bims-medica 2024-12-22 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–12–22
twenty-two papers selected by
Brett Chrest, Wake Forest University

Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.
A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.
Metformin targets mitochondrial complex I to lower blood glucose levels.
Current status of serum metabolites biomarkers for polyps and colorectal cancer: a systematic review.
Fast autofluorescence imaging to evaluate dynamic changes in cell metabolism.
Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients.
Olutasidenib demonstrates significant clinical activity in mutated IDH1 acute myeloid leukaemia arising from a prior myeloproliferative neoplasm.
Deuterium Metabolic Imaging Enables the Tracing of Substrate Fluxes Through the Tricarboxylic Acid Cycle in the Liver.
Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside.
Does the Ketogenic Diet Mediate Inflammation Markers in Obese and Overweight Adults? A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Mitochondrial Membrane Potential and Lactate Dehydrogenase Activity in a Model of Acute In Vitro Ischemia/Reperfusion Injury.
SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.
A Case-Control Study of Dietary Choline Intake and Risk of Colorectal Cancer Modified by Dietary B-Vitamin Intake.
Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.
Dietary intake of isoflavones and coumestrol and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian cancer screening trial.
Association of plasma branched-chain amino acid levels with colorectal cancer risk in a nested case-control study.
Fasting mimicking diet during neo-adjuvant chemotherapy in breast cancer patients: a randomized controlled trial study.
Unveiling the Link Between NADPH Oxidase 2 Activation and Mitochondrial Superoxide Formation in Leukemic Cell Killing Induced by Arsenic Trioxide.
Effects of a 12 Week Ketogenic Diet Intervention on Obese and Overweight Females with Glucose and Lipid Metabolism Disturbance.
The impact of 3-sulfo-taurolithocholic acid on ATPase activity in patients' colorectal cancer and normal colon tissues, and its hepatic effects in rodents.
Investigating Causal Associations of Diet Compositions with the Risk of Lung Cancer.
Spatial transcriptomics in breast cancer reveals tumour microenvironment-driven drug responses and clonal therapeutic heterogeneity.

Int J Mol Sci. 2024 Nov 27. pii: 12740. [Epub ahead of print]25(23):

Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.

Alexander V Panov, Vladimir I Mayorov, Sergey I Dikalov.

  In recent decades, several discoveries have been made that force us to reconsider old ideas about mitochondria and energy metabolism in the light of these discoveries. In this review, we discuss metabolic interaction between various organs, the metabolic significance of the primary substrates and their metabolic pathways, namely aerobic glycolysis, lactate shuttling, and fatty acids β-oxidation. We rely on the new ideas about the supramolecular structure of the mitochondrial respiratory chain (respirasome), the necessity of supporting substrates for fatty acids β-oxidation, and the reverse electron transfer via succinate dehydrogenase during β-oxidation. We conclude that ATP production during fatty acid β-oxidation has its upper limits and thus cannot support high energy demands alone. Meanwhile, β-oxidation creates conditions that significantly accelerate the cycle: glucose-aerobic glycolysis-lactate-gluconeogenesis-glucose. Therefore, glycolytic ATP production becomes an important energy source in high energy demand. In addition, lactate serves as a mitochondrial substrate after converting to pyruvate + H+ by the mitochondrial lactate dehydrogenase. All coupled metabolic pathways are irreversible, and the enzymes are organized into multienzyme structures.

Keywords:  aerobic glycolysis; beta-oxidation; fatty acids; gluconeogenesis; lactate; metabolism; mitochondria; respirasome

DOI:  https://doi.org/10.3390/ijms252312740
Cancer Metab. 2024 Dec 19. 12(1): 38

A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.

TashJaé Q Scales, Bradley Smith, Lisa M Blanchard, Nellie Wixom, Emily T Tuttle, Brian J Altman, Luke J Peppone, Joshua Munger, Thomas M Campbell, Erin K Campbell, Isaac S Harris.

   BACKGROUND: Amino acids are critical to tumor survival. Tumors can acquire amino acids from the surrounding microenvironment, including the serum. Limiting dietary amino acids is suggested to influence their serum levels. Further, a plant-based diet is reported to contain fewer amino acids than an animal-based diet. The extent to which a plant-based diet lowers the serum levels of amino acids in patients with cancer is unclear.
METHODS: Patients with metastatic breast cancer (n = 17) were enrolled in a clinical trial with an ad libitum whole food, plant-based diet for 8 weeks without calorie or portion restriction. Dietary changes by participants were monitored using a three-day food record. Serum was collected from participants at baseline and 8 weeks. Food records and serum were analyzed for metabolic changes.
RESULTS: We found that a whole food, plant-based diet resulted in a lower intake of calories, fat, and amino acids and higher levels of fiber. Additionally, body weight, serum insulin, and IGF were reduced in participants. The diet contained lower levels of essential and non-essential amino acids, except for arginine (glutamine and asparagine were not measured). Importantly, the lowered dietary intake of amino acids translated to reduced serum levels of amino acids in participants (5/9 essential amino acids; 4/11 non-essential amino acids).
CONCLUSIONS: These findings provide a tractable approach to limiting amino acid levels in persons with cancer. This data lays a foundation for studying the relationship between amino acids in patients and tumor progression. Further, a whole-food, plant-based diet has the potential to synergize with cancer therapies that exploit metabolic vulnerabilities.
TRIAL REGISTRATION: The clinical trial was registered with ClinicalTrials.gov identifier NCT03045289 on 2017-02-07.

Keywords:  Amino acids; Calories; Cancer; Carbohydrate; Diet; Fat; Fiber; Plant-based; Protein; Whole food

DOI:  https://doi.org/10.1186/s40170-024-00368-w
Sci Adv. 2024 Dec 20. 10(51): eads5466

Metformin targets mitochondrial complex I to lower blood glucose levels.

Colleen R Reczek, Ram P Chakrabarty, Karis B D'Alessandro, Zachary L Sebo, Rogan A Grant, Peng Gao, G R Budinger, Navdeep S Chandel.

Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.

DOI: https://doi.org/10.1126/sciadv.ads5466
Gastroenterol Rep (Oxf). 2024 ;12 goae106

Current status of serum metabolites biomarkers for polyps and colorectal cancer: a systematic review.

Maryam Fatimah Abu Bakar, Azmawati Mohammed Nawi, Siok Fong Chin, Suzana Makpol.

   Background: Early detection of colorectal cancer (CRC) is crucial to enhance the disease treatment and prognosis of patients. Colonoscopy remains the gold standard for CRC detection; however, it requires trained personnel with expensive tools. Currently, serum metabolites have been discovered to be used to discriminate patients with polyps and CRC. This study aimed to identify the most commonly detected predictive serum metabolites for polyps and CRC.
Methods: A systematic search of the Web of Science, PubMed, and Cochrane Library databases was conducted using PRISMA guidelines. Ten studies investigating serum metabolite biomarkers of CRC and polyps using different analytical platforms and study populations were included. QUADOMICS tool was used to analyse the quality of the included studies. All reported metabolites were then enriched into the pathways using MetaboAnalyst 5.0.
Results: We found that several potential signature metabolites overlapped between studies, including tyrosine, lysine, cystine, arabinose, and lactate for CRC and lactate and glutamate for polyps. The most affected pathways related to CRC were the urea cycle, glutathione metabolism, purine metabolism, glutamate metabolism, and ammonia recycling. In contrast, those affected in the polyps were the urea cycle, glutamate metabolism, glutathione metabolism, arginine and proline metabolism, and carnitine synthesis.
Conclusions: This review has found commonly detected serum metabolites for polyps and CRC with huge potential to be used in clinical settings. However, the differences between altered pathways in polyps and CRC, other external factors, and their effects on the regulation level, sensitivity, and specificity of each identified metabolite remained unclear, which could benefit from a further extensive cohort study and well-defined analysis equipment.

Keywords:  colorectal adenoma; colorectal carcinoma; metabolomics; screening tool; serum biomarker

DOI:  https://doi.org/10.1093/gastro/goae106
J Biomed Opt. 2024 Dec;29(12): 126501

Fast autofluorescence imaging to evaluate dynamic changes in cell metabolism.

Anna Theodossiou, Jocelyn Martinez, Alex J Walsh.

   Significance: Cellular metabolic dynamics can occur within milliseconds, yet there are no optimal tools to spatially and temporally capture these events. Autofluorescence imaging can provide metabolic information on the cellular level due to the intrinsic fluorescence of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and flavin adenine dinucleotide (FAD).
Aim: Our goal is to build and evaluate a widefield microscope optimized for rapid autofluorescence imaging of metabolic changes in cells.
Approach: A widefield, fluorescence microscope was assembled from an inverted microscope base, an light-emitting diode (LED) for excitation, and an image splitter for simultaneous but separate imaging of two bandwidths of emission (451/106 and 560/94 nm) on a single scientific complementary metal-oxide-semiconductor (sCMOS) camera. MCF-7 cells and primary murine hippocampal neurons were metabolically perturbed using cyanide and imaged to optimize illumination and camera exposure. To capture a rapid change in metabolism, MCF-7 cells were starved for 1 h and imaged while reintroduced to glucose.
Results: Significant differences in the optical redox ratio (ORR) and intensity of NAD(P)H divided by the summed intensities of NAD(P)H and FAD were quantified for cyanide-treated neurons and MCF-7 cells at illumination powers above 0.30 mW and camera exposures as low as 5 ms; however, low illumination and camera exposures hindered the ability to identify subcellular features. Minimal photobleaching was quantified for 30 s of continuous imaging for illuminations at 4.14 mW and below. Using the optimized illumination power of 4.14 mW and an exposure of 10 ms, continuous autofluorescence imaging of starved MCF-7 cells demonstrated a rapid, yet heterogeneous, increase in the ORR of cells upon exposure to glucose.
Conclusions: Ultimately, this widefield autofluorescence imaging system allowed for dynamic imaging and quantification of cellular metabolism at 99.6 Hz.

Keywords:  autofluorescence; cellular metabolism; flavin adenine dinucleotide; fluorescence microscopy; live cell imaging; nicotinamide adenine dinucleotide (phosphate)

DOI:  https://doi.org/10.1117/1.JBO.29.12.126501
Cell Metab. 2024 Dec 14. pii: S1550-4131(24)00450-9. [Epub ahead of print]

Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients.

Francesca Ligorio, Andrea Vingiani, Tommaso Torelli, Caterina Sposetti, Lorenzo Drufuca, Fabio Iannelli, Lucrezia Zanenga, Catherine Depretto, Secondo Folli, Gianfranco Scaperrotta, Giuseppe Capri, Giulia V Bianchi, Cristina Ferraris, Gabriele Martelli, Ilaria Maugeri, Leonardo Provenzano, Federico Nichetti, Luca Agnelli, Riccardo Lobefaro, Giovanni Fucà, Giuseppe Fotia, Luigi Mariani, Daniele Morelli, Vito Ladisa, Maria Carmen De Santis, Laura Lozza, Giovanna Trecate, Antonino Belfiore, Silvia Brich, Alessia Bertolotti, Daniele Lorenzini, Angela Ficchì, Antonia Martinetti, Elisa Sottotetti, Alessio Arata, Paola Corsetto, Luca Sorrentino, Mattia Rediti, Giulia Salvadori, Saverio Minucci, Marco Foiani, Giovanni Apolone, Massimiliano Pagani, Giancarlo Pruneri, Filippo de Braud, Claudio Vernieri.

  In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998).

Keywords:  body composition analysis; bulk RNA-seq analysis; fasting-mimicking diet; neoadjuvant treatment; phase 2 trial; single-cell RNA-seq analysis; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.cmet.2024.11.004
Br J Haematol. 2024 Dec 19.

Olutasidenib demonstrates significant clinical activity in mutated IDH1 acute myeloid leukaemia arising from a prior myeloproliferative neoplasm.

Stéphane De Botton, Christian Récher, Jorge Cortes, Antonio Curti, Pierre Fenaux, Pierre Peterlin, Arnaud Pigneux, Karen Yee, Andrew Wei, Alice Mims, Gary Schiller, Mwe Mwe Chao, Hua Tian, Justin M Watts.

  Acute myeloid leukaemia (AML) arising from a myeloproliferative neoplasm (MPN) is more aggressive and less responsive to therapies compared to de novo AML. Olutasidenib, an oral small-molecule inhibitor of mutated IDH1 (mIDH1), showed encouraging and durable responses in a phase 1/2 study of adults with post-MPN mIDH1 AML. Patients received olutasidenib 150 mg BID monotherapy or in combination with azacitidine. Primary end-points: safety and best response defined as complete remission (CR), CR with partial haematological recovery or morphological leukaemia-free state (MLFS). Analysis included 15 patients with post-MPN mIDH1 AML; 10 had relapsed or refractory AML and five had newly diagnosed AML. Six were treated with olutasidenib monotherapy and nine in combination with azacitidine. Treatment emergent adverse events occurred in 15 patients, three of whom discontinued therapy. CR: 40% (n = 6/15); median duration of response: 15.6 months (range: 1.7-44.3); CR with incomplete haematological recovery: 13% (n = 2/15); MLFS: 7% (n = 1/15); composite complete remission (CRc): 53% (n = 8/15); and overall response rate (ORR): 60% (9/18). Median duration of CRc and ORR: 13.15 (range: 2.4-48.7) and 14.3 months (range: 2.4-48.7), respectively, and median overall survival: 13.8 months (95% confidence interval: 3.70-23.7). Olutasidenib demonstrated encouraging response rates with a manageable safety profile for patients with post-MPN mIDH1 AML.

Keywords:  IDH1 mutation; acute myeloid leukaemia; blast‐phase myeloproliferative neoplasm; myeloproliferative neoplasms

DOI:  https://doi.org/10.1111/bjh.19944
NMR Biomed. 2025 Jan;38(1): e5309

Deuterium Metabolic Imaging Enables the Tracing of Substrate Fluxes Through the Tricarboxylic Acid Cycle in the Liver.

Viktoria Ehret, Sabine C Dürr, Usevalad Ustsinau, Joachim Friske, Thomas Scherer, Clemens Fürnsinn, Jana Starčuková, Thomas H Helbich, Cécile Philippe, Martin Krššák.

  Alterations in tricarboxylic acid (TCA) cycle metabolism are associated with hepatic metabolic disorders. Elevated hepatic acetate concentrations, often attributed to high caloric intake, are recognized as a pivotal factor in the etiology of obesity and metabolic syndrome. Therefore, the assessment of acetate breakdown and TCA cycle activity plays a central role in understanding the impact of diet-induced alterations on liver metabolism. Magnetic resonance-based deuterium metabolic imaging (DMI) could help to unravel the underlying mechanisms involved in disease development and progression, however, the application of conventional deuterated glucose does not lead to substantial enrichment in hepatic glutamine and glutamate. This study aimed to demonstrate the feasibility of DMI for tracking deuterated acetate breakdown via the TCA cycle in lean and diet-induced fatty liver (FL) rats using 3D DMI after an intraperitoneal infusion of sodium acetate-d3 at 9.4T. Localized and nonlocalized liver spectra acquired at 10 time points post-injection over a 130-min study revealed similar intrahepatic acetate uptake in both animal groups (AUCFL = 717.9 ± 131.1 mM▯min-1, AUClean = 605.1 ± 119.9 mM▯min-1, p = 0.62). Metabolic breakdown could be observed in both groups with an emerging glutamine/glutamate (Glx) peak as a downstream metabolic product (AUCFL = 113.6 ± 23.8 mM▯min-1, AUClean = 136.7 ± 41.7 mM▯min-1, p = 0.68). This study showed the viability of DMI for tracking substrate flux through the TCA cycle, underscoring its methodological potential for imaging metabolic processes in the body.

Keywords:  MASLD; TCA cycle; acetate; deuterium metabolic imaging; fatty liver disease; metabolism

DOI:  https://doi.org/10.1002/nbm.5309
J Clin Med. 2024 Dec 04. pii: 7391. [Epub ahead of print]13(23):

Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside.

Urna Kansakar, Crystal Nieves Garcia, Gaetano Santulli, Jessica Gambardella, Pasquale Mone, Stanislovas S Jankauskas, Angela Lombardi.

  Ketone bodies are molecules produced from fatty acids in the liver that act as energy carriers to peripheral tissues when glucose levels are low. Carbohydrate- and calorie-restricted diets, known to increase the levels of circulating ketone bodies, have attracted significant attention in recent years due to their potential health benefits in several diseases. Specifically, increasing ketones through dietary modulation has been reported to be beneficial for cardiovascular health and to improve glucose homeostasis and insulin resistance. Interestingly, although excessive production of ketones may lead to life-threatening ketoacidosis in diabetic patients, mounting evidence suggests that modest levels of ketones play adaptive and beneficial roles in pancreatic beta cells, although the exact mechanisms are still unknown. Of note, Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been shown to increase the levels of beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body, which may play a pivotal role in mediating some of their protective effects in cardiovascular health and diabetes. This systematic review provides a comprehensive overview of the scientific literature and presents an analysis of the effects of ketone bodies on cardiovascular pathophysiology and pancreatic beta cell function. The evidence from both preclinical and clinical studies indicates that exogenous ketones may have significant beneficial effects on both cardiomyocytes and pancreatic beta cells, making them intriguing candidates for potential cardioprotective therapies and to preserve beta cell function in patients with diabetes.

Keywords:  BHB; SGLT2 inhibitors; cardiovascular disease; diabetes; exogenous ketones; metabolism; supplements

DOI:  https://doi.org/10.3390/jcm13237391
Nutrients. 2024 Nov 22. pii: 4002. [Epub ahead of print]16(23):

Does the Ketogenic Diet Mediate Inflammation Markers in Obese and Overweight Adults? A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Mariangela Rondanelli, Clara Gasparri, Martina Pirola, Gaetan Claude Barrile, Alessia Moroni, Ignacio Sajoux, Simone Perna.

  Background/Objectives. The ketogenic diet has emerged as a potential treatment strategy for reducing inflammation. The purpose of this meta-analysis and systematic review is to look into how a ketogenic diet affects inflammatory biomarkers in persons who are overweight or obese. Methods. We conducted an extensive search of Web of Science, PubMed, Scopus, and Google Scholar to find pertinent studies reporting changes in inflammatory biomarkers such as C-reactive protein (CRP), the erythrocyte sedimentation rate, and cytokines after a ketogenic diet. Results. Seven randomized controlled trials involving 218 overweight or obese individuals who followed a ketogenic or control diet over 8 weeks to 2 years were included in the review, and five of those were considered for the meta-analysis. The primary outcomes were CRP and IL-6 levels. The results reported significant decreases after treatment for CRP (mean of -0.62 mg/dL (95% CI: -0.84, -0,40), and a slight, but not statistically significant, reduction in IL-6 (mean of -1.31 pg/mL (95% CI: -2.86, 0.25). Conclusions. The ketogenic diet could contribute to modulating inflammation in obese and overweight subjects.

Keywords:  CRP; inflammation; ketogenic diet; ketones; obesity

DOI:  https://doi.org/10.3390/nu16234002
Methods Mol Biol. 2025 ;2894 35-42

Mitochondrial Membrane Potential and Lactate Dehydrogenase Activity in a Model of Acute In Vitro Ischemia/Reperfusion Injury.

Deepthi Ashok, Haley Garbus, Obialunanma V Ebenebe.

  Experimental models of cardiac ischemia/reperfusion injury have served as useful tools in isolating the sequence of events and mechanisms involved following an infarct. The in vitro coverslip ischemia model in neonatal myocytes is key in observing acute cellular and organelle changes during ischemia and in reperfusion. Here we use neonatal mouse ventricular myocytes, and describe two experimental readouts of lactate dehydrogenase assay, for cell damage/injury and measurement of mitochondrial membrane potential.

Keywords:  Acute ischemia/reperfusion; Cell culture; Mitochondria potential; Neonatal mouse ventricular myocytes

DOI:  https://doi.org/10.1007/978-1-0716-4342-6_4
J Clin Invest. 2024 Dec 16. pii: e176708. [Epub ahead of print]134(24):

SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.

Leigh Goedeke, Yina Ma, Rafael C Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J Perry, Gary W Cline, Lawrence H Young, Gerald I Shulman.

  Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.

Keywords:  Cardiology; Glucose metabolism; Intermediary metabolism; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI176708
Nutrients. 2024 Dec 05. pii: 4200. [Epub ahead of print]16(23):

A Case-Control Study of Dietary Choline Intake and Risk of Colorectal Cancer Modified by Dietary B-Vitamin Intake.

Alyssa Y Chen, Eryn K Matich, Jonathan Laryea, Ping-Ching Hsu, Lihchyun Joseph Su.

   BACKGROUND/OBJECTIVES: The incidence of colorectal cancer (CRC) is rising, and Western diets high in red and processed meats may be contributing. It is important to identify dietary nutrients that increase CRC risk and perhaps interventions that may modulate such risk. The relationship between dietary choline intake and CRC is still unclear. We hypothesize that high dietary choline intake is associated with greater CRC risk, and B vitamin supplementation may modify this risk.
METHODS: In this case-control study, we collected demographic and dietary data using the validated National Cancer Institute CRC Risk Assessment Tool and Dietary Health Questionnaire III and analyzed colonoscopy outcomes. Logistic regression and stratified analyses were performed to calculate adjusted odds ratios and evaluate for effect modification.
RESULTS: Of 52 total patients, 21 had a normal colonoscopy result, and 31 were found to either have benign polyps or CRC. The average dietary choline intake was 207 mg/day in the normal group and 297 mg/day in the abnormal outcome group. A doubling in dietary choline intake was significantly associated with increased odds of polyps or CRC (OR 25.32, 95% CI 1.95-327.94). When stratified by vitamin B levels, the effect modification was difficult to confidently quantify due to the limited sample size.
CONCLUSIONS: Our findings suggest that higher dietary choline intake may be associated with an increased risk of CRC and its precursors, such as polyps. Although the potential modifying role of B vitamins was inconclusive, this study underscores the need for larger-scale research to further explore these associations and to assess the potential of dietary interventions in reducing CRC risk.

Keywords:  B vitamins; choline; colorectal cancer

DOI:  https://doi.org/10.3390/nu16234200
Blood. 2024 Dec 18. pii: blood.2024025690. [Epub ahead of print]

Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.

Remya Nair, An Vu, Abigail K Freer, Karanpreet S Bhatia, Dongxue Wang, Milan R Savani, Shannon M Matulis, Sagar Lonial, David L Jaye, Lawrence H Boise, Seung-Yong Seo, Timothy William Corson, Ajay K Nooka, Shruti Bhatt, Samuel K McBrayer, Vikas A Gupta, Xin Hu, Benjamin G Barwick, Amit R Reddi, Mala Shanmugam.

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature. Consistent with this, we identified that VS MM exhibit reduced heme biosynthesis and curiously elevated hemin (oxidized heme) uptake. Supplementation with hemin or protoporphyrin IX (heme lacking iron) promotes Ven resistance while targeting ferrochetalase, the penultimate enzyme involved in heme biosynthesis, increases Ven sensitivity in cell lines and primary MM cells. Mechanistically, heme-mediated activation of pro-survival RAS-RAF-MEK signaling and metabolic rewiring, increasing de novo purine synthesis, were found to contribute to heme-induced Ven resistance. Co-targeting BCL-2 and MCL-1 suppresses heme-induced Ven resistance. Interrogation of the MMRF CoMMpass study of patients shows increased purine and pyrimidine biosynthesis to corelate with poor progression free survival and overall survival. Elevated heme and purine biosynthesis gene signatures were also observed in matched relapse refractory MM, underscoring the relevance of heme metabolism in therapy refractory MM. Overall, our findings reveal for the first time a role for extrinsic heme, a physiologically relevant metabolite, in modulating proximity to the apoptotic threshold with translational implications for BCL-2 antagonism in MM therapy.

DOI: https://doi.org/10.1182/blood.2024025690
Br J Cancer. 2024 Dec 16.

Dietary intake of isoflavones and coumestrol and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian cancer screening trial.

Chunliang Liu, Michael Reger, Hao Fan, Jintao Wang, Jianjun Zhang.

BACKGROUND: Although phytoestrogens modulated pancreatic tumour growth in experimental studies, it remains unclear whether phytoestrogen intake is associated with pancreatic cancer.
METHODS: Of 92,278 persons who completed the Diet History Questionnaire in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, 346 were diagnosed with pancreatic cancer within a median follow-up of 9.4 years. Cox proportional hazards regression was used to evaluate pancreatic cancer risk in relation to phytoestrogen intake.
RESULTS: After adjustment for confounders, intakes of glycitein and formononetin were associated with a reduced risk of pancreatic cancer [highest vs. lowest quartile, hazard ratio (HR) (95% confidence interval (CI)) for glycitein: 0.60 (0.39, 0.92); P for linear trend: 0.01; HR for formononetin: 0.51 (0.37, 0.70); P for linear trend: 0.005]. These associations were stronger and their linear trends across the quartiles of intakes were more statistically significant among ever smokers than never-smokers. A reduced risk was also observed for ever smokers in the highest quartile of total isoflavones or daidzein compared with those in the lowest quartile.
CONCLUSIONS: Our study suggests that high intakes of total isoflavones and some individual isoflavones were inversely associated with pancreatic cancer risk, but this potential protective effect was confined to ever smokers.

DOI: https://doi.org/10.1038/s41416-024-02929-8
Jpn J Clin Oncol. 2024 Dec 13. pii: hyae172. [Epub ahead of print]

Association of plasma branched-chain amino acid levels with colorectal cancer risk in a nested case-control study.

Japan Public Health Center-Based Prospective Study Group

   BACKGROUND: Intake of branched-chain amino acids (BCAA) has been suggested to have a prophylactic effect against carcinogenesis in colorectal cancer (CRC). However, the possible effect of plasma BCAA concentration has not been fully evaluated.
METHODS: We conducted a prospective case-control study within a cohort of four public health center areas for which blood sample and questionnaire data from a 5-year follow-up survey were available. We identified 360 newly diagnosed CRC cases during the follow-up period and selected two matched controls for each case. We estimated odds ratio (OR) and 95% confidence intervals (CI) for CRC using conditional logistic regression models adjusted for potential confounding factors.
RESULTS: Increased plasma concentrations of BCAAs were not inversely associated with CRC risk after adjustment for potential confounders. Compared with the lowest quartile, ORs in the highest quartile of leucine, isoleucine, valine, and total BCAA were 0.74 (95% CI, 0.49-1.12), 0.85 (0.56-1.29), 0.75 (0.50-1.13), and 0.70 (0.47-1.05), respectively. After excluding cases diagnosed within the first 6 years of follow-up, total BCAA and leucine were significantly related to a decreased risk of CRC, with ORs in the highest quartile of total BCAA and leucine of 0.58 (0.35-0.96) and 0.56 (0.33-0.93), respectively.
CONCLUSIONS: We found no statistically significant inverse association between plasma BCAA concentrations and CRC risk in overall analyses, whereas on 6-year exclusion, total BCAA and leucine were associated with decreased CRC risk. Plasma BCAA concentrations may play a prophylactic role in colorectal carcinogenesis, and further investigation is warranted.

Keywords:  branched-chain amino acid; colorectal cancer; leucine, isoleucine; valine

DOI:  https://doi.org/10.1093/jjco/hyae172
Front Nutr. 2024 ;11 1483707

Fasting mimicking diet during neo-adjuvant chemotherapy in breast cancer patients: a randomized controlled trial study.

Alireza Bahrami, Shirin Haghighi, Mona Malekzadeh Moghani, Nastaran Khodakarim, Ehsan Hejazi.

   Objective: Preclinical evidences suggests that while fasting can reduce the side effects and toxicity of chemotherapy, it can make cancer cells more susceptible to chemotherapy. This study aimed to examine the effects of fasting mimicking diet (FMD) during neo-adjuvant chemotherapy in breast cancer (BC) patients.
Methods: Forty-four newly diagnosed human epidermal growth factor receptor 2-negative (HER2-negative) patients with BC were randomized equally into two groups (22 each), to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. This FMD was repeated every 3 weeks for 8 cycles. Efficacy, toxicity, hematologic, metabolic, and inflammatory parameters were measured and compared.
Results: The occurrence of grade III vomiting and neutropenia in the control group was significantly higher than the FMD group (P = <0.001 and p = 0.04 respectively). Erythrocytes (p = 0.01) and neutrophils (p = 0.002) counts were significantly higher in FMD group compared to control group after cycle 8. There was a significant increase in median glucose and median insulin levels (p = 0.01 and p = 0.005, respectively) in the control group between baseline and after cycle 8. While, the median Insulin-like growth factor-1 (IGF1) (p = 0.006) and hs-CRP (p = 0.02) levels were significantly decreased in the FMD group. At the end of study (after cycle 8), the median glucose level was significantly higher in control group (p = 0.008), while the median hs-CRP level was significantly lower in FMD group (p = 0.01). The Miller and Payne pathological response 4/5 (90-100% tumor cell loss) and the radiologically complete or partial response, as measured by MRI or ultrasound before surgery occurred more frequently in FMD group compared to the controls (p = 0.01).
Conclusion: Fasting mimicking diet was well tolerated during chemotherapy and reduced toxicity of chemotherapy and also, had beneficial effects of some metabolic parameters.
Clinical Trial Registration: https://irct.behdasht.gov.ir/user/trial/61386/view.

Keywords:  breast cancer; chemotherapy; fasting; fasting mimicking diet; toxicity

DOI:  https://doi.org/10.3389/fnut.2024.1483707
Pharmacol Res. 2024 Dec 16. pii: S1043-6618(24)00499-7. [Epub ahead of print] 107554

Unveiling the Link Between NADPH Oxidase 2 Activation and Mitochondrial Superoxide Formation in Leukemic Cell Killing Induced by Arsenic Trioxide.

Andrea Spina, Andrea Guidarelli, Gloria Buffi, Mara Fiorani, Orazio Cantoni.

  This study focused on the interplay between NADPH oxidase 2 (NOX 2) activation and mitochondrial superoxide (mitoO2.-) formation induced by clinically relevant concentrations of arsenic trioxide (ATO; As2O3) in acute promyelocytic leukemia (APL) cells. Carefully controlled inhibitor studies and small interfering RNA mediated downregulation of p47phox (a component of the NOX 2 complex) expression demonstrated that, in an APL cell line, ATO promotes upstream NOX 2 activation critically connected with the formation of mitoO2.- and with the ensuing mitochondrial permeability transition (MPT)-dependent apoptosis. Instead, acute myeloid leukemia (AML) cell lines respond to ATO with low NOX 2 activation, resulting in a state that is non-permissive for mitoO2.- formation. Consistently, through rescue experiments, we demonstrate that pharmacological stimulation of NOX 2 overcomes resistance in these cells, thereby initiating the same cascade of downstream events observed in APL cells. As a final note, several lines of evidence, including measurement of glutathione, catalase and glutathione peroxidase levels, indicated that the antioxidant machinery was similar in APL and AML cells. The results regarding nuclear factor erythroid 2 p45-related factor 2-dependent antioxidant responses were instead of more complex interpretation as NB4 cells appeared particularly responsive to ATO. Our findings allow a novel interpretation of the interplay between NOX 2 activation and mitoO2.- formation induced by ATO, ultimately steering leukemic cells towards MPT-dependent apoptosis. These mechanistic insights provide a rationale for the disparate responses of APL and AML cells to ATO, offering potential avenues for the development of therapeutic intervention tailored to specific leukemia subtypes.

Keywords:  Apoptosis; Arsenic trioxide; Mitochondrial permeability transition; Mitochondrial superoxide; NADPH oxidase 2-derived superoxide

DOI:  https://doi.org/10.1016/j.phrs.2024.107554
Nutrients. 2024 Dec 06. pii: 4218. [Epub ahead of print]16(23):

Effects of a 12 Week Ketogenic Diet Intervention on Obese and Overweight Females with Glucose and Lipid Metabolism Disturbance.

Grzegorz Klonek, Grzegorz Zydek, Robert Roczniok, Mariusz Panek, Adam Zając, Małgorzata Magdalena Michalczyk.

   BACKGROUND/OBJECTIVES: We evaluated the effects of a 12-week hypocaloric ketogenic diet (KD) on glucose and lipid metabolism, as well as body mass, in overweight, obese, and healthy-weight females. One hundred adult females completed the study, including 64 obese (97.99 ± 11.48 kg), 23 overweight (75.50 ± 5.12 kg), and 11 with normal body mass (65.93 ± 3.40 kg). All participants followed a KD consisting of less than 30 g of carbohydrates, approximately 60 g of protein, and 140 g of fat per day (80% unsaturated and 20% saturated fat).
METHODS: Glucose (Gl), insulin (I), glycated haemoglobin (HBA1c), HOMA-IR, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) were measured before and after the intervention. Additionally, body mass (BM), BMI (Body Mass Index), waist circumference (WC), hip circumference (HC), and thigh circumference (TC) were recorded.
RESULTS: After 12 weeks of the KD, significant improvements were observed in GL, I, TG, HDL-C, HOMA-IR across all groups. Also BM, BMI, TC, WC, and HC were significantly reduced in all participants. Notably, obese participants showed greater reductions in all variables compared to overweight and healthy-weight females.
CONCLUSIONS: A 12-week KD led to more pronounced improvements in biochemical markers and body mass in obese females compared to other groups. A KD may be particularly beneficial for obese females with hyperglycaemia, hyperinsulinemia, and lipid profile disturbances.

Keywords:  females; hyperglycaemia; ketogenic diet; obese; overweight

DOI:  https://doi.org/10.3390/nu16234218
Front Vet Sci. 2024 ;11 1480122

The impact of 3-sulfo-taurolithocholic acid on ATPase activity in patients' colorectal cancer and normal colon tissues, and its hepatic effects in rodents.

Solomiia Bychkova, Mykola Bychkov, Dani Dordević, Simon K-M R Rittmann, Monika Vítězová, Ivan Kushkevych.

  Colorectal cancer is influenced by genetic mutations, lifestyle factors, and diet, particularly high fat intake, which raises bile acid levels in the intestinal lumen. This study hypothesized that bile acids contribute to tumorigenesis by disrupting ion transport and ATPase activity in the intestinal mucosa. The effects of 3-sulfo-taurolithocholic acid (TLC-S) on ATPase activity were investigated in colorectal cancer samples from 10 patients, using adjacent healthy tissue as controls, and in rodent liver function. ATPase activity was measured spectrophotometrically by determining inorganic phosphorus (Pi) in postmitochondrial fractions. Ca2+ dynamics were assessed in isolated mouse hepatocytes with fluorescence imaging, and rat liver mitochondria were studied using polarographic methods to evaluate respiration and oxidative phosphorylation. TLC-S increased Na+/K+ ATPase activity by 1.5 times in colorectal cancer samples compared to controls (p ≤ 0.05). In healthy mucosa, TLC-S decreased Mg2+ ATPase activity by 3.6 times (p ≤ 0.05), while Mg2+ ATPase activity in cancer tissue remained unchanged. TLC-S had no significant effect on Ca2+ ATPase activity in healthy colon mucosa but showed a trend toward decreased activity in cancer tissue. In rat liver, TLC-S decreased Ca2+ ATPase and Na+/K+ ATPase activities while increasing basal Mg2+ ATPase activity (p ≤ 0.05). Additionally, TLC-S induced cytosolic Ca2+ signals in mouse hepatocytes, partially attenuated by NED-19, an NAADP antagonist (p ≤ 0.05). TLC-S also reduced the V3 respiration rate of isolated rat liver mitochondria during α-ketoglutarate oxidation. These findings suggest that TLC-S modulates ATPase activity differently in cancerous and healthy colon tissues, playing a role in colorectal cancer development. In rat liver, TLC-S affects mitochondrial activity and ATPase function, contributing to altered cytosolic calcium levels, providing insight into the mechanistic effects of bile acids on colorectal cancer and liver function.

Keywords:  Ca2+ ATPase; Na+/K+ ATPase; basal Mg2+ ATPase; bile acid; colon mucosae; colorectal cancer

DOI:  https://doi.org/10.3389/fvets.2024.1480122
Nutr Cancer. 2024 Dec 20. 1-8

Investigating Causal Associations of Diet Compositions with the Risk of Lung Cancer.

Song Wang, Deli Tan.

   OBJECTIVE: This study aimed to investigate the causal relationship between diet compositions and lung cancer (LC) risk.
METHODS: A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between diet and LC risk, including three LC subtypes. Instrumental variables (IVs) for three diet compositions were selected from genome-wide association studies (GWAS). Summary statistics for LC and its subtypes came from the largest meta-analysis. The inverse-variance weighted (IVW) method was used as the main MR analysis, with sensitivity analyses to ensure result robustness. Then, we conducted an observational study using data from National Health and Nutrition Examination Survey (NHANES) to verify the relationship.
RESULTS: Our results showed significant evidence that fat intake was correlated with the lower risk of lung adenocarcinoma. There were also suggestive correlations between fat intake and overall LC. However, no significant associations were found between other macronutrients and LC risk. NHANES data further showed that higher polyunsaturated fatty acid (PUFA) intake was linked to better outcomes in LC patients.
CONCLUSION: PUFA intake may have a protective effect against LC. Adjusting dietary proportions could potentially help in the primary prevention of LC.

Keywords:  Mendelian randomization; NHANES; causal relationship; diet compositions; lung cancer

DOI:  https://doi.org/10.1080/01635581.2024.2443260
NAR Cancer. 2024 Dec;6(4): zcae046

Spatial transcriptomics in breast cancer reveals tumour microenvironment-driven drug responses and clonal therapeutic heterogeneity.

María José Jiménez-Santos, Santiago García-Martín, Marcos Rubio-Fernández, Gonzalo Gómez-López, Fátima Al-Shahrour.

Breast cancer patients are categorized into three subtypes with distinct treatment approaches. Precision oncology has increased patient outcomes by targeting the specific molecular alterations of tumours, yet challenges remain. Treatment failure persists due to the coexistence of several malignant subpopulations with different drug sensitivities within the same tumour, a phenomenon known as intratumour heterogeneity (ITH). This heterogeneity has been extensively studied from a tumour-centric view, but recent insights underscore the role of the tumour microenvironment in treatment response. Our research utilizes spatial transcriptomics data from breast cancer patients to predict drug sensitivity. We observe diverse response patterns across tumour, interphase and microenvironment regions, unveiling a sensitivity and functional gradient from the tumour core to the periphery. Moreover, we find tumour therapeutic clusters with different drug responses associated with distinct biological functions driven by unique ligand-receptor interactions. Importantly, we identify genetically identical subclones with different responses depending on their location within the tumour ducts. This research underscores the significance of considering the distance from the tumour core and microenvironment composition when identifying suitable treatments to target ITH. Our findings provide critical insights into optimizing therapeutic strategies, highlighting the necessity of a comprehensive understanding of tumour biology for effective cancer treatment.

DOI: https://doi.org/10.1093/narcan/zcae046