficient energy acquisition by tumor cells through aerobic glycolysis and lactic acid fermentation, offering metabolic advantages conducive to growth and proliferation. Simultaneously, mitochondrial metabolism, serving as the linchpin of sustained tumor vitality, orchestrates the tricarboxylic acid cycle and electron transport chain, furnishing a steadfast and dependable wellspring of biosynthesis for tumor cells. Regarding targeted therapy, this discourse examines extant strategies targeting tumor glycolysis and mitochondrial metabolism, underscoring their potential efficacy in modulating tumor metabolism while envisaging future research trajectories and treatment paradigms in the realm of tumor metabolism. By means of a thorough exploration of tumor metabolism, this study aspires to furnish crucial insights into the regulation of tumor metabolic processes, thereby furnishing valuable guidance for the development of novel therapeutic modalities. This comprehensive deliberation is poised to catalyze advancements in tumor metabolism research and offer novel perspectives and pathways for the formulation of cancer treatment strategies in the times ahead.

Keywords:  Metabolic reprogramming; Mitochondria; Targeted therapy; Tumor; Warburg effect

DOI:  https://doi.org/10.1016/j.cellsig.2024.111239
Cell Chem Biol. 2024 May 20. pii: S2451-9456(24)00179-X. [Epub ahead of print]

AspSnFR: A genetically encoded biosensor for real-time monitoring of aspartate in live cells.

Lars Hellweg, Martin Pfeifer, Miroslaw Tarnawski, Shao Thing-Teoh, Lena Chang, Andrea Bergner, Jana Kress, Julien Hiblot, Tabea Wiedmer, Giulio Superti-Furga, Jürgen Reinhardt, Kai Johnsson, Philipp Leippe.

Aspartate is crucial for nucleotide synthesis, ammonia detoxification, and maintaining redox balance via the malate-aspartate-shuttle (MAS). To disentangle these multiple roles of aspartate metabolism, tools are required that measure aspartate concentrations in real time and in live cells. We introduce AspSnFR, a genetically encoded green fluorescent biosensor for intracellular aspartate, engineered through displaying and screening biosensor libraries on mammalian cells. In live cells, AspSnFR is able to precisely and quantitatively measure cytosolic aspartate concentrations and dissect its production from glutamine. Combining high-content imaging of AspSnFR with pharmacological perturbations exposes differences in metabolic vulnerabilities of aspartate levels based on nutrient availability. Further, AspSnFR facilitates tracking of aspartate export from mitochondria through SLC25A12, the MAS' key transporter. We show that SLC25A12 is a rapidly responding and direct route to couple Ca2+ signaling with mitochondrial aspartate export. This establishes SLC25A12 as a crucial link between cellular signaling, mitochondrial respiration, and metabolism.

DOI: https://doi.org/10.1016/j.chembiol.2024.05.002
Essays Biochem. 2024 May 30. pii: EBC20230087. [Epub ahead of print]

Insights into the regulation of malate dehydrogenase: inhibitors, activators, and allosteric modulation by small molecules.

Betsy M Martinez-Vaz, Alicia L Howard, Varuni K Jamburuthugoda, Kevin P Callahan.

  Cellular metabolism comprises a complex network of biochemical anabolic and catabolic processes that fuel the growth and survival of living organisms. The enzyme malate dehydrogenase (MDH) is most known for its role in oxidizing malate to oxaloacetate (OAA) in the last step of the tricarboxylic acid (TCA) cycle, but it also participates in the malate-aspartate shuttle in the mitochondria as well as the glyoxylate cycle in plants. These pathways and the specific reactions within them are dynamic and must be carefully calibrated to ensure a balance between nutrient/energy supply and demand. MDH structural and functional complexity requires a variety of regulatory mechanisms, including allosteric regulation, feedback, and competitive inhibition, which are often dependent on whether the enzyme is catalyzing its forward or reverse reaction. Given the role of MDH in central metabolism and its potential as a target for therapeutics in both cancer and infectious diseases, there is a need to better understand its regulation. The involvement of MDH in multiple pathways makes it challenging to identify which effectors are critical to its activity. Many of the in vitro experiments examining MDH regulation were done decades ago, and though allosteric sites have been proposed, none to date have been specifically mapped. This review aims to provide an overview of the current knowledge surrounding MDH regulation by its substrate, products, and other intermediates of the TCA cycle while highlighting all the gaps in our understanding of its regulatory mechanisms.

Keywords:  Malate; activators; allosteric regulation; dehydrogenase; inhibitors; regulation

DOI:  https://doi.org/10.1042/EBC20230087
J Nutr. 2024 May 24. pii: S0022-3166(24)00301-8. [Epub ahead of print]

Review of Nutrition Guidelines and Evidence on Diet and Survival Outcomes for Cancer Survivors: Call for Integrating Nutrition into Oncology Care.

Zhongyao Li, Xinge Ding, Yutong Chen, Laura Keaver, Colin E Champ, Christopher L Fink, Susan Chaityn Lebovits, Mark Corroto, Fang Fang Zhang.

  Several organizations have published nutrition guidelines for cancer survivors during and after treatment. This review compared nutrition guidelines for cancer survivors published in the United States (US) for the topics that are covered in the guidelines and evaluated the evidence that these guidelines are based upon. A team of researchers, patient stakeholders, and healthcare providers collectively identified five nutrition guidelines for cancer survivors in the US: the 2022 American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors, the 2018 American Institute for Cancer Research Cancer Nutrition Guide, the 2022 National Cancer Institute Physician Data Query and Eating Hints, the 2024 National Comprehensive Cancer Network Guidelines for Cancer Survivors, and the 2020 American Society for Clinical Oncology Guidelines. The five guidelines cover a comprehensive list of nutrition topics but overall promote to follow those recommendations for cancer prevention. This review also evaluated the current evidence from meta-analyses on dietary patterns and intakes of foods and nutrients in relation to survival outcomes among cancer survivors. Although the evidence on dietary patterns is strong, the evidence on most dietary factors is still limited and the current research was primarily conducted among breast and colorectal cancer survivors. While nutrition recommendations are available for cancer survivors, practical strategies need to be implemented to integrate nutrition into oncology care and help cancer survivors follow these recommendations. Further research is warranted to provide additional evidence on the role of nutrition in the health outcomes of cancer survivors and guide the development of evidence-based nutrition recommendations. REGISTRY AND REGISTRY NUMBER FOR SYSTEMATIC REVIEWS OR META-ANALYSES: The protocol is registered in PROSPERO: CRD42023429240.

Keywords:  cancer survivors; guidelines; nutrition; practice; umbrella review

DOI:  https://doi.org/10.1016/j.tjnut.2024.05.024
Redox Biol. 2024 May 23. pii: S2213-2317(24)00185-X. [Epub ahead of print]73 103207

Redistribution of defective mitochondria-mediated dihydroorotate dehydrogenase imparts 5-fluorouracil resistance in colorectal cancer.

Shuohui Dong, Mingguang Zhang, Zhiqiang Cheng, Xiang Zhang, Weili Liang, Songhan Li, Linchuan Li, Qian Xu, Siyi Song, Zitian Liu, Guangwei Yang, Xiang Zhao, Ze Tao, Shuo Liang, Kexin Wang, Guangyong Zhang, Sanyuan Hu.

  Although 5-fluorouracil (5-FU) is the primary chemotherapy treatment for colorectal cancer (CRC), its efficacy is limited by drug resistance. Ferroptosis activation is a promising treatment for 5-FU-resistant cancer cells; however, potential therapeutic targets remain elusive. This study investigated ferroptosis vulnerability and dihydroorotate dehydrogenase (DHODH) activity using stable, 5-FU-resistant CRC cell lines and xenograft models. Ferroptosis was characterized by measuring malondialdehyde levels, assessing lipid metabolism and peroxidation, and using mitochondrial imaging and assays. DHODH function is investigated through gene knockdown experiments, tumor behavior assays, mitochondrial import reactions, intramitochondrial localization, enzymatic activity analyses, and metabolomics assessments. Intracellular lipid accumulation and mitochondrial DHODH deficiency led to lipid peroxidation overload, weakening the defense system of 5-FU-resistant CRC cells against ferroptosis. DHODH, primarily located within the inner mitochondrial membrane, played a crucial role in driving intracellular pyrimidine biosynthesis and was redistributed to the cytosol in 5-FU-resistant CRC cells. Cytosolic DHODH, like its mitochondrial counterpart, exhibited dihydroorotate catalytic activity and participated in pyrimidine biosynthesis. This amplified intracellular pyrimidine pools, thereby impeding the efficacy of 5-FU treatment through molecular competition. These findings contribute to the understanding of 5-FU resistance mechanisms and suggest that ferroptosis and DHODH are promising therapeutic targets for patients with CRC exhibiting resistance to 5-FU.

Keywords:  Chemoresistance; Colorectal cancer; Dihydroorotate dehydrogenase; Ferroptosis; Lipid metabolic reprogramming

DOI:  https://doi.org/10.1016/j.redox.2024.103207
Curr Nutr Rep. 2024 May 28.

The Future of Obesity Management through Precision Nutrition: Putting the Individual at the Center.

Hande Gül Ulusoy-Gezer, Neslişah Rakıcıoğlu.

  PURPOSE OF REVIEW: The prevalence of obesity continues to rise steadily. While obesity management typically relies on dietary and lifestyle modifications, individual responses to these interventions vary widely. Clinical guidelines for overweight and obesity stress the importance of personalized approaches to care. This review aims to underscore the role of precision nutrition in delivering tailored interventions for obesity management. RECENT FINDINGS: Recent technological strides have expanded our ability to detect obesity-related genetic polymorphisms, with machine learning algorithms proving pivotal in analyzing intricate genomic data. Machine learning algorithms can also predict postprandial glucose, triglyceride, and insulin levels, facilitating customized dietary interventions and ultimately leading to successful weight loss. Additionally, given that adherence to dietary recommendations is one of the key predictors of weight loss success, employing more objective methods for dietary assessment and monitoring can enhance sustained long-term compliance. Biomarkers of food intake hold promise for a more objective dietary assessment. Acknowledging the multifaceted nature of obesity, precision nutrition stands poised to transform obesity management by tailoring dietary interventions to individuals' genetic backgrounds, gut microbiota, metabolic profiles, and behavioral patterns. However, there is insufficient evidence demonstrating the superiority of precision nutrition over traditional dietary recommendations. The integration of precision nutrition into routine clinical practice requires further validation through randomized controlled trials and the accumulation of a larger body of evidence to strengthen its foundation.

Keywords:  Dietary assessment; Obesity; Personalized nutrition; Polymorphisms; Precision nutrition; Weight loss

DOI:  https://doi.org/10.1007/s13668-024-00550-y
Nutr Cancer. 2024 May 25. 1-7

Diabetes Risk Reduction Diet (DRRD) and Breast Cancer Risk: A Review.

Motahareh Hasani, Haniyeh Ghasemi, Adeleh Khodabakhshi.

BACKGROUND: Considering the significant involvement of insulin resistance in various forms of cancer, it is postulated that the implementation of a diabetic diet, which effectively mitigates insulin resistance, may potentially decrease the susceptibility to breast cancer among female individuals.
METHODS: In this literature review, a comprehensive electronic search of different databases was done using the keywords "Breast cancer" OR "breast tumor" OR "Breast Neoplasms" AND "diet" OR "diabetic diet" OR "Low Carbohydrate Diet" OR "Carbohydrate restricted diet" OR "High-Protein Low-Carbohydrate Diet" OR "diabetes risk reduction diet" OR "DRRD" as the main keywords.
RESULTS: Research has shown that the DRRD score is inversely correlated with breast cancer risk. In fact, for every three-point increase in the DRRD score, the risk of breast cancer decreases by 7%. Studies have shown that higher DRRD scores in breast cancer patients are associated with a reduced risk of cancer and a higher chance of survival.
CONCLUSION: The results of this study indicate a positive correlation between a higher level of adherence to the diabetes risk reduction diet (DRRD) and improved survival rates. This suggests that breast cancer survivors may benefit from making dietary modifications in line with a diabetic diet following their diagnosis.

DOI: https://doi.org/10.1080/01635581.2024.2355686
Haematologica. 2024 May 30.

The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival.

Vesna S Stanulović, Shorog Al Omair, Michelle A C Reed, Jennie Roberts, Sandeep Potluri, Taylor Fulton-Ward, Nancy Gudgeon, Emma L Bishop, Juliette Roels, Tracey A Perry, Sovan Sarkar, Guy Pratt, Tom Taghon, Sarah Dimeloe, Ulrich L Günther, Christian Ludwig, Maarten Hoogenkamp.

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.

DOI: https://doi.org/10.3324/haematol.2023.283471
Asia Pac J Clin Nutr. 2024 Jun;33(2): 153-161

Role of dietary nutrients and metabolism in colorectal cancer.

Jinjun Ye, Xing Bao, Jiufeng Wei, Yuanpeng Zhang, Yu Liu, Le Xin.

  Colorectal cancer (CRC) is one of the most common malignancies and the leading causes of cancer related deaths worldwide. The development of CRC is driven by a combination of genetic and environmental factors. There is growing evidence that changes in dietary nutrition may modulate the CRC risk, and protective effects on the risk of developing CRC have been advocated for specific nutrients such as glucose, amino acids, lipid, vitamins, micronutrients and prebiotics. Metabolic crosstalk between tumor cells, tumor microenvironment components and intestinal flora further promote proliferation, invasion and metastasis of CRC cells and leads to treatment resistance. This review summarizes the research progress on CRC prevention, pathogenesis, and treatment by dietary supplementation or deficiency of glucose, amino acids, lipids, vitamins, micronutri-ents, and prebiotics, respectively. The roles played by different nutrients and dietary crosstalk in the tumor microenvironment and metabolism are discussed, and nutritional modulation is inspired to be beneficial in the prevention and treatment of CRC.

Keywords:  colorectal cancer; metabolism; microenvironment; nutrient; risk factors

DOI:  https://doi.org/10.6133/apjcn.202406_33(2).0002
Curr Nutr Rep. 2024 May 30.

Nutritional Considerations During Major Weight Loss Therapy: Focus on Optimal Protein and a Low-Carbohydrate Dietary Pattern.

Jeff S Volek, Madison L Kackley, Alex Buga.

   PURPOSE OF REVIEW: Considering the high prevalence of obesity and related metabolic impairments in the population, the unique role nutrition has in weight loss, reversing metabolic disorders, and maintaining health cannot be overstated. Normal weight and well-being are compatible with varying dietary patterns, but for the last half century there has been a strong emphasis on low-fat, low-saturated fat, high-carbohydrate based approaches. Whereas low-fat dietary patterns can be effective for a subset of individuals, we now have a population where the vast majority of adults have excess adiposity and some degree of metabolic impairment. We are also entering a new era with greater access to bariatric surgery and approval of anti-obesity medications (glucagon-like peptide-1 analogues) that produce substantial weight loss for many people, but there are concerns about disproportionate loss of lean mass and nutritional deficiencies.
RECENT FINDINGS: No matter the approach used to achieve major weight loss, careful attention to nutritional considerations is necessary. Here, we examine the recent findings regarding the importance of adequate protein to maintain lean mass, the rationale and evidence supporting low-carbohydrate and ketogenic dietary patterns, and the potential benefits of including exercise training in the context of major weight loss. While losing and sustaining weight loss has proven challenging, we are optimistic that application of emerging nutrition science, particularly personalized well-formulated low-carbohydrate dietary patterns that contain adequate protein (1.2 to 2.0 g per kilogram reference weight) and achieve the beneficial metabolic state of euketonemia (circulating ketones 0.5 to 5 mM), is a promising path for many individuals with excess adiposity.

Keywords:  Adiposity; Body composition; Dietary patterns; Ketogenic; Low-carbohydrate; Nutrition; Obesity; Weight loss

DOI:  https://doi.org/10.1007/s13668-024-00548-6
iScience. 2024 Jun 21. 27(6): 109899

Redox modulator iron complexes trigger intrinsic apoptosis pathway in cancer cells.

Sai Kumari Vechalapu, Rakesh Kumar, Niranjan Chatterjee, Sikha Gupta, Shweta Khanna, Pooja Yedehalli Thimmappa, Sathyapriya Senthil, Raju Eerlapally, Manjunath B Joshi, Santosh K Misra, Apparao Draksharapu, Dharmaraja Allimuthu.

  The emergence of multidrug resistance in cancer cells necessitates the development of new therapeutic modalities. One way cancer cells orchestrate energy metabolism and redox homeostasis is through overloaded iron pools directed by iron regulatory proteins, including transferrin. Here, we demonstrate that targeting redox homeostasis using nitrogen-based heterocyclic iron chelators and their iron complexes efficiently prevents the proliferation of liver cancer cells (EC50: 340 nM for IITK4003) and liver cancer 3D spheroids. These iron complexes generate highly reactive Fe(IV)=O species and accumulate lipid peroxides to promote oxidative stress in cells that impair mitochondrial function. Subsequent leakage of mitochondrial cytochrome c activates the caspase cascade to trigger the intrinsic apoptosis pathway in cancer cells. This strategy could be applied to leverage the inherent iron overload in cancer cells to selectively promote intrinsic cellular apoptosis for the development of unique iron-complex-based anticancer therapeutics.

Keywords:  cancer; chemistry

DOI:  https://doi.org/10.1016/j.isci.2024.109899
Obesity (Silver Spring). 2024 Jun;32(6): 1125-1135

Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women.

Andrea M Brennan, Paul M Coen, Theresa Mau, Megan Hetherington-Rauth, Frederico G S Toledo, Erin E Kershaw, Peggy M Cawthon, Philip A Kramer, Sofhia V Ramos, Anne B Newman, Steven R Cummings, Daniel E Forman, Reichelle X Yeo, Giovanna Distefano, Iva Miljkovic, Jamie N Justice, Anthony J A Molina, Michael J Jurczak, Lauren M Sparks, Stephen B Kritchevsky, Bret H Goodpaster.

OBJECTIVE: The aim of this study was to examine associations of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults.
METHODS: Cross-sectional data from 829 adults ≥70 years of age were used. Abdominal, subcutaneous, and visceral AT and thigh muscle fat infiltration (MFI) were quantified by magnetic resonance imaging. SM mitochondrial energetics were characterized in vivo (31P-magnetic resonance spectroscopy; ATPmax) and ex vivo (high-resolution respirometry maximal oxidative phosphorylation [OXPHOS]). ActivPal was used to measure physical activity ([PA]; step count). Linear regression adjusted for covariates was applied, with sequential adjustment for BMI and PA.
RESULTS: Independent of BMI, total abdominal AT (standardized [Std.] β = -0.21; R2 = 0.09) and visceral AT (Std. β = -0.16; R2 = 0.09) were associated with ATPmax (p < 0.01; n = 770) but not following adjustment for PA (p ≥ 0.05; n = 658). Visceral AT (Std. β = -0.16; R2 = 0.25) and thigh MFI (Std. β = -0.11; R2 = 0.24) were associated with carbohydrate-supported maximal OXPHOS independent of BMI and PA (p < 0.05; n = 609). Total abdominal AT (Std. β = -0.19; R2 = 0.24) and visceral AT (Std. β = -0.17; R2 = 0.24) were associated with fatty acid-supported maximal OXPHOS independent of BMI and PA (p < 0.05; n = 447).
CONCLUSIONS: Skeletal MFI and abdominal visceral, but not subcutaneous, AT are inversely associated with SM mitochondrial bioenergetics in older adults independent of BMI. Associations between ectopic AT and in vivo mitochondrial bioenergetics are attenuated by PA.

DOI: https://doi.org/10.1002/oby.24008
NPJ Metab Health Dis. 2024 ;2(1): 6

Multifaceted mitochondria in innate immunity.

Eloïse Marques, Robbin Kramer, Dylan G Ryan.

  The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

Keywords:  Energy metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s44324-024-00008-3
NPJ Metab Health Dis. 2024 ;2(1): 5

Potential roles of sex-linked differences in obesity and cancer immunotherapy: revisiting the obesity paradox.

Logan V Vick, Spencer Rosario, Jonathan W Riess, Robert J Canter, Sarbajit Mukherjee, Arta M Monjazeb, William J Murphy.

  Obesity, a condition of excess adiposity usually defined by a BMI > 30, can have profound effects on both metabolism and immunity, connecting the condition with a broad range of diseases, including cancer and negative outcomes. Obesity and cancer have been associated with increased incidence, progression, and poorer outcomes of multiple cancer types in part due to the pro-inflammatory state that arises. Surprisingly, obesity has also recently been demonstrated in both preclinical models and clinical outcomes to be associated with improved response to immune checkpoint inhibition (ICI). These observations have laid the foundation for what has been termed the "obesity paradox". The mechanisms underlying these augmented immunotherapy responses are still unclear given the pleiotropic effects obesity exerts on cells and tissues. Other important variables such as age and sex are being examined as further affecting the obesity effect. Sex-linked factors exert significant influences on obesity biology, metabolism as well as differential effects of different immune cell-types. Age can be another confounding factor contributing to the effects on both sex-linked changes, immune status, and obesity. This review aims to revisit the current body of literature describing the immune and metabolic changes mediated by obesity, the role of obesity on cancer immunotherapy, and to highlight questions on how sex-linked differences may influence obesity and immunotherapy outcome.

Keywords:  Cancer; Endocrinology; Oncology

DOI:  https://doi.org/10.1038/s44324-024-00007-4