bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2023‒12‒17
forty-six papers selected by
Brett Chrest, East Carolina University
  1. A HIF-1α inhibitor combined with palmitic acid and L-carnitine treatment can prevent the fat metabolic reprogramming under hypoxia and induce apoptosis in hepatocellular carcinoma cells.
  2. Multivariate modeling of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
  3. Glutaminase inhibition as potential cancer therapeutics: current status and future applications.
  4. Label-free spatially maintained measurements of metabolic phenotypes in cells.
  5. Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.
  6. Targeting Metabolic Vulnerabilities to Overcome Prostate Cancer Resistance: Dual Therapy with Apalutamide and Complex I Inhibition.
  7. Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice.
  8. Inhibition of non-small cell lung cancer (NSCLC) proliferation through targeting G6PD.
  9. Clinical forecasting of acute myeloid leukemia using ex vivo drug-sensitivity profiling.
  10. Fecal transfers from children on the ketogenic diet mimic the anti-seizure effect in mice.
  11. Regional quantification of cardiac metabolism with hyperpolarized [1-13C]-pyruvate CMR evaluated in an oral glucose challenge.
  12. Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies.
  13. Mitochondrial temperature homeostasis resists external metabolic stresses.
  14. Durable responses in acute lymphoblastic leukaemia with the use of FLT3 and IDH inhibitors.
  15. Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.
  16. Ketogenic diet does not promote triple-negative and luminal mammary tumor growth and metastasis in experimental mice.
  17. Research progress on the mechanism of glycolysis in ovarian cancer.
  18. Phenotypic profiling of solute carriers characterizes serine transport in cancer.
  19. Heparanase contributes to pancreatic carcinoma progression through insulin-dependent glucose uptake.
  20. Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by 1 H HR-MAS NMR.
  21. Diet-driven microbiome changes and physical activity in cancer patients.
  22. Supraphysiological glutamine as a means of depleting intracellular amino acids to enhance pancreatic cancer chemosensitivity.
  23. Metabolic Messengers: ketone bodies.
  24. Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells.
  25. Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease.
  26. Sperm mitochondria dysfunction in response to testicular cancer.
  27. Application and development of Deuterium Metabolic Imaging in tumor glucose metabolism: visualization of different metabolic pathways.
  28. Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis.
  29. Plate-Based Assays for the Characterization of Mitochondrial and Cellular Phenotypes.
  30. Metabolomic profile of acute myeloid leukaemia parallels of prognosis and response to therapy.
  31. Plastic persisters: revival stem cells in colorectal cancer.
  32. Unraveling the Sweet Secrets of HCC: Glucometabolic Rewiring in Hepatocellular Carcinoma.
  33. Increased Lipogenesis Is Important for Hexavalent Chromium-Transformed Lung Cells and Xenograft Tumor Growth.
  34. MYC protein helps cancer to take its vitamins.
  35. Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?
  36. A flavonoid salt probe for distinguishing between tumor and normal cells.
  37. A hub for regulation of mitochondrial metabolism: Fatty acid and lipoic acid biosynthesis.
  38. Exploring the role of hyperinsulinemia in obesity-associated tumor development.
  39. Integration of proteomics and metabolomics reveals energy and metabolic alterations induced by glucokinase (GCK) partial inactivation in hepatocytes.
  40. Integrative multi-omics analysis reveals different metabolic phenotypes based on molecular characteristics in thyroid cancer.
  41. Tissue Oxygen Depth Explorer: an interactive database for microscopic oxygen imaging data.
  42. Lipidomics Profiling Reveals Differential Alterations after FAS Inhibition in 3D Colon Cancer Cell Culture Models.
  43. Effects of Dietary Methionine Restriction on Cognition in Mice.
  44. Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia.
  45. Suspension Culture System for Isolating Cancer Spheroids using Enzymatically Synthesized Cellulose Oligomers.
  46. Behavior of breast cancer cells under oxygen concentration gradients in a microfluidic device.
  1. Cancer Metab. 2023 Dec 08. 11(1): 25
    A HIF-1α inhibitor combined with palmitic acid and L-carnitine treatment can prevent the fat metabolic reprogramming under hypoxia and induce apoptosis in hepatocellular carcinoma cells.
    Shohei Matsufuji, Yoshihiko Kitajima, Kazuki Higure, Naoya Kimura, Sachiko Maeda, Kohei Yamada, Kotaro Ito, Tomokazu Tanaka, Keita Kai, Hirokazu Noshiro.
      BACKGROUND: A hypoxic environment often persists within solid tumors, including hepatocellular carcinoma (HCC). Hypoxia-inducible factor-1α (HIF-1α) can accelerate cancer malignancy by inducing hypoxia-dependent expression of various genes. Tumor hypoxia can also induce metabolic reprogramming of fatty acid (FA) metabolism, through which HIF-1α plays an essential role in diminishing fatty acid β-oxidation (FAO) in hypoxic cancer cells.METHODS: We aimed to investigate potential new drug therapy options for targeting hypoxic cancer cells within HCC tumors, specifically through combining HIF-1α inhibition with palmitic acid (PA) + L-carnitine (LC) treatment to effectively induce apoptosis in hypoxic HCC cells. To test this hypothesis, in vitro and in vivo studies were performed.
    RESULTS: We first demonstrated that hypoxia-dependent apoptosis was induced by an overload of PA in two HCC cell lines (HepG2 and Hep3B) via excessive production of reactive oxygen species (ROS). Moreover, this observed PA-induced apoptosis was enhanced by HIF-1α knockdown (KD) in these cells under hypoxia. In addition, the combination of PA with FAO activator LC increased FAO activity and led to stronger cell death than PA alone in hypoxic HIF-1α KD cells, specifically through further ROS generation. To clarify the mechanism of hypoxia-induced FA metabolism reprogramming, expression levels of the genes encoding FAO enzymes CPT1A, ACSL1, MCAD, and LCAD, FA transporter CD36, and FA esterification enzymes DGAT and APGAT were analyzed using HIF-1α KD and scramble control (SC) cells. The results suggested that HIF-1α could repress mRNA expression of the FAO-related enzymes and CD36, while it upregulated FA esterification gene expression. This suggested a central role for HIF-1α in hypoxia-induced reprogramming of FA metabolism in HCC cells. Using a nude mouse model, PA administration was found to induce apoptosis from ROS overproduction in HIF-1α KD tumors compared with SC tumors. Additional LC treatment synergistically enhanced the PA-induced apoptosis in HIF-1α KD tumors. Finally, in vivo therapy composed of HIF-1α inhibitor YC-1 with PA + LC could induce ROS-mediated apoptosis in HepG2 tumors without significant toxicity.
    CONCLUSIONS: A combination therapy of YC-1 with PA + LC may be a unique anti-tumor therapy for targeting hypoxic HCC cells, specifically by ROS overproduction leading to forced FAO activation.
    Keywords:  Fatty acid oxidation; HCC; HIF-1α; Hypoxia; L-carnitine; Palmitic acids; ROS; YC-1
    DOI:  https://doi.org/10.1186/s40170-023-00328-w
  2. bioRxiv. 2023 Nov 29. pii: 2023.11.28.569098. [Epub ahead of print]
    Multivariate modeling of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
    Cara Abecunas, Mohammad Fallahi-Sichani.
      Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges in identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tissue lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings using data from an independent set of cell lines, pharmacological screens, and via single-cell analysis of patient-derived tumors. Our analysis uncovers new synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating these relationships could inform the development of more precise and context-specific, metabolism-targeted cancer therapies.
    DOI:  https://doi.org/10.1101/2023.11.28.569098
  3. J Enzyme Inhib Med Chem. 2024 Dec;39(1): 2290911
    Glutaminase inhibition as potential cancer therapeutics: current status and future applications.
    Rajath Cyriac, Kwangho Lee.
      Alterations in normal metabolic processes are defining features of cancer. Glutamine, an abundant amino acid in the human blood, plays a critical role in regulating several biosynthetic and bioenergetic pathways that support tumour growth. Glutaminolysis is a metabolic pathway that converts glutamine into various metabolites involved in the tricarboxylic acid (TCA) cycle and generates antioxidants that are vital for tumour cell survival. As glutaminase catalyses the initial step of this metabolic pathway, it is of great significance in cancer metabolism and tumour progression. Inhibition of glutaminase and targeting of glutaminolysis have emerged as promising strategies for cancer therapy. This review explores the role of glutaminases in cancer metabolism and discusses various glutaminase inhibitors developed as potential therapies for tumour regression.
    Keywords:  GLS; KEAP1 mutation; anticancer; cancer metabolism; glutaminase
    DOI:  https://doi.org/10.1080/14756366.2023.2290911
  4. Front Bioeng Biotechnol. 2023 ;11 1293268
    Label-free spatially maintained measurements of metabolic phenotypes in cells.
    Linghao Hu, Nianchao Wang, Joshua D Bryant, Lin Liu, Linglin Xie, A Phillip West, Alex J Walsh.
      Metabolic reprogramming at a cellular level contributes to many diseases including cancer, yet few assays are capable of measuring metabolic pathway usage by individual cells within living samples. Here, autofluorescence lifetime imaging is combined with single-cell segmentation and machine-learning models to predict the metabolic pathway usage of cancer cells. The metabolic activities of MCF7 breast cancer cells and HepG2 liver cancer cells were controlled by growing the cells in culture media with specific substrates and metabolic inhibitors. Fluorescence lifetime images of two endogenous metabolic coenzymes, reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavin adenine dinucleotide (FAD), were acquired by a multi-photon fluorescence lifetime microscope and analyzed at the cellular level. Quantitative changes of NADH and FAD lifetime components were observed for cells using glycolysis, oxidative phosphorylation, and glutaminolysis. Conventional machine learning models trained with the autofluorescence features classified cells as dependent on glycolytic or oxidative metabolism with 90%-92% accuracy. Furthermore, adapting convolutional neural networks to predict cancer cell metabolic perturbations from the autofluorescence lifetime images provided improved performance, 95% accuracy, over traditional models trained via extracted features. Additionally, the model trained with the lifetime features of cancer cells could be transferred to autofluorescence lifetime images of T cells, with a prediction that 80% of activated T cells were glycolytic, and 97% of quiescent T cells were oxidative. In summary, autofluorescence lifetime imaging combined with machine learning models can detect metabolic perturbations between glycolysis and oxidative metabolism of living samples at a cellular level, providing a label-free technology to study cellular metabolism and metabolic heterogeneity.
    Keywords:  autofluorescence; cancer; fluorescence lifetime; machine learning; metabolism
    DOI:  https://doi.org/10.3389/fbioe.2023.1293268
  5. Prostate. 2023 Dec 12.
    Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.
    David Moon, J Spencer Hauck, Xue Jiang, Holly Quang, Lingfan Xu, Fan Zhang, Xia Gao, Robert Wild, Jeffrey I Everitt, Everardo Macias, Yiping He, Jiaoti Huang.
      BACKGROUND: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear.METHODS: Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, NCI-H660) were treated with DRP-104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP-104 on glutamine pathways. Efficacy of DRP-104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI-H660.
    RESULTS: DRP-104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP-104 treated CRPC cells were rescued by the addition of nucleosides. DRP-104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity.
    CONCLUSIONS: The prodrug DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC.
    Keywords:  DRP-104; cancer metabolism; castration-resistant
    DOI:  https://doi.org/10.1002/pros.24654
  6. Cancers (Basel). 2023 Nov 28. pii: 5612. [Epub ahead of print]15(23):
    Targeting Metabolic Vulnerabilities to Overcome Prostate Cancer Resistance: Dual Therapy with Apalutamide and Complex I Inhibition.
    Valentin Baumgartner, Dominik Schaer, Daniel Eberli, Souzan Salemi.
      Prostate cancer (PCa) often becomes drug-treatment-resistant, posing a significant challenge to effective management. Although initial treatment with androgen deprivation therapy can control advanced PCa, subsequent resistance mechanisms allow tumor cells to continue growing, necessitating alternative approaches. This study delves into the specific metabolic dependencies of different PCa subtypes and explores the potential synergistic effects of combining androgen receptor (AR) inhibition (ARN with mitochondrial complex I inhibition (IACS)). We examined the metabolic behaviors of normal prostate epithelial cells (PNT1A), androgen-sensitive cells (LNCaP and C4-2), and androgen-independent cells (PC-3) when treated with ARN, IACS, or a combination. The results uncovered distinct mitochondrial activities across PCa subtypes, with androgen-dependent cells exhibiting heightened oxidative phosphorylation (OXPHOS). The combination of ARN and IACS significantly curbed cell proliferation in multiple PCa cell lines. Cellular bioenergetics analysis revealed that IACS reduced OXPHOS, while ARN hindered glycolysis in certain PCa cells. Additionally, galactose supplementation disrupted compensatory glycolytic mechanisms induced by metabolic reprogramming. Notably, glucose-deprived conditions heightened the sensitivity of PCa cells to mitochondrial inhibition, especially in the resistant PC-3 cells. Overall, this study illuminates the intricate interplay between AR signaling, metabolic adaptations, and treatment resistance in PCa. The findings offer valuable insights into subtype-specific metabolic profiles and propose a promising strategy to target PCa cells by exploiting their metabolic vulnerabilities.
    Keywords:  IACS-010759; apalutamide; metabolism; mitochondria; prostate cancer
    DOI:  https://doi.org/10.3390/cancers15235612
  7. Cell Rep. 2023 Dec 08. pii: S2211-1247(23)01533-4. [Epub ahead of print]42(12): 113521
    Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice.
    Gregory R Lum, Sung Min Ha, Christine A Olson, Montgomery Blencowe, Jorge Paramo, Beck Reyes, Joyce H Matsumoto, Xia Yang, Elaine Y Hsiao.
      The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human epilepsy is unclear. We find that the clinical KD alters gut microbial function in children with refractory epilepsy. Colonizing mice with KD-associated microbes promotes seizure resistance relative to matched pre-treatment controls. Select metagenomic and metabolomic features, including those related to anaplerosis, fatty acid β-oxidation, and amino acid metabolism, are seen with human KD therapy and preserved upon microbiome transfer to mice. Mice colonized with KD-associated gut microbes exhibit altered hippocampal transcriptomes, including pathways related to ATP synthesis, glutathione metabolism, and oxidative phosphorylation, and are linked to susceptibility genes identified in human epilepsy. Our findings reveal key microbial functions that are altered by KD therapies for pediatric epilepsy and linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.
    Keywords:  CP: Microbiology; CP: Neuroscience; epilepsy; ketogenic diet; microbiome; seizure
    DOI:  https://doi.org/10.1016/j.celrep.2023.113521
  8. PeerJ. 2023 ;11 e16503
    Inhibition of non-small cell lung cancer (NSCLC) proliferation through targeting G6PD.
    Makamas Chanda, Pornchai Anuntasomboon, Komkrit Ruangritchankul, Poonlarp Cheepsunthorn, Chalisa L Cheepsunthorn.
      Background: Mounting evidence has linked cancer metabolic reprogramming with altered redox homeostasis. The pentose phosphate pathway (PPP) is one of the key metabolism-related pathways that has been enhanced to promote cancer growth. The glucose 6-phosphate dehydrogenase (G6PD) of this pathway generates reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for controlling cellular redox homeostasis.Objective: This research aimed to investigate the growth-promoting effects of G6PD in non-small cell lung cancer (NSCLC).
    Methods: Clinical characteristics and G6PD expression levels in lung tissues of 64 patients diagnosed with lung cancer at the King Chulalongkorn Memorial Hospital (Bangkok, Thailand) during 2009-2014 were analyzed. G6PD activity in NSCLC cell lines, including NCI-H1975 and NCI-H292, was experimentally inhibited using DHEA and siG6PD to study cancer cell proliferation and migration.
    Results: The positive expression of G6PD in NSCLC tissues was detected by immunohistochemical staining and was found to be associated with squamous cells. G6PD expression levels and activity also coincided with the proliferation rate of NSCLC cell lines. Suppression of G6PD-induced apoptosis in NSCLC cell lines by increasing Bax/Bcl-2 ratio expression. The addition of D-(-)-ribose, which is an end-product of the PPP, increased the survival of G6PD-deficient NSCLC cell lines.
    Conclusion: Collectively, these findings demonstrated that G6PD might play an important role in the carcinogenesis of NSCLC. Inhibition of G6PD might provide a therapeutic strategy for the treatment of NSCLC.
    Keywords:  DHEA; Glucose 6-phosphate dehydrogenase; Lung cancer; Metabolic reprogramming; NSCLC; Non-small cell lung cancer; PPP; Pentose phosphate pathway; Squamous cells; siG6PD
    DOI:  https://doi.org/10.7717/peerj.16503
  9. Cell Rep Methods. 2023 Dec 05. pii: S2667-2375(23)00325-9. [Epub ahead of print] 100654
    Clinical forecasting of acute myeloid leukemia using ex vivo drug-sensitivity profiling.
    Aram N Andersen, Andrea M Brodersen, Pilar Ayuda-Durán, Laure Piechaczyk, Dagim Shiferaw Tadele, Lizet Baken, Julia Fredriksen, Mia Stoksflod, Andrea Lenartova, Yngvar Fløisand, Sigrid S Skånland, Jorrit M Enserink.
      Current treatment selection for acute myeloid leukemia (AML) patients depends on risk stratification based on cytogenetic and genomic markers. However, the forecasting accuracy of treatment response remains modest, with most patients receiving intensive chemotherapy. Recently, ex vivo drug screening has gained traction in personalized treatment selection and as a tool for mapping patient groups based on relevant cancer dependencies. Here, we systematically evaluated the use of drug sensitivity profiling for predicting patient survival and clinical response to chemotherapy in a cohort of AML patients. We compared computational methodologies for scoring drug efficacy and characterized tools to counter noise and batch-related confounders pervasive in high-throughput drug testing. We show that ex vivo drug sensitivity profiling is a robust and versatile approach to patient prognostics that comprehensively maps functional signatures of treatment response and disease progression. In conclusion, ex vivo drug profiling can assess risk for individual AML patients and may guide clinical decision-making.
    Keywords:  CP: Cancer biology
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100654
  10. Cell Rep. 2023 Dec 08. pii: S2211-1247(23)01582-6. [Epub ahead of print]42(12): 113570
    Fecal transfers from children on the ketogenic diet mimic the anti-seizure effect in mice.
    Stefanie Prast-Nielsen.
      The ketogenic diet (KD) mediates its anti-seizure effect through the gut microbiota in epilepsy mouse models.1 Lum et al.2 demonstrated that fecal microbiota from children with epilepsy treated with the KD decreases seizure susceptibility in mice after transfer.
    DOI:  https://doi.org/10.1016/j.celrep.2023.113570
  11. J Cardiovasc Magn Reson. 2023 Dec 14. 25(1): 77
    Regional quantification of cardiac metabolism with hyperpolarized [1-13C]-pyruvate CMR evaluated in an oral glucose challenge.
    Peder E Z Larson, Shuyu Tang, Xiaoxi Liu, Avantika Sinha, Nicholas Dwork, Sanjay Sivalokanathan, Jing Liu, Robert Bok, Karen G Ordovas, James Slater, Jeremy W Gordon, M Roselle Abraham.
      BACKGROUND: The heart has metabolic flexibility, which is influenced by fed/fasting states, and pathologies such as myocardial ischemia and hypertrophic cardiomyopathy (HCM). Hyperpolarized (HP) 13C-pyruvate MRI is a promising new tool for non-invasive quantification of myocardial glycolytic and Krebs cycle flux. However, human studies of HP 13C-MRI have yet to demonstrate regional quantification of metabolism, which is important in regional ischemia and HCM patients with asymmetric septal/apical hypertrophy.METHODS: We developed and applied methods for whole-heart imaging of 13C-pyruvate, 13C-lactate and 13C-bicarbonate, following intravenous administration of [1-13C]-pyruvate. The image acquisition used an autonomous scanning method including bolus tracking, real-time magnetic field calibrations and metabolite-specific imaging. For quantification of metabolism, we evaluated 13C metabolite images, ratio metrics, and pharmacokinetic modeling to provide measurements of myocardial lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) mediated metabolic conversion in 5 healthy volunteers (fasting & 30 min following oral glucose load).
    RESULTS: We demonstrate whole heart coverage for dynamic measurement of pyruvate-to-lactate conversion via LDH and pyruvate-to-bicarbonate conversion via PDH at a resolution of 6 × 6 × 21 mm3 (13C-pyruvate) and 12 × 12 × 21 mm3 (13C-lactate, 13C-bicarbonate). 13C-pyruvate and 13C-lactate were detected simultaneously in the RV blood pool, immediately after intravenous injection, reflecting LDH activity in blood. In healthy volunteers, myocardial 13C-pyruvate-SNR, 13C-lactate-SNR, 13C-bicarbonate-SNR, 13C-lactate/pyruvate ratio, 13C-pyruvate-to-lactate conversion rate, kPL, and 13C-pyruvate-to-bicarbonate conversion rate, kPB, all had statistically significant increases following oral glucose challenge. kPB, reflecting PDH activity and pyruvate entering the Krebs Cycle, had the highest correlation with blood glucose levels and was statistically significant.
    CONCLUSIONS: We demonstrate first-in-human regional quantifications of cardiac metabolism by HP 13C-pyruvate MRI that aims to reflect LDH and PDH activity.
    DOI:  https://doi.org/10.1186/s12968-023-00972-7
  12. Int J Mol Sci. 2023 Nov 24. pii: 16708. [Epub ahead of print]24(23):
    Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies.
    Maria Leśniak, Justyna Lipniarska, Patrycja Majka, Monika Lejman, Joanna Zawitkowska.
      Venetoclax is a strongly effective B-cell lymphoma-2 inhibitor (BCL-2) with an ability to selectively restore the apoptotic potential of cancerous cells. It has been proven that in combination with immunotherapy, targeted therapies, and lower-intensity therapies such as hypomethylating agents (HMAs) or low-dose cytarabine (LDAC), the drug can improve overall outcomes for adult patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), amongst other hematological malignancies, but its benefit in pediatric hematology remains unclear. With a number of preclinical and clinical trials emerging, the newest findings suggest that in many cases of younger patients, venetoclax combination treatment can be well-tolerated, with a safety profile similar to that in adults, despite often leading to severe infections. Studies aim to determine the activity of BCL-2 inhibitor in the treatment of both primary and refractory acute leukemias in combination with standard and high-dose chemotherapy. Although more research is required to identify the optimal venetoclax-based regimen for the pediatric population and its long-term effects on patients' outcomes, it can become a potential therapeutic agent for pediatric oncology.
    Keywords:  Bcl-2 inhibitors; leukemia; pediatric hematology; treatment; venetoclax
    DOI:  https://doi.org/10.3390/ijms242316708
  13. Elife. 2023 Dec 11. pii: RP89232. [Epub ahead of print]12
    Mitochondrial temperature homeostasis resists external metabolic stresses.
    Mügen Terzioglu, Kristo Veeroja, Toni Montonen, Teemu O Ihalainen, Tiina S Salminen, Paule Bénit, Pierre Rustin, Young-Tae Chang, Takeharu Nagai, Howard T Jacobs.
      Based on studies with a fluorescent reporter dye, Mito Thermo Yellow (MTY), and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell line was estimated to be up to 15°C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of oxidative phosphorylation (OXPHOS) complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of OXPHOS and is homeostatically maintained as a primary feature of mitochondrial metabolism.
    Keywords:  D. melanogaster; OXPHOS; biochemistry; bioenergetics; cell biology; chemical biology; human; mitochondria; mouse; organelle; temperature; thermogenesis
    DOI:  https://doi.org/10.7554/eLife.89232
  14. Br J Haematol. 2023 Dec 10.
    Durable responses in acute lymphoblastic leukaemia with the use of FLT3 and IDH inhibitors.
    Rafael Madero-Marroquin, Adam S DuVall, Caner Saygin, Peng Wang, Sandeep Gurbuxani, Richard A Larson, Wendy Stock, Anand Ashwin Patel.
      Data regarding the use of FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1/2 (IDH1/2) inhibitors in acute lymphoblastic leukaemia (ALL) are lacking. We identified 14 patients with FLT3- or IDH1/2-mutated ALL. Three early T-cell precursor-ALL patients received FLT3 or IDH2 inhibitors. Patient 1 maintains a complete remission (CR) with enasidenib after intolerance to chemotherapy. Patient 2 maintained a CR for 27 months after treatment with enasidenib for relapsed disease. Patient 3 was treated with venetoclax and gilteritinib at the time of relapse and maintained a CR with gilteritinib for 8 months. These cases suggest that FLT3 and IDH inhibitors could represent a viable therapeutic option for ALL patients with these mutations.
    Keywords:  ALL; FLT3; IDH1; IDH2; targeted
    DOI:  https://doi.org/10.1111/bjh.19250
  15. Biochem Pharmacol. 2023 Dec 09. pii: S0006-2952(23)00574-9. [Epub ahead of print] 115981
    Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.
    Katie H Hurrish, Yongwei Su, Shraddha Patel, Cassandra L Ramage, Jianlei Zhao, Brianna R Temby, Jenna L Carter, Holly Edwards, Steven A Buck, Sandra E Wiley, Maik Hüttemann, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Xun Bao, Jing Li, Jay Yang, Julie Boerner, Zhanjun Hou, Gheath Al-Atrash, Sergej N Konoplev, Jonathan Busquets, Stefano Tiziani, Larry H Matherly, Jeffrey W Taub, Marina Konopleva, Yubin Ge, Natalia Baran.
      Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.
    Keywords:  Acute myeloid leukemia; ME-344; Oxidative phosphorylation; Purine biosynthesis; Venetoclax
    DOI:  https://doi.org/10.1016/j.bcp.2023.115981
  16. Clin Exp Metastasis. 2023 Dec 09.
    Ketogenic diet does not promote triple-negative and luminal mammary tumor growth and metastasis in experimental mice.
    Meret Grube, Arno Dimmler, Anja Schmaus, Rafael Saup, Tabea Wagner, Boyan K Garvalov, Jonathan P Sleeman, Wilko Thiele.
      Ketogenic diets (KDs) can improve the well-being and quality of life of breast cancer patients. However, data on the effects of KDs on mammary tumors are inconclusive, and the influence of KDs on metastasis in general remains to be investigated. We therefore assessed the impact of a KD on growth and metastasis of triple negative murine 4T1 mammary tumors, and on the progression of luminal breast tumors in an autochthonous MMTV-PyMT mouse model. We found that KD did not influence the metastasis of 4T1 and MMTV-PyMT mammary tumors, but impaired 4T1 tumor cell proliferation in vivo, and also temporarily reduced 4T1 primary tumor growth. Notably, the ketogenic ratio (the mass of dietary fat in relation to the mass of dietary carbohydrates and protein) that is needed to induce robust ketosis was twice as high in mice as compared to humans. Surprisingly, only female but not male mice responded to KD with a sustained increase in blood β-hydroxybutyrate levels. Together, our data show that ketosis does not foster primary tumor growth and metastasis, suggesting that KDs can be safely applied in the context of luminal breast cancer, and may even be advantageous for patients with triple negative tumors. Furthermore, our data indicate that when performing experiments with KDs in mice, the ketogenic ratio needed to induce ketosis must be verified, and the sex of the mice should also be taken into account.
    Keywords:  Breast cancer; Ketogenic diet; Ketosis; Metastasis; Primary tumor growth
    DOI:  https://doi.org/10.1007/s10585-023-10249-z
  17. Front Immunol. 2023 ;14 1284853
    Research progress on the mechanism of glycolysis in ovarian cancer.
    Chan Li, Fang-Yuan Liu, Ying Shen, Yuan Tian, Feng-Juan Han.
      Glycolysis is the preferred energy metabolism pathway in cancer cells even when the oxygen content is sufficient. Through glycolysis, cancer cells convert glucose into pyruvic acid and then lactate to rapidly produce energy and promote cancer progression. Changes in glycolysis activity play a crucial role in the biosynthesis and energy requirements of cancer cells needed to maintain growth and metastasis. This review focuses on ovarian cancer and the significance of key rate-limiting enzymes (hexokinase, phosphofructokinase, and pyruvate kinase, related signaling pathways (PI3K-AKT, Wnt, MAPK, AMPK), transcription regulators (HIF-1a), and non-coding RNA in the glycolytic pathway. Understanding the relationship between glycolysis and these different mechanisms may provide new opportunities for the future treatment of ovarian cancer.
    Keywords:  glycolysis; hexokinase; ovarian cancer; phosphofructokinase; pyruvate kinase
    DOI:  https://doi.org/10.3389/fimmu.2023.1284853
  18. Nat Metab. 2023 Dec 08.
    Phenotypic profiling of solute carriers characterizes serine transport in cancer.
    Vasileios Papalazarou, Alice C Newman, Alejandro Huerta-Uribe, Nathalie M Legrave, Mattia Falcone, Tong Zhang, Lynn McGarry, Dimitris Athineos, Emma Shanks, Karen Blyth, Karen H Vousden, Oliver D K Maddocks.
      Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.
    DOI:  https://doi.org/10.1038/s42255-023-00936-2
  19. Front Cell Dev Biol. 2023 ;11 1287084
    Heparanase contributes to pancreatic carcinoma progression through insulin-dependent glucose uptake.
    Alexia Abecassis, Esther Hermano, Adi Yifrach, Aron Popovtzer, Amichay Meirovitz, Michael Elkin.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor, which is highly resistant to existing therapies and characterized by one of the lowest survival rates known for solid cancers. Among the reasons for this poor prognosis are unique pathophysiological features of PDAC, such as dense extracellular matrix [ECM] creating barriers to drug delivery, as well as systemically-deregulated glucose metabolism manifested by diabetic conditions (i.e., hyperinsulinemia/hyperglycemia) occurring in the majority of PDAC patients. Moreover, in addition to systemically deregulated glucose homeostasis, intracellular metabolic pathways in PDAC are rewired toward increased glucose uptake/anabolic metabolism by the tumor cells. While the role of oncogene-driven programs in governing these processes is actively studied, mechanisms linking metabolic dysregulation and ECM enzymatic remodeling to PDAC progression/therapy resistance are less appreciated. The aim of the current study was to investigate the action of heparanase (the predominant mammalian enzyme that degrades heparan sulfate glycosaminoglycan in the ECM), as a molecular link between the diabetic state and the intracellular metabolic rewiring in PDAC pathogenesis. Here we show that in PDAC elevated levels of heparanase, coupled with diabetic conditions typical for PDAC patients, promote growth and chemotherapy resistance of pancreatic carcinoma by favoring insulin receptor signaling and GLUT4-mediated glucose uptake into tumor cells. Collectively, our findings underscore previously unknown mechanism through which heparanase acts at the interface of systemic and intracellular metabolic alterations in PDAC and attest the enzyme as an important and potentially modifiable contributor to the chemo-resistance of pancreatic tumors.
    Keywords:  diabetes; gemcitabine; glucose uptake; heparanase; pancreatic cancer
    DOI:  https://doi.org/10.3389/fcell.2023.1287084
  20. J Inherit Metab Dis. 2023 Dec 12.
    Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by 1 H HR-MAS NMR.
    Christoph Meyer, Damian Hertig, Janine Arnold, Christian Urzi, Sandra Kurth, Johannes A Mayr, André Schaller, Peter Vermathen, Jean-Marc Nuoffer.
      In this study, we investigated the metabolic signatures of different mitochondrial defects (two different complex I and complex V, and the one MDH2 defect) in human skin fibroblasts (HSF). We hypothesized that using a selective culture medium would cause defect specific adaptation of the metabolome and further our understanding of the biochemical implications for the studied defects. All cells were cultivated under galactose stress condition and compared to glucose-based cell culture condition. We investigated the bioenergetic profile using Seahorse XFe96 cell analyzer and assessed the extracellular metabolic footprints and the intracellular metabolic fingerprints using NMR. The galactose-based culture condition forced a bioenergetic switch from a glycolytic to an oxidative state in all cell lines which improved overall separation of controls from the different defect groups. The extracellular metabolome was discriminative for separating controls from defects but not the specific defects, whereas the intracellular metabolome suggests CI and CV changes and revealed clear MDH2 defect-specific changes in metabolites associated with the TCA cycle, malate aspartate shuttle, and the choline metabolism, which are pronounced under galactose condition.
    Keywords:  CI; CV; MDH2; NMR; galactose; mitochondrial dysfunction
    DOI:  https://doi.org/10.1002/jimd.12696
  21. Front Nutr. 2023 ;10 1285516
    Diet-driven microbiome changes and physical activity in cancer patients.
    Sona Ciernikova, Aneta Sevcikova, Viola Stevurkova, Michal Mego.
      Exploring the role of the gut microbiome in oncology is gaining more attention, mainly due to its ability to shape the immune system in cancer patients. A well-balanced microbial composition forms a symbiotic relationship with the host organism. Mounting evidence supports the potential of modifiable lifestyle factors, such as diet and physical activity, in restoring intestinal dysbiosis related to cancer development and treatment. In this Minireview, we describe the host-microbiome interplay following different dietary patterns, including a high-fat diet, fiber-rich diet, diet rich in rice and beans, Mediterranean diet, ketogenic diet, and physical activity in preclinical findings and clinical settings. According to the results, nutrition is a critical factor influencing the composition of gut microbial communities. Therefore, knowledge about the patient's nutritional status in pre-treatment and treatment becomes crucial for further management. A combination of individualized dietary habits and professional training plans might help to maintain gut homeostasis, potentially improving the response to anti-cancer therapy and the quality of life in cancer survivors. However, a deep understanding of underlying mechanisms and large clinical trials are needed to uncover clinically relevant correlations for personalized treatment approaches leading to better outcomes for cancer patients.
    Keywords:  cancer; dietary interventions; gut microbiome; physical activity; treatment response
    DOI:  https://doi.org/10.3389/fnut.2023.1285516
  22. Res Sq. 2023 Nov 30. pii: rs.3.rs-3647514. [Epub ahead of print]
    Supraphysiological glutamine as a means of depleting intracellular amino acids to enhance pancreatic cancer chemosensitivity.
    Neil Bhowmick, Hayato Muranaka, Sandrine Billet, Carlos Cruz-Hernández, Johanna Ten Hoeve, Gabrielle Gonzales, Omer Elmadbouh, Le Zhang, Bethany Smith, Mourad Tighiouart, Sungyong You, Mouad Edderkaoui, Andrew Hendifar, Stephen Pandol, Jun Gong.
      Limited efficacy of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) patients contributes to high mortality. Cancer cells develop strategies to secure nutrients in nutrient-deprived conditions and chemotherapy treatment. Despite the dependency of PDAC on glutamine (Gln) for growth and survival, strategies designed to suppress Gln metabolism have limited effects. Here, we demonstrated that supraphysiological concentrations of glutamine (SPG) could produce paradoxical responses leading to tumor growth inhibition alone and in combination with chemotherapy. Integrated metabolic and transcriptomic analysis revealed that the growth inhibitory effect of SPG was the result of a decrease in intracellular amino acid and nucleotide pools. Mechanistically, disruption of the sodium gradient, plasma membrane depolarization, and competitive inhibition of amino acid transport mediated amino acid deprivation. Among standard chemotherapies given to PDAC patients, gemcitabine treatment resulted in a significant enrichment of amino acid and nucleoside pools, exposing a metabolic vulnerability to SPG-induced metabolic alterations. Further analysis highlighted a superior anticancer effect of D-glutamine, a non-metabolizable enantiomer of the L-glutamine, by suppressing both amino acid uptake and glutaminolysis, in gemcitabine-treated preclinical models with no apparent toxicity. Our study suggests supraphysiological glutamine could be a means of inhibiting amino acid uptake and nucleotide biosynthesis, potentiating gemcitabine sensitivity in PDAC.
    DOI:  https://doi.org/10.21203/rs.3.rs-3647514/v1
  23. Nat Metab. 2023 Dec 13.
    Metabolic Messengers: ketone bodies.
    Alisa B Nelson, Eric D Queathem, Patrycja Puchalska, Peter A Crawford.
      Prospective molecular targets and therapeutic applications for ketone body metabolism have increased exponentially in the past decade. Initially considered to be restricted in scope as liver-derived alternative fuel sources during periods of carbohydrate restriction or as toxic mediators during diabetic ketotic states, ketogenesis and ketone bodies modulate cellular homeostasis in multiple physiological states through a diversity of mechanisms. Selective signalling functions also complement the metabolic fates of the ketone bodies acetoacetate and D-β-hydroxybutyrate. Here we discuss recent discoveries revealing the pleiotropic roles of ketone bodies, their endogenous sourcing, signalling mechanisms and impact on target organs, and considerations for when they are either stimulated for endogenous production by diets or pharmacological agents or administered as exogenous wellness-promoting agents.
    DOI:  https://doi.org/10.1038/s42255-023-00935-3
  24. Cancers (Basel). 2023 Nov 28. pii: 5614. [Epub ahead of print]15(23):
    Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells.
    Paweł Przybylski, Anna Lewińska, Iwona Rzeszutek, Dominika Błoniarz, Aleksandra Moskal, Gabriela Betlej, Anna Deręgowska, Martyna Cybularczyk-Cecotka, Tomasz Szmatoła, Grzegorz Litwinienko, Maciej Wnuk.
      Mitochondria, the main cellular power stations, are important modulators of redox-sensitive signaling pathways that may determine cell survival and cell death decisions. As mitochondrial function is essential for tumorigenesis and cancer progression, mitochondrial targeting has been proposed as an attractive anticancer strategy. In the present study, three mitochondria-targeted quercetin derivatives (mitQ3, 5, and 7) were synthesized and tested against six breast cancer cell lines with different mutation and receptor status, namely ER-positive MCF-7, HER2-positive SK-BR-3, and four triple-negative (TNBC) cells, i.e., MDA-MB-231, MDA-MB-468, BT-20, and Hs 578T cells. In general, the mito-quercetin response was modulated by the mutation status. In contrast to unmodified quercetin, 1 µM mitQ7 induced apoptosis in breast cancer cells. In MCF-7 cells, mitQ7-mediated apoptosis was potentiated under glucose-depleted conditions and was accompanied by elevated mitochondrial superoxide production, while AMPK activation-based energetic stress was associated with the alkalization of intracellular milieu and increased levels of NSUN4. Mito-quercetin also eliminated doxorubicin-induced senescent breast cancer cells, which was accompanied by the depolarization of mitochondrial transmembrane potential. Limited glucose availability also sensitized doxorubicin-induced senescent breast cancer cells to apoptosis. In conclusion, we show an increased cytotoxicity of mitochondria-targeted quercetin derivatives compared to unmodified quercetin against breast cancer cells with different mutation status that can be potentiated by modulating glucose availability.
    Keywords:  AMPK; breast cancer; doxorubicin-induced senescence; mito-quercetin; oxidative stress; senolysis
    DOI:  https://doi.org/10.3390/cancers15235614
  25. J Neurochem. 2023 Dec 08.
    Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease.
    Claudia Salcedo, Victoria Pozo Garcia, Bernat García-Adán, Aishat O Ameen, Georgi Gegelashvili, Helle S Waagepetersen, Kristine K Freude, Blanca I Aldana.
      Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)-derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin-1 (PSEN-1) gene as found in familial types of AD (fAD). Methods such as live-cell bioenergetics and metabolic mapping using [13 C]-enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN-1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN-1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN-1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology.
    Keywords:  APP; PSEN-1; energy metabolism; excitotoxicity; hiPSC astrocytes; hiPSC neurons
    DOI:  https://doi.org/10.1111/jnc.16014
  26. Eur J Clin Invest. 2023 Dec 08. e14146
    Sperm mitochondria dysfunction in response to testicular cancer.
    Maryam Qasemi, Vishma Pratap Sur, Ondrej Simonik, Pavla Postlerova, Pavel Skrobanek, Tomas Hradec, Ludmila Boublikova, Libor Zamecnik, Tomas Buchler, Jiri Neuzil, Katerina Komrskova.
      Testicular cancer is the most common form of cancer in young men of reproductive age and its incidence is increasing globally. With the currently successful treatment and 95% survival rate, there is a need for deeper understanding of testicular cancer-related infertility. Most patients with testicular cancer experience semen abnormalities prior to cancer therapy. However, the exact mechanism of the effect of testicular cancer on sperm anomalies is not known. Mitochondria are organelles that play a crucial role in both tumorigenesis and spermatogenesis and their malfunction may be an important factor resulting in sperm abnormalities in testicular cancer patients. Within the scope of this review, we will discuss current knowledge of testicular cancer-related alterations in the ATP production pathway, a possible pathophysiological switch from oxidative phosphorylation (OXPHOS) to glycolysis, as well as the role of oxidative stress promoting sperm dysfunction. In this regard, the review provides a summary of the impact of testicular cancer on sperm quality as a possible consequence of impaired mitochondrial function including the energy metabolic pathways that are known to be altered in the sperm of testicular cancer patients.
    Keywords:  OXPHOS; glycolysis; mitochondrial dysfunction; sperm pathology; testicular cancer
    DOI:  https://doi.org/10.1111/eci.14146
  27. Front Oncol. 2023 ;13 1285209
    Application and development of Deuterium Metabolic Imaging in tumor glucose metabolism: visualization of different metabolic pathways.
    Jiayu Wan, Yusheng Guo, Hebing Chen, Peng Sun, Xiaoxiao Zhang, Tianhe Ye, Lingli Li, Feng Pan, Lian Yang.
      Cancer metabolism has emerged as a pivotal area of research recently. The ability to visualize and comprehend the metabolic processes of cancer holds immense clinical value, particularly in the diagnosis of malignant tumors and the assessment of treatment responses. Deuterium Metabolic Imaging (DMI), as a robust, simple, and versatile MR spectroscopic imaging tool, demonstrates promise in tumor diagnosis and treatment efficacy assessment. This review explored the latest developments and applications of DMI in oncology across various tumor metabolic axes, with a specific emphasis on its potential for clinical translation. DMI offers invaluable insights into tumor biology, treatment responses, and prognostic outcomes. Notably, DMI can identify early responses to immunotherapy, a prominent area of current research interest. In conclusion, DMI harbors the potential to evolve into a convenient and efficient imaging technique in clinical practice, thereby advancing precision medicine and improving the diagnosis and evaluation of cancer treatments.
    Keywords:  cancer immunotherapy; cancer metabolism; deuterium metabolic imaging (DMI); magnetic resonance imaging; molecular imaging
    DOI:  https://doi.org/10.3389/fonc.2023.1285209
  28. Mol Cell Biochem. 2023 Dec 11.
    Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis.
    Wenxin Zhang, Yan Wang, Lu Chen, Haifei Chen, Huijie Qi, Yong Zheng, Yongli Du, Liudi Zhang, Tianxiao Wang, Qunyi Li.
      Malignant gliomas are an exceptionally lethal form of cancer with limited treatment options. Dihydroartemisinin (DHA), a sesquiterpene lactone antimalarial compound, has demonstrated therapeutic effects in various solid tumors. In our study, we aimed to investigate the mechanisms underlying the anticancer effects of DHA in gliomas. To explore the therapeutic and molecular mechanisms of DHA, we employed various assays, including cell viability, flow cytometry, mitochondrial membrane potential, glucose uptake and glioma xenograft models. Our data demonstrated that DHA significantly inhibited glioma cell proliferation in both temozolomide-resistant cells and glioma stem-like cells. We found that DHA-induced apoptosis occurred via the mitochondria-mediated pathway by initiating mitochondrial dysfunction before promoting apoptosis. Moreover, we discovered that DHA treatment substantially reduced the expression of the mitochondrial biogenesis-related gene, ERRα, in glioma cells. And the ERRα pathway is a critical target in treating glioma with DHA. Our results also demonstrated that the combination of DHA and temozolomide synergistically inhibited the proliferation of glioma cells. In vivo, DHA treatment remarkably extended survival time in mice bearing orthotopic glioblastoma xenografts. Thus, our findings suggest that DHA has a novel role in modulating cancer cell metabolism and suppressing glioma progression by activating the ERRα-regulated mitochondrial apoptosis pathway.
    Keywords:  Dihydroartemisinin; Estrogen-related receptor alpha; Glioma; Mitochondrial apoptosis; Temozolomide resistant
    DOI:  https://doi.org/10.1007/s11010-023-04892-z
  29. Methods Mol Biol. 2024 ;2746 1-20
    Plate-Based Assays for the Characterization of Mitochondrial and Cellular Phenotypes.
    Benjamin Henry Arnold, Oana Sanislav, Paul Robert Fisher, Sarah Jane Annesley.
      The mitochondria are essential to eukaryotic life, acting as key drivers of energy generation while also being involved in the regulation of many cellular processes including apoptosis, cell proliferation, calcium homeostasis, and metabolism. Mitochondrial diseases which disrupt these processes lead to a diverse range of pathologies and lack consistency in symptom presentation. In disease, mitochondrial activity and energy homeostasis can be adapted to cellular requirements, and studies using Dictyostelium and human lymphoblastoid cell lines have shown that such changes can be facilitated by the key cellular and energy regulators, TORC1 and AMPK. Fluorescence-based assays are increasingly utilized to measure mitochondrial and cell signalling function in mitochondrial disease research. Here, we describe a streamlined method for the simultaneous measurement of mitochondrial mass, membrane potential, and reactive oxygen species production using MitoTracker Green™ FM, MitoTracker Red™ CMXRos, and DCFH-DA probes. This protocol has been adapted for both Dictyostelium and human lymphoblastoid cell lines. We also describe a method for assessing TORC1 and AMPK activity simultaneously in lymphoblastoid cells. These techniques allow for the characterization of mitochondrial defects in a rapid and easy to implement manner.
    Keywords:  AMPK; Dictyostelium; Lymphoblast; Membrane potential; Mitochondrial mass; ROS; TORC1
    DOI:  https://doi.org/10.1007/978-1-0716-3585-8_1
  30. Sci Rep. 2023 Dec 09. 13(1): 21809
    Metabolomic profile of acute myeloid leukaemia parallels of prognosis and response to therapy.
    Lukasz Bolkun, Tomasz Pienkowski, Julia Sieminska, Joanna Godzien, Karolina Pietrowska, Janusz Kłoczko, Agnieszka Wierzbowska, Marcin Moniuszko, Mariusz Ratajczak, Adam Kretowski, Michal Ciborowski.
      The heterogeneity of acute myeloid leukemia (AML), a complex hematological malignancy, is caused by mutations in myeloid cells affecting their differentiation and proliferation. Thus, various cytogenetic alterations in AML cells may be characterized by a unique metabolome and require different treatment approaches. In this study, we performed untargeted metabolomics to assess metabolomics differences between AML patients and healthy controls, AML patients with different treatment outcomes, AML patients in different risk groups based on the 2017 European LeukemiaNet (ELN) recommendations for the diagnosis and management of AML, AML patients with and without FLT3-ITD mutation, and a comparison between patients with FLT3-ITD, CBF-AML (Core binding factor acute myelogenous leukemia), and MLL AML (mixed-lineage leukemia gene) in comparison to control subjects. Analyses were performed in serum samples using liquid chromatography coupled with mass spectrometry (LC-MS). The obtained metabolomics profiles exhibited many alterations in glycerophospholipid and sphingolipid metabolism and allowed us to propose biomarkers based on each of the above assessments as an aid for diagnosis and eventual classification, allowing physicians to choose the best-suited treatment approach. These results highlight the application of LC-MS-based metabolomics of serum samples as an aid in diagnostics and a potential minimally invasive prognostic tool for identifying various cytogenetic and treatment outcomes of AML.
    DOI:  https://doi.org/10.1038/s41598-023-48970-0
  31. Trends Cancer. 2023 Dec 08. pii: S2405-8033(23)00231-5. [Epub ahead of print]
    Plastic persisters: revival stem cells in colorectal cancer.
    Christopher J Tape.
      Colorectal cancer (CRC) is traditionally considered to be a genetically driven disease. However, nongenetic plasticity has recently emerged as a major driver of tumour initiation, metastasis, and therapy response in CRC. Central to these processes is a recently discovered cell type, the revival colonic stem cell (revCSC). In contrast to traditional proliferative CSCs (proCSCs), revCSCs prioritise survival over propagation. revCSCs play an essential role in primary tumour formation, metastatic dissemination, and nongenetic chemoresistance. Current evidence suggests that CRC tumours leverage intestinal stem cell plasticity to both proliferate (via proCSCs) when unchallenged and survive (via revCSCs) in response to cell-extrinsic pressures. Although revCSCs likely represent a major source of therapeutic failure in CRC, our increasing knowledge of this important stem cell fate provides novel opportunities for therapeutic intervention.
    Keywords:  colorectal cancer (CRC); drug-tolerant persister (DTP); metastasis; plasticity; revival stem cells
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.003
  32. Technol Cancer Res Treat. 2023 Jan-Dec;22:22 15330338231219434
    Unraveling the Sweet Secrets of HCC: Glucometabolic Rewiring in Hepatocellular Carcinoma.
    Sheraz Ahmad Bhat, Zeenat Farooq, Hagar Ismail, Irene Corona-Avila, Md Wasim Khan.
      Hepatocellular carcinoma (HCC) is the primary form of liver cancer. It causes ∼ 800 000 deaths per year, which is expected to increase due to increasing rates of obesity and metabolic dysfunction associated steatotic liver disease (MASLD). Current therapies include immune checkpoint inhibitors, tyrosine kinase inhibitors, and monoclonal antibodies, but these therapies are not satisfactorily effective and often come with multiple side effects and recurrences. Metabolic reprogramming plays a significant role in HCC progression and is often conserved between tumor types. Thus, targeting rewired metabolic pathways could provide an attractive option for targeting tumor cells alone or in conjunction with existing treatments. Therefore, there is an urgent need to identify novel targets involved in cancer-mediated metabolic reprogramming in HCC. In this review, we provide an overview of molecular rewiring and metabolic reprogramming of glucose metabolism in HCC to understand better the concepts that might widen the therapeutic window against this deadly cancer.
    Keywords:  glucose; hepatocellular carcinoma; liver disease; metabolism; reprogramming
    DOI:  https://doi.org/10.1177/15330338231219434
  33. Int J Mol Sci. 2023 Dec 02. pii: 17060. [Epub ahead of print]24(23):
    Increased Lipogenesis Is Important for Hexavalent Chromium-Transformed Lung Cells and Xenograft Tumor Growth.
    James T F Wise, Kazuya Kondo.
      Hexavalent chromium, Cr(VI), is a known carcinogen and environmental health concern. It has been established that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to the Cr(VI)-induced carcinogenesis mechanism. However, some hallmarks of cancer remain under-researched regarding the mechanism behind Cr(VI)-induced carcinogenesis. Increased lipogenesis is important to carcinogenesis and tumorigenesis in multiple types of cancers, yet the role increased lipogenesis has in Cr(VI) carcinogenesis is unclear. We report here that Cr(VI)-induced transformation of three human lung cell lines (BEAS-2B, BEP2D, and WTHBF-6) resulted in increased lipogenesis (palmitic acid levels), and Cr(VI)-transformed cells had an increased expression of key lipogenesis proteins (ATP citrate lyase [ACLY], acetyl-CoA carboxylase [ACC1], and fatty acid synthase [FASN]). We also determined that the Cr(VI)-transformed cells did not exhibit an increase in fatty acid oxidation or lipid droplets compared to their passage-matched control cells. Additionally, we observed increases in ACLY, ACC1, and FASN in lung tumor tissue compared with normal-adjacent lung tissue (in chromate workers that died of chromate-induced tumors). Next, using a known FASN inhibitor (C75), we treated Cr(VI)-transformed BEAS-2B with this inhibitor and measured cell growth, FASN protein expression, and growth in soft agar. We observed that FASN inhibition results in a decreased protein expression, decreased cell growth, and the inhibition of colony growth in soft agar. Next, using shRNA to knock down the FASN protein in Cr(VI)-transformed BEAS-2B cells, we saw a decrease in FASN protein expression and a loss of the xenograft tumor development of Cr(VI)-transformed BEAS-2B cells. These results demonstrate that FASN is important for Cr(VI)-transformed cell growth and cancer properties. In conclusion, these data show that Cr(VI)-transformation in vitro caused an increase in lipogenesis, and that this increase is vital for Cr(VI)-transformed cells.
    Keywords:  cancer metabolism; fatty acid synthase; hexavalent chromium; human lung cells; lipogenesis
    DOI:  https://doi.org/10.3390/ijms242317060
  34. Nature. 2023 Dec;624(7991): 258-260
    MYC protein helps cancer to take its vitamins.
    Martina Wallace.
      
    Keywords:  Cancer; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-03764-2
  35. Int J Mol Sci. 2023 Nov 25. pii: 16746. [Epub ahead of print]24(23):
    Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?
    Federica Conti, Serena Di Martino, Filippo Drago, Claudio Bucolo, Vincenzo Micale, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso, Piervito Lopriore.
      Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features ("red flags") may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity.
    Keywords:  mitochondria; primary mitochondrial diseases; rare diseases; red flags
    DOI:  https://doi.org/10.3390/ijms242316746
  36. Spectrochim Acta A Mol Biomol Spectrosc. 2023 Dec 01. pii: S1386-1425(23)01399-9. [Epub ahead of print]308 123714
    A flavonoid salt probe for distinguishing between tumor and normal cells.
    Jiaying Yu, Shen Yuan, Kai Sun, Xiaofan He, Xianfeng Chu, Lucheng Chen, Jinzhong Hu, Zhifei Wang.
      YH-2 represents an innovative, non-invasive fluorescent probe featuring a structure based on flavonoid onium salts. It is characterized by a well-suited Stokes shift and emits in the near-infrared (NIR) wavelength range. Its capacity to distinguish between HeLa cells, HepG2 cells, and LO2 cells is attributed to differential intracellular viscosity. Experimental results validate the heightened viscosity of organelles, such as the endoplasmic reticulum (ER), mitochondria and lysosomes in tumor cells compared to LO2 cells. Of paramount importance, YH-2 demonstrates the capability to swiftly image tumors within a mere 20 min following tail vein injection and this imaging ability can be sustained for an extended period of up to 5 h. This method offers a potential tumor diagnostic strategy in vivo.
    Keywords:  Density functional theory calculation; Distinguish between tumors and normal tissue; Fast tomur imaging; NIR-Fluorescence; Viscosity sensitivity
    DOI:  https://doi.org/10.1016/j.saa.2023.123714
  37. IUBMB Life. 2023 Dec 13.
    A hub for regulation of mitochondrial metabolism: Fatty acid and lipoic acid biosynthesis.
    Carol L Dieckmann.
      Having evolved from a prokaryotic origin, mitochondria retain pathways required for the catabolism of energy-rich molecules and for the biosynthesis of molecules that aid catabolism and/or participate in other cellular processes essential for life of the cell. Reviewed here are details of the mitochondrial fatty acid biosynthetic pathway (FAS II) and its role in building both the octanoic acid precursor for lipoic acid biosynthesis (LAS) and longer-chain fatty acids functioning in chaperoning the assembly of mitochondrial multisubunit complexes. Also covered are the details of mitochondrial lipoic acid biosynthesis, which is distinct from that of prokaryotes, and the attachment of lipoic acid to subunits of pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and glycine cleavage system complexes. Special emphasis has been placed on presenting what is currently known about the interconnected paths and loops linking the FAS II-LAS pathway and two other mitochondrial realms, the organellar translation machinery and Fe-S cluster biosynthesis and function.
    Keywords:  Saccharomyces; fatty acid biosynthesis; lipoic acid biosynthesis; mitochondrial biogenesis
    DOI:  https://doi.org/10.1002/iub.2802
  38. Cancer Res. 2023 Dec 14.
    Exploring the role of hyperinsulinemia in obesity-associated tumor development.
    Ericka Vélez-Bonet, Kristyn Gumpper-Fedus, Zobeida Cruz-Monserrate.
      Although there has been a long-standing connection between hyperinsulinemia and cancer development, there is a lack of understanding of the role of the insulin receptor on cells that can become cancerous. In a recent issue of Cell Metabolism, Zhang and colleagues, using a diet-induced obesity mouse model, identified a direct function of insulin receptors on pancreatic acinar cells expressing a KRASG12D mutation in promoting obesity-associated pancreatic cancer. Furthermore, insulin receptor signaling from hyperinsulinemia promoted the secretion of digestive enzymes that contributed to acinar to ductal metaplasia. These findings highlight an important connection between obesity, diabetes, and pancreatic tumor development and suggest potential strategies for obesity-associated cancer prevention targeting the insulin receptor signaling pathways.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3932
  39. Cell Signal. 2023 Dec 11. pii: S0898-6568(23)00424-2. [Epub ahead of print]114 111009
    Integration of proteomics and metabolomics reveals energy and metabolic alterations induced by glucokinase (GCK) partial inactivation in hepatocytes.
    Ziyan Xie, Jieying Liu, Ting Xie, Peng Liu, Xiangyi Hui, Qian Zhang, Xinhua Xiao.
      AIMS: Glucokinase (GCK) acts as the glucose sensor in maintaining glucose homeostasis. The inactivating mutation of the GCK gene leads to glucokinase-maturity onset diabetes of the young (GCK-MODY). This study aims to gain further insights into the molecular alterations triggered by GCK partial inactivation in hepatocytes, potentially underlying the favorable prognosis of GCK-MODY.MAIN METHODS: A GCK knockdown HepG2 cell model was established, and the integration of proteomics and metabolomics was used to gain a comprehensive understanding of the molecular pathway changes caused by GCK inactivation in the liver.
    KEY FINDINGS: Proteomic analysis identified 257 differential proteins. KEGG pathway enrichment analysis showed that protein expression changes in the GCK knockdown group were significantly enriched in central carbon metabolism, the TCA cycle, amino acid metabolism and the oxidative phosphorylation pathway. Among them, enzymes in the TCA cycle (PC, IDH2, SDH) were significantly downregulated in GCK-knockdown group. Targeted metabolomics revealed that in the GCK knockdown hepatocytes, TCA cycle intermediates were significantly decreased, including pyruvate, oxaloacetate, citrate and succinic acid, and three metabolites increased including glycine, betaine and homocysteine. These metabolic alterations in turn reduced the accumulation of reactive oxygen species in GCK knockdown hepatocytes. Correlation analysis indicated that TCA cycle metabolites were positively correlated with proteins involved in the TCA cycle, carbon metabolism, glycolysis, Ras signaling, fibrosis and inflammation.
    SIGNIFICANCE: In conclusion, GCK knockdown reduced TCA cycle flux and oxidative stress in hepatocytes by influencing the levels of key transcription factors and enzymes, providing a comprehensive understanding of the effects of GCK partial inactivation on liver metabolism and molecular mechanisms.
    Keywords:  GCK-MODY; Glucokinase; Liver; Metabolomics; Proteomics; TCA cycle
    DOI:  https://doi.org/10.1016/j.cellsig.2023.111009
  40. Clin Cancer Res. 2023 Dec 13.
    Integrative multi-omics analysis reveals different metabolic phenotypes based on molecular characteristics in thyroid cancer.
    Yoo Hyung Kim, Sang Jun Yoon, Mina Kim, Hwan Hee Kim, Young Shin Song, Jin Woo Jung, Dohyun Han, Sun Wook Cho, Sung Won Kwon, Young Joo Park.
      PURPOSE: Thyroid cancer (TC) metabolic characteristics vary depending on the molecular subtype determined by mutational status. We aimed to investigate the molecular subtype-specific metabolic characteristics of TCs.EXPERIMENTAL DESIGN: An integrative multi-omics analysis was conducted, incorporating transcriptomics, metabolomics, and proteomics data obtained from human tissues representing distinct molecular characteristics of TCs; BRAF-like (papillary TC with BRAFV600E mutation; PTC-B), RAS-like (follicular TC with RAS mutation; FTC-R), and ATC-like (anaplastic TC with BRAFV600E or RAS mutation; ATC-B or ATC-R). To validate our findings, we employed tissue microarray of human TC tissues and performed in vitro analyses of cancer cell phenotypes and metabolomic assays after inducing genetic knockdown.
    RESULTS: Metabolic properties differed between differentiated TCs of PTC-B and FTC-R, but were similar in de-differentiated TCs of ATC-B/R, regardless of their mutational status. Tricarboxylic acid (TCA) intermediates and branched-chain amino acids (BCAA) were enriched with the activation of TCA cycle only in FTC-R, whereas one-carbon metabolism and pyrimidine metabolism increased in both PTC-B and FTC-R and to a great extent in ATC-B/R. However, the protein expression levels of the BCAA transporter (SLC7A5) and a key enzyme in one-carbon metabolism (SHMT2) increased in all TCs and were particularly high in ATC-B/R. Knockdown of SLC7A5 or SHMT2 inhibited the migration and proliferation of TC cell lines differently, depending on the mutational status.
    CONCLUSIONS: These findings define the metabolic properties of each molecular subtype of TCs and identify metabolic vulnerabilities, providing a rationale for therapies targeting its altered metabolic pathways in advanced TC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2025
  41. Front Neuroinform. 2023 ;17 1278787
    Tissue Oxygen Depth Explorer: an interactive database for microscopic oxygen imaging data.
    Layth N Amra, Philipp Mächler, Natalie Fomin-Thunemann, Kıvılcım Kılıç, Payam Saisan, Anna Devor, Martin Thunemann.
      
    Keywords:  CMRO2; lifetime; metabolism; phosphorescence; two-photon
    DOI:  https://doi.org/10.3389/fninf.2023.1278787
  42. J Proteome Res. 2023 Dec 08.
    Lipidomics Profiling Reveals Differential Alterations after FAS Inhibition in 3D Colon Cancer Cell Culture Models.
    Brian D Fries, Fernando Tobias, Yijia Wang, Joseph H Holbrook, Amanda B Hummon.
      Cancerous cells synthesize most of their lipids de novo to keep up with their rapid growth and proliferation. Fatty acid synthase (FAS) is a key enzyme in the lipogenesis pathway that is upregulated in many cancers and has gained popularity as a druggable target of interest for cancer treatment. The first FAS inhibitor discovered, cerulenin, initially showed promise for chemotherapeutic purposes until it was observed that it had adverse side effects in mice. TVB-2640 (Denifanstat) is part of the newer generation of inhibitors. With multiple generations of FAS inhibitors being developed, it is vital to understand their distinct molecular downstream effects to elucidate potential interactions in the clinic. Here, we profile the lipidome of two different colorectal cancer (CRC) spheroids treated with a generation 1 inhibitor (cerulenin) or a generation 2 inhibitor (TVB-2640). We observe that the cerulenin causes drastic changes to the spheroid morphology as well as alterations to the lipid droplets found within CRC spheroids. TVB-2640 causes higher abundances of polyunsaturated fatty acids (PUFAs) whereas cerulenin causes a decreased abundance of PUFAs. The increase in PUFAs in TVB-2640 exposed spheroids indicates it is causing cells to die via a ferroptotic mechanism rather than a conventional apoptotic or necrotic mechanism.
    Keywords:  FAS inhibition; apoptosis; colon cancer; ferroptosis; lipidomics; spheroids
    DOI:  https://doi.org/10.1021/acs.jproteome.3c00593
  43. Nutrients. 2023 Nov 29. pii: 4950. [Epub ahead of print]15(23):
    Effects of Dietary Methionine Restriction on Cognition in Mice.
    Hannah Lail, Angela M Mabb, Marise B Parent, Filipe Pinheiro, Desiree Wanders.
      Dietary restriction of the essential amino acid, methionine, has been shown to induce unique metabolic protection. The peripheral benefits of methionine restriction (MR) are well established and include improvements in metabolic, energy, inflammatory, and lifespan parameters in preclinical models. These benefits all occur despite MR increasing energy intake, making MR an attractive dietary intervention for the prevention or reversal of many metabolic and chronic conditions. New and emerging evidence suggests that MR also benefits the brain and promotes cognitive health. Despite widespread interest in MR over the past few decades, many findings are limited in scope, and gaps remain in our understanding of its comprehensive effects on the brain and cognition. This review details the current literature investigating the impact of MR on cognition in various mouse models, highlights some of the key mechanisms responsible for its cognitive benefits, and identifies gaps that should be addressed in MR research moving forward. Overall findings indicate that in animal models, MR is associated with protection against obesity-, age-, and Alzheimer's disease-induced impairments in learning and memory that depend on different brain regions, including the prefrontal cortex, amygdala, and hippocampus. These benefits are likely mediated by increases in fibroblast growth factor 21, alterations in methionine metabolism pathways, reductions in neuroinflammation and central oxidative stress, and potentially alterations in the gut microbiome, mitochondrial function, and synaptic plasticity.
    Keywords:  Alzheimer’s disease; age; behavior; brain; cognition; female; high-fat diet; methionine restriction; obesity; sex
    DOI:  https://doi.org/10.3390/nu15234950
  44. Int J Mol Sci. 2023 Nov 29. pii: 16899. [Epub ahead of print]24(23):
    Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia.
    Keli Lima, Maria Fernanda Lopes Carvalho, Diego Antonio Pereira-Martins, Frederico Lisboa Nogueira, Lívia Bassani Lins de Miranda, Mariane Cristina do Nascimento, Rita de Cássia Cavaglieri, Jan Jacob Schuringa, João Agostinho Machado-Neto, Eduardo Magalhães Rego.
      Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P2, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses.
    Keywords:  THZ-P1-2; acute myeloid leukemia; phosphatidylinositol-5-phosphate 4-kinase type 2; venetoclax
    DOI:  https://doi.org/10.3390/ijms242316899
  45. ACS Appl Bio Mater. 2023 Dec 13.
    Suspension Culture System for Isolating Cancer Spheroids using Enzymatically Synthesized Cellulose Oligomers.
    Natsuki Hayakawa, Masahito Nishiura, Takahisa Anada, Shingo Kobayashi, Toshiki Sawada, Takeshi Serizawa, Masaru Tanaka.
      Isolating cancer cells from tissues and providing an appropriate culture environment are important for a better understanding of cancer behavior. Although various three-dimensional (3D) cell culture systems have been developed, techniques for collecting high-purity spheroids without strong stimulation are required. Herein, we report a 3D cell culture system for the isolation of cancer spheroids using enzymatically synthesized cellulose oligomers (COs) and demonstrate that this system isolates only cancer spheroids under coculture conditions with normal cells. CO suspensions in a serum-containing cell culture medium were prepared to suspend cells without settling. High-purity cancer spheroids could be separated by filtration without strong stimulation because the COs exhibited antibiofouling properties and a viscosity comparable to that of the culture medium. When human hepatocellular carcinoma (HepG2) cells, a model for cancer cells, were cultured in the CO suspensions, they proliferated clonally and efficiently with time. In addition, only developed cancer spheroids from HepG2 cells were collected in the presence of normal cells by using a mesh filter with an appropriate pore size. These results indicate that this approach has potential applications in basic cancer research and cancer drug screening.
    Keywords:  3D cell culture; cancer spheroids; cell isolation; cellulose; coculture
    DOI:  https://doi.org/10.1021/acsabm.3c00901
  46. Annu Int Conf IEEE Eng Med Biol Soc. 2023 Jul;2023 1-4
    Behavior of breast cancer cells under oxygen concentration gradients in a microfluidic device.
    Satoshi Aratake, Naoto Kawahara, Kenichi Funamoto.
      The tumor microenvironment (TME) is known as a chronic hypoxic environment, with spatiotemporal variation in oxygen concentration depending on the distance from blood vessels and the blood supply. In our previous studies, cancer cell behavior was observed under hypoxic conditions with spatial variation of oxygen concentration (oxygen concentration gradients); however, that under oxygen concentration gradients at low oxygen levels found in the TME has not been studied. In this study, we investigated the behavior of breast cancer cells at various oxygen concentration gradients, generated using a microfluidic device with oxygen concentration controllability. The results showed that cell distribution was altered in response to oxygen concentration, and tended to increase in a specific region at around 5% O2. Evaluation of changes in cell numbers due to proliferation, migration, and cell death indicated that proliferation strongly affected cell distribution.
    DOI:  https://doi.org/10.1109/EMBC40787.2023.10340327
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