bims-medica 2024-03-17 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–03–17
29 papers selected by
Brett Chrest, East Carolina University

Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer.
13 C-SpaceM: Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential.
Hypoxia rewires glucose and glutamine metabolism in different sources of skeletal stem and progenitor cells similarly, except for pyruvate.
Metabolic phenotyping of healthy and diseased human RPE cells.
Molecular imaging of tumor metabolism: Insight from pyruvate- and glucose-based deuterium MRI studies.
The Ketone Bridge Between the Heart and the Bladder: How Fast Should We Go?
Ketogenic diet combined with intermittent fasting: an option for type 2 diabetes remission?
Exploring monocarboxylate transporter inhibition for cancer treatment.
Fatty acid oxidation drives mitochondrial hydrogen peroxide production by α-ketoglutarate dehydrogenase.
Dietary lipid is largely deposited in skin and rapidly affects insulating properties.
Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.
The use of NADH anisotropy to investigate mitochondrial cristae alignment.
Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
Study on the correlation between controlling nutritional status score and clinical biochemical indicators in patients with colorectal cancer.
Metabolic plasticity and obesity-associated changes in diurnal postexercise metabolism in mice.
Quantification of metabolic activity from isotope tracing data using automated methodology.
Thermodynamic Analysis to Evaluate the Effect of Diet on Brain Glucose Metabolism: The Case of Fish Oil.
Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet.
OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.
Gene identification and enzymatic characterization of the initial enzyme in pyrimidine oxidative metabolism, uracil-thymine dehydrogenase.
Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions.
Hepatic effects of low carbohydrate diet associated with different lipid sources: insights into oxidative stress, cytotoxicity, and epigenetic markers in a mice model of obesity.
Association between adherence to a dietary approach to stop hypertension and the Mediterranean diets and risk of colorectal cancer: A matched case-control study.
Requirements for essential micronutrients during caloric restriction and fasting.
Screening Metabolic Biomarkers in KRAS Mutated Mouse Acinar and Human Pancreatic Cancer Cells via Single-Cell Mass Spectrometry.
Lifestyle Factors and Cancer: A Narrative Review.
The Effect of Micronutrients on Obese Phenotype of Adult Mice Is Dependent on the Experimental Environment.
Identification of fatty acid oxidation-related subtypes by integrated analysis of bulk- and single-cell transcriptome profiling in colorectal cancer.

ACS Pharmacol Transl Sci. 2024 Mar 08. 7(3): 560-569

Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer.

Reshmi Akter, Muhammad Awais, Vinothini Boopathi, Jong Chan Ahn, Deok Chun Yang, Se Chan Kang, Dong Uk Yang, Seok-Kyu Jung.

Obesity is a well-established risk factor for cancer, significantly impacting both cancer incidence and mortality. However, the intricate molecular mechanisms connecting adipose tissue to cancer cell metabolism are not fully understood. This Review explores the historical context of tumor energy metabolism research, tracing its origins to Otto Warburg's pioneering work in 1920. Warburg's discovery of the "Warburg effect", wherein cancer cells prefer anaerobic glycolysis even in the presence of oxygen, laid the foundation for understanding cancer metabolism. Building upon this foundation, the "reverse Warburg effect" emerged in 2009, elucidating the role of aerobic glycolysis in cancer-associated fibroblasts (CAFs) and its contribution to lactate accumulation in the tumor microenvironment, subsequently serving as a metabolic substrate for cancer cells. In contrast, within high-adiposity contexts, cancer cells exhibit a unique metabolic shift termed the "inversion of the Warburg effect". This phenomenon, distinct from the stromal-dependent reverse Warburg effect, relies on increased nutrient abundance in obesity environments, leading to the generation of glucose from lactate as a metabolic substrate. This Review underscores the heightened tumor proliferation and aggressiveness associated with obesity, introducing the "inversion of the Warburg effect" as a novel mechanism rooted in the altered metabolic landscape within an obese milieu. The insights presented here open promising avenues for therapeutic exploration, offering fresh perspectives and opportunities for the development of innovative cancer treatment strategies.

DOI: https://doi.org/10.1021/acsptsci.3c00301
bioRxiv. 2024 Feb 28. pii: 2023.08.18.553810. [Epub ahead of print]

13 C-SpaceM: Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.

Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Shahraz Mohammed, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov.

Metabolism has emerged as a key factor in homeostasis and disease including cancer. Yet, little is known about the heterogeneity of metabolic activity of cancer cells due to the lack of tools to directly probe it. Here, we present a novel method, 13 C-SpaceM for spatial single-cell isotope tracing of glucose-dependent de novo lipogenesis. The method combines imaging mass spectrometry for spatially-resolved detection of 13 C 6 -glucose-derived 13 C label incorporated into esterified fatty acids with microscopy and computational methods for data integration and analysis. We validated 13 C-SpaceM on a spatially-heterogeneous normoxia-hypoxia model of liver cancer cells. Investigating cultured cells, we revealed single-cell heterogeneity of lipogenic acetyl-CoA pool labelling degree upon ACLY knockdown that is hidden in the bulk analysis and its effect on synthesis of individual fatty acids. Next, we adapted 13 C-SpaceM to analyze tissue sections of mice harboring isocitrate dehydrogenase (IDH)-mutant gliomas. We found a strong induction of de novo fatty acid synthesis in the tumor tissue compared to the surrounding brain. Comparison of fatty acid isotopologue patterns revealed elevated uptake of mono-unsaturated and essential fatty acids in the tumor. Furthermore, our analysis uncovered substantial spatial heterogeneity in the labelling of the lipogenic acetyl-CoA pool indicative of metabolic reprogramming during microenvironmental adaptation. Overall, 13 C-SpaceM enables novel ways for spatial probing of metabolic activity at the single cell level. Additionally, this methodology provides unprecedented insight into fatty acid uptake, synthesis and modification in normal and cancerous tissues.

DOI: https://doi.org/10.1101/2023.08.18.553810
Signal Transduct Target Ther. 2024 Mar 11. 9(1): 59

Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential.

Yu-Ling Xiao, Yue Gong, Ying-Jia Qi, Zhi-Ming Shao, Yi-Zhou Jiang.

Diet, serving as a vital source of nutrients, exerts a profound influence on human health and disease progression. Recently, dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases, autoimmune diseases, cardiovascular diseases, and metabolic disorders. These interventions have demonstrated substantial potential in modulating metabolism, disease trajectory, and therapeutic responses. Metabolic reprogramming is a hallmark of malignant progression, and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication. Dietary intake, as a key environmental factor, can influence tumor metabolism. Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors, thereby increasing the efficacy of cancer treatments. However, the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex. Despite encouraging results, the mechanisms underlying diet-based therapeutic strategies remain largely unexplored, often resulting in underutilization in disease management. In this review, we aim to illuminate the potential effects of various dietary interventions, including calorie restriction, fasting-mimicking diet, ketogenic diet, protein restriction diet, high-salt diet, high-fat diet, and high-fiber diet, on cancer and the aforementioned diseases. We explore the multifaceted impacts of these dietary interventions, encompassing their immunomodulatory effects, other biological impacts, and underlying molecular mechanisms. This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.

DOI: https://doi.org/10.1038/s41392-024-01771-x
J Bone Miner Res. 2024 Jan 11. pii: zjad016. [Epub ahead of print]

Hypoxia rewires glucose and glutamine metabolism in different sources of skeletal stem and progenitor cells similarly, except for pyruvate.

Shauni Loopmans, Guillaume Tournaire, Ingrid Stockmans, Steve Stegen, Geert Carmeliet.

  Skeletal stem and progenitor cells (SSPCs) are crucial for bone development, homeostasis, and repair. SSPCs are considered to reside in a rather hypoxic niche in the bone, but distinct SSPC niches have been described in different skeletal regions, and they likely differ in oxygen and nutrient availability. Currently it remains unknown whether the different SSPC sources have a comparable metabolic profile and respond in a similar manner to hypoxia. In this study, we show that cell proliferation of all SSPCs was increased in hypoxia, suggesting that SSPCs can indeed function in a hypoxic niche in vivo. In addition, low oxygen tension increased glucose consumption and lactate production, but affected pyruvate metabolism cell-specifically. Hypoxia decreased tricarboxylic acid (TCA) cycle anaplerosis and altered glucose entry into the TCA cycle from pyruvate dehydrogenase to pyruvate carboxylase and/or malic enzyme. Finally, a switch from glutamine oxidation to reductive carboxylation was observed in hypoxia, as well as cell-specific adaptations in the metabolism of other amino acids. Collectively, our findings show that SSPCs from different skeletal locations proliferate adequately in hypoxia by rewiring glucose and amino acid metabolism in a cell-specific manner.

Keywords:  cell metabolism; chondrocyte; hypoxia; proliferation; skeletal progenitor

DOI:  https://doi.org/10.1093/jbmr/zjad016
bioRxiv. 2024 Mar 01. pii: 2024.02.28.582405. [Epub ahead of print]

Metabolic phenotyping of healthy and diseased human RPE cells.

Saira Rizwan, Beverly Toothman, Bo Li, Abbi J Engel, Rayne R Lim, Jinyu Lu, Jennifer R Chao, Jianhai Du.

Purpose: Metabolic defects in retinal pigment epithelium (RPE) are underlying many retinal degenerative diseases. This study aims to identify the nutrient requirements of healthy and diseased human RPE cells.
Methods: We profiled the utilization of 183 nutrients in human RPE cells: 1) differentiated and dedifferentiated fetal RPE (fRPE), 2) induced pluripotent stem cell derived-RPE (iPSC RPE), 3) Sorsby fundus dystrophy (SFD) patient-derived iPSC RPE and its CRISPR-corrected isogenic SFD (cSFD) iPSC RPE, and 5) ARPE-19 cell lines cultured under different conditions.
Results: Differentiated fRPE cells and healthy iPSC RPE cells can utilize 51 and 48 nutrients respectively, including sugars, intermediates from glycolysis and tricarboxylic acid (TCA) cycle, fatty acids, ketone bodies, amino acids, and dipeptides. However, when fRPE cells lose epithelial phenotype through dedifferentiated, they can only utilize 17 nutrients, primarily sugar and glutamine-related amino acids. SFD RPE cells can utilize 37 nutrients; however, Compared to cSFD RPE and healthy iPSC RPE, they are unable to utilize lactate, some TCA cycle intermediates, and short-chain fatty acids. Nonetheless, they show increased utilization of branch-chain amino acids (BCAAs) and BCAA-containing dipeptides. The dedifferentiated ARPE-19 cells in traditional culture media cannot utilize lactate and ketone bodies. In contrast, nicotinamide supplementation promotes differentiation into epithelial phenotype, restoring the ability to use these nutrients.
Conclusions: Epithelial phenotype confers metabolic flexibility to the RPE for utilizing various nutrients. SFD RPE cells have reduced metabolic flexibility, relying on the oxidation of BCAAs. Our findings highlight the importance of nutrient availability and utilization in RPE differentiation and diseases.

DOI: https://doi.org/10.1101/2024.02.28.582405
Sci Adv. 2024 Mar 15. 10(11): eadm8600

Molecular imaging of tumor metabolism: Insight from pyruvate- and glucose-based deuterium MRI studies.

Elton T Montrazi, Keren Sasson, Lilach Agemy, Avigdor Scherz, Lucio Frydman.

Cancer diagnosis by metabolic MRI proposes to follow the fate of glycolytic precursors such as pyruvate or glucose, and their in vivo conversion into lactate. This study compares the 2H MRI outlooks afforded by these metabolites when targeting a pancreatic cancer model. Exogenously injected [3,3',3″-2H3]-pyruvate was visible only briefly; it generated a deuterated lactate signal throughout the body that faded after ~5 min, showing a minor concentration bias at the rims of the tumors. [6,6'-2H2]-glucose by contrast originated a lactate signal that localized clearly within the tumors, persisting for over an hour. Investigations alternating deuterated and nondeuterated glucose injections revealed correlations between the lactate generation and the glucose available at the tumor, evidencing a continuous and avid glucose consumption generating well-localized lactate signatures as driven by the Warburg effect. This is by contrast to the transient and more promiscuous pyruvate-to-lactate transformation, which seemed subject to transporter and kinetics effects. The consequences of these observations within metabolic MRI are briefly discussed.

DOI: https://doi.org/10.1126/sciadv.adm8600
Int Neurourol J. 2024 Feb;28(Suppl 1): 2-11

The Ketone Bridge Between the Heart and the Bladder: How Fast Should We Go?

Gabriel Faria-Costa, João Oliveira, Inês Vilas-Boas, Inês Campelo, Elisa Azeredo Silva, Carmen Brás-Silva, Susana Maria Silva, Tiago Antunes-Lopes, Ana Charrua.

  Metabolic syndrome (MS) is associated with both cardiovascular and bladder dysfunction. Insulin resistance (IR) and central obesity, in particular, are the main risk factors. In these patients, vicious pathological cycles exacerbate abnormal carbohydrate metabolism and sustain an inflammatory state, with serious implications for both the heart and bladder. Ketone bodies serve as an alternative energy source in this context. They are considered a "super-fuel" because they generate adenosine triphosphate with less oxygen consumption per molecule, thus enhancing metabolic efficiency. Ketone bodies have a positive impact on all components of MS. They aid in weight loss and glycemic control, lower blood pressure, improve lipid profiles, and enhance endothelial function. Additionally, they possess direct anti-inflammatory, antioxidant, and vasodilatory properties. A shared key player in dysfunction of both the heart and bladder dysfunction is the formation of the NLRP3 inflammasome, which ketone bodies inhibit. Interventions that elevate ketone body levels-such as fasting, a ketogenic diet, ketone supplements, and sodium-glucose cotransporter 2 inhibitors-have been shown to directly affect cardiovascular outcomes and improve lower urinary tract symptoms derived from MS. This review explores the pathophysiological basis of the benefits of ketone bodies in cardiac and bladder dysfunction.

Keywords:  Intermittent fasting; Ketogenic diet; Ketone bodies; Metabolic syndrome; SGLT2 inhibitors

DOI:  https://doi.org/10.5213/inj.2346250.125
Nutr Rev. 2024 Mar 12. pii: nuae014. [Epub ahead of print]

Ketogenic diet combined with intermittent fasting: an option for type 2 diabetes remission?

Xiao-Ying Zhou, Kai-Heng Guo, Shao-Feng Huang, Rui-Ke Liu, Chun-Ping Zeng.

  With increasing attention to diabetes remission, various special dietary patterns have been found to be effective in achieving diabetes remission. The effect of a single dietary pattern on lowering blood glucose is clear, but studies on the synergistic effects of different dietary patterns are limited. This article describes the types of intermittent fasting and ketogenic diets, potential mechanisms, contraindications of combination diets, recommendations for combination diets, and their health outcomes. This paper aims to illustrate the evidence for intermittent fasting combined with a ketogenic diet on outcomes of diabetes remission and effect on blood glucose control. Knowledge of these findings can help doctors and patients determine dietary patterns for achieving diabetes remission and understanding their application.

Keywords:  T2DM; application; diabetes remission; intermittent fasting; ketogenic diet

DOI:  https://doi.org/10.1093/nutrit/nuae014
Explor Target Antitumor Ther. 2024 ;5(1): 135-169

Exploring monocarboxylate transporter inhibition for cancer treatment.

Tomas Koltai, Larry Fliegel.

  Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed.

Keywords:  AZD3965; Monocarboxylate transporters; diclofenac; glycolytic metabolism; lactate; lactate shuttle; quercetin

DOI:  https://doi.org/10.37349/etat.2024.00210
J Biol Chem. 2024 Mar 11. pii: S0021-9258(24)01654-5. [Epub ahead of print] 107159

Fatty acid oxidation drives mitochondrial hydrogen peroxide production by α-ketoglutarate dehydrogenase.

Cathryn Grayson, Ben Faerman, Olivia Koufos, Ryan J Mailloux.

In the present study, we examined the mitochondrial hydrogen peroxide (mH2O2) generating capacity of α-ketoglutarate dehydrogenase (KGDH) and compared it to components of the electron transport chain (ETC) using liver mitochondria isolated from male and female C57BL6N mice. We show for the first time there are some sex dimorphisms in the production of mH2O2 by ETC complexes I and III when mitochondria are fueled with different substrates. However, in our investigations into these sex effects, we made the unexpected discovery that: 1. KGDH serves as a major mH2O2 supplier in male and female liver mitochondria and 2. KGDH can form mH2O2 when mitochondria are energized with fatty acids, but only when malate is used to prime the Krebs cycle. Surprisingly, 2-keto-3-methylvaleric acid (KMV), a site-specific inhibitor for KGDH, nearly abolished mH2O2 generation in both male and female liver mitochondria oxidizing palmitoyl-carnitine. KMV inhibited mH2O2 production in liver mitochondria from male and female mice oxidizing myristoyl-, octanoyl-, or butyryl-carnitine. S1QEL 1.1 (S1) and S3QEL 2 (S3), compounds that inhibit reactive oxygen species (ROS) generation by complexes I and III, respectively, without interfering with OxPhos, had a negligible effect on the rate of mH2O2 production when pyruvate or acyl-carnitines were used as fuels. However, inclusion of KMV in reaction mixtures containing S1 and/or S3 almost abolished mH2O2 generation. Together, our findings suggest KGDH is the main mH2O2 generator in liver mitochondria, even when fatty acids are used as fuel.

DOI: https://doi.org/10.1016/j.jbc.2024.107159
Res Sq. 2024 Feb 22. pii: rs.3.rs-3957002. [Epub ahead of print]

Dietary lipid is largely deposited in skin and rapidly affects insulating properties.

Nick Riley, Ildiko Kasza, Greg Barrett-Wilt, Julian Michaud, Raghav Jain, Michaela E Trautman, Judith A Simcox, Chi-Liang E Yen, Ormond A MacDougald, Dudley W Lamming, Caroline M Alexander.

Skin has been shown to be a regulatory hub for energy expenditure and metabolism: mutations of skin lipid metabolism enzymes can change the rate of thermogenesis and susceptibility to diet-induced obesity. However, little is known about the physiological basis for this function. Here we show that the thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We found that skin was the largest target in a mouse body for dietary fat delivery, and that fat was assimilated both by epidermis and by dermal white adipose tissue. Dietary triglyceride acyl groups persist in skin for weeks after feeding. Using multi-modal lipid profiling, we have implicated both keratinocytes and sebocytes in the altered lipids which correlate with thermal function. In response to high fat feeding, wax diesters and ceramides accumulate, and triglycerides become more saturated. In contrast, in response to the dramatic loss of adipose tissue that accompanies restriction of the branched chain amino acid isoleucine, skin becomes highly heat-permeable: skins shows limited uptake of dietary lipids and editing of wax esters, and acquires a signature of depleted signaling lipids, which include the acyl carnitines and lipid ethers. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality.

DOI: https://doi.org/10.21203/rs.3.rs-3957002/v1
Res Sq. 2024 Feb 23. pii: rs.3.rs-3889456. [Epub ahead of print]

Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.

Christal Sohl, Matthew Mealka, Nicole Sierra, Diego Matteo, Elene Albekioni, Rachel Khoury, Timothy Mai, Brittany Conley, Nalani Coleman, Kaitlyn Sabo, Elizabeth Komives, Andrey Bobkov, Andrew Cooksy, Steve Silletti, Jamie Schiffer, Tom Huxford.

Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.

DOI: https://doi.org/10.21203/rs.3.rs-3889456/v1
Sci Rep. 2024 03 12. 14(1): 5980

The use of NADH anisotropy to investigate mitochondrial cristae alignment.

Holly E Smith, Alasdair M Mackenzie, Chloe Seddon, Rhys Mould, Ifi Kalampouka, Partha Malakar, Sarah R Needham, Konstantinos Beis, Jimmy D Bell, Alistair Nunn, Stanley W Botchway.

Life may be expressed as the flow of electrons, protons, and other ions, resulting in large potential difference. It is also highly photo-sensitive, as a large proportion of the redox capable molecules it relies on are chromophoric. It is thus suggestive that a key organelle in eukaryotes, the mitochondrion, constantly adapt their morphology as part of the homeostatic process. Studying unstained in vivo nano-scale structure in live cells is technically very challenging. One option is to study a central electron carrier in metabolism, reduced nicotinamide adenine dinucleotide (NADH), which is fluorescent and mostly located within mitochondria. Using one and two-photon absorption (340-360 nm and 730 nm, respectively), fluorescence lifetime imaging and anisotropy spectroscopy of NADH in solution and in live cells, we show that mitochondria do indeed appear to be aligned and exhibit high anisotropy (asymmetric directionality). Aqueous solution of NADH showed an anisotropy of ~ 0.20 compared to fluorescein or coumarin of < 0.1 and 0.04 in water respectively and as expected for small organic molecules. The anisotropy of NADH also increased further to 0.30 in the presence of proteins and 0.42 in glycerol (restricted environment) following two-photon excitation, suggesting more ordered structures. Two-photon NADH fluorescence imaging of Michigan Cancer Foundation-7 (MCF7) also showed strong anisotropy of 0.25 to 0.45. NADH has a quantum yield of fluorescence of 2% compared to more than 40% for photoionisation (electron generation), when exposed to light at 360 nm and below. The consequence of such highly ordered and directional NADH patterns with respect to electron ejection upon ultra-violet (UV) excitation could be very informative-especially in relation to ascertaining the extent of quantum effects in biology, including electron and photonic cascade, communication and modulation of effects such as spin and tunnelling.

DOI: https://doi.org/10.1038/s41598-024-55780-5
Nat Commun. 2024 Mar 11. 15(1): 2203

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.

Luca Simula, Mattia Fumagalli, Lene Vimeux, Irena Rajnpreht, Philippe Icard, Gary Birsen, Dongjie An, Frédéric Pendino, Adrien Rouault, Nadège Bercovici, Diane Damotte, Audrey Lupo-Mansuet, Marco Alifano, Marie-Clotilde Alves-Guerra, Emmanuel Donnadieu.

The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

DOI: https://doi.org/10.1038/s41467-024-46377-7
Heliyon. 2024 Mar 15. 10(5): e27202

Study on the correlation between controlling nutritional status score and clinical biochemical indicators in patients with colorectal cancer.

Zhi Wang, Jin Bian, Jiayan Yuan, Sunyan Zhao, Shijia Huang, Rong Wu, Fei Fei.

   Purpose: The controlling nutritional status (CONUT) score is an important tool for predicting the prognosis of colorectal cancer (CRC); however, its effectiveness is relatively insufficient. This study aimed to screen for more effective clinical indicators as supplements to the CONUT scoring system and improve the predictive value of CRC prognosis.
Patients and methods: Between 2014 and 2020, the clinical information of all CRC patients in our unit was retrospectively collected, and the CONUT scores were calculated based on the levels of serum albumin (ALB), lymphocytes (LC), and total cholesterol. The included patients were divided into the following three groups: normal nutrition (0-1), mild malnutrition (2-4), and moderate-to-severe malnutrition (5-12). The correlations between the CONUT score and baseline characteristics and clinical indicators were evaluated.
Results: This study ultimately included 5014 CRC patients. The nutritional status of patients with colon cancer (CC) was worse than that of rectal cancer (RC). The nutritional status was worse in men than in women. The older the patient, the poorer the nutritional status, and the poorer the nutritional status, the longer the hospital stay. In addition, poor nutritional status in patients is indicated by higher values of neutrophils (NE), monocytes (MC), eosinophils (EOS), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), carcinoembryogenic antigen (CEA), and lower values of white blood cells (WBC), basophils (BAS), haemoglobin (HB), total protein (TP), triglycerides (TG), low density lipoprotein (LDL), aspartate transaminase (AST), and blood urea nitrogen (BUN), which was statistically significant (P < 0.05). Indicators that significantly correlated with the CONUT score reflected the immune nutritional status, including WBC (odds ratio [OR] = 0.036, P < 0.001), NE (OR = 30.815, P < 0.001), MC (OR = 41.388, P < 0.001), EOS (OR = 27.577, P < 0.001), BAS (OR = 0.006, P = 0.046), and LDL (OR = 0.319, P < 0.001).
Conclusion: Additional variables such as WBC, NE, MC, EOS, BAS, and LDL may be used as supplementary indicators in the CONUT scoring system to more effectively predict the clinical prognosis of CRC patients.

Keywords:  CONUT score; Colorectal cancer; Immunotrophic status; Prognosis

DOI:  https://doi.org/10.1016/j.heliyon.2024.e27202
Metabolism. 2024 Mar 11. pii: S0026-0495(24)00060-X. [Epub ahead of print] 155834

Metabolic plasticity and obesity-associated changes in diurnal postexercise metabolism in mice.

Logan A Pendergrast, Stephen P Ashcroft, Amy M Ehrlich, Jonas T Treebak, Anna Krook, Lucile Dollet, Juleen R Zierath.

   BACKGROUND: Circadian disruption is widespread and increases the risk of obesity. Timing of therapeutic interventions may promote coherent and efficient gating of metabolic processes and restore energy homeostasis.
AIM: To characterize the diurnal postexercise metabolic state in mice and to identify the influence of diet-induced obesity on identified outcomes.
METHODS: C57BL6/NTac male mice (6wks of age) were fed a standard chow or high-fat diet for 5 weeks. At week 5, mice were subjected to a 60-min (16 m/min, 5 % incline) running bout (or sham) during the early rest (day) or early active (night) phase. Tissue and serum samples were collected immediately post-exercise (n = 6/group). In vivo glucose oxidation was measured after oral administration of 13C-glucose via 13CO2 exhalation analysis in metabolic cages. Basal and isoproterenol-stimulated adipose tissue lipolysis was assessed ex vivo for 1 h following exercise.
RESULTS: Lean mice displayed exercise-timing-specific plasticity in metabolic outcomes, including phase-specificity in systemic glucose metabolism and adipose-tissue-autonomous lipolytic activity depending on time of day. Conversely, obesity impaired temporal postexercise differences in whole-body glucose oxidation, as well as the phase- and exercise-mediated induction of lipolysis in isolated adipose tissue. This obesity-induced alteration in diurnal metabolism, as well as the indistinct response to exercise, was observed concomitant with disruption of core clock gene expression in peripheral tissues.
CONCLUSIONS: Overall, high-fat fed obese mice exhibit metabolic inflexibility, which is also evident in the diurnal exercise response. Our study provides physiological insight into exercise timing-dependent aspects in the dynamic regulation of metabolism and the influence of obesity on this biology.

Keywords:  Adipose tissue; Circadian rhythm; Exercise; Lipolysis; Time of day

DOI:  https://doi.org/10.1016/j.metabol.2024.155834
bioRxiv. 2024 Feb 28. pii: 2024.02.25.581907. [Epub ahead of print]

Quantification of metabolic activity from isotope tracing data using automated methodology.

Shiyu Liu, Xiaojing Liu, Jason W Locasale.

Isotope tracing is a widely used technique to study metabolic activities by introducing heavy labeled nutrients into living cells and organisms. However, interpreting isotope tracing data is often heuristic, and application of automated methods using artificial intelligence is limited due to the paucity of evaluative knowledge. Our study developed a new pipeline that efficiently predicts metabolic activity in expansive metabolic networks and systematically quantifies flux uncertainty of traditional computational methods. We further developed an algorithm adept at significantly reducing this uncertainty, enabling robust evaluations of metabolic activity with limited data. Using this technology, we discovered highly reprogrammed mitochondria-cytosol exchange cycles in tumor tissue of patients, and observed similar metabolic patterns influenced by nutritional conditions in cancer cells. Thus, our refined methodology provides robust automated quantification of metabolism allowing for new insight into metabolic network activity.

DOI: https://doi.org/10.1101/2024.02.25.581907
Nutrients. 2024 Feb 24. pii: 631. [Epub ahead of print]16(5):

Thermodynamic Analysis to Evaluate the Effect of Diet on Brain Glucose Metabolism: The Case of Fish Oil.

Cennet Yildiz, Isabel Medina.

  Inefficient glucose metabolism and decreased ATP production in the brain are linked to ageing, cognitive decline, and neurodegenerative diseases (NDDs). This study employed thermodynamic analysis to assess the effect of fish oil supplementation on glucose metabolism in ageing brains. Data from previous studies on glucose metabolism in the aged human brain and grey mouse lemur brains were examined. The results demonstrated that Omega-3 fish oil supplementation in grey mouse lemurs increased entropy generation and decreased Gibbs free energy across all brain regions. Specifically, there was a 47.4% increase in entropy generation and a 47.4 decrease in Gibbs free energy in the whole brain, indicating improved metabolic efficiency. In the human model, looking at the specific brain regions, supplementation with Omega-3 polyunsaturated fatty acids (n-3 PUFAs) reduced the entropy generation difference between elderly and young individuals in the cerebellum and particular parts of the brain cortex, namely the anterior cingulate and occipital lobe, with 100%, 14.29%, and 20% reductions, respectively. The Gibbs free energy difference was reduced only in the anterior cingulate by 60.64%. This research underscores that the application of thermodynamics is a comparable and powerful tool in comprehending the dynamics and metabolic intricacies within the brain.

Keywords:  Gibbs free energy; brain ageing; brain glucose metabolism; entropy; fish oil supplementation; n-3 PUFAs

DOI:  https://doi.org/10.3390/nu16050631
Endocrinol Diabetes Metab. 2024 Mar;7(2): e00475

Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet.

Anh T Nguyen, Zachary Amigo, Kathleen McDuffie, Victoria C MacQueen, Lane D Bell, Lan K Truong, Gloria Batchi, Sara M McMillin.

   BACKGROUND: Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health.
METHODS: Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted.
RESULTS: In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21.
CONCLUSION: These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.

Keywords:  FGF21; SGLT2 inhibitor; diabetes; metabolism

DOI:  https://doi.org/10.1002/edm2.475
JCI Insight. 2024 Mar 14. pii: e172565. [Epub ahead of print]

OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.

Trang Tt Nguyen, Consuelo Torrini, Enyuan Shang, Chang Shu, Jeong-Yeon Mun, Qiuqiang Gao, Nelson Humala, Hasan O Akman, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin.

  Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the alpha-ketoglutarate dehydrogenase (OGDH) gene, which encodes for an enzyme that is part of the tricarboxylic acid cycle (TCA cycle) as essential for GBM growth. Moreover, by combining a transcriptome and metabolite screening analyses we discovered that loss of function of OGDH by the clinically validated drug compound, CPI-613, was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3-mimetic, ABT263) in patient-derived xenograft as well neurosphere GBM cultures. CPI-613 mediated energy deprivation drove an integrated stress response with an up-regulation of the BH3-only domain protein, Noxa in an ATF4 dependent manner as demonstrated by genetic loss of function experiments. Consistently, silencing of Noxa attenuated cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with interference of the TCA-cycle might be a treatment strategy for GBM.

Keywords:  Apoptosis pathways; Oncology

DOI:  https://doi.org/10.1172/jci.insight.172565
J Biosci Bioeng. 2024 Mar 13. pii: S1389-1723(24)00056-2. [Epub ahead of print]

Gene identification and enzymatic characterization of the initial enzyme in pyrimidine oxidative metabolism, uracil-thymine dehydrogenase.

Chee-Leong Soong, Kengo Deguchi, Michiki Takeuchi, Syoko Kozono, Nobuyuki Horinouchi, Dayong Si, Makoto Hibi, Sakayu Shimizu, Jun Ogawa.

  Uracil-thymine dehydrogenase (UTDH), which catalyzes the irreversible oxidation of uracil to barbituric acid in oxidative pyrimidine metabolism, was purified from Rhodococcus erythropolis JCM 3132. The finding of unusual stabilizing conditions (pH 11, in the presence of NADP+ or NADPH) enabled the enzyme purification. The purified enzyme was a heteromer consisting of three different subunits. The enzyme catalyzed oxidation of uracil to barbituric acid with artificial electron acceptors such as methylene blue, phenazine methosulfate, benzoquinone, and α-naphthoquinone; however, NAD+, NADP+, flavin adenine dinucleotide, and flavin mononucleotide did not serve as electron acceptors. The enzyme acted not only on uracil and thymine but also on 5-halogen-substituted uracil and hydroxypyrimidine (pyrimidone), while dihydropyrimidine, which is an intermediate in reductive pyrimidine metabolism, and purine did not serve as substrates. The activity of UTDH was enhanced by cerium ions, and this activation was observed with all combinations of substrates and electron acceptors.

Keywords:  Cerium ions; Molybdopterin; Pyrimidine oxidative metabolism; Rhodococcus erythropolis; Uracil-thymine dehydrogenase

DOI:  https://doi.org/10.1016/j.jbiosc.2024.02.004
Crit Rev Oncol Hematol. 2024 Mar 08. pii: S1040-8428(24)00067-2. [Epub ahead of print]196 104324

Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions.

Riccardo Gerosa, Rita De Sanctis, Flavia Jacobs, Chiara Benvenuti, Mariangela Gaudio, Giuseppe Saltalamacchia, Rosalba Torrisi, Giovanna Masci, Chiara Miggiano, Francesco Agustoni, Paolo Pedrazzoli, Armando Santoro, Alberto Zambelli.

  Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role in MYC and CCNE1 overexpressed cancer survival, such as triple-negative breast cancers (TNBC), thus representing an appealing and relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, a comprehensive outcomes collection is currently absent from the scientific literature. We aim to provide an overview of ongoing clinical trials involving CDK2i in the context of metastatic breast cancer (mBC), either as monotherapy or in combination with other agents. The review extends beyond CDK2i to encompass novel emerging CDK4 inhibitors, combined CDK2/4/6 inhibitors, and the well-known pan-CDK inhibitors including those specifically directed at CDK2. Delving into the results, we critically appraise the observed clinical efficacy and offer valuable insights into their potential impact and future applications.

Keywords:  Breast cancer (BC); Cyclin-dependent; Cyclin-dependent kinase 2 inhibitor (CDK2i); Cyclindependent; Kinase 2/4/6 inhibitor (CDK2/4/6i); Kinase 4 inhibitor (CDK4i); Metastatic breast cancer (mBC); Pan-Cyclin-dependent kinase inhibitor (Pan-CDKi)

DOI:  https://doi.org/10.1016/j.critrevonc.2024.104324
J Nutr. 2024 Mar 12. pii: S0022-3166(24)00156-1. [Epub ahead of print]

Hepatic effects of low carbohydrate diet associated with different lipid sources: insights into oxidative stress, cytotoxicity, and epigenetic markers in a mice model of obesity.

Aline Boveto Santamarina, Marcela Nascimento Sertorio, Laís Vales Mennitti, Esther Alves de Souza, Daniel Vitor de Souza, Daniel Araki Ribeiro, Luciana Pellegrini Pisani.

   BACKGROUND: Low-carbohydrate and high-fat diet (LCHF) models have been widely explored as alternatives for treating obesity and promoting weight loss. Their effect is attributed to the change in energy substrate that stimulates ketogenic pathways that can metabolically overload the liver. However, little has been studied about the impact of lipid sources prioritized in the LCHF diet.
OBJECTIVE: This study aims to evaluate the impact of different fat sources in the LCHF diet on markers of liver injury, oxidative stress, and epigenetics in obesity.
METHODS: Adult male mice were initially induced to obesity by a high-fat and high-sugar diet for 10 weeks. Subsequently, they underwent a weight-loss treatment intervention involving an LCHF diet with various sources of fats, including saturated (SAT), omega-3 (ω-3), omega-6 (ω-6), and omega-9 (ω-9). At the end of the treatment, markers of liver injury, oxidative stress, and epigenetics were evaluated.
RESULTS: The LCHF diet was effective in inducing weight loss. However, unsaturated lipid sources (omegas) exhibited superior outcomes. Specifically, the ω-9 group displayed diminished oxidative stress levels and decreased markers of liver injury. The ω-3 group demonstrated efficacy in modulating epigenetic markers, thereby reducing oxidative stress, mutagenicity, and markers of liver injury. Correlation tests demonstrated that there was an interaction between the activity of antioxidants and epigenetic enzymes.
CONCLUSIONS: Our results suggest that LCHF diets associated with ω-3 and ω-9 have the potential for weight loss and liver health recovery in obesity through antioxidant and epigenetic mechanisms.

Keywords:  cytotoxicity; epigenetic; fatty acids; liver injury; low-carbohydrate diet; obesity; oxidative stress

DOI:  https://doi.org/10.1016/j.tjnut.2024.03.007
Clin Nutr ESPEN. 2024 Apr;pii: S2405-4577(24)00026-3. [Epub ahead of print]60 195-202

Association between adherence to a dietary approach to stop hypertension and the Mediterranean diets and risk of colorectal cancer: A matched case-control study.

Sazin Yarmand, Nooshin Abdollahi, Elham Tavassoli Nejad, Fateme Souni, Mohebat Vali, Mehran Nouri, Zainab Shateri, Bahram Rashidkhani.

   BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers and is currently the third leading cause of cancer-related deaths worldwide. This study aimed to evaluate whether the dietary approach to stop hypertension (DASH) and Mediterranean (MED) diets are associated with CRC in Iranian adults.
METHODS: This hospital-based case-control study was conducted on 71 cases and 142 controls (40-75 years old) in three general hospitals in Tehran, Iran. The dietary intakes of individuals were collected through face-to-face interviews using a semi-quantitative food frequency questionnaire (FFQ) that included 125 food items. The DASH and MED diet scores were calculated according to food items based on guidelines. Two logistic regression models were applied to evaluate the association between DASH and MED score adherence.
RESULTS: After adjusting for confounding factors, a negative association between DASH diet adherence and CRC risk was observed in the second and last tertile compared to the first tertile (T) (T2: odds ratio (OR) = 0.33; 95% confidence interval (CI): 0.14-0.77 - T3: OR = 0.09; 95% CI: 0.03-0.27). There was no significant association between the MED diet and the risk of CRC.
CONCLUSIONS: In conclusion, the current study's findings presented that adherence to a DASH diet could reduce the odds of CRC.

Keywords:  Colorectal cancer; DASH diet; Iranian; Mediterranean diet

DOI:  https://doi.org/10.1016/j.clnesp.2024.02.003
Front Nutr. 2024 ;11 1363181

Requirements for essential micronutrients during caloric restriction and fasting.

Weiguo Zhang, Peng Chen, Shaofeng Huo, Xiaomin Huang, Youyou Zhao.

  Caloric restriction (CR) or energy restriction, when carefully designed, monitored, and implemented in self-motivated and compliant individuals, proves to be a viable non-pharmacologic strategy for human weight control and obesity management. Beyond its role in weight management, CR has the potential to impede responses involved not only in the pathogenesis of various diseases but also in the aging process in adults, thereby being proposed to promote a healthier and longer life. The core objective of implementing caloric restriction is to establish a balance between energy intake and expenditure, typically involving a reduction in intake and an increase in expenditure-a negative balance at least initially. It may transition toward and maintain a more desired equilibrium over time. However, it is essential to note that CR may lead to a proportional reduction in micronutrient intake unless corresponding supplementation is provided. Historical human case reports on CR have consistently maintained adequate intakes (AI) or recommended dietary allowances (RDA) for essential micronutrients, including vitamins and minerals. Similarly, longevity studies involving non-human primates have upheld micronutrient consumption levels comparable to control groups or baseline measures. Recent randomized controlled trials (RCTs) have also endorsed daily supplementation of multivitamins and minerals to meet micronutrient needs. However, aside from these human case reports, limited human trials, and primate experiments, there remains a notable gap in human research specifically addressing precise micronutrient requirements during CR. While adhering to AI or RDA for minerals and vitamins appears sensible in the current practice, it's important to recognize that these guidelines are formulated for generally healthy populations under standard circumstances. The adequacy of these guidelines in the setting of prolonged and profound negative energy balance remains unclear. From perspectives of evidence-based medicine and precision nutrition, this field necessitates comprehensive exploration to uncover the intricacies of absorption, utilization, and metabolism and the requirement of each hydrophilic and lipophilic vitamin and mineral during these special periods. Such investigations are crucial to determine whether existing daily dietary recommendations for micronutrients are quantitatively inadequate, excessive, or appropriate when energy balance remains negative over extended durations.

Keywords:  aging; caloric restriction; metabolism; micronutrients (vitamins and minerals); non-human primates; obesity

DOI:  https://doi.org/10.3389/fnut.2024.1363181
Anal Chem. 2024 Mar 12.

Screening Metabolic Biomarkers in KRAS Mutated Mouse Acinar and Human Pancreatic Cancer Cells via Single-Cell Mass Spectrometry.

Qinlei Liu, Jiayi Lan, Sandra Martínez-Jarquín, Wenjie Ge, Renato Zenobi.

Pancreatic cancer is a highly aggressive and rapidly progressing disease, often diagnosed in advanced stages due to the absence of early noticeable symptoms. The KRAS mutation is a hallmark of pancreatic cancer, yet the underlying mechanisms driving pancreatic carcinogenesis remain elusive. Cancer cells display significant metabolic heterogeneity, which is relevant to the pathogenesis of cancer. Population measurements may obscure information about the metabolic heterogeneity among cancer cells. Therefore, it is crucial to analyze metabolites at the single-cell level to gain a more comprehensive understanding of metabolic heterogeneity. In this study, we employed a 3D-printed ionization source for metabolite analysis in both mice and human pancreatic cancer cells at the single-cell level. Using advanced machine learning algorithms and mass spectral feature selection, we successfully identified 23 distinct metabolites that are statistically significantly different in KRAS mutant human pancreatic cancer cells and mouse acinar cells bearing the oncogenic KRAS mutation. These metabolites encompass a variety of chemical classes, including organic nitrogen compounds, organic acids and derivatives, organoheterocyclic compounds, benzenoids, and lipids. These findings shed light on the metabolic remodeling associated with KRAS-driven pancreatic cancer initiation and indicate that the identified metabolites hold promise as potential diagnostic markers for early detection in pancreatic cancer patients.

DOI: https://doi.org/10.1021/acs.analchem.3c05741
Mayo Clin Proc Innov Qual Outcomes. 2024 Apr;8(2): 166-183

Lifestyle Factors and Cancer: A Narrative Review.

Reya Sharman, Zoey Harris, Brenda Ernst, Dawn Mussallem, Ashley Larsen, Krisstina Gowin.

Lifestyle factors and their impact on cancer prevention, prognosis, and survivorship are increasingly recognized in the medical literature. Lifestyle factors are primarily defined here as diet and physical activity. We conducted a narrative review of the primary published data, including randomized controlled trials and prospective studies, on the impact of primary lifestyle factors on oncogenesis and clinical outcomes in the preventative and survivorship setting. First, we discuss the oncogenic mechanisms behind primary lifestyle factors (diet, physical activity and, within these 2, obesity). Then, we discuss the impact of adherence to lifestyle guidelines and dietary patterns on cancer incidence based on primary data. Owing to the plethora of published literature, to summarize the data in a more efficient manner, we describe the role of physical activity on cancer incidence using summative systematic reviews. We end by synthesizing the primary data on lifestyle factors in the survivorship setting and conclude with potential future directions. In brief, the various large-scale studies investigating the role diet and physical activity have reported a beneficial effect on cancer prevention and survivorship. Although the impact of single lifestyle factors on cancer incidence risk reduction is generally supported, holistic approaches to address the potential synergistic impact of multiple lifestyle factors together in concert is limited. Future research to identify the potentially synergistic effects of lifestyle modifications on oncogenesis and clinical outcomes is needed, particularly in cancer subtypes beyond colorectal and breast cancers.

DOI: https://doi.org/10.1016/j.mayocpiqo.2024.01.004
Nutrients. 2024 Feb 29. pii: 696. [Epub ahead of print]16(5):

The Effect of Micronutrients on Obese Phenotype of Adult Mice Is Dependent on the Experimental Environment.

Zeyu Yang, Ruslan Kubant, Eva Kranenburg, Clara E Cho, G Harvey Anderson.

  The environment of the test laboratory affects the reproducibility of treatment effects on physiological phenotypes of rodents and may be attributed to the plasticity of the epigenome due to nutrient-gene-environment interactions. Here, we explored the reproducibility of adding a multi-vitamin-mineral (MVM) mix to a nutrient-balanced high-fat (HF) diet on obesity, insulin resistance (IR), and gene expression in the tissues of adult male mice. Experiments of the same design were conducted in three independent animal facilities. Adult C57BL/6J male mice were fed an HF diet for 6 weeks (diet induced-obesity model) and then continued for 9-12 weeks on the HF diet with or without 5-fold additions of vitamins A, B1, B6, B12, Zn, and 2-fold Se. The addition of the MVM affected body weight, fat mass, gene expression, and markers of IR in all three locations (p < 0.05). However, the direction of the main effects was influenced by the interaction with the experimental location and its associated environmental conditions known to affect the epigenome. In conclusion, MVM supplementation influenced phenotypes and expression of genes related to adipose function in obese adult male mice, but the experimental location and its associated conditions were significant interacting factors. Preclinical studies investigating the relationship between diet and metabolic outcomes should acknowledge the plasticity of the epigenome and implement measures to reproduce studies in different locations.

Keywords:  diet; experimental environment; gene expression; insulin resistance; micronutrients; obesity

DOI:  https://doi.org/10.3390/nu16050696
J Gastrointest Oncol. 2024 Feb 29. 15(1): 147-163

Identification of fatty acid oxidation-related subtypes by integrated analysis of bulk- and single-cell transcriptome profiling in colorectal cancer.

Peng Zou, Chengru Chen, Xiaobin Wu.

   Background: As one of the major metabolic reprogramming pathways, fatty acid oxidation (FAO) contributes to rapid progression in tumor cells. Nevertheless, the genomic patterns of patients' FAO levels in colorectal cancer (CRC) remain unknown. Hence, it is crucial to identify the interplay mechanisms of molecular biochemical features of FAO in CRC.
Methods: Data of patients with CRC were accessed from The Cancer Genome Atlas (TCGA). Unsupervised consensus clustering related to FAO sores was conducted. The differentially expressed genes (DEGs) were screened by clustering according to FAO status polarized in TCGA, followed by the construction of the scores of genes related to FAO (GFAO_Score). Enrichment of FAO and carcinogenesis at the cell level were calculated based on the single-cell RNA (scRNA) sequencing analysis. The clinical values and drug analysis of GFAO_Score were evaluated by external validation cohorts from Gene Expression Omnibus (GEO) datasets.
Results: We classified patients into two distinct FAO clusters which indicated those with lower FAO levels had poor prognosis and high enrichment of carcinogenic-gene pathways. Further, the high FAO-enriched subtypes in epithelial cells revealed carcinogenesis. Three FAO-related genes (ZFHX4, AQP8, and AKR1B10) were screened to construct the GFAO_Score. The high GFAO_Score group leaned toward advanced CRC and unfavorable survival outcomes in the validation cohort. The low GFAO_Score group possessed a better response to immunotherapy and exhibited lower IC50 (50% inhibition concentration) values for certain chemotherapy drugs, such as 5-fluorouracil, irinotecan, oxaliplatin, paclitaxel, and camptothecin.
Conclusions: FAO patterns vary in patients with CRC. The GFAO_Score might contribute to the precise screening of patients according to metabolism reprogramming and optimization of strategies in clinical practice.

Keywords:  Fatty acid oxidation (FAO); colorectal cancer (CRC); metabolic reprogramming; prediction; prognosis

DOI:  https://doi.org/10.21037/jgo-23-833