bims-medica 2024-07-28 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–07–28
thirty-six papers selected by
Brett Chrest, East Carolina University

P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle.
Autonomous Oscillatory Mitochondrial Respiratory Activity: Results of a Systematic Analysis Show Heterogeneity in Different In Vitro-Synchronized Cancer Cells.
Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects.
Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
CCL2 and Lactate from Chemotherapeutics-Treated Fibroblasts Drive Malignant Traits by Metabolic Rewiring in Low-Migrating Breast Cancer Cell Lines.
Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.
Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.
Current advances in cancer energy metabolism under dietary restriction: a mini review.
Advances in Diet and Physical Activity in Breast Cancer Prevention and Treatment.
Cyclic fasting-mimicking diet in cancer treatment: Preclinical and clinical evidence.
100 years of the Warburg effect: A cancer metabolism endeavor.
The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity.
Differential Effect of Hyperglycemia on the Odds of Cancer Among the Adult Population of the United States.
Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks.
Venetoclax-based treatment in acute myeloid leukemia: an unexpected bonus on the path to allogeneic hematopoietic stem cell transplant?
Asparagine synthetase and G-protein coupled estrogen receptor are critical responders to nutrient supply in KRAS mutant colorectal cancer.
A three-week ketogenic diet increases skeletal muscle insulin sensitivity in individuals with obesity - a randomized, controlled crossover trial.
Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis.
Commentary: Tracing the fate of metabolic substrates during changes in whole-body energy expenditure in mice.
Challenges of Spatially Resolved Metabolism in Cancer Research.
Nucleoside Diphosphate Kinases Are ATP-Regulated Carriers of Short-Chain Acyl-CoAs.
Inverse FASN and LDHA correlation drives metabolic resistance in breast cancer.
Vitamin K2 sensitizes the efficacy of venetoclax in acute myeloid leukemia by targeting the NOXA-MCL-1 pathway.
Effects of lactate dehydrogenase A and GLUT1 inhibition on human endothelial cell migration in relation to their intracellular nucleotide pool.
Exosome Transfer Between Different Co-implanted Human Pancreatic Cancer Cell Lines Occurs in the Primary Tumor and Multiple Metastatic Sites of Nude Mice But Not in Co-Culture In Vitro.
Prognostic Significance of 18F-FDG PET/CT and Tumor Metabolic Changes in Patients With Pancreatic Ductal Adenocarcinoma.
Effects of Combined Interventions of Physical Activity and Diet in Childhood Cancer Survivors: A Systematic Review.
Mutant IDH modulates suppressive myeloid populations in malignant glioma.
Exploring the causal relationship between glutamine metabolism and leukemia risk: a Mendelian randomization and LC-MS/MS analysis.
13C Tracer Analysis and Metabolomics in Dormant Cancer Cells.
Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing.
SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.
Solanidine Metabolites as Diet-Derived Biomarkers of CYP2D6-Mediated Tamoxifen Metabolism in Breast Cancer Patients.
The Effects of Different Dietary Patterns on Bone Health.
An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
International consensus on fasting terminology.

Int J Mol Sci. 2024 Jul 16. pii: 7789. [Epub ahead of print]25(14):

P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle.

Liron Waingerten-Kedem, Sharon Aviram, Achinoam Blau, Tony Hayek, Eyal Bengal.

  Excessive calorie intake leads to mitochondrial overload and triggers metabolic inflexibility and insulin resistance. In this study, we examined how attenuated p38α activity affects glucose and fat metabolism in the skeletal muscles of mice on a high-fat diet (HFD). Mice exhibiting diminished p38α activity (referred to as p38αAF) gained more weight and displayed elevated serum insulin levels, as well as a compromised response in the insulin tolerance test, compared to the control mice. Additionally, their skeletal muscle tissue manifested impaired insulin signaling, leading to resistance in insulin-mediated glucose uptake. Examination of muscle metabolites in p38αAF mice revealed lower levels of glycolytic intermediates and decreased levels of acyl-carnitine metabolites, suggesting reduced glycolysis and β-oxidation compared to the controls. Additionally, muscles of p38αAF mice exhibited severe abnormalities in their mitochondria. Analysis of myotubes derived from p38αAF mice revealed reduced mitochondrial respiratory capacity relative to the myotubes of the control mice. Furthermore, these myotubes showed decreased expression of Acetyl CoA Carboxylase 2 (ACC2), leading to increased fatty acid oxidation and diminished inhibitory phosphorylation of pyruvate dehydrogenase (PDH), which resulted in elevated mitochondrial pyruvate oxidation. The expected consequence of reduced mitochondrial respiratory function and uncontrolled nutrient oxidation observed in p38αAF myotubes mitochondrial overload and metabolic inflexibility. This scenario explains the increased likelihood of insulin resistance development in the muscles of p38αAF mice compared to the control mice on a high-fat diet. In summary, within skeletal muscles, p38α assumes a crucial role in orchestrating the mitochondrial adaptation to caloric surplus by promoting mitochondrial biogenesis and regulating the selective oxidation of nutrients, thereby preventing mitochondrial overload, metabolic inflexibility, and insulin resistance.

Keywords:  high-fat diet; insulin resistance; metabolomics; mitochondrial metabolism; p38α MAPK; skeletal muscle

DOI:  https://doi.org/10.3390/ijms25147789
Int J Mol Sci. 2024 Jul 16. pii: 7797. [Epub ahead of print]25(14):

Autonomous Oscillatory Mitochondrial Respiratory Activity: Results of a Systematic Analysis Show Heterogeneity in Different In Vitro-Synchronized Cancer Cells.

Olga Cela, Rosella Scrima, Consiglia Pacelli, Michela Rosiello, Claudia Piccoli, Nazzareno Capitanio.

  Circadian oscillations of several physiological and behavioral processes are an established process in all the organisms anticipating the geophysical changes recurring during the day. The time-keeping mechanism is controlled by a transcription translation feedback loop involving a set of well-characterized transcription factors. The synchronization of cells, controlled at the organismal level by a brain central clock, can be mimicked in vitro, pointing to the notion that all the cells are endowed with an autonomous time-keeping system. Metabolism undergoes circadian control, including the mitochondrial terminal catabolic pathways, culminating under aerobic conditions in the electron transfer to oxygen through the respiratory chain coupled to the ATP synthesis according to the oxidative phosphorylation chemiosmotic mechanism. In this study, we expanded upon previous isolated observations by utilizing multiple cell types, employing various synchronization protocols and different methodologies to measure mitochondrial oxygen consumption rates under conditions simulating various metabolic stressors. The results obtained clearly demonstrate that mitochondrial respiratory activity undergoes rhythmic oscillations in all tested cell types, regardless of their individual respiratory proficiency, indicating a phenomenon that can be generalized. However, notably, while primary cell types exhibited similar rhythmic respiratory profiles, cancer-derived cell lines displayed highly heterogeneous rhythmic changes. This observation confirms on the one hand the dysregulation of the circadian control of the oxidative metabolism observed in cancer, likely contributing to its development, and on the other hand underscores the necessity of personalized chronotherapy, which necessitates a detailed characterization of the cancer chronotype.

Keywords:  Cosinor analysis; circadian rhythms; in vitro synchronization; mitochondrial respiration; oxygen consumption measurement

DOI:  https://doi.org/10.3390/ijms25147797
Int J Mol Sci. 2024 Jul 19. pii: 7916. [Epub ahead of print]25(14):

Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects.

Adrian Kowalczyk, Julia Zarychta, Monika Lejman, Eryk Latoch, Joanna Zawitkowska.

  Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy still remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Recently, the Food and Drug Administration approved three mutant IDH (mIDH) inhibitors for the treatment of AML. However, the use of mIDH inhibitors in monotherapy usually leads to the development of resistance and the subsequent recurrence of the cancer, despite the initial effectiveness of the therapy. A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.

Keywords:  acute myeloid leukemia; enasidenib; isocitrate dehydrogenase inhibitors; ivosidenib; targeted therapy

DOI:  https://doi.org/10.3390/ijms25147916
JCI Insight. 2024 Jul 25. pii: e180906. [Epub ahead of print]

Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.

Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeno-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.

  The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.

Keywords:  Carbohydrate metabolism; Cardiology; Cardiovascular disease; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.180906
Antioxidants (Basel). 2024 Jul 01. pii: 801. [Epub ahead of print]13(7):

CCL2 and Lactate from Chemotherapeutics-Treated Fibroblasts Drive Malignant Traits by Metabolic Rewiring in Low-Migrating Breast Cancer Cell Lines.

Maria Jesus Vera, Iván Ponce, Cristopher Almarza, Gonzalo Ramirez, Francisco Guajardo, Karen Dubois-Camacho, Nicolás Tobar, Félix A Urra, Jorge Martinez.

  While cytostatic chemotherapy targeting DNA is known to induce genotoxicity, leading to cell cycle arrest and cytokine secretion, the impact of these drugs on fibroblast-epithelial cancer cell communication and metabolism remains understudied. Our research focused on human breast fibroblast RMF-621 exposed to nonlethal concentrations of cisplatin and doxorubicin, revealing reduced proliferation, diminished basal and maximal mitochondrial respirations, heightened mitochondrial ROS and lactate production, and elevated MCT4 protein levels. Interestingly, RMF-621 cells enhanced glucose uptake, promoting lactate export. Breast cancer cells MCF-7 exposed to conditioned media (CM) from drug-treated stromal RMF-621 cells increased MCT1 protein levels, lactate-driven mitochondrial respiration, and a significantly high mitochondrial spare capacity for lactate. These changes occurred alongside altered mitochondrial respiration, mitochondrial membrane potential, and superoxide levels. Furthermore, CM with doxorubicin and cisplatin increased migratory capacity in MCF-7 cells, which was inhibited by MCT1 (BAY-8002), glutamate dehydrogenase (EGCG), mitochondrial pyruvate carrier (UK5099), and complex I (rotenone) inhibitors. A similar behavior was observed in T47-D and ZR-75-1 breast cancer cells. This suggests that CM induces metabolic rewiring involving elevated lactate uptake to sustain mitochondrial bioenergetics during migration. Treatment with the mitochondrial-targeting antioxidant mitoTEMPO in RMF-621 and the addition of an anti-CCL2 antibody in the CM prevented the promigratory MCF-7 phenotype. Similar effects were observed in THP1 monocyte cells, where CM increased monocyte recruitment. We propose that nonlethal concentrations of DNA-damaging drugs induce changes in the cellular environment favoring a promalignant state dependent on mitochondrial bioenergetics.

Keywords:  antineoplastic drugs; bioenergetics; desmoplastic lesion; immune response; mitochondrial respiration

DOI:  https://doi.org/10.3390/antiox13070801
Adv Pharmacol. 2024 ;pii: S1054-3589(24)00014-0. [Epub ahead of print]100 157-180

Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.

Kateřina Novotná, Lukáš Tenora, Barbara S Slusher, Rana Rais.

  The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivotal role as a carbon source for synthesizing lipids and metabolites through the TCA cycle, as well as a nitrogen source for synthesis of amino acid and nucleotides. Numerous studies have explored the significance of glutamine metabolism in cancer, providing a robust rationale for targeting this metabolic pathway in cancer treatment. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has been explored as an anticancer therapeutic for nearly six decades. Initial investigations revealed remarkable efficacy in preclinical studies and promising outcomes in early clinical trials. However, further advancement of DON was hindered due to dose-limiting gastrointestinal (GI) toxicities as the GI system is highly dependent on glutamine for regulating growth and repair. In an effort to repurpose DON and mitigate gastrointestinal (GI) toxicity concerns, prodrug strategies were utilized. These strategies aimed to enhance the delivery of DON to specific target tissues, such as tumors and the central nervous system (CNS), while sparing DON delivery to normal tissues, particularly the GI tract. When administered at low daily doses, optimized for metabolic inhibition, these prodrugs exhibit remarkable effectiveness without inducing significant toxicity to normal tissues. This approach holds promise for overcoming past challenges associated with DON, offering an avenue for its successful utilization in cancer treatment.

Keywords:  6-Diazo-5-oxo-L-norleucine (DON); Gastrointestinal; Glutamine addiction; Glutamine antagonist; Metabolic inhibition; Prodrug

DOI:  https://doi.org/10.1016/bs.apha.2024.04.003
Redox Biol. 2024 Jul 20. pii: S2213-2317(24)00254-4. [Epub ahead of print]75 103276

Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.

Marco Biondini, Camille Lehuédé, Sébastien Tabariès, Matthew G Annis, Alain Pacis, Eric H Ma, Christine Tam, Brian E Hsu, Yannick Audet-Delage, Afnan Abu-Thuraia, Charlotte Girondel, Valerie Sabourin, Stephanie P Totten, Mariana de Sá Tavares Russo, Gaëlle Bridon, Daina Avizonis, Marie-Christine Guiot, Julie St-Pierre, Josie Ursini-Siegel, Russell Jones, Peter M Siegel.

  Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations. Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.

Keywords:  Breast cancer; GCLC; Glutathione; Glycolysis; HIF-1α; Liver metastasis; Metabolism; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2024.103276
Med Oncol. 2024 Jul 26. 41(9): 209

Current advances in cancer energy metabolism under dietary restriction: a mini review.

Liuxin Yang, Yudian Shao, Tingting Gao, Ousman Bajinka, Xingxing Yuan.

  The manipulation of the energy or source of food for cancer cells has attracted significant attention in oncology research. Metabolic reprogramming of the immune system allows for a deeper understanding of cancer cell mechanisms, thereby impeding their progression. A more targeted approach is the restriction of cancer cells through dietary restriction (CR), which deprives cancer cells of the preferred energy sources within the tumor microenvironment, thereby enhancing immune cell efficacy. Although there is a plethora of CR strategies that can be employed to impede cancer progression, there is currently no comprehensive review that delineates the specific dietary restrictions that target the diverse metabolic pathways of cancer cells. This mini-review introduces amino acids as anti-cancer agents and discusses the role of dietary interventions in cancer prevention and treatment. It highlights the potential of a ketogenic diet as a therapeutic approach for cancer, elucidating its distinct mechanisms of action in tumor progression. Additionally, the potential of plant-based diets as anti-cancer agents and the role of polyphenols and vitamins in anti-cancer therapy were also discussed, along with some prospective interventions for CR as anti-tumor progression.

Keywords:  Anti-cancer; Cancer; Dietary restriction; Energy reprograming; Ketogenic diet; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12032-024-02452-z
Nutrients. 2024 Jul 13. pii: 2262. [Epub ahead of print]16(14):

Advances in Diet and Physical Activity in Breast Cancer Prevention and Treatment.

Amr Khalifa, Ana Guijarro, Alessio Nencioni.

  There is currently a growing interest in diets and physical activity patterns that may be beneficial in preventing and treating breast cancer (BC). Mounting evidence indicates that indeed, the so-called Mediterranean diet (MedDiet) and regular physical activity likely both help reduce the risk of developing BC. For those who have already received a BC diagnosis, these interventions may decrease the risk of tumor recurrence after treatment and improve quality of life. Studies also show the potential of other dietary interventions, including fasting or modified fasting, calorie restriction, ketogenic diets, and vegan or plant-based diets, to enhance the efficacy of BC therapies. In this review article, we discuss the biological rationale for utilizing these dietary interventions and physical activity in BC prevention and treatment. We highlight published and ongoing clinical studies that have applied these lifestyle interventions to BC patients. This review offers valuable insights into the potential application of these dietary interventions and physical activity as complimentary therapies in BC management.

Keywords:  Mediterranean diet; breast cancer; calorie restriction; fasting; ketogenic diets; lifestyle interventions; physical activity; vegan or plant-based diets

DOI:  https://doi.org/10.3390/nu16142262
Cell Metab. 2024 Jul 23. pii: S1550-4131(24)00270-5. [Epub ahead of print]

Cyclic fasting-mimicking diet in cancer treatment: Preclinical and clinical evidence.

Claudio Vernieri, Francesca Ligorio, Debu Tripathy, Valter D Longo.

  In preclinical tumor models, cyclic fasting and fasting-mimicking diets (FMDs) produce antitumor effects that become synergistic when combined with a wide range of standard anticancer treatments while protecting normal tissues from treatment-induced adverse events. More recently, results of phase 1/2 clinical trials showed that cyclic FMD is safe, feasible, and associated with positive metabolic and immunomodulatory effects in patients with different tumor types, thus paving the way for larger clinical trials to investigate FMD anticancer activity in different clinical contexts. Here, we review the tumor-cell-autonomous and immune-system-mediated mechanisms of fasting/FMD antitumor effects, and we critically discuss new metabolic interventions that could synergize with nutrient starvation to boost its anticancer activity and prevent or reverse tumor resistance while minimizing toxicity to patients. Finally, we highlight potential future applications of FMD approaches in combination with standard anticancer strategies as well as strategies to implement the design and conduction of clinical trials.

Keywords:  cancer therapy; clinical trials; combination treatments; fasting-mimicking diet; resistance mechanisms

DOI:  https://doi.org/10.1016/j.cmet.2024.06.014
Cell. 2024 Jul 25. pii: S0092-8674(24)00700-1. [Epub ahead of print]187(15): 3824-3828

100 years of the Warburg effect: A cancer metabolism endeavor.

Sarah-Maria Fendt.

If you are a scientist and you only know one thing about tumor metabolism, it's likely the Warburg effect. But who was Otto Warburg, and how did his discoveries regarding the metabolism of tumors shape our current thinking about the metabolic needs of cancer cells?

DOI: https://doi.org/10.1016/j.cell.2024.06.026
Antioxidants (Basel). 2024 Jul 08. pii: 820. [Epub ahead of print]13(7):

The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity.

Leah E Jamerson, Patrick C Bradshaw.

  Dietary restriction (DR) protocols frequently employ intermittent fasting. Following a period of fasting, meal consumption increases lipogenic gene expression, including that of NADPH-generating enzymes that fuel lipogenesis in white adipose tissue (WAT) through the induction of transcriptional regulators SREBP-1c and CHREBP. SREBP-1c knockout mice, unlike controls, did not show an extended lifespan on the DR diet. WAT cytoplasmic NADPH is generated by both malic enzyme 1 (ME1) and the pentose phosphate pathway (PPP), while liver cytoplasmic NADPH is primarily synthesized by folate cycle enzymes provided one-carbon units through serine catabolism. During the daily fasting period of the DR diet, fatty acids are released from WAT and are transported to peripheral tissues, where they are used for beta-oxidation and for phospholipid and lipid droplet synthesis, where monounsaturated fatty acids (MUFAs) may activate Nrf1 and inhibit ferroptosis to promote longevity. Decreased WAT NADPH from PPP gene knockout stimulated the browning of WAT and protected from a high-fat diet, while high levels of NADPH-generating enzymes in WAT and macrophages are linked to obesity. But oscillations in WAT [NADPH]/[NADP+] from feeding and fasting cycles may play an important role in maintaining metabolic plasticity to drive longevity. Studies measuring the WAT malate/pyruvate as a proxy for the cytoplasmic [NADPH]/[NADP+], as well as studies using fluorescent biosensors expressed in the WAT of animal models to monitor the changes in cytoplasmic [NADPH]/[NADP+], are needed during ad libitum and DR diets to determine the changes that are associated with longevity.

Keywords:  NADPH; aging; dietary restriction; lifespan; metabolism; white adipose

DOI:  https://doi.org/10.3390/antiox13070820
Cureus. 2024 Jun;16(6): e63061

Differential Effect of Hyperglycemia on the Odds of Cancer Among the Adult Population of the United States.

Parinaz Ayat, Diana Sawass Najjar, Hussam Alkaissi, Harjinder Gill, Jennifer Otey, Marwa AlFaraj, Samy I McFarlane.

  Objective Accumulating evidence indicates a relationship between diabetes and cancer risk, with obesity, insulin resistance, and hyperglycemia being implicated as the major underlying pathogenetic mechanisms of increased cancer risk among people with diabetes. We aim to assess the differential effect of dysglycemia (prediabetes and diabetes) on the strength of association (odds) of cancer amongst the adult US diabetic population. Material and methods We analyzed data from the 1997-2013 National Health Interview Survey (NHIS) dataset, which applies a multistage area probability sampling design. We used descriptive statistics and logistic regression analyses to test the strengths of the association between diabetes, prediabetes, and cancer before and after adjusting for major risk factors for cancer, including age and body mass index (BMI). Results A total of 722,532 individuals were surveyed, with a mean age of 47.18 ±0.3 years (±SEM) and a BMI of 26.9 ±0.01 kg/m2. Between 1997 and 2013, BMI increased from 26.0 to 27.4 kg/m2, the diabetes rate increased from 4.1% to 7.6%, and associated cancer rates increased from 6.6% to 9.0%. Body mass index was 27.1 vs. 26.8 kg/m2, P < 0.01, for those with and without cancer, respectively. The unadjusted odds ratio for cancer was 1.92 (1.78-2.08) (95% CI) and 2.20 (2.13-2.27) for prediabetes and diabetes, respectively. After adjusting for age, BMI, race, and cigarette smoking, the odds ratio for cancer was 1.12 (1.03-1.22), P < 0.01, and 1.15 (1.11-1.18), P <0.01, for prediabetes and diabetes, respectively. Conclusion Among US adults, the increasing rate of diabetes over the years was associated with an increased rate of cancer. Diabetes and prediabetes have a graduated effect on cancer risk. While obesity is generally implicated as an underlying pathophysiologic link between diabetes and cancer, our study showed a modest difference in BMI between those with and without cancer. In addition, the effect of diabetes and prediabetes on the odds of cancer persisted after adjusting for BMI. These data collectively suggest that hyperglycemia is an attractive pathophysiologic mechanism that may play a role in increasing the odds of cancer among diabetic and prediabetic populations. Our study is consistent with the accumulating evidence implicating hyperglycemia in the pathogenesis of cancer, where glucose is used in PET scanning to detect cancer (the Warburg effect), and the ketogenic diet appears to be useful in cancer management, enhancing the effect of chemotherapeutic agents.

Keywords:  cancer; diabetes; dysglycemia; hyperglycemia; insulin resistance; ketogenic diet; obesity; prediabetes

DOI:  https://doi.org/10.7759/cureus.63061
Cell Rep. 2024 Jul 23. pii: S2211-1247(24)00852-0. [Epub ahead of print]43(8): 114523

Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks.

Victoria A Acosta-Rodríguez, Filipa Rijo-Ferreira, Laura van Rosmalen, Mariko Izumo, Noheon Park, Chryshanthi Joseph, Chelsea Hepler, Anneke K Thorne, Jeremy Stubblefield, Joseph Bass, Carla B Green, Joseph S Takahashi.

  Extended food consumption during the rest period perturbs the phase relationship between circadian clocks in the periphery and the brain, leading to adverse health effects. Beyond the liver, how metabolic organs respond to a timed hypocaloric diet is largely unexplored. We investigated how feeding schedules impacted circadian gene expression in epididymal white and brown adipose tissue (eWAT and BAT) compared to the liver and hypothalamus. We restricted food to either daytime or nighttime in C57BL/6J male mice, with or without caloric restriction. Unlike the liver and eWAT, rhythmic clock genes in the BAT remained insensitive to feeding time, similar to the hypothalamus. We uncovered an internal split within the BAT in response to conflicting environmental cues, displaying inverted oscillations on a subset of metabolic genes without modifying its local core circadian machinery. Integrating tissue-specific responses on circadian transcriptional networks with metabolic outcomes may help elucidate the mechanism underlying the health burden of eating at unusual times.

Keywords:  CP: Metabolism; brown adipose tissue; caloric restriction; circadian clocks; dietary interventions; liver; misaligned feeding; mouse behavior; time-restricted feeding

DOI:  https://doi.org/10.1016/j.celrep.2024.114523
Leuk Lymphoma. 2024 Jul 23. 1-12

Venetoclax-based treatment in acute myeloid leukemia: an unexpected bonus on the path to allogeneic hematopoietic stem cell transplant?

Francesco Tarantini, Cosimo Cumbo, Luisa Anelli, Antonella Zagaria, Nicoletta Coccaro, Giuseppina Tota, Angela Minervini, Crescenzio Francesco Minervini, Elisa Parciante, Maria Rosa Conserva, Immacolata Redavid, Giorgina Specchia, Pellegrino Musto, Francesco Albano.

  Despite the approval of new drugs, the inclusion of -omics-derived data and the integration of machine learning in both the diagnostic and therapeutic process, the prognosis of acute myeloid leukemia (AML) remains dismal. The curative path is still aimed at achieving a successful allogeneic hematopoietic stem cell transplant (HSCT) in most patients. Nevertheless, access to this procedure is limited to eligible patients. Moreover, post-HSCT outcomes are influenced by AML heterogeneity and patient-related factors. The rise of venetoclax (VEN)-based combinations as standard of care in the treatment of older or unfit AML patients, together with their peculiar management profile, has led researchers to evaluate the feasibility of this approach in patients proceeding toward HSCT. We reviewed the available evidence to weigh up the advantages and pitfalls of this new therapeutic strategy.

Keywords:  Venetoclax; acute myeloid leukemia; hematopoietic stem cell transplant

DOI:  https://doi.org/10.1080/10428194.2024.2381649
Int J Cancer. 2024 Jul 22.

Asparagine synthetase and G-protein coupled estrogen receptor are critical responders to nutrient supply in KRAS mutant colorectal cancer.

Lingeng Lu, Qian Zhang, Oladimeji Aladelokun, Domenica Berardi, Xinyi Shen, Audrey Marin, Rolando Garcia-Milian, Jatin Roper, Sajid A Khan, Caroline H Johnson.

  Survival differences exist in colorectal cancer (CRC) patients by sex and disease stage. However, the potential molecular mechanism(s) are not well understood. Here we show that asparagine synthetase (ASNS) and G protein-coupled estrogen receptor-1 (GPER1) are critical sensors of nutrient depletion and linked to poorer outcomes for females with CRC. Using a 3D spheroid model of isogenic SW48 KRAS wild-type (WT) and G12A mutant (MT) cells grown under a restricted nutrient supply, we found that glutamine depletion inhibited cell growth in both cell lines, whereas ASNS and GPER1 expression were upregulated in KRAS MT versus WT. Estradiol decreased growth in KRAS WT but had no effect on MT cells. Selective GPER1 and ASNS inhibitors suppressed cell proliferation with increased caspase-3 activity of MT cells under glutamine depletion condition particularly in the presence of estradiol. In a clinical colon cancer cohort from The Cancer Genome Atlas, both high GPER1 and ASNS expression were associated with poorer overall survival for females only in advanced stage tumors. These results suggest KRAS MT cells have mechanisms in place that respond to decreased nutrient supply, typically observed in advanced tumors, by increasing the expression of ASNS and GPER1 to drive cell growth. Furthermore, KRAS MT cells are resistant to the protective effects of estradiol under nutrient deplete conditions. The findings indicate that GPER1 and ASNS expression, along with the interaction between nutrient supply and KRAS mutations shed additional light on the mechanisms underlying sex differences in metabolism and growth in CRC, and have clinical implications in the precision management of KRAS mutant CRC.

Keywords:  ASNS; GPER1; colorectal cancer; estradiol; glutamine; survival

DOI:  https://doi.org/10.1002/ijc.35104
Diabetes. 2024 Jul 25. pii: db240162. [Epub ahead of print]

A three-week ketogenic diet increases skeletal muscle insulin sensitivity in individuals with obesity - a randomized, controlled crossover trial.

Thien Vinh Luong, Mette Glavind Bülow Pedersen, Caroline Bruun Abild, Katrine Meyer Lauritsen, Mette Louise Gram Kjærulff, Niels Møller, Lars Christian Gormsen, Esben Søndergaard.

A ketogenic diet (KD) can induce weight loss and improve glycemic regulation, potentially reducing the risk of developing type 2 diabetes. To elucidate the underlying mechanisms behind these beneficial effects of a KD, we investigated the impact of a KD on organ-specific insulin sensitivity (IS) in skeletal muscle, liver, and adipose tissue. We hypothesized that a KD would increase IS in skeletal muscle. The study included 11 individuals with obesity who underwent a randomized, crossover trial with two three-week interventions: 1) KD and 2) standard diet. Skeletal muscle IS was quantified as the increase in glucose disposal during a hyperinsulinemic-euglycemic clamp (HEC). Hepatic IS and adipose tissue IS were quantified as the relative suppression of endogenous glucose production (EGP) and the relative suppression of palmitate flux during the HEC. The KD led to a 2.2 kg weight loss, increased insulin-stimulated glucose disposal, whereas the relative suppression of EGP during the HEC was similar. In addition, the KD decreased insulin-mediated suppression of lipolysis. In conclusion, a KD increased skeletal muscle IS in individuals with obesity.

DOI: https://doi.org/10.2337/db24-0162
Int J Mol Sci. 2024 Jul 09. pii: 7544. [Epub ahead of print]25(14):

Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis.

Junichi Fujii, Hirotaka Imai.

  Ferroptosis is a type of nonapoptotic cell death that is characteristically caused by phospholipid peroxidation promoted by radical reactions involving iron. Researchers have identified many of the protein factors that are encoded by genes that promote ferroptosis. Glutathione peroxidase 4 (GPX4) is a key enzyme that protects phospholipids from peroxidation and suppresses ferroptosis in a glutathione-dependent manner. Thus, the dysregulation of genes involved in cysteine and/or glutathione metabolism is closely associated with ferroptosis. From the perspective of cell dynamics, actively proliferating cells are more prone to ferroptosis than quiescent cells, which suggests that radical species generated during oxygen-involved metabolism are responsible for lipid peroxidation. Herein, we discuss the initial events involved in ferroptosis that dominantly occur in the process of energy metabolism, in association with cysteine deficiency. Accordingly, dysregulation of the tricarboxylic acid cycle coupled with the respiratory chain in mitochondria are the main subjects here, and this suggests that mitochondria are the likely source of both radical electrons and free iron. Since not only carbohydrates, but also amino acids, especially glutamate, are major substrates for central metabolism, dealing with nitrogen derived from amino groups also contributes to lipid peroxidation and is a subject of this discussion.

Keywords:  glycolysis; metabolic remodeling; tricarboxylic acid cycle; urea cycle

DOI:  https://doi.org/10.3390/ijms25147544
Comp Biochem Physiol B Biochem Mol Biol. 2024 Jul 24. pii: S1096-4959(24)00075-7. [Epub ahead of print] 111008

Commentary: Tracing the fate of metabolic substrates during changes in whole-body energy expenditure in mice.

Sulayman A Lyons, Grant B McClelland.

  For small mammals, such as mice, cannulation procedures can be quite challenging, limiting research associated with tracing isotopically labelled substrates at the whole-animal level. When cannulation in mice is possible, assessment of substrate use is further limited to when mice are either under anesthesia or are at rest, as there are no studies directly quantifying substrate use during exercise in mice. The use of isotopic tracer techniques has greatly advanced our knowledge in understanding how metabolic substrates (carbohydrates, amino acids, and fatty acids) contribute to whole-body metabolism. However, research regarding tissue-specific fuel use contributions to whole-body energy expenditure in mice at varying metabolic intensities (i.e., exercise) is lacking, despite the popularity of using mice in a variety of metabolic models. In this commentary, we briefly discuss the methodologies, advantages, and disadvantages of using radiolabelled, positron emission, and stable isotopes with a specific focus on fatty acids. We highlight recent mouse studies that have used creative experimental designs employing the use of isotopic tracer techniques and we briefly discuss how these methodologies can be further pursued to deepen our understanding of substrate use during exercise. Lastly, we show findings of a recent study we performed using a radiolabelled fatty acid tracer (14C-bromopalmitic acid) to determine fatty acid uptake in 16 muscles, two brown and two white adipose tissue depots during submaximal exercise in deer mice.

Keywords:  (14)C-2-bromopalmitic acid; Open-flow respirometry; Positron emission isotopes; Radiolabelled isotopes; Stable isotopes

DOI:  https://doi.org/10.1016/j.cbpb.2024.111008
Metabolites. 2024 Jul 11. pii: 383. [Epub ahead of print]14(7):

Challenges of Spatially Resolved Metabolism in Cancer Research.

Andrew N Lane, Richard M Higashi, Teresa W-M Fan.

  Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further into spatially resolved biology, new technical problems have to be overcome owing to the small number of analytes present in the confines of a single cell or cell compartment. Here, we review the overall goals and solutions made possible by stable isotope tracing and their applications to models of increasing complexity. Finally, we discuss progress and outstanding difficulties in high-resolution spatially resolved tracer-based metabolic studies.

Keywords:  cancer metabolism; experimental models; spatially resolved metabolism; stable isotope-resolved metabolomics

DOI:  https://doi.org/10.3390/metabo14070383
Int J Mol Sci. 2024 Jul 09. pii: 7528. [Epub ahead of print]25(14):

Nucleoside Diphosphate Kinases Are ATP-Regulated Carriers of Short-Chain Acyl-CoAs.

Domenico Iuso, Julie Guilliaumet, Uwe Schlattner, Saadi Khochbin.

  Nucleoside diphosphate (NDP) kinases 1 and 2 (NME1/2) are well-characterized enzymes known for their NDP kinase activity. Recently, these enzymes have been shown by independent studies to bind coenzyme A (CoA) or acyl-CoA. These findings suggest a hitherto unknown role for NME1/2 in the regulation of CoA/acyl-CoA-dependent metabolic pathways, in tight correlation with the cellular NTP/NDP ratio. Accordingly, the regulation of NME1/2 functions by CoA/acyl-CoA binding has been described, and additionally, NME1/2 have been shown to control the cellular pathways consuming acetyl-CoA, such as histone acetylation and fatty acid synthesis. NME1/2-controlled histone acetylation in turn mediates an important transcriptional response to metabolic changes, such as those induced following a high-fat diet (HFD). This review discusses the CoA/acyl-CoA-dependent NME1/2 activities and proposes that these enzymes be considered as the first identified carriers of CoA/short-chain acyl-CoAs.

Keywords:  acyl-CoAs; fatty acid synthesis; histone acetylation; nucleoside diphosphate (NDP) kinases 1 and 2 (NME1/2)

DOI:  https://doi.org/10.3390/ijms25147528
J Transl Med. 2024 Jul 24. 22(1): 676

Inverse FASN and LDHA correlation drives metabolic resistance in breast cancer.

Chiara Papulino, Ugo Chianese, Ahmad Ali, Gregorio Favale, Concetta Tuccillo, Fortunato Ciardiello, Annabella Di Mauro, Chiara Mignogna, Gerardo Ferrara, Alfredo Budillon, Wouter Leonard Megchelenbrink, Nunzio Del Gaudio, Mariarosaria Conte, Fabrizio Merciai, Pietro Campiglia, Lucia Altucci, Vincenzo Carafa, Eduardo Sommella, Rosaria Benedetti.

   BACKGROUND: Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear.
METHODS: In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes.
RESULTS: Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions.
CONCLUSIONS: These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.

Keywords:  Breast cancer; FASN; LDHA; Metabolism; Tamoxifen resistance

DOI:  https://doi.org/10.1186/s12967-024-05517-9
PLoS One. 2024 ;19(7): e0307662

Vitamin K2 sensitizes the efficacy of venetoclax in acute myeloid leukemia by targeting the NOXA-MCL-1 pathway.

Tetsuzo Tauchi, Shota Moriya, Seiichi Okabe, Hiromi Kazama, Keisuke Miyazawa, Naoharu Takano.

Promising outcomes have been reported in elder patients with acute myeloid leukemia (AML) using combined therapy of venetoclax (VEN) and azacytidine (AZA) in recent years. However, approximately one-third of patients appear to be refractory to this therapy. Vitamin K2 (VK2) shows apoptosis-inducing activity in AML cells, and daily oral VK2 (menaquinone-4, GlakayR) has been approved for patients with osteoporosis in Japan. We observed a high response rate to AZA plus VEN therapy, with no 8-week mortality in the newly diagnosed AML patients consuming daily VK2 in our hospital. The median age of the patients was 75.9 years (range 66-84) with high-risk features. Patients received AZA 75 mg/m2 on D1-7, VEN 400 mg on D1-28, and daily VK2 45 mg. The CR/CRi ratio was 94.7% (18/19), with a CR rate of 79%. Complete cytogenetic CR was achieved in 15 of 19 (79%) patients, and MRD negativity in 2 of 15 (13%) evaluable CR patients. Owing to the extremely high response rate in clinical settings, we further attempted to investigate the underlying mechanisms. The combination of VK2 and VEN synergistically induced apoptosis in all five AML cell lines tested. VK2, but not VEN, induced mitochondrial reactive oxygen species (ROS), leading to the transcriptional upregulation of NOXA, followed by MCL-1 repression. ROS scavengers repressed VK2 induced-NOXA expression and led to the cancellation of pronounced apoptosis and the downregulation of MCL-1 by VK2 plus VEN. Additionally, knockdown and knockout of NOXA resulted in abrogation of the MCL-1 repression as well as enhanced cytotoxicity by the two-drug combination, indicating that VK2 suppresses MCL-1 via ROS-mediated NOXA induction. These data suggest that the dual inhibition of BCL-2 by VEN and MCL-1 by VK2 is responsible for the remarkable clinical outcomes in our patients. Therefore, large-scale clinical trials are required.

DOI: https://doi.org/10.1371/journal.pone.0307662
Nucleosides Nucleotides Nucleic Acids. 2024 Jul 22. 1-9

Effects of lactate dehydrogenase A and GLUT1 inhibition on human endothelial cell migration in relation to their intracellular nucleotide pool.

Gabriela Harasim, Marika A Frańczak, Filippo Minutolo, Carlotta Granchi, Elisa Giovannetti, Ewa M Słomińska, Ryszard T Smoleński, Godefridus J Peters.

  The expression of both lactate dehydrogenase A (LDH-A) and glucose transporter type 1 (GLUT1) is high in pancreatic, thoracic and many other types of cancer. GLUT1 is also highly expressed in endothelial cells (EC), that play an important role in tumor metastasis. We investigated the effect of inhibition of LDH-A by NHI-2 and GLUT1 by PGL14 on cellular migration, a hallmark of metastasis, in relation to changes in intracellular purine nucleotide and nicotinamide adenine dinucleotide pools in a human microvascular endothelial cell line (HMEC-1). HMEC-1 were treated with NHI-2 and PGL14 alone or in combination. Cell migration was tested by the wound healing assay. The intracellular purine nucleotides and NAD+/NADH concentrations were measured using Reversed-Phase High Performance Liquid Chromatography (RP-HPLC). Both NHI-2 at 15 µM and 45 µM and PGL14 at 10 µM and 30 µM inhibited migration by 5 to 28% while the combination led to 46% inhibition. The drugs also decreased intracellular nucleotide pools, but only 45 µM NHI-2 altered energy charge and redox status in HMEC-1 cells. Inhibitors of glycolysis attenuated migration and the energy charge of EC and support further development of LDH-A and GLUT1 inhibitors to target cancer aggressiveness and metastasis.

Keywords:  Lactate dehydrogenase A; cell energy status; glucose transporter type 1; human endothelial cells; malignant cancer; metastasis

DOI:  https://doi.org/10.1080/15257770.2024.2379321
Anticancer Res. 2024 Aug;44(8): 3307-3315

Exosome Transfer Between Different Co-implanted Human Pancreatic Cancer Cell Lines Occurs in the Primary Tumor and Multiple Metastatic Sites of Nude Mice But Not in Co-Culture In Vitro.

Koji Yamashita, Atsushi Suetsugu, Sadanari Hayashi, Masahito Shimizu, Robert M Hoffman.

   BACKGROUND/AIM: Exosome exchange between cancer cells or between cancer and stromal cells is involved in cancer metastasis. We have previously developed in vivo color-coded labeling of cancer cells and stromal cells with spectrally-distinct fluorescent genetic reporters to demonstrate the role of exosomes in metastasis. In the present study, we studied exosome transfer between different pancreatic-cancer cell lines in vivo and in vitro and its potential role in metastasis.
MATERIALS AND METHODS: Human pancreatic-cancer cell lines AsPC-1 and MiaPaCa-2 were used in the present study. AsPC-1 cells contain a genetic exosome reporter gene labeled with green fluorescent protein (pCT-CD63-GFP) and MiaPaCa-2 cells express red fluorescent protein (RFP). Both cell lines were co-injected into the spleen of nude mice (n=5) to further study the role of exosome exchange in metastasis. Three weeks later mice were sacrificed and tumors at the primary and metastatic sites were cultured and observed by confocal fluorescence microscopy for exosome transfer.
RESULTS: The primary tumor formed in the spleen and metastasized to the liver, as observed macroscopically. Cells were cultured from the spleen, liver, lung, bone marrow and ascites. Transfer of exosomes from AsPC-1 to MiaPaCa-2 was demonstrated in the cultured cells by confocal fluorescence microscopy. Moreover, cell fusion was also observed along with exosome transfer. Exosome transfer did not occur during in vitro co-culture between the two pancreatic-cancer cell lines, suggesting a role of the tumor microenvironment (TME) in exosome transfer.
CONCLUSION: The transfer of exosomes between different pancreatic-cancer cell lines was observed during primary-tumor and metastatic growth in nude mice. This cell-cell communication might be a trigger of cell fusion and promotion of cancer metastasis. Exosome transfer between the two pancreatic-cancer cell lines appears to be facilitated by the TME, as it did not occur during in vitro co-culture.

Keywords:  AsPC-1; GFP; MiaPaCa-2; RFP; cell fusion; color-coded imaging; exosome; metastasis; nude mice; transfer

DOI:  https://doi.org/10.21873/anticanres.17149
Anticancer Res. 2024 Aug;44(8): 3321-3330

Prognostic Significance of 18F-FDG PET/CT and Tumor Metabolic Changes in Patients With Pancreatic Ductal Adenocarcinoma.

Ayaka Shimomura, Minoru Oshima, Hironobu Suto, Hiroyuki Matsukawa, Akihiro Kondo, Yasuhisa Ando, Takayoshi Kishino, Kensuke Kumamoto, Kiyotoshi Sato, Masahiro Sugimoto, Mina Nagao, Nobuyuki Miyatake, Takashi Norikane, Tomoyoshi Soga, Keiichi Okano.

   BACKGROUND/AIM: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is reportedly associated with the malignant potential of cancer. This study aimed to evaluate the association between FDG accumulation and tumor metabolism in pancreatic ductal adenocarcinoma (PDAC).
PATIENTS AND METHODS: A prognostic analysis of data from 131 patients with PDAC who underwent FDG-PET/CT before curative-intent pancreatic surgery was performed. Capillary electrophoresis-mass spectrometry (CE-MS) was used to analyze the metabolome of tumor and non-neoplastic pancreas from 80 patients. These patients were divided into two groups: low SUVmax group (SUVmax <6.09) and high SUVmax group (SUVmax ≥6.09).
RESULTS: Carbohydrate antigen 19-9 (CA19-9), maximum standardized uptake value (SUVmax) of PET, N stage, and postoperative chemotherapy were identified as significant prognostic factors by univariate analysis. SUVmax emerged as an independent prognostic factor for overall survival [hazard ratio (HR)=1.88, p<0.05] and disease-free survival (HR=2.01, p<0.05) in multivariate analysis. Metabolic analyses confirmed that 43 metabolites significantly differed depending on the accumulation of SUV in tumors. Metabolites involved in the removal of reactive oxygen species (e.g., hypotaurine, glutathione, Met), treatment resistance (UDP-N-acetylglucosamine), and proliferation (e.g., choline, leucine, isoleucine) were increased in the high SUVmax group.
CONCLUSION: FDG accumulation is an important independent prognostic factor reflecting tumor activity associated with metabolic changes in cancer cells.

Keywords:  CE-MS; FDG-PET; Metabolomics; PDAC; SUVmax

DOI:  https://doi.org/10.21873/anticanres.17151
Children (Basel). 2024 Jul 13. pii: 853. [Epub ahead of print]11(7):

Effects of Combined Interventions of Physical Activity and Diet in Childhood Cancer Survivors: A Systematic Review.

Carlos Vasconcelos, Patrícia Sousa.

  Physical activity and diet have complementary benefits for attenuating adverse health effects that childhood cancer survivors experience after the end of treatment. This review aimed to explore the impact of combined physical activity and diet interventions on the health status of childhood cancer survivors. A thorough review of the literature was carried out using the Cochrane Library, PubMed, Scielo, LILACS and Web of Science databases for studies published until June 2024. Studies concerning survivors of childhood cancer of any type engaged exclusively in combined diet/physical activity interventions were included in this review. Three manuscripts met the inclusion criteria. The results indicated that combined physical activity plus diet interventions showed beneficial impacts for the intestinal microbiome, percentage of calories from sweet foods, daily consumption of sugary beverages, reduction in sedentary activity, and mood (1 out of 1 study for each of the presented outcomes). Although more rigorous studies are needed, these findings showed promising results regarding the impact of interventions involving both physical activity and diet on childhood cancer survivors.

Keywords:  exercise; nutrition; pediatric oncology; survivorship

DOI:  https://doi.org/10.3390/children11070853
Clin Cancer Res. 2024 Jul 23.

Mutant IDH modulates suppressive myeloid populations in malignant glioma.

Eric P Grewal, Leland G K Richardson, Jing Sun, Rishab Ramapriyan, Maria Martinez-Lage, Julie J Miller, Bob S Carter, Daniel P Cahill, William T Curry, Bryan D Choi.

PURPOSE: Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 have critical diagnostic and prognostic significance in diffuse gliomas. Neomorphic mutant IDH activity has been previously implicated in T-cell suppression; however, the effects of IDH mutations on intratumoral myeloid populations remain underexplored. Here, we investigate the influence of IDH status on the myeloid compartment using human glioma specimens and preclinical models.
EXPERIMENTAL DESIGN: We performed RNA-sequencing and quantitative immunofluorescence on newly diagnosed, treatment-naive IDH-mutant grade 4 astrocytoma and IDH-wildtype glioblastoma (GBM) specimens. We also generated a syngeneic murine model, comparing transcriptomic and cell-level changes in paired isogenic glioma lines that differ only in IDH mutational status.
RESULTS: Among patient samples, IDH-mutant tumors displayed underrepresentation of suppressive myeloid transcriptional signatures, which was confirmed at the cellular level with decreased numbers of intratumoral M2-like macrophages and MDSCs. Introduction of the IDH-mutant enzyme into murine glioma was sufficient to recapitulate the transcriptomic and cellular shifts observed in patient samples.
CONCLUSIONS: We provide transcriptomic and cellular evidence that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model. These data advance our understanding of high-grade gliomas by identifying key myeloid cell populations that are reprogrammed by mutant-IDH and may be targetable through therapeutic approaches.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1056
Front Immunol. 2024 ;15 1418738

Exploring the causal relationship between glutamine metabolism and leukemia risk: a Mendelian randomization and LC-MS/MS analysis.

Na Li, Tianyi Wang, Huiying Zhang, Xiao Li, Haochen Bai, Ning Lu, Kaizhi Lu.

   Objective: This investigation sought to delineate the causal nexus between plasma glutamine concentrations and leukemia susceptibility utilizing bidirectional Mendelian Randomization (MR) analysis and to elucidate the metabolic ramifications of asparaginase therapy on glutamine dynamics in leukemia patients.
Methods: A bidirectional two-sample MR framework was implemented, leveraging genetic variants as instrumental variables from extensive genome-wide association studies (GWAS) tailored to populations of European descent. Glutamine quantification was executed through a rigorously validated Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) protocol. Comparative analyses of glutamine levels were conducted across leukemia patients versus healthy controls, pre- and post-asparaginase administration. Statistical evaluations employed inverse variance weighted (IVW) models, MR-Egger regression, and sensitivity tests addressing pleiotropy and heterogeneity.
Results: The MR findings underscored a significant inverse association between glutamine levels and leukemia risk (IVW p = 0.03558833), positing lower glutamine levels as a contributory factor to heightened leukemia susceptibility. Conversely, the analysis disclosed no substantive causal impact of leukemia on glutamine modulation (IVW p = 0.9694758). Notably, post-asparaginase treatment, a marked decrement in plasma glutamine concentrations was observed in patients (p = 0.0068), underlining the profound metabolic influence of the therapeutic regimen.
Conclusion: This study corroborates the hypothesized inverse relationship between plasma glutamine levels and leukemia risk, enhancing our understanding of glutamine's role in leukemia pathophysiology. The pronounced reduction in glutamine levels following asparaginase intervention highlights the critical need for meticulous metabolic monitoring to refine therapeutic efficacy and optimize patient management in clinical oncology. These insights pave the way for more tailored and efficacious treatment modalities in the realm of personalized medicine.

Keywords:  LC-MS/MS; Mendelian randomization; asparaginase treatment; glutamine; leukemia; personalized medicine; therapeutic drug monitoring

DOI:  https://doi.org/10.3389/fimmu.2024.1418738
Methods Mol Biol. 2024 ;2811 195-206

13C Tracer Analysis and Metabolomics in Dormant Cancer Cells.

Patricia Altea-Manzano, Sarah-Maria Fendt, Laura Vera-Ramirez.

  Over the last two decades, major advances in the field of tumor dormancy have been made. Yet, it is not completely understood how dormant disseminated tumor cells survive and transition to a proliferative state to generate a metastatic lesion. On the other hand, metabolic rewiring has been shown to influence metastasis development through the modulation of both intracellular signaling and the crosstalk between metastatic cells and their microenvironment. Thus, studying the metabolic features of dormant disseminated tumor cells has gained importance in understanding the dormancy process. Here, we describe a method to perform metabolomics and 13C tracer analysis in 3D cultures of dormant breast cancer cells.

Keywords:  13C tracing; 3D cell culture; Cancer; Disseminated tumor cells; Mass spectrometry; Metabolomics; Metastasis; Tumor cell dormancy

DOI:  https://doi.org/10.1007/978-1-0716-3882-8_15
Sports Med. 2024 Jul 26.

Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing.

Sophie C Broome, Jamie Whitfield, Leonidas G Karagounis, John A Hawley.

The age-related loss of skeletal muscle mass and physical function leads to a loss of independence and an increased reliance on health-care. Mitochondria are crucial in the aetiology of sarcopenia and have been identified as key targets for interventions that can attenuate declines in physical capacity. Exercise training is a primary intervention that reduces many of the deleterious effects of ageing in skeletal muscle quality and function. However, habitual levels of physical activity decline with age, making it necessary to implement adjunct treatments to maintain skeletal muscle mitochondrial health and physical function. This review provides an overview of the effects of ageing and exercise training on human skeletal muscle mitochondria and considers several supplements that have plausible mechanistic underpinning to improve physical function in ageing through their interactions with mitochondria. Several supplements, including MitoQ, urolithin A, omega-3 polyunsaturated fatty acids (n3-PUFAs), and a combination of glycine and N-acetylcysteine (GlyNAC) can improve physical function in older individuals through a variety of inter-dependent mechanisms including increases in mitochondrial biogenesis and energetics, decreases in mitochondrial reactive oxygen species emission and oxidative damage, and improvements in mitochondrial quality control. While there is evidence that some nicotinamide adenine dinucleotide precursors can improve physical function in older individuals, such an outcome seems unrelated to and independent of changes in skeletal muscle mitochondrial function. Future research should investigate the safety and efficacy of compounds that can improve skeletal muscle health in preclinical models through mechanisms involving mitochondria, such as mitochondrial-derived peptides and mitochondrial uncouplers, with a view to extending the human health-span.

DOI: https://doi.org/10.1007/s40279-024-02072-7
Mol Genet Metab. 2024 Jun 20. pii: S1096-7192(24)00402-5. [Epub ahead of print]143(1-2): 108518

SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.

David J Bernard, Faith Pangilinan, Caitlin Mendina, Tara Desporte, Stephen M Wincovitch, Darren J Walsh, Richard K Porter, Anne M Molloy, Barry Shane, Lawrence C Brody.

  Choline contributes to the biogenesis of methyl groups, neurotransmitters, and cell membranes. Our genome-wide association study (GWAS) of circulating choline in 2228 college students found that alleles in SLC25A48 (rs6596270) influence choline concentrations in men (p = 9.6 × 10-8), but not women. Previously, the subcellular location and function of SLC25A48 were unknown. Using super-resolution immunofluorescence microscopy, we localized SLC25A48 to the inner mitochondrial membrane. Our results suggest that SLC25A48 transports choline across the inner mitochondrial membrane.

Keywords:  Betaine; Choline; Inner mitochondrial membrane transport; Mitochondria; One carbon metabolism; SLC25A48

DOI:  https://doi.org/10.1016/j.ymgme.2024.108518
Clin Pharmacol Ther. 2024 Jul 22.

Solanidine Metabolites as Diet-Derived Biomarkers of CYP2D6-Mediated Tamoxifen Metabolism in Breast Cancer Patients.

Samantha Medwid, Ute I Schwarz, Yun-Hee Choi, Denise Keller, Cameron Ross, Richard B Kim.

Tamoxifen is an important antiestrogen for the treatment of hormone receptor-positive breast cancer and undergoes bioactivation by CYP2D6 to its active metabolite endoxifen. Genetic variation in CYP2D6 has been linked to endoxifen levels during tamoxifen therapy. Recent studies have suggested solanidine, a glycoalkaloid phytochemical in potatoes, undergoes CYP2D6-mediated metabolism to 4-OH-solanidine (m/z 414) and 3,4-seco-solanidine-3,4-dioic acid (SSDA; m/z 444). Using a retrospective cohort of 1,032 breast cancer patients on tamoxifen therapy, we examined the association of solanidine metabolites with CYP2D6 activity and its correlation with tamoxifen metabolism. Solanidine, 4-OH-solanidine, or SSDA was detected in 99.7% (N = 1,029) of plasma samples. Decreased solanidine metabolite ratios were found in CYP2D6 intermediate and poor metabolizers (P < 0.0001). Patients on CYP2D6 strong inhibitors had a 77.6% and 94.2% decrease in 4-OH-solandine/solanidine (P < 0.0001) and SSDA/solanidine (P < 0.0001), respectively. The ratio of endoxifen to tamoxifen was highly correlated with both 4-OH-solandine/solanidine (ρ = 0.3207, P < 0.0001) and SSDA/solanidine (ρ = 0.5022, P < 0.0001) ratios. Logistic regression modeling was used to determine that 4-OH-solanidine/solanidine and SSDA/solanidine ratios below 2.1 and 0.8, respectively, predicted endoxifen concentrations of <16 nM. In conclusion, solanidine, 4-OH-solanidine, and SSDA are diet-derived biomarkers of CYP2D6 activity. Moreover, in patients on tamoxifen therapy, 4-OH-solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6-interacting medications. Accordingly, 4-OH-solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen.

DOI: https://doi.org/10.1002/cpt.3380
Nutrients. 2024 Jul 17. pii: 2289. [Epub ahead of print]16(14):

The Effects of Different Dietary Patterns on Bone Health.

Xiaohua Liu, Yangming Wu, Samuel Bennett, Jun Zou, Jiake Xu, Lingli Zhang.

  Bone metabolism is a process in which osteoclasts continuously clear old bone and osteoblasts form osteoid and mineralization within basic multicellular units, which are in a dynamic balance. The process of bone metabolism is affected by many factors, including diet. Reasonable dietary patterns play a vital role in the prevention and treatment of bone-related diseases. In recent years, dietary patterns have changed dramatically. With the continuous improvement in the quality of life, high amounts of sugar, fat and protein have become a part of people's daily diets. However, people have gradually realized the importance of a healthy diet, intermittent fasting, calorie restriction, a vegetarian diet, and moderate exercise. Although these dietary patterns have traditionally been considered healthy, their true impact on bone health are still unclear. Studies have found that caloric restriction and a vegetarian diet can reduce bone mass, the negative impact of a high-sugar and high-fat dietary (HSFD) pattern on bone health is far greater than the positive impact of the mechanical load, and the relationship between a high-protein diet (HPD) and bone health remains controversial. Calcium, vitamin D, and dairy products play an important role in preventing bone loss. In this article, we further explore the relationship between different dietary patterns and bone health, and provide a reference for how to choose the appropriate dietary pattern in the future and for how to prevent bone loss caused by long-term poor dietary patterns in children, adolescents, and the elderly. In addition, this review provides dietary references for the clinical treatment of bone-related diseases and suggests that health policy makers should consider dietary measures to prevent and treat bone loss.

Keywords:  bone health; caloric restriction; dietary patterns; high-fat and high-sugar diet; high-protein diet; intermittent fasting; vegetarian diets

DOI:  https://doi.org/10.3390/nu16142289
Nat Aging. 2024 Jul 23.

An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.

Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.

How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.

DOI: https://doi.org/10.1038/s43587-024-00670-8
Cell Metab. 2024 Jul 23. pii: S1550-4131(24)00269-9. [Epub ahead of print]

International consensus on fasting terminology.

Daniela A Koppold, Carolin Breinlinger, Etienne Hanslian, Christian Kessler, Holger Cramer, Anika Rajput Khokhar, Courtney M Peterson, Grant Tinsley, Claudio Vernieri, Richard J Bloomer, Michael Boschmann, Nicola L Bragazzi, Sebastian Brandhorst, Kelsey Gabel, Alan C Goldhamer, Martin M Grajower, Michelle Harvie, Leonie Heilbronn, Benjamin D Horne, Spyridon N Karras, Jost Langhorst, Eva Lischka, Frank Madeo, Sarah J Mitchell, Ioannis-Eleemon Papagiannopoulos-Vatopaidinos, Maria Papagiannopoulou, Hanno Pijl, Eric Ravussin, Martha Ritzmann-Widderich, Krista Varady, Lilian Adamidou, Melika Chihaoui, Rafael de Cabo, Mohamed Hassanein, Nader Lessan, Valter Longo, Emily N C Manoogian, Mark P Mattson, J Brent Muhlestein, Satchidananda Panda, Sousana K Papadopoulou, Nikolaos E Rodopaios, Rainer Stange, Andreas Michalsen.

  Although fasting is increasingly applied for disease prevention and treatment, consensus on terminology is lacking. Using Delphi methodology, an international, multidisciplinary panel of researchers and clinicians standardized definitions of various fasting approaches in humans. Five online surveys and a live online conference were conducted with 38 experts, 25 of whom completed all 5 surveys. Consensus was achieved for the following terms: "fasting" (voluntary abstinence from some or all foods or foods and beverages), "modified fasting" (restriction of energy intake to max. 25% of energy needs), "fluid-only fasting," "alternate-day fasting," "short-term fasting" (lasting 2-3 days), "prolonged fasting" (≥4 consecutive days), and "religious fasting." "Intermittent fasting" (repetitive fasting periods lasting ≤48 h), "time-restricted eating," and "fasting-mimicking diet" were discussed most. This study provides expert recommendations on fasting terminology for future research and clinical applications, facilitating communication and cross-referencing in the field.

Keywords:  Delphi method; alternate-day fasting; dry fasting; fasting; fasting-mimicking diet; intermittent energy restriction; intermittent fasting; periodic fasting; therapeutic fasting; time-restricted eating

DOI:  https://doi.org/10.1016/j.cmet.2024.06.013