bims-medica 2024-08-04 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–08–04
twenty papers selected by
Brett Chrest, East Carolina University

ASCT2 is a major contributor to serine uptake in cancer cells.
The Warburg Effect Revisited through Blood and Electron Flow.
The impact of different FLT3-inhibitors on overall survival of de novo acute myeloid leukemia: A network meta-analysis.
BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE.
The pyruvate dehydrogenase complex at the epigenetic crossroads of acetylation and lactylation.
SLC45A4 encodes a mitochondrial putrescine transporter that promotes GABA de novo synthesis.
Stable isotope-resolved metabolomics analyses of metabolic phenotypes reveal variable glutamine metabolism in different patient-derived models of non-small cell lung cancer from a single patient.
Isocitrate dehydrogenases 2-mediated dysfunctional metabolic reprogramming promotes intestinal cancer progression via regulating HIF-1A signaling pathway.
A MULTIPHASE VERY-LOW CALORIE KETOGENIC DIET IMPROVES SERUM REDOX BALANCE BY REDUCING OXIDATIVE STATUS IN OBESE PATIENTS.
Lactate-carried Mitochondrial Energy Overflow.
Emerging mechanisms and promising approaches in pancreatic cancer metabolism.
Greater molecular potential for glucose metabolism in adipose tissue and skeletal muscle of women compared with men.
Recent advances in fluorescent probes for ATP imaging.
Significance of targeting DNMT3A mutations in AML.
Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration.
Size-related variability of oxygen consumption rates in individual human hepatic cells.
Relationship of Ketosis With Myocardial Glucose Uptake Among Patients Undergoing FDG PET/CT for Evaluation of Cardiac Sarcoidosis.
A healthful plant-based diet can reduce the risk of developing colorectal cancer: case-control study.
Microenvironment matters: In vitro 3D bone marrow niches differentially modulate survival, phenotype and drug responses of acute myeloid leukemia (AML) cells.
Nutritional self-management in colorectal cancer patients and survivors: A scoping review.

Cell Rep. 2024 Jul 26. pii: S2211-1247(24)00881-7. [Epub ahead of print]43(8): 114552

ASCT2 is a major contributor to serine uptake in cancer cells.

Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Lina Lietuvninkas, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, Jonathan L Coloff.

  The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporters that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that estrogen receptor α (ERα) promotes serine uptake by directly activating SLC1A5 transcription. Collectively, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target.

Keywords:  ASCT2; CP: Cancer; ERα; SLC1A5; amino acid uptake; breast cancer; cancer metabolism; diet; purine biosynthesis; serine starvation; serine transporter

DOI:  https://doi.org/10.1016/j.celrep.2024.114552
Cancer Res. 2024 Jul 02. 84(13): 2046-2048

The Warburg Effect Revisited through Blood and Electron Flow.

Yahui Wang, Chi V Dang.

The Warburg effect describes the propensity of many cancers to consume glucose avidly and convert it to lactate in the presence of oxygen. The benefit of the Warburg effect on cancer cells remains enigmatic, particularly because extracellular disposal of incompletely oxidized lactate is wasteful. However, lactate is not discarded from the body, but rather recycled as pyruvate for metabolism through the tricarboxylic acid cycle in oxidative tissues and cells. Hence, tissue and interorgan metabolism play important roles in tumor metabolism. The production of tumor lactate to be recycled elsewhere parallels the Cori cycle, in which lactate produced by muscle activity is shuttled to the liver, where it is converted to pyruvate and subsequently stored as glucose moieties in glycogen. This perspective will consider this organismal contextwhile discussing how glucose is used in tumors. We highlight several key articles published decades ago in Cancer Research that are foundational to our current understanding of cancer biology and metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0474
Leuk Res. 2024 Jul 17. pii: S0145-2126(24)00115-2. [Epub ahead of print]144 107549

The impact of different FLT3-inhibitors on overall survival of de novo acute myeloid leukemia: A network meta-analysis.

Matteo Molica, Salvatore Perrone, Marco Rossi, Diana Giannarelli.

  FLT3 inhibitors combined with chemotherapy are the standard of care for newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, no head-to-head studies have established the superiority of one FLT3 inhibitor over another. We conducted a network meta-analysis (NMA) to evaluate overall survival (OS) among different FLT3 inhibitors. Three relevant randomized controlled trials (RCTs), involving 1.358 patients treated with midostaurin, quizartinib, and sorafenib, were included in our analysis. The hazard ratios (HRs) revealed no significant differences in OS between midostaurin and quizartinib (HR, 1.00; 95 % CI, 0.73-1.36), midostaurin and sorafenib (HR, 0.97; 95 % CI, 0.52-1.84), or quizartinib and sorafenib (HR, 0.97; 95 % CI, 0.51-1.85). This NMA, the first to explore this issue, found no OS differences among the different FLT3 inhibitors. In the absence of direct comparison trials, our findings provide practical insights for clinical decision-making.

Keywords:  Acute myeloid leukemia; FLT3 inhibitors; Head-to-head studies; Network meta-analysis

DOI:  https://doi.org/10.1016/j.leukres.2024.107549
bioRxiv. 2024 Jul 22. pii: 2024.01.23.576931. [Epub ahead of print]

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE.

Rocío Rojas, Christian Griñán-Ferré, Aida Castellanos, Ernesto Griego, Marc Martínez, Juan de Dios Navarro-López, Lydia Jiménez-Díaz, José Rodríguez-Álvarez, David Soto Del Cerro, Pablo E Castillo, Mercè Pallàs, Rut Fadó, Núria Casals.

The ketogenic diet, characterized by high fat and low carbohydrates, has gained popularity not only as a strategy for managing body weight but also for its efficacy in delaying cognitive decline associated with neurodegenerative diseases and the aging process. Since this dietary approach stimulates the liver's production of ketone bodies, primarily β-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons, we investigated whether BHB could mitigate impaired AMPA receptor trafficking, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as saturated fatty acids. Here, we observe that, in cultured primary cortical neurons, exposure to palmitic acid (200μM) decreased surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids, such as oleic acid and ω-3 docosahexaenoic acid (200μM), and BHB (5mM) increased them. Furthermore, BHB countered the adverse effects of palmitic acid on synaptic GluA1 levels in hippocampal neurons, as well as excitability and plasticity in hippocampal slices. Additionally, daily intragastric administration of BHB (100 mg/kg/day) for two months reversed cognitive impairment induced by a saturated high-fat diet (49% of calories from fat) in a mouse experimental model of obesity. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptors abundance, synaptic function and neuroplasticity, shedding light on the potential use of BHB to delay cognitive impairments associated with metabolic diseases.

DOI: https://doi.org/10.1101/2024.01.23.576931
Mol Genet Metab. 2024 Jul 16. pii: S1096-7192(24)00424-4. [Epub ahead of print]143(1-2): 108540

The pyruvate dehydrogenase complex at the epigenetic crossroads of acetylation and lactylation.

Peter W Stacpoole, Carolyn O Dirain.

  The pyruvate dehydrogenase complex (PDC) is remarkable for its size and structure as well as for its physiological and pathological importance. Its canonical location is in the mitochondrial matrix, where it primes the tricarboxylic acid (TCA) cycle by decarboxylating glycolytically-derived pyruvate to acetyl-CoA. Less well appreciated is its role in helping to shape the epigenetic landscape, from early development throughout mammalian life by its ability to "moonlight" in the nucleus, with major repercussions for human healthspan and lifespan. The PDC's influence on two crucial modifiers of the epigenome, acetylation and lactylation, is the focus of this brief review.

Keywords:  Acetylation; Epigenetics; Glycolysis; Histones; Inborn metabolic disorders; Lactylation; Nuclear translocation; Pyruvate dehydrogenase complex; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.ymgme.2024.108540
bioRxiv. 2024 Jul 24. pii: 2024.07.23.604788. [Epub ahead of print]

SLC45A4 encodes a mitochondrial putrescine transporter that promotes GABA de novo synthesis.

Cecilia Colson, Yujue Wang, James Atherton, Xiaoyang Su.

Solute carriers (SLC) are membrane proteins that facilitate the transportation of ions and metabolites across either the plasma membrane or the membrane of intracellular organelles. With more than 450 human genes annotated as SLCs, many of them are still orphan transporters without known biochemical functions. We developed a metabolomic-transcriptomic association analysis, and we found that the expression of SLC45A4 has a strong positive correlation with the cellular level of γ-aminobutyric acid (GABA). Using mass spectrometry and the stable isotope tracing approach, we demonstrated that SLC45A4 promotes GABA de novo synthesis through the Arginine/Ornithine/Putrescine (AOP) pathway. SLC45A4 functions as a putrescine transporter localized to the mitochondrial membrane to facilitate GABA production. Taken together, our results revealed a new biochemical mechanism where SLC45A4 controls GABA production.

DOI: https://doi.org/10.1101/2024.07.23.604788
Metabolomics. 2024 Jul 27. 20(4): 87

Stable isotope-resolved metabolomics analyses of metabolic phenotypes reveal variable glutamine metabolism in different patient-derived models of non-small cell lung cancer from a single patient.

Connor J Kinslow, Michael Bousamra Ll, Yihua Cai, Jun Yan, Pawel K Lorkiewicz, Ahmad Al-Attar, Jinlian Tan, Richard M Higashi, Andrew N Lane, Teresa W-M Fan.

   INTRODUCTION: Stable isotope tracers have been increasingly used in preclinical cancer model systems, including cell culture and mouse xenografts, to probe the altered metabolism of a variety of cancers, such as accelerated glycolysis and glutaminolysis and generation of oncometabolites. Comparatively little has been reported on the fidelity of the different preclinical model systems in recapitulating the aberrant metabolism of tumors.
OBJECTIVES: We have been developing several different experimental model systems for systems biochemistry analyses of non-small cell lung cancer (NSCLC1) using patient-derived tissues to evaluate appropriate models for metabolic and phenotypic analyses.
METHODS: To address the issue of fidelity, we have carried out a detailed Stable Isotope-Resolved Metabolomics study of freshly resected tissue slices, mouse patient derived xenografts (PDXs), and cells derived from a single patient using both 13C6-glucose and 13C5,15N2-glutamine tracers.
RESULTS: Although we found similar glucose metabolism in the three models, glutamine utilization was markedly higher in the isolated cell culture and in cell culture-derived xenografts compared with the primary cancer tissue or direct tissue xenografts (PDX).
CONCLUSIONS: This suggests that caution is needed in interpreting cancer biochemistry using patient-derived cancer cells in vitro or in xenografts, even at very early passage, and that direct analysis of patient derived tissue slices provides the optimal model for ex vivo metabolomics. Further research is needed to determine the generality of these observations.

Keywords:  Cancer metabolism; Non-small cell lung cancer; Patient-derived xenografts; Preclinical models; Primary cell culture; Stable isotope-resolved metabolomics

DOI:  https://doi.org/10.1007/s11306-024-02126-x
Int Immunopharmacol. 2024 Aug 01. pii: S1567-5769(24)01349-3. [Epub ahead of print]140 112828

Isocitrate dehydrogenases 2-mediated dysfunctional metabolic reprogramming promotes intestinal cancer progression via regulating HIF-1A signaling pathway.

Shixiong Liu, Yun Zhou, Yarong Chen, Yuqin Qiao, Lumucao Bai, Shenhua Zhang, Dongfang Men, Haibu Zhang, Fen Pan, Yongshen Gao, Jijing Wang, Yuping Wang.

  Changes in isocitrate dehydrogenases (IDH) lead to the production of the cancer-causing metabolite 2-hydroxyglutarate, making them a cause of cancer. However, the specific role of IDH in the progression of colon cancer is still not well understood. Our current study provides evidence that IDH2 is significantly increased in colorectal cancer (CRC) cells and actively promotes cell growth in vitro and the development of tumors in vivo. Inhibiting the activity of IDH2, either through genetic silencing or pharmacological inhibition, results in a significant increase in α-ketoglutarate (α-KG), indicating a decrease in the reductive citric acid cycle. The excessive accumulation of α-KG caused by the inactivation of IDH2 obstructs the generation of ATP in mitochondria and promotes the downregulation of HIF-1A, eventually inhibiting glycolysis. This dual metabolic impact results in a reduction in ATP levels and the suppression of tumor growth. Our study reveals a metabolic trait of colorectal cancer cells, which involves the active utilization of glutamine through reductive citric acid cycle metabolism. The data suggests that IDH2 plays a crucial role in this metabolic process and has the potential to be a valuable target for the advancement of treatments for colorectal cancer.

Keywords:  Citric acid cycle; Colorectal cancer; Glycolysis; Isocitrate dehydrogenases; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.intimp.2024.112828
Free Radic Biol Med. 2024 Jul 31. pii: S0891-5849(24)00584-7. [Epub ahead of print]

A MULTIPHASE VERY-LOW CALORIE KETOGENIC DIET IMPROVES SERUM REDOX BALANCE BY REDUCING OXIDATIVE STATUS IN OBESE PATIENTS.

Francesco Bellanti, Francesca Losavio, Stefano Quiete, Aurelio Lo Buglio, Chiara Calvanese, Michał Dobrakowski, Aleksandra Kasperczyk, Sławomir Kasperczyk, Gianluigi Vendemiale, Raffaele Ivan Cincione.

  The very-low calorie ketogenic diet (VLCKD) is recommended as an effective dietary approach for the management of obesity. This study investigated changes in circulating biomarkers of redox homeostasis induced by a multiphase VLCKD in obese individuals. A total of 40 obese subjects were prescribed a multiphasic VLCKD for eleven weeks. Anthropometric measurements, body composition parameters, calorimetric measures, and standard laboratory markers of glucose and lipid metabolism were evaluated at baseline (T0) and at the end of the dietary intervention (T1). Additionally, circulating markers of oxidative damage and antioxidant status were analyzed in serum and erythrocytes. Compared to T0, at T1 the multiphase VLCKD induced significant weight loss and reduction of waist circumference, with beneficial effects on body composition parameters and the glucose/lipid biochemical profile. Moreover, a decrease in serum markers of oxidative damage was reported at T1, while no changes in serum markers of antioxidant status and in erythrocyte redox markers were observed. In addition, a significant association was found between variations in anthropometric measurements, body composition, glucose metabolism parameters, and changes in circulating markers of oxidative damage. Regression models showed that variation in lipofuscin was significant predictor of changes in body mass index, fat mass, visceral adiposity, and insulin sensitivity. In conclusion, this study demonstrated that the multiphase VLCKD improves serum redox balance by reducing markers of oxidative damage in obese individuals, highlighting the interplay between adiposity, glucose metabolism, and redox homeostasis in the pathogenesis of obesity. Furthermore, these data provide a rationale for future investigations aimed at testing serum lipofuscin as a reliable redox marker in obesity.

Keywords:  fat mass; ketogenic diet; lipofuscin; obesity

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.07.038
bioRxiv. 2024 Jul 20. pii: 2024.07.19.604361. [Epub ahead of print]

Lactate-carried Mitochondrial Energy Overflow.

Daniela Rauseo, Yasna Contreras-Baeza, Hugo Faurand, Nataly Cárcamo, Raibel Suárez, Alexandra von Faber-Castell, Franco Silva, Valentina Mora-González, Matthias T Wyss, Felipe Baeza-Lehnert, Iván Ruminot, Carlos Alvarez-Navarro, Alejandro San Martín, Bruno Weber, Pamela Y Sandoval, L Felipe Barros.

We addressed the question of mitochondrial lactate metabolism using genetically-encoded sensors. The organelle was found to contain a dynamic lactate pool that leads to dose- and time-dependent protein lactylation. In neurons, mitochondrial lactate reported blood lactate levels with high fidelity. The exchange of lactate across the inner mitochondrial membrane was found to be mediated by a high affinity H+-coupled transport system involving the mitochondrial pyruvate carrier MPC. Assessment of electron transport chain activity and determination of lactate flux showed that mitochondria are tonic lactate producers, a phenomenon driven by energization and stimulated by hypoxia. We conclude that an overflow mechanism caps the redox level of mitochondria, while saving energy in the form of lactate.

DOI: https://doi.org/10.1101/2024.07.19.604361
Cell Death Dis. 2024 Aug 01. 15(8): 553

Emerging mechanisms and promising approaches in pancreatic cancer metabolism.

Hao Wu, Mengdi Fu, Mengwei Wu, Zhen Cao, Qiyao Zhang, Ziwen Liu.

Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. Pancreatic cancer cells can use glucose, amino acids, and lipids as energy to maintain malignant growth. Moreover, they also metabolically interact with cells in the tumour microenvironment to change cell fate, promote tumour progression, and even affect immune responses. Importantly, metabolic changes at the body level deserve more attention. Basic research and clinical trials based on targeted metabolic therapy or in combination with other treatments are in full swing. A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches.

DOI: https://doi.org/10.1038/s41419-024-06930-0
FASEB J. 2024 Aug 15. 38(15): e23845

Greater molecular potential for glucose metabolism in adipose tissue and skeletal muscle of women compared with men.

Trine S Nicolaisen, Kim A Sjøberg, Christian S Carl, Erik A Richter, Bente Kiens, Andreas M Fritzen, Anne-Marie Lundsgaard.

  Women typically have less muscle mass and more fat mass than men, while at the same time possessing similar or even greater whole-body insulin sensitivity. Our study aimed to investigate the molecular factors in primarily adipose tissue, but also in skeletal muscle, contributing to this sex difference. In healthy, moderately active premenopausal women and men with normal weight (28 ± 5 and 23 ± 3 years old; BMI 22.2 ± 1.9 and 23.7 ± 1.7) and in healthy, recreationally active women and men with overweight (32.2 ± 6 and 31.0 ± 5 years old; BMI 29.8 ± 4.3 & 30.9 ± 3.7) matched at age, BMI, and fitness level, we assessed insulin sensitivity and glucose tolerance with a hyperinsulinemic-euglycemic clamp or oral glucose tolerance test and studied subcutaneous adipose tissue and skeletal muscle samples with western blotting. Additionally, we traced glucose-stimulated glucose disposal in adipose tissues of female and male C57BL/6J littermate mice aged 16 weeks and measured glucose metabolic proteins. Our findings revealed greater protein expression related to glucose disposal in the subcutaneous adipose tissue (AKT2, insulin receptor, glucose transport 4) and skeletal muscle (hexokinase II, pyruvate dehydrogenase) in women compared to matched men with normal weight and with overweight. This increased protein capacity for glucose uptake extended to white adipose tissues of mice accompanied with ~2-fold greater glucose uptake compared to male mice. Furthermore, even in the obese state, women displayed better glucose tolerance than matched men, despite having 46% body fat and 20 kg less lean mass. In conclusion, our findings suggest that the superior potential for glucose disposal in female subcutaneous adipose tissue and skeletal muscle, driven by greater expression of various glucose metabolic proteins, compensates for their lower muscle mass. This likely explains women's superior glucose tolerance and tissue insulin sensitivity compared to men.

Keywords:  adipocytes; adiponectin; gender; glucose metabolism; insulin action; obesity; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202302377R
Talanta. 2024 Jul 28. pii: S0039-9140(24)01001-4. [Epub ahead of print]279 126622

Recent advances in fluorescent probes for ATP imaging.

Chen Zhang, Guanzhao Wu.

  Adenosine-5'-triphosphate (ATP) is a critical biological molecule that functions as the primary energy currency within cells. ATP synthesis occurs in the mitochondria, and variations in its concentration can significantly influence mitochondrial and cellular performance. Prior studies have established a link between ATP levels and a variety of diseases, such as cancer, neurodegenerative conditions, ischemia, and hypoglycemia. Consequently, researchers have developed many fluorescent probes for ATP detection, recognizing the importance of monitoring intracellular ATP levels to understand cellular processes. These probes have been effectively utilized for visualizing ATP in living cells and biological samples. In this comprehensive review, we categorize fluorescent sensors developed in the last five years for ATP detection. We base our classification on fluorophores, structure, multi-response channels, and application. We also evaluate the challenges and potential for advancing new generations of fluorescence imaging probes for monitoring ATP in living cells. We hope this summary motivates researchers to design innovative and effective probes tailored to ATP sensing. We foresee imminent progress in the development of highly sophisticated ATP probes.

Keywords:  ATP detection; Adenosine-5′-triphosphate; Fluorescence imaging; Nanoprobes; Small-molecule probes

DOI:  https://doi.org/10.1016/j.talanta.2024.126622
Ann Hematol. 2024 Jul 30.

Significance of targeting DNMT3A mutations in AML.

Guiqin Huang, Xiaoya Cai, Dengju Li.

  Acute myeloid leukemia (AML) is the most prevalent form of leukemia among adults, characterized by aggressive behavior and significant genetic diversity. Despite decades of reliance on conventional chemotherapy as the mainstay treatment, patients often struggle with achieving remission, experience rapid relapses, and have limited survival prospects. While intensified induction chemotherapy and allogeneic stem cell transplantation have enhanced patient outcomes, these benefits are largely confined to younger AML patients capable of tolerating intensive treatments. DNMT3A, a crucial enzyme responsible for establishing de novo DNA methylation, plays a pivotal role in maintaining the delicate balance between hematopoietic stem cell differentiation and self-renewal, thereby influencing gene expression programs through epigenetic regulation. DNMT3A mutations are the most frequently observed genetic abnormalities in AML, predominantly in older patients, occurring in approximately 20-30% of adult AML cases and over 30% of AML with a normal karyotype. Consequently, the molecular underpinnings and potential therapeutic targets of DNMT3A mutations in AML are currently being thoroughly investigated. This article provides a comprehensive summary and the latest insights into the structure and function of DNMT3A, examines the impact of DNMT3A mutations on the progression and prognosis of AML, and explores potential therapeutic approaches for AML patients harboring DNMT3A mutations.

Keywords:   DNMT3A mutations; Acute myeloid leukemia (AML); Epigenetics; Oncogenesis; Targeted therapy

DOI:  https://doi.org/10.1007/s00277-024-05885-8
J Lipid Res. 2024 Jul 31. pii: S0022-2275(24)00116-0. [Epub ahead of print] 100611

Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration.

Sung Ho Moon, Xinping Liu, Christopher M Jenkins, Beverly Gibson Dilthey, Gary J Patti, Richard W Gross.

  Mitochondrial fatty acid oxidation serves as an essential process for cellular survival, differentiation, proliferation, and energy metabolism. Numerous studies have utilized etomoxir (ETO) for the irreversible inhibition of carnitine palmitoylcarnitine transferase 1 (CPT1) which catalyzes the rate-limiting step for mitochondrial long-chain fatty acid β-oxidation to examine the bioenergetic roles of mitochondrial fatty acid metabolism in many tissues in multiple diverse disease states. Herein, we demonstrate that intact mitochondria robustly metabolize etomoxir to etomoxir-carnitine (ETO-carnitine) prior to nearly complete etomoxir-mediated inhibition of CPT1. The novel pharmaco-metabolite, ETO-carnitine, was conclusively identified by accurate mass, fragmentation patterns, and isotopic fine structure. On the basis of these data, ETO-carnitine was successfully differentiated from isobaric structures (e.g., 3-hydroxy-C18:0 carnitine and 3-hydroxy-C18:1 carnitine). Mechanistically, generation of ETO-carnitine from mitochondria required exogenous Mg2+, ATP or ADP, CoASH, and L-carnitine indicating that thioesterification by long-chain acyl-CoA synthetase to form ETO-CoA precedes its conversion to ETO-carnitine by CPT1. CPT1-dependent generation of ETO-carnitine was substantiated by an orthogonal approach using ST1326 (a CPT1 inhibitor) which effectively inhibits mitochondrial ETO-carnitine production. Surprisingly, purified ETO-carnitine potently inhibited calcium-independent PLA2γ and PLA2β as well as mitochondrial respiration independent of CPT1. Robust production and release of ETO-carnitine from HepG2 cells incubated in the presence of ETO was also demonstrated. Collectively, this study identifies the chemical mechanism for the biosynthesis of a novel pharmaco-metabolite of etomoxir, ETO-carnitine, that is generated by CPT1 in mitochondria and likely impacts multiple downstream (non-CPT1 related) enzymes and processes in multiple subcellular compartments.

Keywords:  Lipidomics; Lipids/Chemistry; Lipolysis and fatty acid metabolism; carnitine palmitoyltransferase (CPT); etomoxir; etomoxir-carnitine; mitochondria; off-target effects; pharmaco-metabolite; phospholipases A(2)

DOI:  https://doi.org/10.1016/j.jlr.2024.100611
Lab Chip. 2024 Jul 29.

Size-related variability of oxygen consumption rates in individual human hepatic cells.

Ermes Botte, Yuan Cui, Chiara Magliaro, Maria Tenje, Klaus Koren, Andrea Rinaldo, Roman Stocker, Lars Behrendt, Arti Ahluwalia.

Accurate descriptions of the variability in single-cell oxygen consumption and its size-dependency are key to establishing more robust tissue models. By combining microfabricated devices with multiparameter identification algorithms, we demonstrate that single human hepatocytes exhibit an oxygen level-dependent consumption rate and that their maximal oxygen consumption rate is significantly lower than that of typical hepatic cell cultures. Moreover, we found that clusters of two or more cells competing for a limited oxygen supply reduced their maximal consumption rate, highlighting their ability to adapt to local resource availability and the presence of nearby cells. We used our approach to characterize the covariance of size and oxygen consumption rate within a cell population, showing that size matters, since oxygen metabolism covaries lognormally with cell size. Our study paves the way for linking the metabolic activity of single human hepatocytes to their tissue- or organ-level metabolism and describing its size-related variability through scaling laws.

DOI: https://doi.org/10.1039/d4lc00204k
Circ Cardiovasc Imaging. 2024 Jul 31. e016774

Relationship of Ketosis With Myocardial Glucose Uptake Among Patients Undergoing FDG PET/CT for Evaluation of Cardiac Sarcoidosis.

Mahesh K Vidula, Senthil Selvaraj, Chaitanya Rojulpote, Abhijit Bhattaru, Wumesh Kc, Mary Hansbury, Erin Schubert, Caitlin B Clancy, Milton Rossman, Lee R Goldberg, Michael Farwell, Daniel Pryma, Paco E Bravo.

   BACKGROUND: Fluorine-18 fluorodeoxyglucose (FDG) with positron emission tomography (PET) is the standard for detecting myocardial inflammation in cardiac sarcoidosis, requiring preparation with the ketogenic diet (KD) to achieve myocardial glucose suppression. Despite this, incomplete myocardial glucose suppression remains a significant issue, and strategies to reduce myocardial glucose uptake (MGU) and identify incomplete myocardial glucose suppression are required. This study sought to understand the relationship between point-of-care beta-hydroxybutyrate (BHB) and different patterns of MGU and between KD and fasting duration with MGU in patients undergoing evaluation for cardiac sarcoidosis.
METHODS: We prospectively included 471 outpatients who underwent FDG-PET for cardiac sarcoidosis evaluation, followed the KD for 1 (n=100), 2 (n=29), and ≥3 days (n=342), fasted for at least 12 hours, and had BHB levels measured immediately before FDG injection. Images were classified as (1) no MGU (negative), (2) focal/multifocal (positive), (3) diffuse (nondiagnostic), or (4) nonspecific uptake (NS-MGU).
RESULTS: Cardiac FDG-PET scans were interpreted as the following: 376 (79.83%) negative; 61 (12.95%) positive; 14 (2.97%) diffuse; and 20 (4.25%) NS-MGU. There was a strong negative relationship between BHB levels and MGU (P<0.0001). BHB levels increased significantly with KD duration (P<0.0001) and fasting time (P=0.0067). The combined rate of diffuse, NS-MGU, and positive scans (34%, 28%, 16%) decreased inversely with KD duration (1, 2, and ≥3 days, respectively). However, MGU was not different across different fasting times (P=0.6). Blood glucose levels were not associated with MGU (P=0.17) and only weakly associated with BHB levels (R2=0.03; P<0.001).
CONCLUSIONS: We observed a strong inverse relationship between ketosis and patterns of MGU. Longer KD and fasting durations are associated with higher ketosis. However, only KD duration was associated with lower rates of MGU. Measurement of BHB levels before FDG-PET using point-of-care testing is feasible and may facilitate the management of patients referred for myocardial inflammation.

Keywords:  blood glucose; fasting; inflammation; outpatient; sarcoidosis

DOI:  https://doi.org/10.1161/CIRCIMAGING.124.016774
J Health Popul Nutr. 2024 Jul 31. 43(1): 111

A healthful plant-based diet can reduce the risk of developing colorectal cancer: case-control study.

Sazin Yarmand, Bahram Rashidkhani, Arezoo Alimohammadi, Zainab Shateri, Mahboobeh Shakeri, Zahra Sohrabi, Mehran Nouri.

   INTRODUCTION: The benefit of adherence to a plant-based diet concerning colorectal cancer (CRC) has not been investigated among Middle Eastern population. This study aimed to investigate how adherence to a plant-based diet influences the risk of CRC in this understudied population.
METHODS: This case-control study was conducted in the CRC surgery departments of general hospitals in Tehran, Iran. A total of 71 individuals with newly diagnosed CRC (cases) and 142 controls subjects free of cancer and acute illness were concurrently recruited from the same hospital. Dietary information was collected using a semi-quantitative 168-item food frequency questionnaire. Dietary patterns were characterized using the plant-based diet index (PDI), unhealthy plant-based diet index (uPDI) and healthy plant-based diet index (hPDI). Multivariate logistic regression was employed to assess the association between these dietary patterns and the risk of CRC.
RESULTS: After adjusting the potential confounders, the risk of CRC was significantly lower in the highest tertile of hPDI compared to the lowest tertile (odds ratio (OR) = 0.21; 95% confidence interval (CI): 0.07-0.56, representing 79% risk reduction). Conversely, the risk of CRC was significantly higher in the highest tertile of uPDI compared to the lowest tertile (OR = 6.76; 95% CI: 2.41-18.94). PDI was no significant associated with the risk of CRC.
CONCLUSIONS: This study found that higher scores on the hPDI was significantly associated with a decrease risk of CRC, while greater adherence to the uPDI contributed to a significantly increase risk.

Keywords:  Colorectal cancer; Colorectal neoplasms; Diets; Plant-based; Plant-based diet

DOI:  https://doi.org/10.1186/s41043-024-00605-4
Biomaterials. 2024 Jul 27. pii: S0142-9612(24)00253-9. [Epub ahead of print]312 122719

Microenvironment matters: In vitro 3D bone marrow niches differentially modulate survival, phenotype and drug responses of acute myeloid leukemia (AML) cells.

Hoi Lam Cheung, Yu Hin Wong, Yuk Yin Li, Xingxing Yang, Lok Him Ko, Jessica Evangeline Tan Kabigting, Koon Chuen Chan, Anskar Yu Hung Leung, Barbara Pui Chan.

  Acute myeloid leukemia (AML) is a deadly form of leukemia with ineffective traditional treatment and frequent chemoresistance-associated relapse. Personalized drug screening holds promise in identifying optimal regimen, nevertheless, primary AML cells undergo spontaneous apoptosis during cultures, invalidating the drug screening results. Here, we reconstitute a 3D osteogenic niche (3DON) mimicking that in bone marrow to support primary AML cell survival and phenotype maintenance in cultures. Specifically, 3DON derived from osteogenically differentiated mesenchymal stem cells (MSC) from healthy and AML donors are co-cultured with primary AML cells. The AML cells under the AML_3DON niche showed enhanced viability, reduced apoptosis and maintained CD33+ CD34-phenotype, associating with elevated secretion of anti-apoptotic cytokines in the AML_3DON niche. Moreover, AML cells under the AML_3DON niche exhibited low sensitivity to two FDA-approved chemotherapeutic drugs, further suggesting the physiological resemblance of the AML_3DON niche. Most interestingly, AML cells co-cultured with the healthy_3DON niche are highly sensitive to the same sample drugs. This study demonstrates the differential responses of AML cells towards leukemic and healthy bone marrow niches, suggesting the impact of native cancer cell niche in drug screening, and the potential of re-engineering healthy bone marrow niche in AML patients as chemotherapeutic adjuvants overcoming chemoresistance, respectively.

Keywords:  3D osteogenic niche; AML; Cancer microenvironment; Personalized drug screening

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122719
Colorectal Dis. 2024 Jul 30.

Nutritional self-management in colorectal cancer patients and survivors: A scoping review.

Khadijah Abedin, Qi Ying Lean, Sally Wheelwright.

   AIM: Colorectal cancer (CRC) patients need CRC-specific dietary guidance, but often lack access to adequate nutritional information and support. This scoping review identified study interventions, online resources, which have been produced to support nutritional care self-management for CRC patients from diagnosis, through treatment and into survivorship and guidelines to underpin these.
METHODS: The review was carried out in accordance with the JBI method for Scoping Reviews. Study interventions, online resources that support the self-management of nutrition and diet in CRC patients were eligible for inclusion, along with CRC-specific guidelines. Searches up to February 2023, were carried out via MEDLINE, CINAHL, PsycInfo, Embase, and Web of Science for published literature and ProQuest Dissertations, Theses Global, TRIP Medical Database, and Google search engines for grey literature. Two reviewers independently screened titles and abstracts, and relevant full texts for inclusion. Data were analysed descriptively.
RESULTS: Eight study interventions, 74 online resources and three guidelines specifically aimed at CRC patients were included in the review. Study interventions were heterogenous with respect to duration, whether it was personalized, who supported delivery and which guidelines underpinned the intervention. Three study interventions resulted in improved quality of life and one lengthened survival. A total of 36 (48.6%) online resources were produced by UK charity organizations. Most of the included information was for patients after completing treatment. Specific advice for patients with a stoma was lacking. Some of the online resources provided conflicting advice. The three guidelines explained how dietary adjustments can help address symptoms related to cancer or treatment and two provided more specific guidance on making dietary changes, with specific examples of how to tailor dietary advice to patient needs.
CONCLUSION: This scoping review of study interventions, online resources, and guidelines highlighted the need for reliable, detailed, and personalized information to help CRC patients to self-manage their nutritional care.

Keywords:  colorectal cancer; diet; malnutrition; nutrition; self‐management

DOI:  https://doi.org/10.1111/codi.17108