bims-medica 2025-05-11 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–05–11
23 papers selected by
Brett Chrest, Wake Forest University

Induction of Fructose Mediated De Novo Lipogenesis Co-exists with the Upregulation of Mitochondrial Oxidative Function in Mice Liver.
Revisiting the thrifty substrate hypothesis: Ketone bodies as cardioprotective fuels in diabetes and SGLT2 inhibitor therapy.
Functional mitochondrial respiration is essential for glioblastoma tumour growth.
Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias.
Mechanism and application of thiol-disulfide redox biosensors with a fluorescence-lifetime readout.
Vitamins and dietary supplements in cancer treatment: is there a need for increased usage?
Effects of tetrahydroindenoindole supplementation on metabolism: A systematic review with meta-analysis of rodent-based studies.
Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.
No detectable impact of short-term treatment delays on lung cancer survival.
m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.
Combined sedentarism and high-fat diet induce early signs of kidney injury in C57BL/6J mice.
Transient increase in mitochondrial respiration in blood cells from breast cancer patients following chemo- and radiotherapy.
Cellular metabolomics study in colorectal cancer cells and media following treatment with 5-fluorouracil by gas chromatography-tandem mass spectrometry.
The m5C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.
Spreading depolarizations exhaust neuronal ATP in a model of cerebral ischemia.
The central benefit of physiologically induced ketogenic states.
Dietary polyphenol intake and risk of overall and site-specific cancers: The Japan Public Health Center-based Prospective Study.
[Metabolic Characteristics of 18F-FDG in Different Types of Myeloid Leukemia Cells and Tumor-Bearing Nude Mice].
A quantitative characterization of the heterogeneous response of glioblastoma U-87 MG cell line to temozolomide.
Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
(R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation.
A pathway toward clinical translation of hyperpolarized [1,4-13C2,2,3-d2]fumarate as an imaging biomarker for early cellular necrosis in vivo.
Exploring cellular metabolic kinetics through spectroscopic analysis of extracellular environments.

J Nutr. 2025 May 05. pii: S0022-3166(25)00276-7. [Epub ahead of print]

Induction of Fructose Mediated De Novo Lipogenesis Co-exists with the Upregulation of Mitochondrial Oxidative Function in Mice Liver.

Parama Bhattacharjee, Ayeesha Fadlaoui, Caitlin E Ryan, Courtney B Carlson, Daoning Zhang, Nishanth E Sunny.

   BACKGROUND: Dysfunctional mitochondrial metabolism and sustained de novo lipogenesis (DNL) are characteristics of metabolic dysfunction-associated steatotic liver disease (MASLD), a comorbidity of obesity and type 2 diabetes. Fructose, a common sweetener and a potent inducer of lipogenesis, contributes to the etiology of MASLD.
OBJECTIVES: Our goal was to determine whether higher rates of DNL, through its biochemical relationships with mitochondria, can contribute to dysfunctional induction of oxidative networks in the liver.
METHODS: Male C57BL/6JN mice were given a low-fat (LF; 10% fat Kcal, 49.9% corn starch Kcal), high-fat (HF; 60% fat Kcal), or HF/ high-fructose diet (HF/HFr; 25% fat Kcal, 34.9% fructose Kcal) for 24-wks. In a follow-up study, mice on normal chow were provided either 30% fructose in drinking water (FW) to induce hepatic DNL or regular water (NW) for 14 days. Hepatic mitochondria and liver tissue were used to determine oxygen consumption, reactive oxygen species (ROS) generation, tricarboxylic acid (TCA) cycle activity and gene/protein expression profiles.
RESULTS: Hepatic steatosis remained similar between HF and HF/HFr fed mice livers. However, lipogenic and lipid oxidation gene expression profiles and the induction of TCA cycle metabolism were all higher (P ≤ 0.05) in HF/HFr livers. Under fed conditions, the upregulation of DNL in FW livers occurred in concert with higher mitochondrial oxygen consumption (basal; 1.7±0.21 vs. 3.3±0.14 nmoles/min, P ≤ 0.05), higher ROS (0.87±0.09 vs. 1.25±0.12 μM, P ≤ 0.05) and higher flux through TCA cycle components P ≤ 0.05. Further, TCA cycle activity and lipid oxidation remained higher during fasting in the FW livers P ≤ 0.05.
CONCLUSIONS: Our results show that fructose administration to mice led to the concurrent induction of mitochondrial oxidative networks and DNL in the liver. Sustained induction of both de novo lipogenesis and mitochondrial oxidative function could accelerate cellular stress and metabolic dysfunction during MASLD.

Keywords:  De novo lipogenesis; fructose; ketogenesis; lipid oxidation; liver; mitochondrial metabolism; tri-carboxylic acid cycle

DOI:  https://doi.org/10.1016/j.tjnut.2025.04.030
J Diabetes Investig. 2025 May 07.

Revisiting the thrifty substrate hypothesis: Ketone bodies as cardioprotective fuels in diabetes and SGLT2 inhibitor therapy.

Yoriyasu Suzuki, Tetsuya Amano.

SGLT2 inhibitors increase circulating β-hydroxybutyrate (β-OH-B), a ketone body that may enhance cardiac efficiency in HFrEF. The "thrifty substrate hypothesis" suggests β-OH-B provides more ATP per oxygen consumed than glucose or fatty acids. Clinical studies by Nielsen et al. and Solis-Herrera et al. show that β-OH-B infusion improves cardiac output, ejection fraction, and myocardial blood flow in HFrEF patients-with and without diabetes-without increasing oxygen demand or reducing glucose uptake. These findings support β-OH-B as an additive metabolic fuel, highlighting the therapeutic potential of enhancing cardiac metabolic flexibility.

DOI: https://doi.org/10.1111/jdi.70068
Oncogene. 2025 May 05.

Functional mitochondrial respiration is essential for glioblastoma tumour growth.

Petra Brisudova, Dana Stojanovic, Jaromir Novak, Zuzana Nahacka, Gabriela Lopes Oliveira, Ondrej Vanatko, Sarka Dvorakova, Berwini Endaya, Jaroslav Truksa, Monika Kubiskova, Alice Foltynova, Daniel Jirak, Natalia Jirat-Ziolkowska, Lukas Kucera, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Paulo Oliveira, Carole Grasso, Michael V Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil.

Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.

DOI: https://doi.org/10.1038/s41388-025-03429-6
Clin Cancer Res. 2025 May 06.

Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias.

Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L Bixby, Harry P Erba, Nikolai Podoltsev, Gary J Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff.

PURPOSE: Acute myeloid leukemia (AML) is characterized by frequent mutation of fms-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. Here, we investigated the antileukemia efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3-internal tandem duplication (ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase 1 clinical trial.
METHODS: Preclinical studies used human and murine cell lines carrying FLT3-ITD, and/or TKD mutations and TP53 WT/knockdown, leukemia cell xenograft models and a PDX model. Assays were conducted using milademetan (DS-3032b) and murine-specific MDM2i (DS-5272). An open-label, phase 1, dose-escalation clinical trial (ClinicalTrials.gov NCT03552029) was conducted.
RESULTS: Dual inhibition of FLT3-ITD and MDM2 synergistically induced apoptosis in FLT3-ITD/TP53 WT AML and venetoclax-resistant cell lines, reduced tumor burden, and improved survival in xenograft and PDX models of FLT3-ITD AML. Phase 1 clinical data indicated favorable safety and tolerability for the Q/M combination treatment. Complete responses with incomplete hematologic recovery were achieved in 40% of relapsed/refractory AML patients. Unsupervised single-cell proteomics analysis showed Q/M treatment decreased the expression of prosurvival (pERK, pAKT, Mcl-1) proteins and activated protein signaling downstream of p53 including PUMA. YTHDF2 was increased post therapy in resistant cells. Q/M combination demonstrated higher activity in CD34+ versus CD34- leukemia blasts.
CONCLUSIONS: Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2764
Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2503978122

Mechanism and application of thiol-disulfide redox biosensors with a fluorescence-lifetime readout.

Paul C Rosen, Andrew Glaser, Juan R Martínez-François, Daniel C Lim, Daniel J Brooks, Panhui Fu, Erica Kim, Dorothee Kern, Gary Yellen.

  Genetically encoded biosensors with changes in fluorescence lifetime (as opposed to fluorescence intensity) can quantify small molecules in complex contexts, even in vivo. However, lifetime-readout sensors are poorly understood at a molecular level, complicating their development. Although there are many sensors that have fluorescence-intensity changes, there are currently only a few with fluorescence-lifetime changes. Here, we optimized two biosensors for thiol-disulfide redox (RoTq-Off and RoTq-On) with opposite changes in fluorescence lifetime in response to oxidation. Using biophysical approaches, we showed that the high-lifetime states of these sensors lock the chromophore more firmly in place than their low-lifetime states do. Two-photon fluorescence lifetime imaging of RoTq-On fused to a glutaredoxin (Grx1) enabled robust, straightforward monitoring of cytosolic glutathione redox state in acute mouse brain slices. The motional mechanism described here is probably common and may inform the design of other lifetime-readout sensors; the Grx1-RoTq-On fusion sensor will be useful for studying glutathione redox in physiology.

Keywords:  conformational change; fluorescence lifetime; genetically encoded fluorescent biosensor; glutathione redox

DOI:  https://doi.org/10.1073/pnas.2503978122
Expert Rev Anticancer Ther. 2025 May 07. 1-24

Vitamins and dietary supplements in cancer treatment: is there a need for increased usage?

Teresa Esposito, Francesca Pentimalli, Antonio Giordano, Salvatore Cortellino.

   INTRODUCTION: Vitamins are essential for homeostasis and proper functioning of organisms. These micronutrients prevent tumor onset by functioning as antioxidants and enzymatic cofactors involved in anti-stress and immune responses, modulating epigenetic regulators, and shaping the microbiota composition. Unbalanced diets and sedentary lifestyles contribute to obesity, associated with increasing cancer risk. Cancer patients often exhibit vitamin deficiencies due to chronic inflammation, anticancer therapies, and tumor-induced metabolic changes, leading to malnutrition and cachexia.
AREAS COVERED: This review critically analyzes preclinical and clinical studies, sourced from PubMed and ClinicalTrials.gov databases, that investigate the potential benefits of vitamin supplementation and dietary interventions, such as intermittent fasting and ketogenic diets, in mouse tumor models and cancer patients. This analysis elucidates the limitations of such interventions and suggests optimal dietary strategies to prevent cancer and enhance patients' quality of life and prognosis.
EXPERT OPINION: To date, clinical studies have found no substantial benefit of over-the-counter vitamin supplements and dietary interventions on cancer patients' health and prognosis. To prevent the spread of useless and potentially harmful products by the nutraceutical industry, establishing a regulatory authority is necessary to monitor and ensure product quality and validity before commercialization.

Keywords:  Vitamin supplement; cachexia; cancer treatment; healthy diet; periodic fasting

DOI:  https://doi.org/10.1080/14737140.2025.2501077
Geroscience. 2025 May 05.

Effects of tetrahydroindenoindole supplementation on metabolism: A systematic review with meta-analysis of rodent-based studies.

Miguel Pérez-Rodríguez, Rafael A Casuso, Sandra Rodríguez-López, José A González-Reyes, José M Villalba.

  Identifying novel compounds with therapeutic potential is a main area of interest in biomedical research. Tetrahydroindenoindole (THII) has emerged as a compound of interest due to both its antioxidant properties and its action as a pharmacological activator of the enzyme cytochrome b5 reductase 3. However, there is a lack of comprehensive synthesis of findings, particularly concerning the effects of THII on metabolism in mice under non-disease conditions. This systematic review with meta-analysis aims to bridge this gap by analyzing existing studies. Our findings demonstrated that THII supplementation reduced body weight gain, while fat mass remained unchanged. Fasting blood glucose and plasma insulin levels, as well as insulin levels during the glucose tolerance test, showed no changes. However, glucose tolerance improved with THII supplementation during the glucose tolerance test, particularly in animals under a high-fat diet. THII supplementation also increased O2 consumption and CO2 production, with a tendency to lower respiratory quotient. In mitochondria, THII supplementation did not affect state 3 respiration, while increased state 4, and decreased the respiratory exchange ratio. Notably, mitochondrial H2O2 production during state 4 respiration and ATP levels also remained unchanged. Furthermore, THII supplementation reduced NADPH-dependent O2 uptake, NADPH-dependent H2O2 production, and lipid peroxidation. Despite the limitations and potential sources of bias identified, we observed valuable outcomes linked to THII supplementation. The significant impact on energy metabolism, mitochondrial function, and oxidative stress underscores THII as a promising intervention with translational relevance for aging-related alterations, enhancing healthspan, and targeting metabolic-associated diseases such as obesity or diabetes.

Keywords:  Meta-analysis; Metabolism; Mice; Rodents; Systematic review; Tetrahydroindenoindole

DOI:  https://doi.org/10.1007/s11357-025-01680-z
Genes Dev. 2025 May 05.

Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.

Rayna Y Magesh, Arshia N Kaur, Faith N Keller, Abdulrazak Frederick, Tenzin Tseyang, John A Haley, Alejandra M Rivera-Nieves, Anthony C Liang, David A Guertin, Jessica B Spinelli, Stephen J Elledge, Emma V Watson.

  Despite the general detriment of aneuploidy to cellular fitness, >90% of solid tumors carry an imbalanced karyotype. This existing paradox and the molecular responses to aneuploidy remain poorly understood. Here, we explore these cellular stresses and unique vulnerabilities of aneuploidy in human mammary epithelial cells (HMECs) enriched for breast cancer-associated copy number alterations (CNAs). To uncover the genetic dependencies specific to aneuploid cells, we conducted a comprehensive, genome-wide CRISPR knockout screen in isogenic aneuploid and diploid HMEC lines. Our study reveals that aneuploid HMECs exhibit an increased reliance on pyrimidine biosynthesis and mitochondrial oxidative phosphorylation genes and demonstrate heightened fitness advantages upon loss of tumor suppressor genes. Using an integrative multiomic analysis, we confirmed nucleotide pool insufficiency as a key contributor to widespread cellular dysfunction in aneuploid HMECs with net copy number gain. Although diploid cells can switch seamlessly between pyrimidine synthesis and salvage, cells with increased chromosomal content exhibit p53 activation and S-phase arrest when relying on salvage alone, alongside increased sensitivity to DNA-damaging chemotherapeutics. This work advances our understanding of the consequences of aneuploidy and uncovers potential avenues for patient stratification and therapeutic intervention based on tumor ploidy.

Keywords:  CRISPR; aneuploidy; cancer; genomics; metabolism

DOI:  https://doi.org/10.1101/gad.352512.124
Geroscience. 2025 May 07.

No detectable impact of short-term treatment delays on lung cancer survival.

Zoltan Ungvari, Mónika Fekete, Annamaria Buda, Andrea Lehoczki, János Tibor Fekete, Gyöngyi Munkácsy, Péter Varga, Anna Ungvari, Balázs Győrffy.

  Timely initiation of treatment is a core principle of oncologic care, especially for aggressive cancers such as lung cancer. However, the real-world impact of short-term delays in treatment initiation on survival outcomes in lung cancer remains unclear. This meta-analysis evaluates the association between treatment delays of 4, 8, and 12 weeks and all-cause mortality in lung cancer patients. A systematic search was conducted in PubMed, Scopus, and Web of Science for studies published between 2000 and 2025. Of 5360 screened records, 15 studies were included, comprising 16 cohorts for overall survival of lung cancer patients. Hazard ratios (HRs) for 4-, 8-, and 12-week treatment delays were estimated using random-effects meta-analyses. Heterogeneity was measured with the I2 statistic, and publication bias was assessed using funnel plots and Egger's test. No significant association was found between treatment delay and survival at any of the time points. Pooled HRs were 1.00 (95% CI, 0.99-1.02) for a 4-week delay, 1.01 (95% CI, 0.99-1.03) for an 8-week delay, and 1.01 (95% CI, 0.98-1.05) for a 12-week delay. Despite high heterogeneity (I2 = 97%), no evidence of publication bias was detected. This meta-analysis found no significant impact of short-term treatment delays (up to 12 weeks) on mortality in lung cancer patients. These findings challenge the assumption that brief delays universally worsen outcomes and underscore the importance of individualized treatment planning and prioritization.

Keywords:  Cancer prognosis; Clinical outcomes; Cohort study; Disease progression; Hazard ratio; Lung cancer; Mortality; Oncology; Treatment initiation

DOI:  https://doi.org/10.1007/s11357-025-01684-9
Nat Commun. 2025 May 06. 16(1): 4214

m6A/IGF2BP3-driven serine biosynthesis fuels AML stemness and metabolic vulnerability.

Feng Huang, Yushuai Wang, Xiuxin Zhang, Weiwei Gao, Jingwen Li, Ying Yang, Hongjie Mo, Emily Prince, Yifei Long, Jiacheng Hu, Chuang Jiang, Yalin Kang, Zhenhua Chen, Yueh-Chiang Hu, Chengwu Zeng, Lu Yang, Chun-Wei Chen, Jianjun Chen, Huilin Huang, Hengyou Weng.

Metabolic reprogramming of amino acids represents a vulnerability in cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA N6-methyladenosine (m6A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m6A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m6A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m6A/SSP axis as a promising therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-58966-1
Am J Physiol Renal Physiol. 2025 May 06.

Combined sedentarism and high-fat diet induce early signs of kidney injury in C57BL/6J mice.

Precious C Opurum, Stephen T Decker, Deborah Stuart, Alek D Peterlin, Venisia L Paula, Piyarat Siripoksup, Micah J Drummond, Alejandro Sanchez, Nirupama Ramkumar, Katsuhiko Funai.

  Chronic kidney disease (CKD) is a progressive disorder marked by a decline in kidney function. Obesity and sedentary behavior contribute to the development of CKD, though mechanisms by which this occurs are poorly understood. This knowledge gap is worsened by the lack of a reliable murine CKD model that does not rely on injury, toxin, or gene deletion to induce a reduction in kidney function. High-fat diet (HFD) feeding alone is insufficient to cause reduced kidney function until later in life. Here, we employed a small mouse cage (SMC), a recently developed mouse model of sedentariness, to study its effect on kidney function. Wildtype C57BL/6J male mice were housed in sham or SMC housing for six months with HFD in room (22°C) or thermoneutral (30°C) conditions. Despite hyperinsulinemia induced by the SMC+HFD intervention, kidneys from these mice displayed normal glomerular filtration rate (GFR). However, the kidneys showed early signs of kidney injury, including increases in Col1a1 and NGAL transcripts, as well as fibrosis by histology, primarily in the inner medullary/papilla region. High-resolution respirometry and fluorometry experiments showed no statistically significant changes in the capacities for respiration, ATP synthesis, or electron leak. These data confirm the technical challenge in modeling human CKD. They further support the notion that obesity and a sedentary lifestyle make the kidneys more vulnerable, but additional insults are likely required for the pathogenesis of CKD.

Keywords:  Chronic kidney disease; Mitochondria; Physical inactivity

DOI:  https://doi.org/10.1152/ajprenal.00259.2024
Clin Exp Med. 2025 May 08. 25(1): 142

Transient increase in mitochondrial respiration in blood cells from breast cancer patients following chemo- and radiotherapy.

Marie-Louise Abrahamsen, Ida Bager Christensen, Linda Laizāne, Haboon Ismail Ahmed, Kristian Buch-Larsen, Djordje Marina, Michael Andersson, Peter Schwarz, Flemming Dela, Linn Gillberg.

  Mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) has previously been shown to increase after chemo- and radiotherapy in early-stage breast cancer (BC) patients, but the persistence of the increase remains unknown. This study assessed whether changes in mitochondrial respiration and content in PBMCs from postmenopausal BC patients persist up to 1 year after treatment. Thirty-four early-stage BC patients were studied before, shortly after, and six- and twelve-months post-treatment along with 20 healthy controls. Mitochondrial respiration was measured using high-resolution respirometry of intact and permeabilized PBMCs. Mitochondrial content was estimated by quantifying mitochondrial DNA relative to nuclear DNA via qPCR. The mitochondrial respiratory capacity of intact and permeabilized PBMCs from BC patients significantly increased after adjuvant chemo- and radiotherapy (+ 33% and + 30% for the maximal capacity of the electron transport system, ETS), consistent with previous findings. Importantly, the respiratory capacity returned to pre-treatment levels six months after treatment completion in both intact and permeabilized cells (- 23% and - 26% for the ETS). Healthy controls exhibited similar mitochondrial respiration but had increased mitochondrial content (+ 20%) compared to BC patients before treatment. In summary, chemo- and radiotherapy transiently increased mitochondrial respiration in PBMCs, returning to baseline within six months after treatment completion. This temporary rise in oxygen demand may reflect immune system activation.

Keywords:  Adjuvant therapy; Breast cancer; High-resolution respirometry; Inflammation; Mitochondria; Peripheral blood mononuclear cells

DOI:  https://doi.org/10.1007/s10238-025-01665-4
Metabolomics. 2025 May 07. 21(3): 62

Cellular metabolomics study in colorectal cancer cells and media following treatment with 5-fluorouracil by gas chromatography-tandem mass spectrometry.

Songjin Oh, Hyun Bo Sim, Hyeongyeong Kim, Seul-Ki Mun, Moongi Ji, Byeongchan Choi, Doo-Young Kim, Jong-Jin Kim, Man-Jeong Paik.

   BACKGROUND: Metabolic reprogramming is a distinctive characteristic of colorectal cancer (CRC) which provides energy and nutrients for rapid proliferation. Although numerous studies have explored the rewired metabolism of CRC, the metabolic alterations occurring in CRC when the cell cycle is arrested by treatment with 5-fluorouracil (5-FU), an anticancer drug that arrests the S phase, remain unclear.
METHODS: A systematic profiling analysis was conducted as ethoxycarbonyl/methoxime/tert-butyldimethylsilyl derivatives using gas chromatography-tandem mass spectrometry in HT29 cells and media following 5-FU treatment in a concentration- and time-dependent manner.
RESULTS: In HT29 cells of 24 h after 5-FU treatment (3-100 μM) and 48 h after 5-FU treatment (1-10 μM), six amino acids, including valine, leucine, isoleucine, serine, glycine, and alanine and two organic acids, including pyruvic acid and lactic acid, were significantly increased compared to the DMSO-treated group. However, 48 h after 5-FU treatment (30-100 μM) in HT29 cells, the levels of these metabolites decreased along with an approximately 50% reduction in viability, an increase in the level of reactive oxygen species, induction of cycle arrest in the G1 phase, and the induction of apoptosis. On the other hand, the levels of fatty acids showed a continuous increase in HT29 cells 48 h after 5-FU treatment (1-100 μM). In the media, the decreased availabilities in the cellular uptake of nutrient metabolites, including valine, leucine, isoleucine, serine, and glutamine, were observed at 48 h after 5-FU treatment in a dose-dependent manner.
CONCLUSION: It is assumed that there is a possible shift in energy dependence from the tricarboxylic acid cycle to fatty acid metabolism. Thus, metabolic profiling analysis revealed altered energy metabolism in CRC cells following 5-FU treatment.

Keywords:  5-Fluorouracil; Colorectal cancer; HT29 cells; Mass spectrometry; Metabolite profiling analysis; Metabolomics

DOI:  https://doi.org/10.1007/s11306-025-02263-x
Cell Rep. 2025 May 07. pii: S2211-1247(25)00432-2. [Epub ahead of print]44(5): 115661

The m5C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.

Songyu Li, Ya Liu, Xiang Wu, Minjia Pan, Hongxia Zhao, Yunguang Hong, Qinghua Zhang, Shushu Hu, Aorong Ouyang, Guangru Li, Minhui Wu, Shanshan Fan, Zhirong Jia, Shanchao Zhao, Guocai Wu, Xiangwei Gao, Zhigang Yang, Zhanghui Chen.

  Acute myeloid leukemia (AML) is one of the most prevalent heterogeneous hematologic malignancies with a complicated etiology. RNA post-transcriptional modifications have been linked to the incidence and progression of AML, while the detailed mechanism remains to be elucidated. In this study, we find that NOP2/Sun domain family member 2 (NSUN2), a methyltransferase of 5-methylcytosine (m5C) RNA methylation, is upregulated in AML and predicts a poor prognosis for patients with AML. Knockdown of NSUN2 in AML cells inhibits proliferation and colony formation and promotes apoptosis. Depletion of NSUN2 in AML mice reduces the tumor burden and prolongs survival. Mechanistically, NSUN2 promotes the expression of phosphoglycerate dehydrogenase (PHGDH) and serine hydroxymethyltransferase 2 (SHMT2), two key enzymes in the serine/glycine biosynthesis pathway, by stabilizing the corresponding mRNAs through regulation of m5C modifications. Overall, our findings demonstrate a critical role of NSUN2 in AML development and highlight the therapeutic potential of targeting the NSUN2/m5C axis for the treatment of this cancer.

Keywords:  5-methylcytosine; AML; Acute myeloid leukemia; CP: Cancer; CP: Metabolism; NOP2/Sun RNA methyltransferase 2; NSUN2; m(5)C; serine metabolism

DOI:  https://doi.org/10.1016/j.celrep.2025.115661
Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2415358122

Spreading depolarizations exhaust neuronal ATP in a model of cerebral ischemia.

Karl Schoknecht, Felipe Baeza-Lehnert, Johannes Hirrlinger, Jens P Dreier, Jens Eilers.

  Spreading depolarizations (SDs) have been identified in various brain pathologies. SDs increase the cerebral energy demand and, concomitantly, oxygen consumption, which indicates enhanced synthesis of adenosine triphosphate (ATP) by oxidative phosphorylation. Therefore, SDs are considered particularly detrimental during reduced supply of oxygen and glucose. However, measurements of intracellular neuronal ATP ([ATP]i), ultimately reporting the balance of ATP synthesis and consumption during SDs, have not yet been conducted. Here, we investigated neuronal ATP homeostasis during SDs using two-photon imaging in acute brain slices from adult mice expressing the ATP sensor ATeam1.03YEMK in neurons. SDs were induced by application of potassium chloride or by oxygen and glucose deprivation (OGD) and detected by recording the local field potential, extracellular potassium, as well as the intrinsic optical signal. We found that, in the presence of oxygen and glucose, SDs were accompanied by a substantial but transient drop in neuronal ATP sensor signals, corresponding to a drop in ATP. OGD, which prior to SDs was accompanied by only a slight reduction in ATP signals, led to a large, terminal drop in ATP signals during SDs. Subsequently, we investigated whether neurons could still regenerate ATP if oxygen and glucose were promptly resupplied following SD detection, and show that ATP depletion was essentially reversible in most cells. Our findings indicate that SDs are accompanied by a substantial increase in ATP consumption beyond production. This, under conditions that mimic reduced blood supply, leads to a breakdown of [ATP]i. Therefore, our findings support therapeutic strategies targeting SDs after cerebral ischemia.

Keywords:  adenosine triphosphate; cerebral ischemia; neuron; spreading depolarization

DOI:  https://doi.org/10.1073/pnas.2415358122
J Physiol. 2025 May 05.

The central benefit of physiologically induced ketogenic states.

Antonia Giacco, Giuseppe Petito, Rosalba Senese, Maria Moreno, Assunta Lombardi, Antonia Lanni, Pieter de Lange.

  Ketones not only act as metabolic fuel for the brain in periods of carbohydrate shortage, but also serve as signalling molecules that improve cognition. Ketogenic states can be induced peripherally by physiological interventions such as fasting and exercise, or ketogenic diets/exogenous supplementation. These interventions beneficially act on the brain through partially overlapping peripheral metabolic pathways. We focus on the role of peripheral organs such as the intestine, liver and skeletal muscle in mediating cognitive benefits in response to these interventions and discuss the prominent roles of the nuclear receptor peroxisome proliferator-activated receptor δ, which serves as a nutrient sensor guiding ketones to the brain, where they stimulate the multifunctional cognition-improving factor, brain-derived neurotrophic factor.

Keywords:  BDNF; cognition; exercise; fasting; ketogenic diet; ketones

DOI:  https://doi.org/10.1113/JP287462
J Nutr. 2025 May 03. pii: S0022-3166(25)00273-1. [Epub ahead of print]

Dietary polyphenol intake and risk of overall and site-specific cancers: The Japan Public Health Center-based Prospective Study.

Madoka Kishino, Rieko Kanehara, Nagisa Mori, Junko Ishihara, Ribeka Takachi, Taiki Yamaji, Motoki Iwasaki, Shoichiro Tsugane, Norie Sawada.

   BACKGROUND: Polyphenols may play a protective role in carcinogenesis through a wide range of properties, including antioxidant and anti-inflammatory. However, evidence for the association between total dietary polyphenol intake and cancer risk in Asian populations is limited.
OBJECTIVE: This population-based prospective study aimed to investigate the association between polyphenol intake and risk of overall and site-specific cancer among Japanese.
METHODS: Participants were 41,907 men and 48,268 women aged 45-74 years with no previous cancer diagnosis in the Japan Public Health Center-based (JPHC) Prospective Study. Dietary polyphenol intake was estimated by a 147-item food frequency questionnaire administered in 1995-1998. Participants were divided into quintiles (Q) according to intakes of total polyphenol and polyphenol from foods not including high-polyphenolic beverages (tea, coffee, and alcoholic beverages). Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer risk were estimated using Cox proportional hazard regression models adjusted for potential confounders.
RESULTS: During a median of 15.8 years of follow-up, 12,970 incident cancer cases (7,999 men and 4,971 women) were identified. We did not observe associations of lower risk of overall cancer with polyphenol intake. For site-specific cancers, as compared with the lowest quintile (Q1), higher total polyphenol intake was associated with a lower risk of liver cancer in men (HRQ4=0.67, 95% CI=0.51-0.89; HRQ5=0.66, 95% CI=0.48-0.89, p-trend=0.003) and women (HRQ5=0.63, 95% CI=0.39-1.02, p-trend=0.003), while higher polyphenol intake from foods not including tea, coffee and alcoholic beverages was associated with a lower risk of colon cancer in men (HRQ4=0.73, 95% CI=0.58-0.92; HRQ5=0.72, 95% CI=0.54-0.96, p-trend=0.07).
CONCLUSIONS: The results of the present study do not support a substantial role for dietary polyphenols in overall cancer prevention. Total polyphenol may reduce the risk of liver cancer, and polyphenol from foods not including tea, coffee, and alcoholic beverages may reduce the risk of colon cancer.

Keywords:  Asian population; Cancer incidence; Cohort study; Middle-age and older adults; Polyphenol intake

DOI:  https://doi.org/10.1016/j.tjnut.2025.04.028
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Apr;33(2): 325-330

[Metabolic Characteristics of 18F-FDG in Different Types of Myeloid Leukemia Cells and Tumor-Bearing Nude Mice].

Xi Chen, Qin Yan, Xiang Qin, Li Zhang, Yue Feng, Qian Chen, Si-Li Long, Wen-Jun Liu.

   OBJECTIVE: To investigate the metabolic characteristics of 18F-fluorodeoxyglucose (18F-FDG) in myeloid leukemia by in vitro culture of myeloid leukemia cells and construction of tumor-bearing nude mouse model.
METHODS: U937, THP-1, HL60 and K562 cells were cultured in vitro. The cells in logarithmic growth phase (l×10 5 cells/well) were added with 18F-FDG, and the uptake rate of 18F-FDG was measured at 15, 30, 60 and 120 min after addation, respectively. The four kinds of cells were inoculated subcutaneously into the hind limbs of nude mice to establish a tumor-bearing nude mouse model. When the tumor size was about 500 mm3, 18F-FDG was injected through the tail vein of the mice, and positron emission tomography/computed tomography was performed at 60 min after injection. The morphology of tumor-bearing cells was observed by hematoxylin-eosin (HE) staining in serial pathological sections.
RESULTS: After co-incubation with 18F-FDG, the 18F-FDG uptake rates of U937 cells were significantly higher than THP-1, HL60 and K562 cells at 4 time points (all P <0.05), and THP-1 cells were higher than K562 cells (all P <0.05). The uptake rate of 18F-FDG by leukemia cells was rapid in the first 60 min, then tended to be stable. Pathological analysis showed that subcutaneous inoculation of U937, THP-1, HL60 and K562 cells could successfully establish tumor-bearing nude mouse models of myeloid leukemia. The 18F-FDG uptake value in U937 tumor-bearing nude mice was significantly higher than THP-1, HL60 and K562 tumor-bearing nude mice (all P <0.01). The 18F-FDG uptake values in THP-1 and HL60 tumor-bearing nude mice were significantly higher than that in K562 tumor-bearing nude mice (both P <0.01).
CONCLUSION: The tumor-bearing nude mouse model of myeloid leukemia can be successfully constructed by subcutaneous inoculation. The 18F-FDG uptake rate of acute myeloid leukemia (AML) cells is higher in cells cultured in vitro and tumor-bearing nude mouse model. 18F-FDG may have better clinical application value for AML.

Keywords:  leukemia; 18F-fluorodeoxyglucose; tumor-bearing nude mice

DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.02.003
Sci Rep. 2025 May 08. 15(1): 16017

A quantitative characterization of the heterogeneous response of glioblastoma U-87 MG cell line to temozolomide.

Pragyesh Dixit, Ilyas Djafer-Cherif, Saumil Shah, Karolina Drabik, Arne Traulsen, Bartlomiej Waclaw.

  Most cancers are genetically and phenotypically heterogeneous. This includes subpopulations of cells with different levels of sensitivity to chemotherapy, which may lead to treatment failure as the more resistant cells can survive drug treatment and continue to proliferate. While the genetic basis of resistance to many drugs is relatively well characterised, non-genetic factors are much less understood. Here we investigate the role of non-genetic, phenotypic heterogeneity in the response of glioblastoma cancer cells to the drug temozolomide (TMZ) often used to treat this type of cancer. Using a combination of live imaging, machine-learning image analysis and agent-based modelling, we show that even if all cells share the same genetic background, individual cells respond differently to TMZ. We quantitatively characterise this response by measuring the doubling time, lifespan, cell cycle phase, area and motility of cells, and determine how these quantities correlate with each other as well as between the mother and daughter cell. We also show that these responses do not correlate with the cellular level of the enzyme MGMT which has been implicated in the response to TMZ.

Keywords:  Cancer; Glioblastoma; Mathematical modelling; Phenotypic heterogeneity; Temozolomide

DOI:  https://doi.org/10.1038/s41598-025-99426-6
Cell Rep. 2025 May 07. pii: S2211-1247(25)00453-X. [Epub ahead of print]44(5): 115682

Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.

Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu.

  The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.

Keywords:  CP: Cell biology; CP: Metabolism; MICOS; OXPHOS; YME1L; beige; mitochondria; mitochondrial crista remodeling; white adipose tissue

DOI:  https://doi.org/10.1016/j.celrep.2025.115682
Sci Rep. 2025 May 08. 15(1): 16018

(R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation.

Hiroshi Ureshino, Taichi Ueshima, Tomonori Yamaguchi, Miyuki Takashima, Yusuke Sanuki, Tatsuo Ichinohe.

  Hypomethylating agents combined with venetoclax (VEN), a BCL-2 inhibitor, represent a standard treatment strategy for patients with acute myeloid leukemia (AML). Although this combination is highly effective, acquired resistance commonly occurs. MCL-1, a BCL-2 family molecule, is frequently upregulated in VEN-resistant cells, playing a major role in VEN resistance. Previously, we demonstrated that (R)-WAC-224 is effective against AML with minimal cardiac toxicity. (R)-WAC-224 combined with VEN demonstrated strong antileukemia effects on VEN-resistant AML cells overexpressing MCL-1 in vitro. Gene expression profiles revealed that (R)-WAC-224 with VEN induced DNA damage pathways leading to cell apoptosis. (R)-WAC-224 elicited caspase 3 activation, which cleaved MCL-1; this effect was reversed by a caspase inhibitor, thus overcoming VEN resistance. A combination of azacitidine (AZA), a hypomethylating agent, VEN, and (R)-WAC-224 was highly effective against VEN-resistant AML in vivo without increasing toxicity. (R)-WAC-224 exhibited antileukemia effects on VEN-resistant AML via MCL-1 downregulation in vitro and in vivo. The combination of AZA, VEN, and (R)-WAC-224 may be a promising treatment strategy for patients with AML.

Keywords:  (R)-WAC-224; Acute myeloid leukemia; Anticancer quinolone; MCL-1; Venetoclax

DOI:  https://doi.org/10.1038/s41598-025-98534-7
Magn Reson Med. 2025 May 07.

A pathway toward clinical translation of hyperpolarized [1,4-13C2,2,3-d2]fumarate as an imaging biomarker for early cellular necrosis in vivo.

Jonathan R Birchall, Pascal Wodtke, Ashley Grimmer, Esben S S Hansen, Lotte B Bertelsen, Nikolaj Bøgh, Marta Wylot, Maria J Zamora-Morales, Otso Arponen, Ines Horvat-Menih, Elizabeth C Latimer, Fung Tan, Evita Pappa, Johann Graggaber, Joseph Cheriyan, Kelly Holmes, Matthew J Locke, Helen Sladen, Joan Boren, Mikko I Kettunen, Anita Chhabra, Ian B Wilkinson, Christoffer Laustsen, Kevin Brindle, Mary A McLean, Ferdia A Gallagher.

   PURPOSE: The detection of hyperpolarized carbon-13 (HP 13C)-fumarate conversion to 13C-malate using 13C-MRSI is a biomarker for early detection of cellular necrosis. Here, we describe the translation of HP 13C-fumarate as a novel human imaging agent, including the evaluation of biocompatibility and scaling up of the hyperpolarization methods for clinical use.
METHODS: Preclinical biological validation was undertaken in fumarate hydratase-deficient murine tumor models and controls. Safety and biocompatibility of 13C-fumarate was assessed in healthy rats (N = 18) and in healthy human volunteers (N = 9). The dissolution dynamic nuclear polarization process for human doses of HP 13C-fumarate was optimized in phantoms. Finally, 2D 13C-MRSI following injection of HP 13C-fumarate was performed in an ischemia-reperfusion porcine kidney model (N = 6).
RESULTS: Fumarate-to-malate conversion was reduced by 42%-71% in the knockdown murine tumor model compared to wildtype tumors. Twice-daily injection of 13C-fumarate in healthy rats at the maximum evaluated dose (120 mg/kg/day) showed no significant persistent blood or tissue effects. Healthy human volunteers injected at the maximum dose (3.84 mg/kg) and injection rate (5 mL/s) showed no statistically significant changes in vital signs or blood measurements 1 h post-injection. Spectroscopic evidence of fumarate-to-malate conversion was observed in the ischemic porcine kidney (0.96 mg/kg).
CONCLUSION: HP 13C-fumarate has shown promise as a novel and safe hyperpolarized agent for monitoring cellular necrosis. This work provides the basis for future imaging of HP 13C-fumarate metabolism in humans.

Keywords:  HP 13C‐MRI; clinical translation; hyperpolarization; imaging biomarker; necrosis; preclinical

DOI:  https://doi.org/10.1002/mrm.30519
Spectrochim Acta A Mol Biomol Spectrosc. 2025 May 01. pii: S1386-1425(25)00614-6. [Epub ahead of print]340 126308

Exploring cellular metabolic kinetics through spectroscopic analysis of extracellular environments.

Zohreh Mirveis, Nitin Patil, Hugh J Byrne.

  Studying the kinetics of metabolic pathways, such as glycolysis and glutaminolysis, is valuable due to their fundamental links to various diseases, including cancer. This study explores the potential of Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy for analysing low concentrations of metabolites in extracellular media. It also evaluates the use of the Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) method to data mine the kinetic evolution of the spectroscopic signatures of the glycolysis metabolic pathway and to explore the impact of the presence of glutamine on it. By extracting samples at specific time intervals and drying them on the ATR crystal, ATR-FTIR could effectively measure individual metabolites of glucose, glutamine and lactate at low concentrations, providing clear spectra with strong correlations between peak absorbance and metabolite concentrations. In data mining, MCR-ALS successfully resolved two components, glucose and lactate, from time-series data of cellular glucose metabolism (glycolysis), showing approximately 28 % glucose consumption and 1 mM lactate production at a constant rate of 0.0016 min-1. However, when glutamine was introduced as a third component, the overlap of the peaks of glutamine and lactate limited the method's ability to deconvolute the data, highlighting constraints of MCR-ALS in complex mixtures.

Keywords:  ATR-FTIR spectroscopy; Glutaminolysis; Glycolysis; MCR-ALS data analysis; Metabolic pathways kinetics; Spectral data mining

DOI:  https://doi.org/10.1016/j.saa.2025.126308