bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2025–04–20
forty-one papers selected by
Brett Chrest, Wake Forest University
  1. Ketone body supported respiration in murine isolated brain mitochondria is augmented by alpha-ketoglutarate and is optimized by neuronal SCOT expression.
  2. Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation.
  3. Can the Tumor Microenvironment Alter Ion Channels? Unraveling Their Role in Cancer.
  4. Genetically encoded tool for manipulation of ΔΨm identifies its role as the driver of ISR induced by ATP synthase dysfunction.
  5. GL261 glioblastoma induces delayed body weight gain and stunted skeletal muscle growth in young mice.
  6. Investigating the Therapeutic Potential of the Ketogenic Diet in Modulating Neurodegenerative Pathophysiology: An Interdisciplinary Approach.
  7. Dietary nutrient intake and cancer presence: evidence from a cross-sectional study.
  8. Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas.
  9. UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.
  10. 3-Bromopyruvate boosts the effect of chemotherapy in acute myeloid leukemia by a pro-oxidant mechanism.
  11. NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
  12. Ex Vivo Measurement of Stable Isotope-Labeled Fatty Acid Incorporation Into Phospholipids in Isolated Mice Muscle.
  13. Effect of Different Fatty Acid Types on Mitochondrial Dysfunction Associated With Brown and Beige Adipose Tissue.
  14. MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).
  15. Impact of Venetoclax Treatment Schedule on Hematologic Recovery and Treatment Response in AML Patients Unfit for Intensive Chemotherapy.
  16. Six-Day Fasting Causes Temporary Increases in Both Antioxidant Capacity and Oxidative Stress in Healthy Young Men: A Randomized Controlled Trial.
  17. Real-world (RW) study of outcomes for acute myeloid leukemia (AML) patients treated with glasdegib or venetoclax in US community oncology practices.
  18. Associations between vitamins intake and risk of cancer in United States adults: 2003 to 2016 national health and nutrition examination survey.
  19. Exercise and survival benefit in cancer patients: evidence from a comprehensive meta-analysis.
  20. Field guide to Nath's research work on ATP synthesis and hydrolysis.
  21. Mitochondrial classic metabolism and its often-underappreciated facets.
  22. Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.
  23. Starvation Induces Upregulation of Monocarboxylate Transport in Glial Cells at the Drosophila Blood-Brain Barrier.
  24. Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.
  25. Ceramide(d18:1/18:1)-Ndufa6 Interaction Inactivates Respiratory Complex I to Attenuate Oxidative-stress-driven Pathogenesis in Liver Ischemia/Reperfusion Injury.
  26. GLUT1 inhibition by BAY-876 induces metabolic changes and cell death in human colorectal cancer cells.
  27. Lack of consistent effect of dietary fiber on immune checkpoint blockade efficacy across diverse murine tumor models.
  28. Analyzing Ex Vivo Metabolic Flux in Splenic and Cardiac Macrophages and Bone Marrow Monocytes.
  29. Approaches to reduce succinate accumulation by restoration of succinate dehydrogenase activity in cultured adrenal cells.
  30. Housing Temperature Impacts the Systemic and Tissue-Specific Molecular Responses to Cancer in Mice.
  31. Time-Restricted Eating Versus Daily Calorie Restriction: Effects on Inflammatory Markers over 12 Months in Adults with Obesity.
  32. Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells.
  33. Weight Loss Reverses the Effects of Aging and Obesity on Mammary Tumor Immunosuppression and Progression.
  34. Low-Carbohydrate Diets for the Management of Pediatric Obesity: A Systematic Review and Meta-analysis.
  35. Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
  36. Assessment of early response to neoadjuvant chemotherapy in multi-site high-grade serous ovarian cancer using hyperpolarized-13C MRI.
  37. The effect of low-carbohydrate diets, based on changes in intake of dietary saturated fats on circulating TNF-α and interleukin- 6 levels in adults: a systematic review and meta-analysis of randomized controlled trials.
  38. Migration Strategy and Diet Affect the Metabolism of Passerine Birds During Endurance Flight.
  39. Differences in chemotherapeutic drug sensitivity before and after patient-derived tumor organoid construction.
  40. Comparative efficacy and safety in low-intensity treatment for acute myeloid leukemia in older patients: a systematic review and network meta-analysis.
  41. Central and peripheral adiposity and premenopausal breast cancer risk: a pooled analysis of 440,179 women.
  1. Am J Physiol Endocrinol Metab. 2025 Apr 17.
    Ketone body supported respiration in murine isolated brain mitochondria is augmented by alpha-ketoglutarate and is optimized by neuronal SCOT expression.
    Xin C Davis, Colin S McCoin, E Matthew Morris, Julie Allen, Harrison D Stierwalt, Edziu Franczak, Eric D Queathem, Kyle L Fulghum, Patrycja Puchalska, Peter A Crawford, John P Thyfault.
      Ketone bodies are increasingly examined as an alternative fuel source for the known decreases in glucose utilization that occur with neurodegeneration. Here, we established a protocol to maximize ketone body respiration in isolated brain mitochondria, while quantifying acetyl-CoA and energy charge via liquid chromatography-tandem mass spectrometry in control mice compared to mice with neuron-specific deletion of succinyl- CoA-3-oxoacid-CoA transferase (SCOT), required for CoA transfer from succinyl-CoA to AcAc to support its oxidation. Maximal ADP-dependent AcAc respiration occurred at 1 mM; however, the percent increase above basal was minimal (~15%). Alpha- ketoglutarate (αKG) substantially increased AcAc-dependent respiration in isolated brain mitochondria, putatively through the generation of succinyl-CoA. Using mice with neuron- specific deletion of SCOT, we also examined brain mitochondrial respiration of AcAc and resulting acetyl CoA and energy charge (cellular energy availability via adenosine nucleotide ratios of ATP, ADP, and AMP). As expected, isolated brain mitochondria from SCOT-KO mice had lower AcAc State 3 respiration than control mice. Surprisingly, we did not find differences in mitochondrial energy charge between SCOT control and neuron SCOT-KO mice despite decreased acetyl-CoA level in SCOT-KO mice when AcAc was used as the substrate. In conclusion, we show that KG enhances ketone-supported respiration rate in isolated brain mitochondria, and ketone metabolism in neurons affects acetyl-CoA level in brain mitochondria but not energy charge. Future work will determine if diet, exercise, sex, or age impacts ketone-supported respiration rates in conjunction with differences in markers of brain health.
    Keywords:  Brain; Ketone; Mitochondria respiration; SCOT
    DOI:  https://doi.org/10.1152/ajpendo.00058.2025
  2. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 16. pii: S0925-4439(25)00204-2. [Epub ahead of print] 167859
    Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation.
    Wenying Shan, Shao-Lin Zhang, Yehuda G Assaraf, Kin Yip Tam.
      KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the in vitro and in vivo efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation in vitro, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.
    Keywords:  Cancer metabolism; Combination therapy; KRAS Q61H mutation; Small molecule inhibitors
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167859
  3. Cancers (Basel). 2025 Apr 06. pii: 1244. [Epub ahead of print]17(7):
    Can the Tumor Microenvironment Alter Ion Channels? Unraveling Their Role in Cancer.
    Rosaria Gentile, Davide Feudi, Luana Sallicandro, Andrea Biagini.
      Neoplastic cells are characterized by metabolic reprogramming, known as the Warburg effect, in which glucose metabolism is predominantly directed toward aerobic glycolysis, with reduced mitochondrial oxidative phosphorylation and increased lactate production even in the presence of oxygen. This phenomenon provides cancer cells with a proliferative advantage, allowing them to rapidly produce energy (in the form of ATP) and generate metabolic intermediates necessary for the biosynthesis of macromolecules essential for cell growth. It is important to understand the role of ion channels in the tumor context since they participate in various physiological processes and in the regulation of the tumor microenvironment. These changes may contribute to the development and transformation of cancer cells, as well as affect the communication between cells and the surrounding microenvironment, including impaired or altered expression and functionality of ion channels. Therefore, the aim of this review is to elucidate the impact of the tumor microenvironment on the electrical properties of the cellular membranes in several cancers as a possible therapeutic target.
    Keywords:  KATP; TRPM5; connexins; ion channels; pannexins; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17071244
  4. Cell Chem Biol. 2025 Apr 17. pii: S2451-9456(25)00097-2. [Epub ahead of print]32(4): 620-630.e6
    Genetically encoded tool for manipulation of ΔΨm identifies its role as the driver of ISR induced by ATP synthase dysfunction.
    Mangyu Choe, Alex E Ekvik, Gretchen Stalnaker, Hijai R Shin, Denis V Titov.
      Mitochondrial membrane potential (ΔΨm) is one of the key parameters controlling cellular bioenergetics. Investigation of the role of ΔΨm in live cells is complicated by a lack of tools for its direct manipulation without off-target effects. Here, we adopted the uncoupling protein UCP1 from brown adipocytes as a genetically encoded tool for direct manipulation of ΔΨm. We validated the ability of exogenously expressed UCP1 to induce uncoupled respiration and lower ΔΨm in mammalian cells. UCP1 expression lowered ΔΨm to the same extent as chemical uncouplers but did not inhibit cell proliferation, suggesting that it manipulates ΔΨm without the off-target effects of chemical uncouplers. Using UCP1, we revealed that elevated ΔΨm is the driver of the integrated stress response induced by ATP synthase inhibition in mammalian cells.
    Keywords:  ATP synthase inhibition; GEMMs; ISR; UCP1; genetically encoded tools for manipulation of metabolism; integrated stress response,; mitochondrial membrane potential; ΔΨm
    DOI:  https://doi.org/10.1016/j.chembiol.2025.03.007
  5. Am J Physiol Regul Integr Comp Physiol. 2025 Apr 18.
    GL261 glioblastoma induces delayed body weight gain and stunted skeletal muscle growth in young mice.
    Joshua R Huot, Nicholas A Jamnick, Fabrizio Pin, Patrick D Livingston, Chandler S Callaway, Andrea Bonetto.
       INTRODUCTION: The survival rate for children and adolescents has increased to over 85%. However, there is limited understanding of the impact of pediatric cancers on muscle development and physiology. Given that brain tumors alone account for 26% of all pediatric cancers, this study aimed to investigate the skeletal muscle consequences of tumor growth in young mice.
    METHODS: C2C12 myotubes were co-cultured with GL261 murine glioblastoma cells to assess myotube size. GL261 cells were then injected subcutaneously into 4-week-old male C57BL/6J mice. Animals were euthanized 28 days post-GL261 implantation. Muscle function was tested in vivo and ex vivo. Muscle protein synthesis was estimated via the SUnSET method, and gene/protein expression levels were assessed via Western blotting and qPCR.
    RESULTS: In vitro, the C2C12 cultures exposed to GL261 exhibited myotube atrophy, consistent with a disrupted anabolic/catabolic balance. In vivo, carcass, heart, and fat mass were significantly reduced in the tumor-bearing mice. Skeletal muscle growth was impeded in the GL261 hosts, along with smaller muscle CSA. Both in vivo muscle torque and the ex vivo EDL muscle force were unchanged. At molecular level, the tumor hosts displayed reduced estimations of muscle protein synthesis and increased muscle protein ubiquitination, in disagreement with decreased muscle ubiquitin ligase mRNA expression.
    CONCLUSIONS: Overall, we showed that GL261 tumors impact the growth of pediatric mice by stunting skeletal muscle development, decreasing muscle mass, reducing muscle fiber size, diminishing muscle protein synthesis, and altering protein catabolism signaling.
    Keywords:  animal model; bone; cachexia; cancer; glioblastoma; muscle
    DOI:  https://doi.org/10.1152/ajpregu.00035.2025
  6. Nutrients. 2025 Apr 04. pii: 1268. [Epub ahead of print]17(7):
    Investigating the Therapeutic Potential of the Ketogenic Diet in Modulating Neurodegenerative Pathophysiology: An Interdisciplinary Approach.
    Iqra Shabbir, Keying Liu, Bakhtawar Riaz, Muhammad Farhan Rahim, Saiyi Zhong, Jude Juventus Aweya, Kit-Leong Cheong.
      The ketogenic diet (KD) is a dietary intervention comprising a high-fat, low-carbohydrate, and moderate-protein intake designed to induce a metabolic state known as ketosis, whereby ketone bodies are produced as an alternative source of energy. Initially established as a treatment for intractable epilepsy, the KD has subsequently gained significant attention for its potential to manage neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease. Ketone bodies, such as beta-hydroxybutyrate (BHB), have been demonstrated to possess neuroprotective properties. The increasing prevalence of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, poses a significant public health challenge worldwide. With neurological disorders being the second-leading cause of death globally, the need for effective therapeutic interventions has never been more urgent. Recent evidence suggests that dietary interventions, particularly the ketogenic diet, offer promising potential in mitigating the progression of these diseases by influencing metabolic processes and providing neuroprotective benefits. The ketogenic diet, characterized by high-fat and low-carbohydrate intake, induces ketosis, leading to the production of ketone bodies like beta-hydroxybutyrate, which enhance mitochondrial efficiency, reduce oxidative stress, and modulate inflammatory pathways-mechanisms critical in neurodegenerative pathophysiology. This review explores the role of the ketogenic diet in managing neurological conditions, examining its mechanisms of action, historical context, and therapeutic efficacy. The paper also discusses emerging evidence linking the ketogenic diet to improved cognitive function, reduced motor symptoms, and enhanced mitochondrial activity in patients with neurodegenerative disorders. Additionally, the review highlights the need for further research to refine the therapeutic applications of the ketogenic diet, investigate its impact on various neurodegenerative diseases, and better understand its potential long-term effects. This study underscores the importance of nutrition as a vital aspect of the treatment strategy for neurological diseases, advocating for continued exploration of dietary interventions to improve brain health and function.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; beta-hydroxybutyrate; cognitive function; ketogenic diet; mitochondrial function; neurodegenerative diseases; neuroprotection
    DOI:  https://doi.org/10.3390/nu17071268
  7. Front Nutr. 2025 ;12 1551822
    Dietary nutrient intake and cancer presence: evidence from a cross-sectional study.
    Youjia Qin, Liu Chen, Zilong Zhao, Yuguan Li, Xuan Tian, Mingqian Feng, Jing Tang, Kangkang Ji.
       Background: While the role of specific nutrients in cancer is established, associations between comprehensive between dietary nutrient intake and cancer presence remain underexplored. This cross-sectional study investigates global dietary nutrient profiles in relation to solid and blood cancers.
    Methods: A total of 42,732 mobile adults from the National Health and Nutrition Examination Survey (NHANES, 2001-2023) were enrolled in this study. The potential associations of dietary intakes of 34 nutrients and 4 common trace components with cancer presence were investigated by weighted logistic regression and restricted cubic spline.
    Results: Higher intake of saturated fatty acid (OR = 1.1082, 95% CI: 1.0110-1.2146), β-carotene (OR = 1.0431, 1.0096-1.0777) and vitamin K (OR = 1.0370, 1.0094-1.0654) was positively associated with overall cancer presence, while phosphorus intake (OR = 0.9016, 0.8218-0.9892) showed a protective association. For solid tumors, dietary intakes of saturated fatty acid (OR = 1.1099), α-carotene (OR = 1.0353), β-carotene (OR = 1.0484), and vitamin K (OR = 1.0405) exhibited positive associations. Retinol intake was linked to blood carcinoma (OR = 1.0935, 1.0222-1.1698). Dose-response analyses revealed linear relationships without non-linear thresholds.
    Conclusion: Specific dietary nutrients, notably saturated fats, carotenoids, and vitamin K, are associated with increased cancer presence, whereas phosphorus intake is associated with the reduced cancer presence. Due to the cross-sectional nature of the study and the measurement of dietary intake after cancer diagnosis, a causal relationship could not be established. These findings underscore the need for longitudinal studies to establish causality and inform dietary interventions in cancer management.
    Keywords:  NHANES; blood cancer; cancer; dietary nutrient intake; solid cancer
    DOI:  https://doi.org/10.3389/fnut.2025.1551822
  8. bioRxiv. 2025 Apr 06. pii: 2025.04.04.645324. [Epub ahead of print]
    Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas.
    Christian Felipe Ruiz, Xiangyu Ge, Rylee McDonnell, Sherry S Agabiti, Daniel C McQuaid, Andy Tang, Meera Kharwa, Jennifer Goodell, Rocío Del M Saavedra-Peña, Allison Wing, Guangtao Li, Natasha Pinto Medici, Marie E Robert, Rohan R Varshney, Michael C Rudolph, Fred S Gorelick, John Wysolmerski, Daniel Canals, John D Haley, Matthew S Rodeheffer, Mandar Deepak Muzumdar.
      High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras -driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.
    DOI:  https://doi.org/10.1101/2025.04.04.645324
  9. Nat Cancer. 2025 Apr 18.
    UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.
    Amy X Xie, Wesley Tansey, Ed Reznik.
      Comprehensively studying metabolism requires metabolite measurements. Such measurements, however, are often unavailable in large cohorts of tissue samples. To address this basic barrier, we propose a Bayesian framework ('UnitedMet') that leverages RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. UnitedMet is equally capable of imputing whole pool sizes and outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying an association between BAP1 and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to anti-angiogenic therapy and that kidney cancer metastases demonstrate elevated oxidative phosphorylation. UnitedMet provides a scalable tool for assessing metabolic phenotypes when direct measurements are infeasible, facilitating unexplored avenues for metabolite-focused hypothesis generation.
    DOI:  https://doi.org/10.1038/s43018-025-00943-0
  10. Free Radic Biol Med. 2025 Apr 11. pii: S0891-5849(25)00227-8. [Epub ahead of print]
    3-Bromopyruvate boosts the effect of chemotherapy in acute myeloid leukemia by a pro-oxidant mechanism.
    Joana Pereira-Vieira, Sara Granja, Sónia Pires Celeiro, Catarina Barbosa-Matos, Ana Preto, Odília Queirós, Young Hee Ko, Margarida Casal, Fátima Baltazar.
      Acute myeloid leukemia (AML) comprises a diverse group of blood cancers with varying genetic, phenotypic, and clinical traits, making development of targeted therapy challenging. Metabolic reprogramming in AML has been described as relevant for chemotherapy effectiveness. 3-Bromopyruvate (3-BP) is an anticancer agent that undermines energy metabolism of cancer cells. However, the effect of 3-BP in hematologic malignancies, such as AML, needs further investigation. Thus, we aimed to explore 3-BP as a chemo-sensitizing agent in AML. Different approaches of combining 3-BP with classical chemotherapy (daunorubicin and cytarabin) were tested in diverse AML cell lines. Cell sensitivity to the different drug combinations was analyzed by Trypan blue staining. The effect of pre-treatment with a non-toxic concentration of 3-BP was assessed on the AML cell metabolic profile (Western blot and immunofluorescence), mitochondrial activity (cytometry flow), and antioxidant capacity (colorimetric detection kit). KG-1 and MOLM13 cells showed increased sensitivity to chemotherapy (decreased EC50 values) after exposure to a non-toxic concentration (5 μM) of 3-BP. In both cell lines, 5 μM 3-BP decreased glucose consumption without changing extracellular lactate levels. 5 μM 3-BP treatment increased reactive oxygen species levels and decreased cell antioxidant capacity by depleting reduced glutathione levels in both KG-1 and MOLM13 cells. Our results demonstrate that non-toxic concentrations of 3-BP enhance the effect of classical chemotherapy in AML cells through a pro-oxidant mechanism. These data unveiled a new approach for AML treatment, using 3-BP or other pro-oxidant agents as co-adjuvants of chemotherapy, subsiding chemotherapy-induced side effects.
    Keywords:  Blood Cancer; Cancer Metabolism; Cytarabine; Daunorubicin; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.017
  11. bioRxiv. 2025 Apr 01. pii: 2025.03.29.646096. [Epub ahead of print]
    NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
    Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Tao Dai, Jui-Chung Chiang, Zengfu Shang, Feng Cai, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Ralph J DeBerardinis.
      Cells generate purine nucleotides through both de novo purine biosynthesis (DNPB) and purine salvage. Purine accumulation represses energetically costly DNPB through feedback inhibition of the enzymatic steps that produce the precursor phosphoribosylamine. Excessive DNPB is associated with human diseases including neurological dysfunction and hyperuricemia. However, the mechanisms explaining how cells balance DNPB and purine salvage are incompletely understood. Data from a genome-wide CRISPR loss-of-function screen and extensive stable isotope tracing identified Nudix hydrolase 5 (NUDT5) as a suppressor of DNPB during purine salvage. NUDT5 ablation allows DNPB to persist in the presence of either native purines or thiopurine drugs; this renders NUDT5-deficient cells insensitive to thiopurine treatment. Surprisingly, this regulation occurs independently of NUDT5's known function in hydrolyzing ADP-ribose to AMP and ribose-5-phosphate. Rather, NUDT5 interacts with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in DNPB that generates phosphoribosylamine. Upon induction of purine salvage, the PPAT-NUDT5 interaction is required to trigger disassembly of the purinosome, a cytosolic metabolon involved in efficient DNPB. Mutations that disrupt NUDT5's interaction with PPAT but leave its catalytic activity intact permit excessive DNPB during purine salvage, inducing thiopurine resistance. Collectively, our findings identify NUDT5 as a regulator governing the balance between DNPB and purine salvage, underscoring its impact on nucleotide metabolism and efficacy of thiopurine treatment.
    DOI:  https://doi.org/10.1101/2025.03.29.646096
  12. Bio Protoc. 2025 Apr 05. 15(7): e5257
    Ex Vivo Measurement of Stable Isotope-Labeled Fatty Acid Incorporation Into Phospholipids in Isolated Mice Muscle.
    Tomoki Sato, Shinji Miura.
      With the advancement of liquid chromatography-mass spectrometry (LC-MS/MS), the quantification of glycerophospholipid (PL) molecules has become more accessible, leading to the discovery of numerous enzymes responsible for determining the acyl groups attached to these molecules. Metabolic tracer experiments using radioisotopes and stable isotopes are powerful tools for defining the function of metabolic enzymes and metabolic flux. We have established an ex vivo muscle experimental system using stable isotope-labeled fatty acids to evaluate fatty acid incorporation into PL molecules. Here, we describe a method to incorporate fatty acids with stable isotope labels into excised skeletal muscle and detect the PL molecules containing labeled acyl chains by LC-MS/MS. Key features • Quantify the metabolism of fatty acids into phospholipid acyl chains. • Enable measurements in excised muscle samples. • Assess the effects of genetic recombination of acyltransferases.
    Keywords:  Acyl chain; Free-fatty acid; Liquid chromatography–mass spectrometry; Phospholipid; Skeletal muscle; Stable isotope tracer
    DOI:  https://doi.org/10.21769/BioProtoc.5257
  13. Nutr Rev. 2025 Apr 15. pii: nuaf048. [Epub ahead of print]
    Effect of Different Fatty Acid Types on Mitochondrial Dysfunction Associated With Brown and Beige Adipose Tissue.
    Yasmin Alaby Martins Ferreira, Débora Estadella, Luciana Pellegrini Pisani.
      Adipose tissue serves as a dynamic endocrine organ that is pivotal in metabolic regulation. Augmenting mitochondrial activity within this tissue holds promise in combating obesity. Mitochondrial function is intricately modulated by diverse fatty acid compositions. This comprehensive review aimed to elucidate the molecular mechanisms underlying mitochondrial dysfunction induced by various fatty acid profiles. While saturated fatty acids (SFAs) pose a threat to mitochondrial integrity, polyunsaturated fatty acids (PUFAs), notably n-3, mitigate SFA-induced damage, concurrently regulating thermogenic gene expression. With regard to monounsaturated fatty acids (MUFAs), their impact on mitochondrial function in adipose tissue remains relatively unexplored. Although human studies are imperative for comprehensive insights, prioritizing the consumption of n-3 fatty acids and MUFAs has emerged as a strategic approach, potentially enhancing mitochondrial biogenesis and metabolic pathways. This synthesis underscores the critical need for further investigation of the differential effects of fatty acid types on adipose tissue mitochondria, offering potential avenues for obesity intervention.
    Keywords:  adipose tissue; fatty acids; mitochondrial biogenesis; oxidative phosphorylation
    DOI:  https://doi.org/10.1093/nutrit/nuaf048
  14. J Biol Chem. 2025 Apr 16. pii: S0021-9258(25)00359-X. [Epub ahead of print] 108510
    MitoSNO inhibits mitochondrial hydrogen peroxide (mtH2O2) generation by α-ketoglutarate dehydrogenase (KGDH).
    Olivia Chalifoux, Samantha Sterman, Ben Faerman, Meijing Li, Stephanie Trezza, Marek Michalak, Luis B Agellon, Ryan J Mailloux.
      Here, we demonstrate mitochondrial hydrogen peroxide (mtH2O2) production by α-ketoglutarate dehydrogenase (KGDH) can be inhibited by MitoSNO, alleviating lipotoxicity. MitoSNO in the nanomolar range inhibits mtH2O2 by ∼50% in isolated liver mitochondria without disrupting respiration, whereas the mitochondria-selective derivative used to synthesize MitoSNO, mitochondria-selective N-acetyl-penicillamine (MitoNAP), had no effect on either mtH2O2 generation or oxidative phosphorylation (OxPhos). Additionally, mtH2O2 generation in isolated liver mitochondria was almost abolished when MitoSNO was administered in the low micromolar range. The potent inhibitory effect of MitoSNO was comparable to 2-keto-3-methyl-valeric acid (KMV) and valproic acid (VA), selective inhibitors for KGDH-mediate mH2O2 production. S1QEL 1.1 (S1) and S3QEL (S3), which are known to selectively suppress mtH2O2 genesis through inhibition of complex I and complex III respectively, without disrupting respiration, had little to no effect on mtH2O2 production by liver mitochondria. We also identified it was a major mtH2O2 source as well but MitoSNO and MitoNAP did not affect mtH2O2 production by this ETC-linked enzyme. The MitoSNO also suppressed mtH2O2 production and partially rescued mitochondrial respiration in Huh-7 cells subjected to palmitate (PA) and fructose (Fruc) induced lipotoxicity. MitoSNO also prevented cell death and abrogated intrahepatic lipid accumulation in these Huh-7 cells. MitoSNO nullified mtH2O2 overgeneration and partially rescued OxPhos in liver mitochondria from mice fed a high fat diet (HFD). Our findings demonstrate that MitoSNO interferes with mtH2O2 production through KGDH S-nitrosation and may be useful in alleviating non-alcoholic fatty liver disease (NAFLD).
    DOI:  https://doi.org/10.1016/j.jbc.2025.108510
  15. Cancers (Basel). 2025 Mar 28. pii: 1138. [Epub ahead of print]17(7):
    Impact of Venetoclax Treatment Schedule on Hematologic Recovery and Treatment Response in AML Patients Unfit for Intensive Chemotherapy.
    Anja Schüpbach, Dilara Akhoundova, Ulrike Bacher, Henning Nilius, Michèle Hoffmann, Carlo R Largiadèr, Yolanda Aebi, Michael Hayoz, Marie-Noëlle Kronig, Thomas Pabst.
      (1) Background: The combination of venetoclax and hypomethylating agents (HMAs) is a standard first-line regimen for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Since venetoclax-HMAs are usually administered until progression and delayed hematologic recovery is one of the limiting toxicities, cyclic administration including 7-14-day breaks is recommended. However, whether longer venetoclax schedules lead to higher response rates and how venetoclax pharmacokinetics correlate with toxicity and efficacy remains unclarified. In this single-center retrospective study, we analyzed how venetoclax plasma levels and treatment duration impact hematologic toxicity and treatment responses. (2) Methods: We analyzed the safety and efficacy of venetoclax-HMA combination regimens in a cohort of AML patients unfit for intensive chemotherapy treated at our institution between June 2020 and September 2023. The primary endpoint was the correlation between venetoclax plasma levels or administration schedule with hematologic recovery after the first cycle. Secondary endpoints included the following clinical outcomes: correlation with complete response (CR) status, progression-free survival, and overall survival. (3) Results: Within our cohort of 75 AML patients, we found no correlation between venetoclax plasma peak and trough levels, or venetoclax treatment duration (≤ or >14 days), and hematologic toxicity. Patients receiving shorter venetoclax schedules (≤14 days) had similar CR rates compared to patients treated with longer schedules. (4) Conclusions: Our results suggest that shorter (≤14 days) venetoclax schedules may have no negative impact on tumor responses in AML patients receiving venetoclax and HMA combinations. However, prospective validation studies would be required to confirm these findings.
    Keywords:  acute myeloid leukemia (AML); complete response rate; efficacy; hematologic toxicity; pharmacokinetics; treatment duration; venetoclax
    DOI:  https://doi.org/10.3390/cancers17071138
  16. Antioxidants (Basel). 2025 Feb 26. pii: 269. [Epub ahead of print]14(3):
    Six-Day Fasting Causes Temporary Increases in Both Antioxidant Capacity and Oxidative Stress in Healthy Young Men: A Randomized Controlled Trial.
    Marius Brazaitis, Katerina Židonienė, Nerijus Eimantas, Rima Solianik.
      The impact of prolonged fasting on human oxidative stress (OS) levels and antioxidant defence mechanisms remains poorly understood. The aim of this current study was to investigate the redox response to a 6-day fast in a cohort of healthy men. Twenty-six participants were randomly allocated to a 6-day complete fasting or a control trial. Sympathetic activity, substrate oxidation, redox status, blood glucose, ketones, and testosterone concentrations were assessed. Throughout the fasting period, ketone concentration and fat oxidation increased, and carbohydrate oxidation and glucose and testosterone concentrations decreased. Heart rate increased on fasting days 2 and 4 and returned to the pre-fasting level on fasting day 6. Malondialdehyde (MDA) concentration increased after fasting days 4 and 6, and this increase was accompanied by an increase in the total antioxidant capacity (TAC), but the TAC/MDA ratio remained constant. Notably, all fasting-evoked changes returned to the baseline values after resumption of the regular diet. Thus, prolonged fasting activated both antioxidant defence and OS, but the redox balance was maintained. Consistent with this response, ketone concentration and sympathetic nervous system activity increased, and testosterone concentration decreased. These variables returned to the pre-fasting state after resumption of the usual eating habits.
    Keywords:  males; malondialdehyde; oxidative status; starvation; total antioxidant capacity
    DOI:  https://doi.org/10.3390/antiox14030269
  17. Expert Rev Hematol. 2025 Apr 17.
    Real-world (RW) study of outcomes for acute myeloid leukemia (AML) patients treated with glasdegib or venetoclax in US community oncology practices.
    Kristin M Zimmerman Savill, Jonathan K Kish, Choo Hyung Lee, Prathamesh Pathak, Paul D'Amico, Alexander Russell-Smith, Ajeet Gajra.
       BACKGROUND: Glasdegib (GLAS) and venetoclax (VEN) are approved in the US for treating AML in patients aged 75+ or with comorbidities precluding intensive induction chemotherapy. Community oncology outcomes for these therapies are limited.
    RESEARCH DESIGN AND METHODS: This retrospective chart review summarized characteristics, treatment patterns, and outcomes of US patients treated with first-line (1 L) GLAS or VEN for AML using descriptive statistics. The study was not designed or powered to compare GLAS and VEN cohorts.
    RESULTS: Among 50 patients receiving 1 L GLAS (82.0% with low-dose cytarabine), 50.0% achieved complete remission (CR), morphological leukemia-free state (MLFS), or partial response (PR). Median overall survival (OS) was 6.9 months (95% CI: 5.4-8.9). A trial-matched GLAS cohort represented 80.0% of all GLAS-treated patients in the study. Among 83 patients receiving 1 L VEN (94.0% with a hypomethylating agent), 51.8% achieved CR, MLFS, or PR, median OS was 8.4 months (95% CI: 5.7-16.2), and 31.3% met pivotal trial eligibility criteria.
    CONCLUSIONS: This observational study supports the clinical benefit of GLAS and VEN in treating AML patients in the real-world setting.
    Keywords:  AML; BCL-2; RWE; glasdegib; hedgehog; venetoclax
    DOI:  https://doi.org/10.1080/17474086.2025.2492886
  18. Front Nutr. 2025 ;12 1561251
    Associations between vitamins intake and risk of cancer in United States adults: 2003 to 2016 national health and nutrition examination survey.
    Youfei Wen, Xiuzhen Yang, Yan Huang.
       Introduction: National Health and Nutrition Examination Survey (NHANES) is a cross-sectional survey that gathered information about people's health and nutrition. The aim of this study is to investigate potential associations between vitamin intake and cancer risk using this database.
    Methods: The NHANES data set encompassed a wide range of variables, including vitamins, cancer, and others. Logistic regression models, restricted cubic splines (RCS) and subgroup analysis were used to test the potential link between vitamin consumption and cancer risk.
    Results: In total, 29, 138 individuals were included in this study, while 2,924 of them had a diagnosis of cancer. The odds of developing cancer were reduced for persons consuming the highest quartile of dietary niacin compared to those consuming the lowest quartile [odds ratio (OR) = 0.78, 95% confidence range = 0.65, 0.95, p = 0.015]. However, after adjusting for all confounding factors, as the intake of vitamin A gradually increased, the risk of tumor occurrence correspondingly increased (OR = 1.38, 95% CI 1.13, 1.69, p = 0.002). Subgroup analysis and RCS models showed similar results. Only when the intake of folic acid is 267-367 mcg, folic acid is positively correlated with the risk of tumors. Vitamins E, B1, B2, B6, B12, C, K, alpha-carotene and beta-carotene were not associated with the risk of tumor development.
    Conclusion: Vitamin A intake is positively correlated with the occurrence of tumors, while niacin intake is negatively correlated with the incidence of tumors. Further longitudinal studies are needed to verify these findings.
    Keywords:  NHANES; cancer; niacin; vitamin A; vitamins
    DOI:  https://doi.org/10.3389/fnut.2025.1561251
  19. Geroscience. 2025 Apr 12.
    Exercise and survival benefit in cancer patients: evidence from a comprehensive meta-analysis.
    Zoltan Ungvari, Mónika Fekete, Péter Varga, Gyöngyi Munkácsy, János Tibor Fekete, Andrea Lehoczki, Annamaria Buda, Csaba Kiss, Anna Ungvari, Balázs Győrffy.
      Cancer remains a major global health challenge, and growing evidence suggests that physical activity is a key modifiable factor that may improve survival outcomes in cancer patients. However, a comprehensive, large-scale synthesis of the effects of post-diagnosis physical activity across multiple cancer types remains lacking. This meta-analysis aims to systematically evaluate the association between physical activity and survival in patients diagnosed with breast, lung, prostate, colorectal, and skin cancers. We conducted a comprehensive search in PubMed, Web of Science, Scopus, and Cochrane Library for studies on physical activity and cancer survival. Eligible studies (January 2000-November 2024) included adults (≥ 18 years) with breast, lung, prostate, colorectal, or skin cancer. Only prospective cohort and case-control studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall or cancer-specific mortality were included, with a minimum sample size of 100 and at least six months of follow-up. Meta-analysis was performed using metaanalysisonline.com, applying random-effects models and assessing heterogeneity via the I2 statistic. Sensitivity analyses and publication bias (Egger's test, funnel plots) were evaluated. The meta-analysis included 151 cohorts with almost 1.5 million cancer patients. Post-diagnosis physical activity was associated with significantly lower cancer-specific mortality across all five cancer types. The greatest benefit was observed in breast cancer, with a pooled hazard ratio (HR) of 0.69 (95% CI: 0.63-0.75), followed by prostate cancer (HR: 0.73, 95% CI: 0.62-0.87). Lung cancer patients who engaged in physical activity had a 24% lower risk of cancer-specific death (HR: 0.76, 95% CI: 0.69-0.84), while colorectal cancer patients experienced a similar benefit (HR: 0.71, 95% CI: 0.63-0.80). In skin cancer, physical activity was associated with a non-significant reduction in mortality (HR: 0.86, 95% CI: 0.71-1.05). These findings provide robust evidence supporting the survival benefits of post-diagnosis physical activity in cancer patients, particularly for breast, prostate, lung, and colorectal cancers. The results underscore the potential for incorporating structured physical activity interventions into oncological care to improve long-term patient outcomes.
    Keywords:  Breast cancer; Colorectal cancer; Lung cancer; Physical activity; Prostate cancer; Skin cancer; Survival
    DOI:  https://doi.org/10.1007/s11357-025-01647-0
  20. Biosystems. 2025 Apr 15. pii: S0303-2647(25)00071-1. [Epub ahead of print] 105461
    Field guide to Nath's research work on ATP synthesis and hydrolysis.
    Victor Wray.
      Adenosine triphosphate (ATP) is the universal biological energy source that participates in the most prevalent chemical reactions in all cell life through the vital processes of oxidative phosphorylation (OXPHOS) and photosynthesis. Its synthesis and utilisation is an area of basic research that has seen significant progress over the last three decades. A series of Nath's publications in the 1990s culminated in a detailed description of the molecular mechanism of ATP synthesis in the FO and F1 portions of FOF1-ATP synthase in which energy from transmembrane ion gradients in FO are converted into chemical energy of ATP in F1. Subsequent papers provided a thorough theoretical basis and exploration of the validity of the new theory-named by other authors as Nath's torsional mechanism of energy transduction and ATP synthesis and Nath's two-ion theory of energy coupling. Violation of several physical laws by previous theories have been dealt with in considerable detail. In particular he has reevaluated the extensive literature on ATP hydrolysis and provides a rigorously argued tri-site molecular mechanism involving the three filled β-catalytic sites during hydrolysis by FO F1/F1-ATPase. Numerous applications have been proposed throughout his work that has resulted in four substantial publications dealing with re-interpretation of the Warburg Effect in cancer cells and a trilogy of papers dealing with biological thermodynamics of ATP synthesis applied to problems in comparative physiology, biochemistry and ecology. Finally strict mathematical methods have opened up new approaches to validate mechanistic events in ATP synthesis/hydrolysis. Here we provide a field guide for easy access to the different aspects of this body of work.
    Keywords:  ATP hydrolysis; ATP synthesis; Bioenergetics; F(O)F(1)-ATP synthase; Fourth law of thermodynamics; Metabolic scaling; Molecular mechanism; Molecular motors; Muscle contraction; Oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.1016/j.biosystems.2025.105461
  21. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 10. pii: S0925-4439(25)00184-X. [Epub ahead of print] 167839
    Mitochondrial classic metabolism and its often-underappreciated facets.
    João P Moura, Paulo J Oliveira, Ana M Urbano.
      For many decades, mitochondria were essentially regarded as the main providers of the adenosine triphosphate (ATP) required to maintain the viability and function of eukaryotic cells, thus the widely popular metaphor "powerhouses of the cell". Besides ATP generation - via intermediary metabolism - these organelles have also traditionally been known, albeit to a lesser degree, for their notable role in biosynthesis, both as generators of biosynthetic intermediates and/or as the sites of biosynthesis. From the 1990s onwards, the concept of mitochondria as passive organelles providing the rest of the cell, from which they were otherwise isolated, with ATP and biomolecules on an on-demand basis has been challenged by a series of paradigm-shifting discoveries. Namely, it was shown that mitochondria act as signaling effectors to upregulate ATP generation in response to growth-promoting stimuli and that they are actively engaged, through signaling and epigenetics, in the regulation of a plethora of cellular processes, ultimately deciding cell function and fate. With the focus of mitochondrial research increasingly placed in these "non-classical" functions, the centrality of mitochondrial intermediary metabolism to biosynthesis and other mitochondrial functions tends to be overlooked. In this article, we revisit mitochondrial intermediary metabolism and illustrate how its intermediates, by-products and molecular machinery underpin other mitochondrial functions. A certain emphasis is given to frequently overlooked functions, namely the biosynthesis of iron‑sulfur (FeS) clusters, the only known function shared by all mitochondria and mitochondrion-related organelles. The generation of reactive oxygen species (ROS) and their putative role in signaling is also discussed in detail.
    Keywords:  Educational article; Intermediary metabolism; Iron‑sulfur clusters; Metabolic energy; Mitochondrion-related organelles; ROS signaling
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167839
  22. Nature. 2025 Apr 16.
    Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.
    Malgorzata Gozdecka, Monika Dudek, Sean Wen, Muxin Gu, Richard J Stopforth, Justyna Rak, Aristi Damaskou, Guinevere L Grice, Matthew A McLoughlin, Laura Bond, Rachael Wilson, George Giotopoulos, Vijaya Mahalingam Shanmugiah, Rula Bany Bakar, Eliza Yankova, Jonathan L Cooper, Nisha Narayan, Sarah J Horton, Ryan Asby, Dean C Pask, Annalisa Mupo, Graham Duddy, Ludovica Marando, Theodoros Georgomanolis, Paul Carter, Amirtha Priya Ramesh, William G Dunn, Clea Barcena, Paolo Gallipoli, Kosuke Yusa, Slavé Petrovski, Penny Wright, Pedro M Quiros, Christian Frezza, James A Nathan, Arthur Kaser, Siddhartha Kar, Konstantinos Tzelepis, Jonathan Mitchell, Margarete A Fabre, Brian J P Huntly, George S Vassiliou.
      Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.
    DOI:  https://doi.org/10.1038/s41586-025-08980-6
  23. Glia. 2025 Apr 16.
    Starvation Induces Upregulation of Monocarboxylate Transport in Glial Cells at the Drosophila Blood-Brain Barrier.
    Andrés González-Gutiérrez, Jorge Gaete, Andrés Esparza, Andrés Ibacache, Esteban G Contreras, Jimena Sierralta.
      Living organisms can sense and adapt to constant changes in food availability. Maintaining a homeostatic supply of energy molecules is crucial for animal survival and normal organ functioning, particularly the brain, due to its high-energy demands. However, the mechanisms underlying brain adaptive responses to food availability have not been completely established. The nervous system is separated from the rest of the body by a physical barrier called the blood-brain barrier (BBB). In addition to its structural role, the BBB regulates the transport of metabolites and nutrients into the nervous system. This regulation is achieved through adaptive mechanisms that control the transport of nutrients, including glucose and monocarboxylates such as lactate, pyruvate, and ketone bodies. In Drosophila melanogaster, carbohydrate transporters increase their expression in glial cells of the BBB in response to starvation. However, changes in the expression or activity of Drosophila monocarboxylate transporters (dMCTs) at the BBB have not yet been reported. Here, we show that neuronal ATP levels remain unaffected despite reduced energy-related metabolites in the hemolymph of Drosophila larvae during starvation. Simultaneously, the transport of lactate and beta-hydroxybutyrate increases in the glial cells of the BBB. Using genetically encoded sensors, we identified Yarqay as a proton-coupled monocarboxylate transporter whose expression is upregulated in the subperineurial glia of the BBB during starvation. Our findings reveal a novel component of the adaptive response of the brain to starvation: the increase in the transport of monocarboxylates across the BBB, mediated by Yarqay, a novel dMCT enriched in the BBB.
    Keywords:   Drosophila melanogaster ; blood–brain barrier; brain energy metabolism; genetically encoded sensors; monocarboxylate transporters; subperineurial glial cells
    DOI:  https://doi.org/10.1002/glia.70021
  24. Cell Rep. 2025 Apr 16. pii: S2211-1247(25)00362-6. [Epub ahead of print]44(5): 115591
    Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.
    Mohsin Rahim, Tomasz K Bednarski, Clinton M Hasenour, Deveena R Banerjee, Irina Trenary, Jamey D Young.
      We present an isotope-based metabolic flux analysis (MFA) approach to simultaneously quantify metabolic fluxes in the liver, heart, and skeletal muscle of individual mice. The platform was scaled to examine metabolic flux adaptations in age-matched cohorts of mice exhibiting varying levels of chronic obesity. We found that severe obesity increases hepatic gluconeogenesis and citric acid cycle flux, accompanied by elevated glucose oxidation in the heart that compensates for impaired fatty acid oxidation. In contrast, skeletal muscle fluxes exhibit an overall reduction in substrate oxidation. These findings demonstrate the dichotomy in fuel utilization between cardiac and skeletal muscle during worsening metabolic disease and demonstrate the divergent effects of obesity on metabolic fluxes in different organs. This multi-tissue MFA technology can be extended to address important questions about in vivo regulation of metabolism and its dysregulation in disease, which cannot be fully answered through studies of single organs or isolated cells/tissues.
    Keywords:  CP: Metabolism; cardiac metabolism; fluxomics; isotope labeling; liver metabolism; metabolic flux analysis; metabolomics; muscle metabolism; obesity; steatotic liver disease; systems biology
    DOI:  https://doi.org/10.1016/j.celrep.2025.115591
  25. JCI Insight. 2025 Apr 17. pii: e187083. [Epub ahead of print]
    Ceramide(d18:1/18:1)-Ndufa6 Interaction Inactivates Respiratory Complex I to Attenuate Oxidative-stress-driven Pathogenesis in Liver Ischemia/Reperfusion Injury.
    Kai Wang, Leyi Liao, Hanbiao Liang, Pengxiang Huang, Qingping Li, Baoxiong Zhuang, Chen Xie, Xiangyue Mo, Xuesong Deng, Jieyuan Li, Yang Lei, Minghui Zeng, Cungui Mao, Ruijuan Xu, Cuiting Liu, Xianqiu Wu, Jie Zhou, Biao Wang, Yiyi Li, Chuanjiang Li.
      Oxidative stress driven by malfunctioning respiratory complex I (RC-I) is a crucial pathogenic factor in liver ischemia/reperfusion (I/R) injury. This study investigates the role of alkaline ceramidase 3 (ACER3) and its unsaturated long-chain ceramide (CER) substrates in regulating liver I/R injury through RC-I. Our findings demonstrated that I/R upregulated ACER3/Acer3 and decreased unsaturated long-chain CER levels in human and mouse livers. Both global and hepatocyte-specific Acer3 ablation, as well as treatment with CER(d18:1/18:1), led to a significant increase of CER(d18:1/18:1) levels in the liver, which mitigated the I/R-induced hepatocyte damage and inflammation in mice. Mechanistically, Acer3 modulated CER(d18:1/18:1) levels in mitochondria-associated membranes and endoplasmic reticulum (ER), thereby influencing the transport of CER(d18:1/18:1) from ER to mitochondria. Acer3 ablation and CER(d18:1/18:1) treatment elevated CER(d18:1/18:1) in mitochondria, where CER(d18:1/18:1) bound to the RC-I subunit Ndufa6 to inactivate RC-I and reduced reactive oxygen species production in the I/R-injured mouse liver. These findings underscore the role of CER(d18:1/18:1)-Ndufa6 interaction in suppressing RC-I-mediated oxidative-stress-driven pathogenesis in liver I/R Injury.
    Keywords:  Cell stress; Hepatology; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.187083
  26. BMC Cancer. 2025 Apr 17. 25(1): 716
    GLUT1 inhibition by BAY-876 induces metabolic changes and cell death in human colorectal cancer cells.
    Masato Hayashi, Keishi Nakamura, Shinichi Harada, Mariko Tanaka, Akiko Kobayashi, Hiroto Saito, Toshikatsu Tsuji, Daisuke Yamamoto, Hideki Moriyama, Jun Kinoshita, Noriyuki Inaki.
       BACKGROUND: Glucose transporter 1 (GLUT1) is known to play a crucial role in glucose uptake in malignant tumors. GLUT1 inhibitors reportedly exhibit anti-tumor effects by suppressing cancer cell proliferation. BAY-876, a selective GLUT1 inhibitor, has been shown to inhibit tumor growth in ovarian and breast cancers. In this study, we investigated the anti-proliferative effects of BAY-876 treatment in human colorectal cancer (CRC) cell lines.
    METHODS: We investigated the metabolic changes and effects on proliferation from BAY-876 treatment in HCT116, DLD1, COLO205, LoVo, and Caco-2 cells in vitro. Additionally, a mouse xenograft model was established using HCT116 cells to examine the tumor-inhibitory effects of BAY-876 treatment in vivo.
    RESULTS: BAY-876 treatment inhibited cell proliferation in HCT116, DLD1, COLO205, and LoVo cells. Reduced GLUT1 protein expression levels were observed through western blot analysis. Flux analysis indicated enhanced mitochondrial respiration, accompanied by increased reactive oxygen species levels and apoptosis rates. Tumor-inhibitory effects were also observed in the xenograft model, with the BAY-876-treated groups showing GLUT1 suppression.
    CONCLUSIONS: BAY-876 treatment induced metabolic changes and inhibited cell proliferation in human CRC cell lines. Using BAY-876 is a potential novel approach for treating CRC.
    Keywords:  Apoptosis; BAY-876; Colorectal cancer; Glucose transporter 1
    DOI:  https://doi.org/10.1186/s12885-025-14141-9
  27. bioRxiv. 2025 Apr 02. pii: 2025.03.28.645975. [Epub ahead of print]
    Lack of consistent effect of dietary fiber on immune checkpoint blockade efficacy across diverse murine tumor models.
    Asael Roichman, Gabriela Reyes-Castellanos, Ziqing Chen, Zihong Chen, Sarah J Mitchell, Michael R MacArthur, Akshada Sawant, Llewelyn Levett, Jesse Powers, Maria Gomez, Maria Ibrahim, Xincheng Xu, Beianka Tomlinson, Xiang Hang, Yong Wei, Yibin Kang, Eileen White, Joshua D Rabinowitz.
      Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain low in most cancers. Recent research suggest that dietary fiber enhances ICB response in melanoma patients and murine preclinical models through microbiome-dependent mechanisms. Yet, the robustness of this effect across cancer types and dietary contexts remains unclear. Specifically, prior literature compared grain-based chow (high fiber) to low-fiber purified diet, but these diets differ also on other dimensions including phytochemicals. Here we investigated, in mice fed grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin), metabolite levels and ICB activity in multiple tumor models. The blood and fecal metabolome were relatively similar between mice fed high- and low-fiber purified diets, but differed massively between mice fed purified diets or chow, identifying the factor as diet type, independent of fiber. Tumor growth studies in three implantable and two spontaneous genetically engineered tumor models revealed that fiber has a weaker impact on ICB (anti-PD-1) efficacy than previously reported. In some models, dietary modulation impacted ICB activity, but not in a consistent direction across models. In none of the models did we observe the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high-fiber purified diet but low efficacy in low-fiber purified diet. Thus, dietary fiber appears to have limited or inconsistent effect on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie the clinical correlations between fiber consumption and immunotherapy outcomes.
    DOI:  https://doi.org/10.1101/2025.03.28.645975
  28. J Vis Exp. 2025 Mar 28.
    Analyzing Ex Vivo Metabolic Flux in Splenic and Cardiac Macrophages and Bone Marrow Monocytes.
    Erin B Taylor, Robert W Spitz, Katherine R O'Quinn, Alan J Mouton.
      Metabolic reprogramming is a hallmark of monocyte/macrophage activation and polarization between pro- and anti-inflammatory states. For example, pro-inflammatory (i.e., M1-like) monocytes/macrophages display more reliance on anaerobic glycolysis and less reliance on mitochondrial oxidative phosphorylation, whereas anti-inflammatory (M2-like) macrophages display more reliance on glucose and fatty acid oxidation in the mitochondria. Here, we describe in-depth protocols for extracting macrophages from the two major monocyte/macrophage reservoirs in the body, the spleen and bone marrow, as well as injured tissues such as the heart following myocardial infarction. Macrophages or monocytes are extracted by immunomagnetic sorting by using antibody-tagged microbeads, which easily bind to cells without compromising their phenotypes. The extracted cells are then cultured in 96-well plates, followed by extracellular flux analysis using a metabolic flux analyzer. Both glycolysis and mitochondrial oxidative phosphorylation can be measured simultaneously in small numbers of cells (as little as 2-3 × 105 cells). This method can easily be performed in 1 day and produces reliable and repeatable results. Ultimately, these methods help to enhance our understanding of metabolic changes during immune and inflammatory responses to injury and disease, which could lead to the development of novel therapeutic targets for immunometabolic pathways.
    DOI:  https://doi.org/10.3791/67824
  29. J Cell Sci. 2025 Apr 16. pii: jcs.263925. [Epub ahead of print]
    Approaches to reduce succinate accumulation by restoration of succinate dehydrogenase activity in cultured adrenal cells.
    Fatimah Al Khazal, Leili Rahimi, Fan Feng, Nicole A Becker, Clifford D Folmes, Judith Favier, L James Maher.
      The rare human neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL) can result from loss of mitochondrial succinate dehydrogenase. The resulting succinate accumulation is tumorigenic in certain neuroendocrine cells. Here we explore two theoretical approaches to mitigate tumorigenic succinate accumulation in a cell culture model of PPGL. We first study a gene replacement strategy using transposition technology and conclude that many aspects of mitochondrial morphology, oxidative cell metabolism and succinate accumulation are reversible by this process. We then investigate if riboflavin supplementation has the potential to rescue succinate dehydrogenase activity in the intact SDHA catalytic subunit to suppress succinate accumulation even in the absence of SDHB. We show that this latter strategy is not successful.
    Keywords:  Paraganglioma; Pheochromocytoma; Riboflavin; Succinate dehydrogenase
    DOI:  https://doi.org/10.1242/jcs.263925
  30. J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13781
    Housing Temperature Impacts the Systemic and Tissue-Specific Molecular Responses to Cancer in Mice.
    Andrea Irazoki, Emma Frank, Tang Cam Phung Pham, Jessica L Braun, Amy M Ehrlich, Mark Haid, Fabien Riols, Camilla Hartmann Friis Hansen, Anne-Sofie Rydal Jørgensen, Nicoline Resen Andersen, Laura Hidalgo-Corbacho, Roberto Meneses-Valdes, Mona Sadek Ali, Steffen Henning Raun, Johanne Louise Modvig, Samantha Gallero, Steen Larsen, Zach Gerhart-Hines, Thomas Elbenhardt Jensen, Maria Rohm, Jonas T Treebak, Val Andrew Fajardo, Lykke Sylow.
       BACKGROUND: Cancer cachexia, affecting up to 80% of patients with cancer, is characterized by muscle and fat loss with functional decline. Preclinical research seeks to uncover the molecular mechanisms underlying cachexia to identify potential targets. Housing laboratory mice at ambient temperature induces cold stress, triggering thermogenic activity and metabolic adaptations. Yet, the impact of housing temperature on preclinical cachexia remains unknown.
    METHODS: Colon 26 carcinoma (C26)-bearing and PBS-inoculated (Ctrl) mice were housed at standard (ST; 20°C-22°C) or thermoneutral temperature (TN; 28°C-32°C). They were monitored for body weight, composition, food intake and systemic factors. Upon necropsy, tissues were weighed and used for evaluation of ex vivo force and respiration, or snap frozen for biochemical assays.
    RESULTS: C26 mice lost 7.5% body weight (p = 0.0001 vs. Ctrls), accounted by decreased fat mass (-35%, p < 0.0001 vs. Ctrls), showing mild cachexia irrespective of housing temperature. All C26 mice exhibited reduced force (-40%, p < 0.0001 vs. Ctrls) and increased atrogene expression (3-fold, p < 0.003 vs. Ctrls). Cancer altered white adipose tissue (WAT)'s functional gene signature (49%, p < 0.05 vs. Ctrls), whereas housing temperature reduced brown adipose tissue (BAT)'s (-78%, p < 0.05 vs. ST Ctrl). Thermogenic capacity measured by Ucp1 expression decreased upon cancer in both WAT and BAT (-93% and -63%, p < 0.0044 vs. Ctrls). Cancer-driven glucose intolerance was noted at ST (26%, p = 0.0192 vs. ST Ctrl), but restored at TN (-23%, p = 0.005 vs. ST C26). Circulating FGF21, GDF-15 and IL-6 increased in all C26 mice (4-fold, p < 0.009 vs. Ctrls), with a greater effect on IL-6 at TN (76%, p = 0.0018 vs. ST C26). Tumour and WAT Il6 mRNA levels remained unchanged, while cancer induced skeletal muscle (SkM) Il6 (2-fold, p = 0.0016 vs. Ctrls) at both temperatures. BAT Il6 was only induced in C26 mice at TN (116%, p = 0.0087 vs. ST C26). At the bioenergetics level, cancer increased SkM SERCA ATPase activity at ST (4-fold, p = 0.0108 vs. ST Ctrl) but not at TN. In BAT, O2 consumption enhanced in C26 mice at ST (119%, p < 0.03 vs. ST Ctrl) but was blunted at TN (-44%, p < 0.0001 vs. ST C26). Cancer increased BAT ATP levels regardless of temperature (2-fold, p = 0.0046 vs. Ctrls), while SERCA ATPase activity remained unchanged at ST and decreased at TN (-59%, p = 0.0213 vs. TN Ctrl).
    CONCLUSIONS: In mild cachexia, BAT and SkM bioenergetics are susceptible to different housing temperatures, which influences cancer-induced alterations in glucose metabolism and systemic responses.
    Keywords:  bioenergetics; cancer cachexia; cold‐induced stress; thermogenic tissues; thermoneutrality
    DOI:  https://doi.org/10.1002/jcsm.13781
  31. Nutrients. 2025 Mar 25. pii: 1130. [Epub ahead of print]17(7):
    Time-Restricted Eating Versus Daily Calorie Restriction: Effects on Inflammatory Markers over 12 Months in Adults with Obesity.
    Shuhao Lin, Sofia Cienfuegos, Mark Ezpeleta, Vasiliki Pavlou, Sarah Corapi, Mary-Claire Runchey, Shaina J Alexandria, Lisa Tussing-Humphreys, Krista A Varady.
      Background/Objectives: Obesity is associated with chronic systemic inflammation and elevated levels of inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). Weight loss through lifestyle interventions can reduce inflammation in adults with obesity. Time-restricted eating (TRE) and calorie restriction (CR) are two popular diet interventions that can produce clinically significant weight loss. However, to date, no studies have directly compared the effects of TRE versus CR on inflammatory cytokines in adults with obesity. Methods: Here, we performed a secondary analysis on a recently published study to compare the long-term (12-month) effects of TRE versus CR on key inflammatory cytokines. Results: We found that while TRE and CR produced similar amounts of weight loss (4-5% from baseline), no statistically significant changes in circulating levels of TNF-alpha, IL-6, and CRP were noted in the TRE or CR groups, compared to the controls, by month 12. However, we did observe that circulating CRP levels were positively related to body weight, visceral fat mass, and insulin resistance, while IL-6 and TNF-alpha were not related to any metabolic marker. Conclusions: Thus, TRE and CR may not affect key inflammatory mediators with 4-5% weight loss, but more research is warranted.
    Keywords:  C-reactive protein (CRP); calorie restriction; inflammation; interleukin-6 (IL-6); intermittent fasting; obesity; time-restricted eating; tumor necrosis factor alpha (TNF-alpha); weight loss
    DOI:  https://doi.org/10.3390/nu17071130
  32. J Microbiol Biotechnol. 2025 Apr 10. 35 e2412032
    Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells.
    Dong-Hwan Kim, Dong Joon Kim, Seong-Jun Park, Won-Jun Jang, Chul-Ho Jeong.
      Pancreatic cancer, a leading cause of cancer-related deaths, is characterized by increased dependence on glutamine metabolism. Telaglenastat (CB-839), a glutaminase (GLS) inhibitor targets glutamine metabolism; however, its efficacy as monotherapy is limited owing to metabolic adaptations. In this study, we demonstrated that CB-839 effectively inhibited cell growth in pancreatic cancer cells, but activated the general control nonderepressible 2 (GCN2)-activating transcription factor 4 (ATF4) signaling pathway. ATF4 knockdown reduced glutamine transporter alanine, serine, and cysteine transporter 2 (ASCT2) expression, glutamine uptake, and cell viability under glutamine deprivation-recovery conditions, confirming its protective role in mitigating glutamine-related metabolic stress. Notably, the combination of CB-839 and the ASCT2 inhibitor V-9302 demonstrated a synergistic effect, significantly suppressing pancreatic cancer cell survival. These findings highlight ATF4 and ASCT2 as crucial therapeutic targets and indicate that dual inhibition of GLS and ASCT2 may enhance treatment outcomes for pancreatic cancer.
    Keywords:  ATF4; CB-839; Pancreatic cancer; V-9302; glutamine metabolism
    DOI:  https://doi.org/10.4014/jmb.2412.12032
  33. Cancer Prev Res (Phila). 2025 Apr 15.
    Weight Loss Reverses the Effects of Aging and Obesity on Mammary Tumor Immunosuppression and Progression.
    Laura A Smith, Dalton M Craven, Alyssa N Ho, Elaine M Glenny, Erika T Rezeli, Meredith S Carson, Evan M Paules, Magdalena Fay, Alyssa J Cozzo, Stephen D Hursting, Michael F Coleman.
      Advanced age and obesity are each a major risk factor for breast cancer progression, including triple-negative breast cancer (TNBC). Here we interrogated: a) whether these factors interact to promote TNBC progression, and b) if weight loss mitigates the separate and combined effects of aging and obesity on TNBC. We demonstrate that aging and diet-induced obesity (DIO) interact to promote TNBC growth in mice. Transcriptomic analysis revealed suppression of antitumor immunity in tumors from aged and/or obese mice. Weight loss via intermittent calorie restriction (ICR) reduced tumor growth and restored immune-related gene signatures to reverse the protumor effects of aging and/or obesity. Using publicly available genomic datasets from murine studies of obesity, weight loss, and TNBC, we identified a consensus transcriptomic signature of obesity-driven immunosuppression that predicted survival of patients with breast cancer. This consensus signature was also suppressed by aging, obesity, and their combination. ICR reversed aging and/or obesity effects on the consensus signature. We conclude that aging and obesity interact to limit antitumor immunity and enhance TNBC progression and that these adverse effects can be disrupted by weight loss.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-24-0514
  34. Nutr Rev. 2025 Apr 15. pii: nuaf029. [Epub ahead of print]
    Low-Carbohydrate Diets for the Management of Pediatric Obesity: A Systematic Review and Meta-analysis.
    Elora Fournier, Halim Moore, Zainab S Alghamdi, David Thivel.
       CONTEXT: Although low-carbohydrate (LC) diets have been shown to be beneficial for weight loss and improvements in cardiometabolic health in adults with obesity, their efficacy in youth has not yet been established.
    OBJECTIVES: A systematic review and meta-analysis was conducted to qualitatively and quantitively synthesize the evidence from clinical trials testing the efficacy of LC diets to improve anthropometric and cardiometabolic-related parameters in children and adolescents with obesity.
    DATA SOURCES: Searches in Medline, EMBASE, and Cochrane databases were undertaken for LC interventions with or without control comparisons.
    DATA EXTRACTION AND ANALYSIS: Data before and after the LC intervention and control comparisons (if applicable) were extracted from 19 studies, 17 of which were pooled in random-effects meta-analyses.
    RESULTS: Children on LC diets (Mean = 30 [IQR: 30-60] g/d), for approximately 3 months (IQR: 3-4 months) significantly reduced their weight (mean change [MC] = -7.09 [95% CI: -9.60, -4.58] kg; P < .001), body mass index (BMI) (MC = -3.01 [-3.71, -2.30] kg/m2; P < .001), and BMI z-score (MC = -0.27 [-0.48, -0.06]; P = .020), on average, with concomitant improvements in different metabolic biomarkers, such as serum triglycerides (MC = -29.16 [-45.06, -13.26] mg/dL; P = .002) and insulin (MC = -7.13 [-9.27, -4.99] µU/mL; P < .001). Evidence from 5 out of 7 controlled trials suggests that LC diets without caloric restriction may lead to similar or greater improvements in anthropometric and lipid-related outcomes relative to caloric-restricted or low-fat diets. However, meta-analyses demonstrated high between-study heterogeneity, indicative of a wide variety of methodologies, including intervention duration and degree of carbohydrate restriction.
    CONCLUSION: Overall, this review found that short-term LC diets can be beneficial for weight loss and improving cardiometabolic parameters with or without calorie restriction. However, the limited number of controlled trials and the demonstrable diversity in methods prevent firm conclusions regarding their efficacy relative to traditional approaches, such as energy restriction.
    SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023440835.
    Keywords:  adolescent; children; ketogenic diet; low-carb diet; obesity; weight loss
    DOI:  https://doi.org/10.1093/nutrit/nuaf029
  35. Sci Adv. 2025 Apr 18. 11(16): eadw1489
    Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
    Maximilian Sichrovsky, Denis Lacabanne, Jonathan J Ruprecht, Jessica J Rana, Klaudia Stanik, Mariangela Dionysopoulou, Alice P Sowton, Martin S King, Scott A Jones, Lee Cooper, Steven W Hardwick, Giulia Paris, Dimitri Y Chirgadze, Shujing Ding, Ian M Fearnley, Shane M Palmer, Els Pardon, Jan Steyaert, Vanessa Leone, Lucy R Forrest, Sotiria Tavoulari, Edmund R S Kunji.
      The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.
    DOI:  https://doi.org/10.1126/sciadv.adw1489
  36. EJNMMI Res. 2025 Apr 17. 15(1): 40
    Assessment of early response to neoadjuvant chemotherapy in multi-site high-grade serous ovarian cancer using hyperpolarized-13C MRI.
    Lucian Beer, Vlad Bura, Stephan Ursprung, Ramona Woitek, Mary A McLean, Joo Ern Ang, Mercedes Jimenez-Linan, Andrew B Gill, Joshua Kaggie, Matthew Locke, Amy Frary, Johanna Field-Rayner, Ilse Patterson, Marika Reinius, Martin J Graves, Surrin Deen, Gabriel Funingana, Leonardo Rundo, Andrew Priest, Luigi Aloj, Roido Manavaki, Iosif A Mendichovszky, Fraser Robb, Rolf F Schulte, Dominique-Laurent Couturier, Clive S D'Santos, Valar Franklin, Kamal Kishore, Iris Allajbeu, Carolin Sauer, Ferdia A Gallagher, Kevin M Brindle, James D Brenton, Evis Sala.
       BACKGROUND: To evaluate the capability of hyperpolarized [1-13C] pyruvate MRI to predict pathologic response to neoadjuvant treatment in multi-site abdominopelvic disease of high-grade serous ovarian cancer (HGSOC) patients and to compare 13C MRI and [18F]-FDG PET/CT measurements for detecting early treatment response. We recruited eight patients with HGSOC in this prospective study who underwent 13C MRI and [18F]-FDG PET/CT before and after the first cycle of neoadjuvant chemotherapy treatment (NACT). Imaging parameters were compared with clinical and histophatologic parameters.
    RESULTS: We demonstrate here that 13C MRI of hyperpolarized [1-13C]pyruvate metabolism in multiple abdominal metastases resulted in rapid labeling of the endogenous tumor lactate pool. The rate of labeling was similar between the different anatomical disease sites and independent of tumor volume. The apparent rate constant describing exchange of 13C label between pyruvate and lactate (kPL) was positively correlated with PET standard uptake values (SUVmax) for [18F]-FDG in metastatic tumor deposits in the ovary/pelvis (R = 0.471, P = 0.02). Decreased lactate labeling could be detected after the first cycle of neoadjuvant chemotherapy and was associated with pathological response. There was no overall decrease in lactate labeling in a single patient who lacked a complete histopathologic response. kPL was associated with cancer tissue LDHA concentration (rho = 0.641; P = 0.02).
    CONCLUSION: This exploratory study demonstrates the potential of 13C MRI measurements for assessing early response to neoadjuvant chemotherapy in patients with HGSOC.
    Keywords:  Functional imaging; Hybrid imaging; Hyperpolarized MRI; Oncologic imaging; Ovarian cancer
    DOI:  https://doi.org/10.1186/s13550-025-01219-5
  37. BMC Nutr. 2025 Apr 14. 11(1): 76
    The effect of low-carbohydrate diets, based on changes in intake of dietary saturated fats on circulating TNF-α and interleukin- 6 levels in adults: a systematic review and meta-analysis of randomized controlled trials.
    Mahdieh Khodarahmi, Fatemeh Pourteymour Fard Tabrizi, Gholamreza Askari.
       BACKGROUND: Low-carbohydrate diets (LCDs) have been associated with inflammation while there is still conflicting evidence regarding the effects of this type of diet on inflammatory markers and the clinical benefit of them remains uncertain. So, we aimed to ascertain the effects of LCDs on serum concentrations of tumor necrosis factor alpha (TNF-α) and interleukin- 6 (IL- 6) by performing a systematic review and meta-analysis of randomized clinical trials (RCTs).
    METHODS: The online databases PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, and Scopus were comprehensively searched up to February 2024, to find pertinent RCTs. Pooled weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using the random-effects model.
    RESULTS: This meta-analysis of 33 studies assessed a total of 2106 adults irrespective of their health status. Compared with control group, participants on LCDs experienced a decline in IL- 6 levels (WMD: - 0.31 pg/mL; 95% CI: - 0.49 to - 0.12; P = 0.001). However, no significant effect was revealed for TNF-α (WMD: - 0.02 pg/mL; 95% CI: - 0.08 to - 0.03; P = 0.449). Stratification analyses indicated that beneficial effects of LCDs on inflammatory cytokines (WMD: - 0.28 pg/mL; 95% CI: - 0.47 to - 0.10; P = 0.003, WMD: - 0.26 pg/mL; 95% CI: - 0.48 to - 0.03; P = 0.027, for TNF-α and IL- 6, respectively) were stronger when carbohydrate intake was < 10%. The results of Meta-regression analyses suggested that baseline level of both markers remained as a strong predictor of the effect size (P = 0.038 and P = 0.001 for TNF-α and IL- 6, respectively).
    CONCLUSION: Adherence to LCDs appeared to be effective at improving inflammatory cytokines particularly, when carbohydrate intake was restricted to less than 10% of total energy. Nevertheless, further rigorously designed clinical trials considering factors such as race and genetic, the sources and quality of dietary carbohydrates, protein, and fat are required to gain a deeper understanding of the impact of LCDs on inflammatory markers.
    TRIAL REGISTRATION: PROSPERO, registration no: CRD42023387452.
    Keywords:  Carbohydrate restriction; Inflammation; Interleukin- 6; Low-carbohydrate diet; Meta-analysis; TNF-α
    DOI:  https://doi.org/10.1186/s40795-025-01062-w
  38. Ecol Evol. 2025 Apr;15(4): e71299
    Migration Strategy and Diet Affect the Metabolism of Passerine Birds During Endurance Flight.
    Susanne Jenni-Eiermann, Lukas Jenni.
      Bird migration varies greatly in overall distance and length of single flight bouts. Therefore, we expect that metabolic adaptations may also differ widely among migrants. Endurance flight is mainly fuelled by fat and complemented by protein. The proportions of lipids and protein accumulated before flights, and spent during flight, depend on food type. A fruit diet facilitates fattening more than a proteinous arthropod or seed diet. Adaptations to maximize lipid use during flight vary with the length of flight bouts. We expect that the type of diet and migration strategy (length of flight bouts, overall migration distance) affects flight metabolism. On a Swiss Alpine pass, we caught 30 species of nocturnal and diurnal migrant passerines out of natural migratory flight and compared them with conspecifics kept inactive. We examined the effects of migration strategy, primary diet, and body fat stores on plasma concentrations of six metabolites of the fat, protein, and carbohydrate metabolism, used as indicators of relative fuel use. During migratory flight, immediate migration strategy (short hops during day or long bouts during night), general migration strategy (long- and short-distance migration) and diet affected metabolite levels, while fat stores had an additional effect. Triglyceride and free fatty acid levels were high in night-migrants and frugivores. Uric acid and glucose levels were high in insectivores. Glucose, ß-hydroxy-butyrate, and glycerol were less dependent on day/night-migration or diet. The metabolic profiles indicate that migrant passerines vary in the degree of fat use depending on migration strategy, diet, and current fat stores. Day-migrating short-distance migrant insectivores and granivores used protein or glycogen to a higher degree than night migrants. Frugivores maximized fat use. Long-distance migrants favored fat use even further. Hence, long-distance night-migrant frugivores with high fat loads appear best adapted for fat use during migratory flight.
    Keywords:  day/night migration; diet composition; fat metabolism; migration distance; plasma metabolites; protein metabolism
    DOI:  https://doi.org/10.1002/ece3.71299
  39. Toxicol Appl Pharmacol. 2025 Apr 12. pii: S0041-008X(25)00116-4. [Epub ahead of print]499 117340
    Differences in chemotherapeutic drug sensitivity before and after patient-derived tumor organoid construction.
    Fang Shao, Xin Huang, Zhihong Ma, Liqin Li, Chunjian Qi.
       BACKGROUND: Patient-derived organoids (PDOs) have emerged as promising preclinical models for various tumor types. This study aimed to optimize the process of constructing 3D organoid models and facilitate the development of personalized therapies for gastric and colon cancers.
    METHODS: Tumor tissues were divided into two parts: one part was dissociated into a single-cell suspension, and the other part was used to culture tumor organoids. RNA sequencing (RNA-seq) was performed on both tumor cells and cultured organoids. Four chemotherapeutic agents-Oxaliplatin (L-OHP), Gemcitabine (GEM), 5-Fluorouracil (5-FU), and Paclitaxel (PTX)-were utilized to assess cytotoxicity and proliferation in both organoids and freshly isolated tumor cells, then the effects of these agents were evaluated.
    RESULTS: Organoids were successfully established from both surgically resected and biopsy-derived tumor tissues. Phenotypic analysis indicated that the organoids retained the histological features and expression profiles of the original tumors. Notably, the morphological characteristics of the organoids remained stable across passages, demonstrating robust growth over time. Differentially expressed genes were identified in both gastric and colon cancer PDOs. GO and KEGG pathway analyses revealed similar gene enrichment in gastric and colon PDOs. Both gastric and colon cancer PDOs exhibited increased significant sensitivity to PTX and 5-FU compared to freshly isolated cancer cells. Furthermore, the expression of most stemness-related genes was reduced after organoid culture.
    CONCLUSIONS: We successfully established organoid models that demonstrated robust growth and heightened drug sensitivity compared to freshly isolated tumor cells. These findings suggest that caution should be exercised when interpreting drug sensitivity results from organoid-based assays.
    Keywords:  Colon cancer; Drug sensitivity; Gastric cancer; Patient-derived organoids (PDOs)
    DOI:  https://doi.org/10.1016/j.taap.2025.117340
  40. Eur J Med Res. 2025 Apr 15. 30(1): 280
    Comparative efficacy and safety in low-intensity treatment for acute myeloid leukemia in older patients: a systematic review and network meta-analysis.
    Wenze Li, Sijing Kang, Yu Jiao, Pengjie Yue, Weilin Dong, Rui Ge, Ziyi Wang, Xiaojing Yan.
       BACKGROUND: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age at diagnosis of 68 years. The outcomes in older or unfit AML patients on intensive chemotherapy are poor, and thus, it is necessary to explore alternative strategies. In recent years, non-intensive therapies have transformed the standard of care for this population. Despite the increasing number of randomized clinical trials (RCTs) and cohort studies in this area, the optimal treatment approach remains unclear.
    METHODS: We sourced four databases, PubMed, Embase, Cochrane, and Web of Science, until July 07, 2024, to identify all Phase II/III randomized controlled trials (RCTs) and cohort studies evaluating low-intensity treatments for older AML patients. Overall survival (OS), recurrence-free survival (RFS), complete remission (CR), complete remission with incomplete hematologic recovery (CRi), overall response rate (ORR), and adverse events (AEs) graded ≥ 3 were analyzed using a Bayesian fixed-effects network meta-analysis (NMA).
    RESULTS: A total of 4920 patients across 26 trials were included. In terms of improving OS, AZA + VEN, LDAC + glasdegib, and LDAC + VEN (SUCRA = 0.936, 0.898, and 0.718, respectively) were the most effective treatments. For CR, ORR, and CRi, AZA + VEN ranked highest among all therapies (SUCRA = 0.836, 0.911, and 0.829, respectively).
    CONCLUSION: This systematic review and network meta-analysis suggest that AZA + VEN is superior to the current standard of care, particularly in improving OS, CR, ORR, and CRi. LDAC + glasdegib also demonstrated promising efficacy and warrants further investigation.
    Keywords:  Acute myeloid leukemia; Elderly; Hypomethylating agents; Network meta-analysis; Venetoclax
    DOI:  https://doi.org/10.1186/s40001-025-02476-9
  41. Breast Cancer Res. 2025 Apr 15. 27(1): 55
    Central and peripheral adiposity and premenopausal breast cancer risk: a pooled analysis of 440,179 women.
    Premenopausal Breast Cancer Collaborative Group
       BACKGROUND: Among premenopausal women, higher body mass index (BMI) is associated with lower breast cancer risk, although the underlying mechanisms are unclear. Investigating adiposity distribution may help clarify impacts on breast cancer risk. This study was initiated to investigate associations of central and peripheral adiposity with premenopausal breast cancer risk overall and by other risk factors and breast cancer characteristics.
    METHODS: We used individual-level data from 14 prospective cohort studies to estimate hazard ratios (HRs) for premenopausal breast cancer using Cox proportional hazards regression. Analyses included 440,179 women followed for a median of 7.5 years (interquartile range: 4.0-11.3) between 1976 and 2017, with 6,779 incident premenopausal breast cancers.
    RESULTS: All central adiposity measures were inversely associated with breast cancer risk overall when not controlling for BMI (e.g. for waist circumference, HR per 10 cm increase: 0.92, 95% confidence interval (CI): 0.90-0.94) whereas in models adjusting for BMI, these measures were no longer associated with risk (e.g. for waist circumference: HR 0.99, 95% CI: 0.95-1.03). This finding was consistent across age categories, with some evidence that BMI-adjusted associations differed by breast cancer subtype. Inverse associations for in situ breast cancer were observed with waist-to-height and waist-to-hip ratios and a positive association was observed for oestrogen-receptor-positive breast cancer with hip circumference (HR per 10 cm increase: 1.08, 95% CI: 1.10-1.14). For luminal B, HER2-positive breast cancer, we observed an inverse association with hip circumference (HR per 10 cm: 0.84, 95% CI: 0.71-0.98), but positive associations with waist circumference (HR per 10 cm: 1.18, 95% CI: 1.03-1.36), waist-to-hip ratio (HR per 0.1 units: 1.29, 95% CI: 1.15-1.45) and waist-to height ratio (HR per 0.1 units: 1.46, 95% CI: 1.17-1.84).
    CONCLUSIONS: Our analyses did not support an association between central adiposity and overall premenopausal breast cancer risk after adjustment for BMI. However, our findings suggest associations might differ by breast cancer hormone receptor and intrinsic subtypes.
    Keywords:  Adiposity; Breast cancer; Cohort study
    DOI:  https://doi.org/10.1186/s13058-025-01995-x
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