bims-medica 2024-03-31 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒03‒31
35 papers selected by
Brett Chrest, East Carolina University

Complex I activity in hypoxia: implications for oncometabolism.
Effect of Ketogenic Diet on Obesity and Other Metabolic Disorders: Narrative Review.
Targeting the Warburg Effect in Cancer: Where Do We Stand?
Targeting metabolic adaptive responses induced by glucose starvation inhibits cell proliferation and enhances cell death in osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines.
Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation.
Elevation of hypothalamic ketone bodies induces a decrease in energy expenditures and an increase risk of metabolic disorder.
Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML).
Spatially resolved quantification of oxygen consumption rate in ex vivo lymph node slices.
BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria.
Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
Reduction of Tumor Biomarkers from very High to Normal and Extensive Metastatic Lesions to Undetectability in a Patient With Stage IV HER2-positive Breast Cancer Treated With Low-dose Trastuzumab Deruxtecan in Combination With Oral Recombinant Methioninase and a Low-methionine Diet.
A practical and robust method to evaluate metabolic fluxes in primary pancreatic islets.
Metabolic pathways of glucose and fructose: II spatiotemporal expression of genes involved in synthesis and transport of lactate in ovine conceptuses.
Western diet-induced ultrastructural changes in mouse pancreatic acinar cells.
Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.
Targeting Solute Carrier Transporters (SLCs) as a Therapeutic Target in Different Cancers.
Palmitate Compromises C6 Astrocytic Cell Viability and Mitochondrial Function.
A Cross-Sectional Quantitative Metabolomics Study Evidencing the Metabolic Signature in Six Organs during a 14-Week High-Fat High-Sucrose and Standard Diet in Mice.
Oxygen imaging of hypoxic pockets in the mouse cerebral cortex.
Lifestyle interventions with dietary strategies after breast cancer diagnosis: a systematic review.
Intermittent Methionine Restriction Reduces Marrow Fat Accumulation and Preserves More Bone Mass than Continuous Methionine Restriction.
Diet, exercise, and supplements: what is their role in the management of the metabolic dysfunction-associated steatotic liver disease in children?
The Association of Low-Carbohydrate Diet and HECTD4 rs11066280 Polymorphism with Risk of Colorectal Cancer: A Case-Control Study in Korea.
Proteomics for optimizing therapy in acute myeloid leukemia: venetoclax plus hypomethylating agents versus conventional chemotherapy.
Keto Clarity: A Comprehensive Systematic Review Exploring the Efficacy, Safety, and Mechanisms of Ketogenic Diet in Pediatric Epilepsy.
BCL-2 inhibition in haematological malignancies: Clinical application and complications.
The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner.
DISRUPTION OF POLYUNSATURATED FATTY ACID BIOSYNTHESIS DRIVES STING-DEPENDENT ACUTE MYELOID LEUKEMIA CELL MATURATION AND DEATH.
Healthy Lifestyle and Cancer Risk: Modifiable Risk Factors to Prevent Cancer.
Heterogeneity in precision oncology.
Artificially sweetened beverages consumption and risk of obesity-related cancers: a wide-angled Mendelian randomization study.
Venetoclax Resistance in Acute Myeloid Leukemia.
Real-time glioblastoma tumor microenvironment assessment by SpiderMass for improved patient management.
Solute Transport through Mitochondrial Porins In Vitro and In Vivo.
Humanized mouse models for anti-cancer therapy.

Biochem Soc Trans. 2024 Mar 25. pii: BST20230189. [Epub ahead of print]

Complex I activity in hypoxia: implications for oncometabolism.

Christos Chinopoulos.

  Certain cancer cells within solid tumors experience hypoxia, rendering them incapable of oxidative phosphorylation (OXPHOS). Despite this oxygen deficiency, these cells exhibit biochemical pathway activity that relies on NAD+. This mini-review scrutinizes the persistent, residual Complex I activity that oxidizes NADH in the absence of oxygen as the electron acceptor. The resulting NAD+ assumes a pivotal role in fueling the α-ketoglutarate dehydrogenase complex, a critical component in the oxidative decarboxylation branch of glutaminolysis - a hallmark oncometabolic pathway. The proposition is that through glutamine catabolism, high-energy phosphate intermediates are produced via substrate-level phosphorylation in the mitochondrial matrix substantiated by succinyl-CoA ligase, partially compensating for an OXPHOS deficiency. These insights provide a rationale for exploring Complex I inhibitors in cancer treatment, even when OXPHOS functionality is already compromised.

Keywords:  OXPHOS; cancer; hypoxia; mitochondria; mtSLP

DOI:  https://doi.org/10.1042/BST20230189
Diabetes Metab Syndr Obes. 2024 ;17 1391-1401

Effect of Ketogenic Diet on Obesity and Other Metabolic Disorders: Narrative Review.

Temesgen Baylie, Tiget Ayelgn, Markeshaw Tiruneh, Kibur Hunie Tesfa.

  Obesity is defined as an abnormal or excessive accumulation of fat that increases the burden of different chronic diseases in the population. It has reached epidemic proportions and is a major risk factor for a variety of diseases, including hypertension, cardiovascular disease, type 2 diabetes, dyslipidaemia, atherosclerosis, and some malignancies. Weight gain is a result of excessive energy intake compared to energy expenditure (energy loss from metabolism and physical exercise). A ketogenic diet has a more useful effect on obesity than other diets. A ketogenic diet is a low-carbohydrate, high-fat, moderate-protein diet that induces the production of ketone bodies by mimicking the breakdown of a fasting state. The mechanism behind the ketogenic diet is still unknown, although it obviously helps people with obesity lose weight. Several pathways for the ketogenic diet effect on weight loss have been hypothesized by researchers, including reduced appetite due to effects on appetite control hormones and a possible direct appetite suppressant action of ketone bodies; reduced lipogenesis and increased lipolysis; greater metabolic efficiency; and increased metabolic costs.

Keywords:  Ketone Body; ketogenic diet; metabolic disorder; obesity

DOI:  https://doi.org/10.2147/DMSO.S447659
Int J Mol Sci. 2024 Mar 08. pii: 3142. [Epub ahead of print]25(6):

Targeting the Warburg Effect in Cancer: Where Do We Stand?

Ignasi Barba, Laura Carrillo-Bosch, Joan Seoane.

  The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms. This review provides an overview of the current understanding of the Warburg effect in cancer and its implications. We summarize recent pharmacological strategies aimed at targeting glycolytic enzymes, highlighting the challenges encountered in achieving therapeutic efficacy. Additionally, we examine the utility of the Warburg effect as an early diagnostic tool. Finally, we discuss the multifaceted roles of lactate within the TME, emphasizing its potential as a therapeutic target to disrupt metabolic interactions between tumor and immune cells, thereby enhancing anti-tumor immunity.

Keywords:  Warburg effect; aerobic glycolysis; immunomodulation; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25063142
Biochem Pharmacol. 2024 Mar 24. pii: S0006-2952(24)00144-8. [Epub ahead of print] 116161

Targeting metabolic adaptive responses induced by glucose starvation inhibits cell proliferation and enhances cell death in osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines.

Kamal Eltayeb, Roberta Alfieri, Claudia Fumarola, Mara Bonelli, Maricla Galetti, Andrea Cavazzoni, Graziana Digiacomo, Francesca Galvani, Federica Vacondio, Alessio Lodola, Marco Mor, Roberta Minari, Marcello Tiseo, Silvia La Monica, Pier Giorgio Petronini.

  Osimertinib, a tyrosine kinase inhibitor targeting mutant EGFR, has received approval for initial treatment in patients with Non-Small Cell Lung Cancer (NSCLC). While effective in both first- and second-line treatments, patients eventually develop acquired resistance. Metabolic reprogramming represents a strategy through which cancer cells may resist and adapt to the selective pressure exerted by the drug. In the current study, we investigated the metabolic adaptations associated with osimertinib-resistance in NSCLC cells under low glucose culture conditions. We demonstrated that, unlike osimertinib-sensitive cells, osimertinib-resistant cells were able to survive under low glucose conditions by increasing the rate of glucose and glutamine uptake and by shifting towards mitochondrial metabolism. Inhibiting glucose/pyruvate contribution to mitochondrial respiration, glutamine deamination to glutamate, and oxidative phosphorylation decreased the proliferation and survival abilities of osimertinib-resistant cells to glucose starvation. Our findings underscore the remarkable adaptability of osimertinib-resistant NSCLC cells in a low glucose environment and highlight the pivotal role of mitochondrial metabolism in mediating this adaptation. Targeting the metabolic adaptive responses triggered by glucose shortage emerges as a promising strategy, effectively inhibiting cell proliferation and promoting cell death in osimertinib-resistant cells.

Keywords:  EGFR; Glucose; Metabolism; NSCLC; Osimertinib; Resistance

DOI:  https://doi.org/10.1016/j.bcp.2024.116161
Cancers (Basel). 2024 Mar 16. pii: 1171. [Epub ahead of print]16(6):

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation.

Can Chen, Ji Zhang.

  Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.

Keywords:  GCN2; amino acid starvation; combination therapy; immunosuppression; leukemia

DOI:  https://doi.org/10.3390/cancers16061171
Mol Metab. 2024 Mar 27. pii: S2212-8778(24)00057-7. [Epub ahead of print] 101926

Elevation of hypothalamic ketone bodies induces a decrease in energy expenditures and an increase risk of metabolic disorder.

Lionel Carneiro, Rocco Bernasconi, Adriano Bernini, Cendrine Repond, Luc Pellerin.

  OBJECTIVE: Ketone bodies (such as β-hydroxybutyrate or BHB) have been recently proposed as signals involved in brain regulation of energy homeostasis and obesity development. However, the precise role of ketone bodies sensing by the brain, and its impact on metabolic disorder development remains unclear. Nevertheless, partial deletion of the ubiquitous ketone bodies transporter MCT1 in mice (HE mice) results in diet-induced obesity resistance, while there is no alteration under normal chow diet. These results suggest that ketone bodies produced during the high fat diet would be important signals involved in obesity onset.METHODS: In the present study we used a specific BHB infusion of the hypothalamus and analyzed the energy homeostasis of WT or HE mice fed a normal chow diet.
RESULTS: Our results indicate that high BHB levels sensed by the hypothalamus disrupt the brain regulation of energy homeostasis. This brain control dysregulation leads to peripheral alterations of energy expenditure mechanisms.
CONCLUSION: Altogether, the changes induced by high ketone bodies levels sensed by the brain increase the risk of obesity onset in mice.

Keywords:  ketone bodies; metabolism; neuroscience; obesity

DOI:  https://doi.org/10.1016/j.molmet.2024.101926
Leuk Lymphoma. 2024 Mar 27. 1-8

Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML).

Jorge Cortes, Brian A Jonas, Gary Schiller, Alice Mims, Gail J Roboz, Andrew H Wei, Pau Montesinos, P Brent Ferrell, Karen Wl Yee, Pierre Fenaux, Anthony Schwarer, Justin M Watts.

  Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1-2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax.

Keywords:  IDH1 mutation; Olutasidenib; acute myeloid leukemia

DOI:  https://doi.org/10.1080/10428194.2024.2333451
Analyst. 2024 Mar 27.

Spatially resolved quantification of oxygen consumption rate in ex vivo lymph node slices.

Parastoo Anbaei, Marissa G Stevens, Alexander G Ball, Timothy N J Bullock, Rebecca R Pompano.

Cellular metabolism has been closely linked to activation state in cells of the immune system, and the oxygen consumption rate (OCR) in particular serves as a valuable metric for assessing metabolic activity. Several oxygen sensing assays have been reported for cells in standard culture conditions. However, none have provided a spatially resolved, optical measurement of local oxygen consumption in intact tissue samples, making it challenging to understand regional dynamics of consumption. Therefore, here we established a system to monitor the rates of oxygen consumption in ex vivo tissue slices, using murine lymphoid tissue as a case study. By integrating an optical oxygen sensor into a sealed perfusion chamber and incorporating appropriate correction for photobleaching of the sensor and of tissue autofluorescence, we were able to visualize and quantify rates of oxygen consumption in tissue. This method revealed for the first time that the rate of oxygen consumption in naïve lymphoid tissue was higher in the T cell region compared to the B cell and cortical regions. To validate the method, we measured OCR in the T cell regions of naïve lymph node slices using the optical assay and estimated the consumption rate per cell. The predictions from the optical assay were similar to reported values and were not significantly different from those of the Seahorse metabolic assay, a gold standard method for measuring OCR in cell suspensions. Finally, we used this method to quantify the rate of onset of tissue hypoxia for lymph node slices cultured in a sealed chamber and showed that continuous perfusion was sufficient to maintain oxygenation. In summary, this work establishes a method to monitor oxygen consumption with regional resolution in intact tissue explants, suitable for future use to compare tissue culture conditions and responses to stimulation.

DOI: https://doi.org/10.1039/d4an00028e
Cancer Metab. 2024 Mar 26. 12(1): 10

BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria.

Klára Gotvaldová, Jitka Špačková, Jiří Novotný, Kamila Baslarová, Petr Ježek, Lenka Rossmeislová, Jan Gojda, Katarína Smolková.

  BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been associated with the host dysmetabolism of branched-chain amino acids (BCAAs), however, the implications for the role of BCAA metabolism in PDAC development or progression are not clear. The mitochondrial catabolism of valine, leucine, and isoleucine is a multistep process leading to the production of short-chain R-CoA species. They can be subsequently exported from mitochondria as short-chain carnitines (SC-CARs), utilized in anabolic pathways, or released from the cells.METHODS: We examined the specificities of BCAA catabolism and cellular adaptation strategies to BCAA starvation in PDAC cells in vitro. We used metabolomics and lipidomics to quantify major metabolic changes in response to BCAA withdrawal. Using confocal microscopy and flow cytometry we quantified the fluorescence of BODIPY probe and the level of lipid droplets (LDs). We used BODIPY-conjugated palmitate to evaluate transport of fatty acids (FAs) into mitochondria. Also, we have developed a protocol for quantification of SC-CARs, BCAA-derived metabolites.
RESULTS: Using metabolic profiling, we found that BCAA starvation leads to massive triglyceride (TG) synthesis and LD accumulation. This was associated with the suppression of activated FA transport into the mitochondrial matrix. The suppression of FA import into mitochondria was rescued with the inhibitor of the acetyl-CoA carboxylase (ACC) and the activator of AMP kinase (AMPK), which both regulate carnitine palmitoyltransferase 1A (CPT1) activation status.
CONCLUSIONS: Our data suggest that BCAA catabolism is required for the import of long chain carnitines (LC-CARs) into mitochondria, whereas the disruption of this link results in the redirection of activated FAs into TG synthesis and its deposition into LDs. We propose that this mechanism protects cells against mitochondrial overload with LC-CARs and it might be part of the universal reaction to amino acid perturbations during cancer growth, regulating FA handling and storage.

Keywords:  BCAA metabolism; Fatty acid/Transport; Fluorescence microscopy; Lipid droplets; Lipidomics; Mitochondria; Pancreatic cancer; Triglycerides

DOI:  https://doi.org/10.1186/s40170-024-00335-5
Science. 2024 Mar 29. 383(6690): 1484-1492

Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.

Umakant Sahu, Elodie Villa, Colleen R Reczek, Zibo Zhao, Brendan P O'Hara, Michael D Torno, Rohan Mishra, William D Shannon, John M Asara, Peng Gao, Ali Shilatifard, Navdeep S Chandel, Issam Ben-Sahra.

Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.

DOI: https://doi.org/10.1126/science.adh2771
Anticancer Res. 2024 Apr;44(4): 1499-1504

Reduction of Tumor Biomarkers from very High to Normal and Extensive Metastatic Lesions to Undetectability in a Patient With Stage IV HER2-positive Breast Cancer Treated With Low-dose Trastuzumab Deruxtecan in Combination With Oral Recombinant Methioninase and a Low-methionine Diet.

Motokazu Sato, Qinghong Han, Ryosuke Mori, Kohei Mizuta, Byung Mo Kang, Sei Morinaga, Noritoshi Kobayashi, Yasushi Ichikawa, Atsushi Nakajima, Robert M Hoffman.

  BACKGROUND/AIM: Breast cancer is the most common and the deadliest cancer among women in the world. Treatment options for HER2-positive metastatic breast cancer patients are limited. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), has recently been introduced as second-line chemotherapy for HER2-positive metastatic breast cancer. The aim of the present study was to evaluate the efficacy of methionine restriction with oral recombinant methioninase (o-rMETase) and a low-methionine diet combined with T-DXd, on a patient with HER2-positive recurrent stage IV breast cancer.CASE REPORT: A 66-year-old female was diagnosed with HER2-positive metastatic breast cancer. Computed tomography (CT) indicated peritoneal dissemination, thickening of the sigmoid colon and splenic flexure and widespread bone metastases. The patient was previously treated with fulvestrant, trastuzumab, pertuzumab, paclitaxel and capecitabine which were ineffective. T-DXd was administered as a second-line chemotherapy. Since the patient experienced strong side effects, the dose of T-Dxd was decreased. The patient began methionine restriction using o-rMETase and a low-methionine diet along with T-DXd. After the start of the combined treatment, CA15-3 and CA27.29, tumor markers for breast cancer, decreased rapidly from a very high level. The levels of both tumor markers are currently normal. Additionally, peritoneal-dissemination nodules, ascites and the thickness of the sigmoid colon and splenic flexure are no longer detected on CT. The patient maintains a high performance status, without severe side effects of the combination treatment.
CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with T-DXd as second-line chemotherapy, was highly effective in a patient with HER2-positive stage IV breast cancer.

Keywords:  Breast cancer; Enhertu; HER2-positive; Hoffman effect; combination therapy; irinotecan; methionine addiction; methionine restriction; oral methioninase; synergy; trastuzumab deruxtecan

DOI:  https://doi.org/10.21873/anticanres.16946
Mol Metab. 2024 Mar 21. pii: S2212-8778(24)00053-X. [Epub ahead of print] 101922

A practical and robust method to evaluate metabolic fluxes in primary pancreatic islets.

Debora S Rocha, Antonio C Manucci, Alexandre Bruni-Cardoso, Alicia J Kowaltowski, Eloisa A Vilas-Boas.

  OBJECTIVE: Evaluation of mitochondrial oxygen consumption and ATP production is important to investigate pancreatic islet pathophysiology. Most studies use cell lines due to difficulties in measuring primary islet respiration, which requires specific equipment and consumables, is expensive and poorly reproducible. Our aim was to establish a practical method to assess primary islet metabolic fluxes using standard commercial consumables.METHODS: Pancreatic islets were isolated from mice/rats, dispersed with trypsin, and adhered to pre-coated standard Seahorse or Resipher microplates. Oxygen consumption was evaluated using a Seahorse Extracellular Flux Analyzer or a Resipher Real-time Cell Analyzer.
RESULTS: We provide a detailed protocol with all steps to optimize islet isolation with high yield and functionality. Our method requires a few islets per replicate; both rat and mouse islets present robust basal respiration and proper response to mitochondrial modulators and glucose. The technique was validated by other functional assays, which show these cells present conserved calcium influx and insulin secretion in response to glucose. We also show that our dispersed islets maintain robust basal respiration levels, in addition to maintaining up to 89% viability after five days in dispersed cultures. Furthermore, OCRs can be measured in Seahorse analyzers and in other plate respirometry systems, using standard materials.
CONCLUSIONS: Overall, we established a practical and robust method to assess islet metabolic fluxes and oxidative phosphorylation, a valuable tool to uncover basic β-cell metabolic mechanisms as well as for translational investigations, such as pharmacological candidate discovery and islet transplantation protocols.

Keywords:  Mitochondrial respiration; Oxidative phosphorylation; Oxygen consumption; Pancreatic islets

DOI:  https://doi.org/10.1016/j.molmet.2024.101922
Biol Reprod. 2024 Mar 26. pii: ioae047. [Epub ahead of print]

Metabolic pathways of glucose and fructose: II spatiotemporal expression of genes involved in synthesis and transport of lactate in ovine conceptuses.

Robyn M Moses, Claire Stenhouse, Katherine M Halloran, Nirvay Sah, Makenzie G Newton, Emily C Hoskins, Shannon E Washburn, Gregory A Johnson, Guoyao Wu, Fuller W Bazer.

  Lactate, an abundant molecule in fetal fluids and blood of mammalian species is often overlooked as a metabolic waste product generated during pregnancy. Most of the glucose and fructose consumed by ovine conceptuses is converted to lactate, but proteins involved in lactate metabolism and transport have not been investigated. This study characterized total lactate produced by ovine conceptuses throughout gestation, as well as expression of mRNAs and proteins involved in lactate metabolism. Lactate increased in abundance in the uterine lumen during the preimplantation period and was more abundant than pyruvate. The abundance of lactate in allantoic and amniotic fluids increased with advancing days of gestation and most abundant on Day 125 of pregnancy (P < 0.05). Lactate dehydrogenase (LDH) subunits A (converts pyruvate to lactate) and B (converts lactate to pyruvate) were expressed by conceptuses throughout gestation. Lactate is transported via monocarboxylic acid transporters SLC16A1 and SLC16A3, both of which were expressed by the conceptus throughout gestation. Additionally, the interplacentomal chorioallantois from Day 126 expressed SLC16A1 and SLC16A3 and transported lactate across the tissue. Hydrocarboxylic acid receptor 1 (HCAR1), a receptor for lactate, was localized to the uterine luminal and superficial glandular epithelia of pregnant ewes throughout gestation, and conceptus trophectoderm during the peri-implantation period of gestation. These results provide novel insights into the spatiotemporal profiles of enzymes, transporters, and receptor for lactate by ovine conceptuses throughout pregnancy.

Keywords:  Conceptus; Fructose; Glucose; Lactate; Metabolism; Ovine; Placentome

DOI:  https://doi.org/10.1093/biolre/ioae047
Front Cell Dev Biol. 2024 ;12 1380564

Western diet-induced ultrastructural changes in mouse pancreatic acinar cells.

Saška Lipovšek, Jurij Dolenšek, Barbara Dariš, Ismael Valladolid-Acebes, Tanja Vajs, Gerd Leitinger, Andraž Stožer, Maša Skelin Klemen.

  Mouse models of diet-induced type 2 diabetes mellitus provide powerful tools for studying the structural and physiological changes that are related to the disease progression. In this study, diabetic-like glucose dysregulation was induced in mice by feeding them a western diet, and light and transmission electron microscopy were used to study the ultrastructural changes in the pancreatic acinar cells. Acinar necrosis and vacuolization of the cytoplasm were the most prominent features. Furthermore, we observed intracellular and extracellular accumulation of lipid compounds in the form of lipid droplets, structural enlargement of the cisternae of the rough endoplasmic reticulum (RER), and altered mitochondrial morphology, with mitochondria lacking the typical organization of the inner membrane. Last, autophagic structures, i.e., autophagosomes, autolysosomes, and residual bodies, were abundant within the acinar cells of western diet-fed mice, and the autolysosomes contained lipids and material of varying electron density. While diets inducing obesity and type 2 diabetes are clearly associated with structural changes and dysfunction of the endocrine pancreas, we here demonstrate the strong effect of dietary intervention on the structure of acinar cells in the exocrine part of the organ before detectable changes in plasma amylase activity, which may help us better understand the development of non-alcoholic fatty pancreas disease and its association with endo- and exocrine dysfunction.

Keywords:  acinar cells; autophagy; lipid droplets; mitochondria; necrotic cells; rough endoplasmic reticulum; western diet

DOI:  https://doi.org/10.3389/fcell.2024.1380564
Nutrients. 2024 Mar 13. pii: 812. [Epub ahead of print]16(6):

Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.

Dorota Wesół-Kucharska, Milena Greczan, Magdalena Kaczor, Ewa Ehmke Vel Emczyńska-Seliga, Małgorzata Hajdacka, Edyta Czekuć-Kryśkiewicz, Dorota Piekutowska-Abramczuk, Paulina Halat-Wolska, Elżbieta Ciara, Maciej Jaworski, Aleksandra Jezela-Stanek, Dariusz Rokicki.

  Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from abnormal mitochondrial function. Currently, there is no causal treatment for MDs. The aim of the study was to assess the effectiveness and safety of the ketogenic diet (KD) in patients with MD and to analyse selected biochemical and clinical parameters evaluating the effectiveness of KD treatment in patients with MDs. A total of 42 paediatric patients were assigned to four groups: group 1-patients with MD in whom KD treatment was started (n = 11); group 2-patients with MD remaining on an ordinary diet (n = 10); group 3-patients without MD in whom KD treatment was initiated (n = 10), group 4-patients without MD on a regular diet (n = 11). Clinical improvement was observed in 9/11 patients with MD treated with KD. Among patients with MD without KD, the clinical condition deteriorated in 7/10 patients, improved in 2/10 patients, and remained unchanged in one patient. Adverse events of KD occurred with a comparable frequency in groups 1 and 3. There was no significant difference in changes in biomarker concentrations over the course of the study among patients treated and untreated with KD.

Keywords:  IPMDS; ketogenic diet; mitochondrial diseases; mtDNA; nDNA

DOI:  https://doi.org/10.3390/nu16060812
Diseases. 2024 Mar 21. pii: 63. [Epub ahead of print]12(3):

Targeting Solute Carrier Transporters (SLCs) as a Therapeutic Target in Different Cancers.

Ravi Bharadwaj, Swati Jaiswal, Erandi E Velarde de la Cruz, Ritesh P Thakare.

  Solute carrier (SLC) transporters constitute a vast superfamily of transmembrane proteins tasked with regulating the transport of various substances such as metabolites, nutrients, ions, and drugs across cellular membranes. SLC transporters exhibit coordinated expression patterns across normal tissues, suggesting a tightly regulated regulatory network governing normal cellular functions. These transporters are crucial for the transport of various metabolites, including carbohydrates, proteins, lipids, and nucleic acids. However, during tumor development, metabolic changes drive an increased demand for energy and nutrients. Consequently, tumor cells alter the expression of SLC transporters to meet their heightened nutrient requirements. Targeting SLCs through inhibition or activation presents a promising therapeutic approach in cancer treatment. Certain SLCs also serve as intriguing chemo-sensitizing targets, as modulating their activity can potentially alter the response to chemotherapy. This review underscores the significance of various SLCs in tumor progression and underscores their potential as both direct and indirect targets for cancer therapy.

Keywords:  SLC; colon cancer; liver cancer; lung cancer; pancreatic cancer; transporter

DOI:  https://doi.org/10.3390/diseases12030063
Metabolites. 2024 Mar 12. pii: 161. [Epub ahead of print]14(3):

Palmitate Compromises C6 Astrocytic Cell Viability and Mitochondrial Function.

Luisa O Schmitt, Antonella Blanco, Sheila V Lima, Gianni Mancini, Natalia F Mendes, Alexandra Latini, Joana M Gaspar.

  Consumption of high-fat diets (HFD) is associated with brain alterations, including changes in feeding behavior, cognitive decline, and dementia. Astrocytes play a role in HFD-induced neuroinflammation and brain dysfunction; however, this process is not entirely understood. We hypothesized that exposure to saturated fatty acids can compromise astrocyte viability and mitochondrial function. The C6 (astrocytes) cell line was treated with palmitate or stearate (200 µM and 400 µM) for 6 h. Cell viability, morphology, inflammatory markers, and oxidative stress were evaluated. To assess mitochondrial function, various parameters were measured (membrane potential, mass, respiration, and complex activities). We observed that 6 h of treatment with 400 µM palmitate decreased cell viability, and treatment with 200 µM palmitate changed the astrocyte morphology. Palmitate increased inflammatory markers (TNF-α and IL6) but did not induce oxidative stress. Palmitate significantly decreased the mitochondrial membrane potential and mitochondrial mass. Complex I activity also decreased in palmitate-treated cells; however, no changes were observed in mitochondrial respiration. In conclusion, palmitate, a saturated fatty acid, induces inflammation and impairs mitochondrial function, leading to reduced astrocytic cell viability and changes in cellular morphology. Our study provides valuable insights into the potential mechanisms underlying the relationship between saturated fatty acids, astrocytes, and mitochondrial function in obesity-related brain dysfunction.

Keywords:  astrocytes; inflammation; mitochondria; obesity; saturated fatty acids

DOI:  https://doi.org/10.3390/metabo14030161
Nutrients. 2024 Mar 12. pii: 803. [Epub ahead of print]16(6):

A Cross-Sectional Quantitative Metabolomics Study Evidencing the Metabolic Signature in Six Organs during a 14-Week High-Fat High-Sucrose and Standard Diet in Mice.

Eva Drevet Mulard, Sylvie Guibert, Anne Mey, Camille Lefevre, Marie-Agnès Chauvin, Claudie Pinteur, Marie-Ambre Monet, Murielle Godet, Anne-Marie Madec, Béatrice Morio, Jennifer Rieusset, Gilles J P Rautureau, Baptiste Panthu.

  Obesity is a risk factor for many diseases, such as type 2 diabetes and cardiovascular diseases. In line with the need for precision medicine, the search for biomarkers reporting the progression of obesity- and diet-associated disorders is urgent. We used NMR to determine the metabolomics profile of key organs (lung, liver, heart, skeletal muscle, kidney, and brain) and serum from male C57Bl/6J mice (5 weeks old) fed for 6, 10, and 14 weeks on a high-fat and high-sucrose diet (HFHSD) vs. a standard diet (STD). We determined metabolite concentrations in the organs at each time point, which allowed us to discriminate age- and diet-related effects as well as the interactions between both, highlighting the need to evaluate the influence of age as a confounding factor on metabolic signatures. Notably, the analysis revealed the influence of time on metabolite concentrations in the STD condition, probably reflecting the juvenile-to-adult transition. Variations impacted the liver and lung metabolites, revealing the strong influence of the HFHS diet on normal metabolism maturation during youth.

Keywords:  NMR; metabolite trajectories; metabolomics; obesogenic diet; quantitative metabolomics

DOI:  https://doi.org/10.3390/nu16060803
Science. 2024 Mar 29. 383(6690): 1471-1478

Oxygen imaging of hypoxic pockets in the mouse cerebral cortex.

Felix R M Beinlich, Antonios Asiminas, Verena Untiet, Zuzanna Bojarowska, Virginia Plá, Björn Sigurdsson, Vincenzo Timmel, Lukas Gehrig, Michael H Graber, Hajime Hirase, Maiken Nedergaard.

Consciousness is lost within seconds upon cessation of cerebral blood flow. The brain cannot store oxygen, and interruption of oxidative phosphorylation is fatal within minutes. Yet only rudimentary knowledge exists regarding cortical partial oxygen tension (Po2) dynamics under physiological conditions. Here we introduce Green enhanced Nano-lantern (GeNL), a genetically encoded bioluminescent oxygen indicator for Po2 imaging. In awake behaving mice, we uncover the existence of spontaneous, spatially defined "hypoxic pockets" and demonstrate their linkage to the abrogation of local capillary flow. Exercise reduced the burden of hypoxic pockets by 52% compared with rest. The study provides insight into cortical oxygen dynamics in awake behaving animals and concurrently establishes a tool to delineate the importance of oxygen tension in physiological processes and neurological diseases.

DOI: https://doi.org/10.1126/science.adn1011
Breast Cancer Res Treat. 2024 Mar 29.

Lifestyle interventions with dietary strategies after breast cancer diagnosis: a systematic review.

Acadia W Buro, Tam Nguyen, Michael Abaskaron, Mary Katherine Haver, Tiffany L Carson.

  PURPOSE: Obesity can increase mortality and morbidity in breast cancer survivors. Healthy lifestyle factors such as diet can help manage weight in this population. This systematic review examined lifestyle interventions with dietary strategies for breast cancer survivors and their effect on diet and/or weight-related outcomes.METHODS: Searches were conducted in Ovid MEDLINE® ALL (1946-February 14, 2022), Embase (Elsevier), CINAHL Complete (EBSCO), and APA PsycArticles (EBSCO), using keywords for diet, breast cancer, and intervention. The search was limited to human studies, English language, and publication processing date 2016-2023.
RESULTS: The search yielded 3427 articles. After title and abstract review, 225 full-text articles were screened, and 67 articles with 61 distinct samples and interventions met inclusion criteria. Of these 61 lifestyle interventions with dietary strategies, 43 interventions also addressed physical activity. Most studies were randomized controlled trials (n = 41) and conducted post-treatment (n = 45). Mean participant age was 54 years. Of 29 studies that reported race/ethnicity, 20 (69%) reported ≥50% White participants. Of 36 that reported dietary outcomes, 29 (81%) reported significant findings. Of 57 that reported weight-related outcomes, 51 (89%) reported significant findings.
CONCLUSION: This review demonstrated promising evidence for the efficacy of lifestyle interventions with dietary strategies in breast cancer survivors. However, culturally tailored interventions and interventions conducted before and during treatment are lacking.

Keywords:  Breast cancer; Dietary interventions; Obesity; Survivorship

DOI:  https://doi.org/10.1007/s10549-024-07278-x
Aging Biol. 2024 ;pii: 20230019. [Epub ahead of print]2

Intermittent Methionine Restriction Reduces Marrow Fat Accumulation and Preserves More Bone Mass than Continuous Methionine Restriction.

Jason D Plummer, Mark C Horowitz, Jay E Johnson.

Continuous methionine restriction (MR) is one of only a few dietary interventions known to dramatically extend mammalian healthspan. For example, continuously methionine-restricted rodents show less age-related pathology and are up to 45% longer-lived than controls. Intriguingly, MR is feasible for humans, andanumberofstudieshavesuggestedthatmethionine-restrictedindividualsmayreceivesimilarhealthspan benefits as rodents. However, long-term adherence to a continuously methionine-restricted diet is likely to be challenging (or even undesirable) for many individuals. To address this, we previously developed an intermittent version of MR (IMR) and demonstrated that it confers nearly identical metabolic health benefits to mice as the continuous intervention, despite having a relatively short interventional period (i.e., only three days per week). We also observed that female mice undergoing IMR show a more pronounced amelioration of diet-induced dysglycemia than continuously methionine-restricted counterparts, while male mice undergoing IMR retain more lean body mass as compared with continuously methionine-restricted controls. Prompted by such findings, we sought to determine other ways in which IMR might compare favorably with continuous MR. While it is known that continuous MR has deleterious effects on bone in mice, including loss of both trabecular and cortical bone, we considered that mice undergoing IMR might retain more bone mass. Here, we report that, as compared with continuous MR, IMR results in a preservation of both trabecular and cortical bone, as well as a dramatic reduction in the accumulation of marrow fat. Consistent with such findings, mechanical testing revealed that the bones of intermittently methionine-restricted mice are significantly stronger than those of mice subjected to the continuous intervention. Finally, static histomorphometric analyses suggest that IMR likely results in more bone mass than that produced by continuous MR, primarily by increasing the number of osteoblasts. Together, our results demonstrate that the more practicable intermittent form of MR not only confers similar metabolic health benefits to the continuous intervention but does so without markedly deleterious effects on either the amount or strength of bone. These data provide further support for the use of IMR in humans.

DOI: https://doi.org/10.59368/agingbio.20230019
Endocrine. 2024 Mar 22.

Diet, exercise, and supplements: what is their role in the management of the metabolic dysfunction-associated steatotic liver disease in children?

Anastasios Serbis, Stergios A Polyzos, Stavroula A Paschou, Ekaterini Siomou, Dimitrios N Kiortsis.

  Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the main cause of chronic liver disease in children and adolescents. Indeed, epidemiological studies have shown that MASLD affects up to 40% of children with obesity. Despite the recent approval of medications that target weight loss in adolescents that could have benefits on pediatric MASLD, lifestyle interventions, such as diet and exercise, remain the mainstay of our therapeutic approach. More specifically, studies on diet alone have focused on the possible role of carbohydrate or fat restriction, albeit without a definite answer on the best approach. Weight loss after dietary intervention in children with obesity and MASLD has a beneficial effect, regardless of the diet used. In relation to the role of exercise in MASLD reversal, indirect evidence comes from studies showing that a sedentary lifestyle leading to poor fitness, and low muscle mass is associated with MASLD. However, research on the direct effect of exercise on MASLD in children is scarce. A combination of diet and exercise seems to be beneficial with several studies showing improvement in surrogate markers of MASLD, such as serum alanine aminotransferase and hepatic fat fraction, the latter evaluated with imaging studies. Several dietary supplements, such as vitamin E, probiotics, and omega-3 fatty acid supplements have also been studied in children and adolescents with MASLD, but with equivocal results. This review aims to critically present available data on the effects of lifestyle interventions, including diet, exercise, and dietary supplements, on pediatric MASLD, thus suggesting a frame for future research that could enhance our knowledge on pediatric MASLD management and optimize clinicians' approach to this vexing medical condition.

Keywords:  Children; Diet; Dietary supplements; Exercise; Lifestyle interventions; NAFLD

DOI:  https://doi.org/10.1007/s12020-024-03783-7
Curr Dev Nutr. 2024 Mar;8(3): 102127

The Association of Low-Carbohydrate Diet and HECTD4 rs11066280 Polymorphism with Risk of Colorectal Cancer: A Case-Control Study in Korea.

Tao Thi Tran, Madhawa Gunathilake, Jeonghee Lee, Jae Hwan Oh, Hee Jin Chang, Dae Kyung Sohn, Aesun Shin, Jeongseon Kim.

  Background: Glucose is a main source of energy for tumor cells. Thus, a low-carbohydrate diet (LCD) is thought to make a significant contribution to cancer prevention. In addition, LCD and HECT domain E3 ubiquitin protein ligase 4 (HECTD4) gene may be related to insulin resistance.Objectives: We explored whether LCD score and HECTD4 rs11066280 are etiological factors for colorectal cancer (CRC) and whether LCD score interacts with HECTD4 rs11066280 to modify CRC risk.
Methods: We included 1457 controls and 1062 cases in a case-control study. The LCD score was computed based on the proportion of energy obtained from carbohydrate, protein, and fat, as determined by a semiquantitative food frequency questionnaire. We used unconditional logistic regression models to explore the association of HECTD4 with CRC prevention and interaction of LCD score and HECTD4 polymorphism with CRC preventability.
Results: Individuals with AA/AT genotypes who carried a minor allele (A) of HECTD4 rs11066280 exhibited a decreased CRC risk [odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.62, 0.91]. In addition, a protective effect of high LCD score against CRC development was identified (OR = 0.52, 95% CI: 0.40, 0.68, P for trend <0.001). However, the effect of LCD depended on individual's genetic background, which appears only in participants with TT genotype of HECTD4 rs11066280 [OR = 0.49 (0.36-0.68), P interaction = 0.044].
Conclusions: Our findings suggest a protective effect of LCD and a minor allele of HECTD4 rs11066280 against CRC development. In addition, we provide an understanding of the interaction effect of LCD and HECTD4 rs11066280 on CRC, which may be helpful for establishing diet plans regarding cancer prevention.

Keywords:  HECTD4 rs11066280; Korea; case-control study; colorectal cancer; low-carbohydrate diet

DOI:  https://doi.org/10.1016/j.cdnut.2024.102127
Leukemia. 2024 Mar 26.

Proteomics for optimizing therapy in acute myeloid leukemia: venetoclax plus hypomethylating agents versus conventional chemotherapy.

Eduardo Sabino de Camargo Magalhães, Stefan Edward Hubner, Brandon Douglas Brown, Yihua Qiu, Steven Mitchell Kornblau.

The use of Hypomethylating agents combined with Venetoclax (VH) for the treatment of Acute Myeloid Leukemia (AML) has greatly improved outcomes in recent years. However not all patients benefit from the VH regimen and a way to rationally select between VH and Conventional Chemotherapy (CC) for individual AML patients is needed. Here, we developed a proteomic-based triaging strategy using Reverse-phase Protein Arrays (RPPA) to optimize therapy selection. We evaluated the expression of 411 proteins in 810 newly diagnosed adult AML patients, identifying 109 prognostic proteins, that divided into five patient expression profiles, which are useful for optimizing therapy selection. Furthermore, using machine learning algorithms, we determined a set of 14 proteins, among those 109, that were able to accurately recommend therapy, making it feasible for clinical application. Next, we identified a group of patients who did not benefit from either VH or CC and proposed target-based approaches to improve outcomes. Finally, we calculated that the clinical use of our proteomic strategy would have led to a change in therapy for 30% of patients, resulting in a 43% improvement in OS, resulting in around 2600 more cures from AML per year in the United States.

DOI: https://doi.org/10.1038/s41375-024-02208-8
Cureus. 2024 Feb;16(2): e54863

Keto Clarity: A Comprehensive Systematic Review Exploring the Efficacy, Safety, and Mechanisms of Ketogenic Diet in Pediatric Epilepsy.

Youmna Faheem, Amisha Jaiswal, Kainaat Shergill, Kusalik Boppana, Naiela E Almansouri, Saloni Bakkannavar, Ann Kashmer Yu.

  Epilepsy, a widespread neurological disorder characterized by recurrent seizures, affects millions globally, with a significant impact on the pediatric population. Antiepileptic drugs (AEDs) constitute the primary treatment; however, drug-resistant epilepsy (DRE), especially in children, poses a therapeutic challenge. Alternative interventions, such as surgery, vagus nerve stimulation, and the ketogenic diet (KD), have been explored. This systematic review aims to investigate various types of KDs, their distinctions, their effectiveness, and their safety concerning the reduction of seizure frequency, achieving seizure freedom, and the occurrence of adverse events. The study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive search was conducted using databases such as PubMed Central (PMC), MedLine, and Science Direct to identify relevant articles. Eligibility criteria and quality assessment tools were applied to evaluate the potential risk of bias and select 11 articles for inclusion in this review. The selected articles encompassed four randomized controlled trials (RCTs), two systematic reviews, and five narrative reviews. The data collected for this review was completed on October 2, 2023. Challenges, such as palatability, cultural factors, and adherence difficulties, were identified. Family or caregiver involvement plays a pivotal role in treatment success. Despite numerous RCTs and reviews, information gaps persist, hindering conclusive outcomes. Evaluating the risk-benefit ratio is crucial, considering potential side effects. The highly individualized nature of KD therapy, influenced by diverse seizure types and syndromes, necessitates a trial-and-error approach monitored by a multidisciplinary team. Long-term safety and efficacy demand continuous real-life patient data review. In summary, while KD presents a promising alternative for DRE, its success relies on meticulous planning, individualized implementation, and ongoing research to address existing challenges and information gaps.

Keywords:  classic ketogenic diet; drug-resistant epilepsy (dre); epilepsy; ketogenic diet; low glycemic index treatment (lgit); medium-chain triglyceride ketogenic diet (mctkd); modified atkins diet (mad); pediatric neurology; pediatrics; seizure

DOI:  https://doi.org/10.7759/cureus.54863
Blood Rev. 2024 Mar 21. pii: S0268-960X(24)00028-6. [Epub ahead of print] 101195

BCL-2 inhibition in haematological malignancies: Clinical application and complications.

Dominic J Fowler-Shorten, Charlotte Hellmich, Matthew Markham, Kristian M Bowles, Stuart A Rushworth.

  B-cell lymphoma-2 (BCL-2) family proteins are fundamental regulators of the intrinsic apoptotic pathway which modulate cellular fate. In many haematological malignancies, overexpression of anti-apoptotic factors (BCL-2, BCL-XL and MCL-1) circumvent apoptosis. To address this cancer hallmark, a concerted effort has been made to induce apoptosis by inhibiting BCL-2 family proteins. A series of highly selective BCL-2 homology 3 (BH3) domain mimetics are in clinical use and in ongoing clinical trials for acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), and multiple myeloma (MM). These inhibitors serve as promising candidates, both as single agents or in combination therapy to improve patient outcomes. In other diseases such as follicular lymphoma, efficacy has been notably limited. There are also clinical problems with BCL-2 family inhibition, including drug resistance, disease relapse, tumour lysis syndrome, and clinically relevant cytopenias. Here, we provide a balanced view on both the clinical benefits of BCL-2 inhibition as well as the associated challenges.

Keywords:  BCL-2 family inhibitors; Cytopenias; Drug resistance; Haematological malignancies; Venetoclax

DOI:  https://doi.org/10.1016/j.blre.2024.101195
Int J Mol Sci. 2024 Mar 20. pii: 3475. [Epub ahead of print]25(6):

The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner.

Jennifer E Norman, Dragan Milenkovic, Saivageethi Nuthikattu, Amparo C Villablanca.

  Obesity is linked to cognitive decline and metabolic dysregulation in the brain, yet the role of sex is relatively unexplored. We sought to explore the effects of obesity and sex on the brain metabolome. In male and female ob/ob and wild-type mice, we assessed whole brain untargeted metabolomics by liquid chromatography-mass spectrometry, behavior by open field test, and cognitive function by Y-maze and Morris water maze. The metabolic profiles of ob/ob and wild-type mice differed in both sexes. There were more obesity-altered brain metabolites in males than females. Thirty-nine metabolites were unique to males, 15 were unique to females, and five were common to both sexes. Two of the common metabolites were involved in nicotinamide adenine dinucleotide homeostasis. A key feature of the metabolites identified in males was an increase in free fatty acids. In females, a unique feature was the presence of the neuro-modulatory metabolites 2-linoleoyl glycerol and taurine. The behavioral effects of obesity were only seen in females. These results demonstrate that most impacts of obesity on the brain metabolomic profile are sex-specific. Our work has implications for understanding the role of obesity in brain metabolism and the differential contribution of obesity to cognitive decline in males and females.

Keywords:  brain; cognitive function; metabolomics; obesity; sex differences

DOI:  https://doi.org/10.3390/ijms25063475
J Biol Chem. 2024 Mar 22. pii: S0021-9258(24)01709-5. [Epub ahead of print] 107214

DISRUPTION OF POLYUNSATURATED FATTY ACID BIOSYNTHESIS DRIVES STING-DEPENDENT ACUTE MYELOID LEUKEMIA CELL MATURATION AND DEATH.

Joice Kanefsky, Mary Basse, Judith Sokei, Orsola di Martino, Liana Valin, Yorrick Jaspers, Esteban Martinez, Jacklyn Huhn, Daniela Di Marcantonio, Jeffrey A Magee, Aaron R Goldman, Hsin-Yao Tang, Francesca Ferraro, Stephan Kemp, David L Wiest, Stephen M Sykes.

The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that Fatty Acid Desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to health controls, and that elevated FADS1 expression correlates with worse overall AML patient survival. Functionally, shRNA-mediated inhibition of FADS1 reduced AML cell growth in vitro and significantly delayed leukemia onset in an AML mouse model. AML cell lines depleted of FADS1 arrested in the G1/S-phase of the cell cycle, acquired characteristics of myeloid maturation and subsequently died. To understand the molecular consequences of FADS1 inhibition, a combination of mass spectrometry-based analysis of complex lipids and gene expression analysis (RNA-seq) was performed. FADS1 inhibition caused AML cells to exhibit significant lipidomic remodeling including depletion of PUFAs from the phospholipids, phosphatidylserine and phosphatidylethanolamine. These lipidomic alterations were accompanied by an induction of inflammatory and STING-mediated type-1 interferon signaling. Remarkably, genetic deletion of STING largely prevented the AML cell maturation and death phenotypes mediated by FADS1 inhibition. Highlighting the therapeutic implications of these findings, pharmacological blockade of PUFA biosynthesis reduced patient-derived AML (PD-AML) cell numbers ex vivo but not that of healthy donor cells. Similarly, STING agonism attenuated PD-AML survival, however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death.

DOI: https://doi.org/10.1016/j.jbc.2024.107214
Nutrients. 2024 Mar 11. pii: 800. [Epub ahead of print]16(6):

Healthy Lifestyle and Cancer Risk: Modifiable Risk Factors to Prevent Cancer.

Pasquale Marino, Mariangela Mininni, Giovanni Deiana, Graziella Marino, Rosa Divella, Ilaria Bochicchio, Alda Giuliano, Stefania Lapadula, Alessandro Rocco Lettini, Francesca Sanseverino.

  Cancer has become a serious problem worldwide, as it represents the main cause of death, and its incidence has increased over the years. A potential strategy to counter the growing spread of various forms of cancer is the adoption of prevention strategies, in particular, the use of healthy lifestyles, such as maintaining a healthy weight, following a healthy diet; being physically active; avoiding smoking, alcohol consumption, and sun exposure; and vitamin D supplementation. These modifiable risk factors are associated with this disease, contributing to its development, progression, and severity. This review evaluates the relationship between potentially modifiable risk factors and overall cancer development, specifically breast, colorectal, and prostate cancer, and highlights updated recommendations on cancer prevention. The results of numerous clinical and epidemiological studies clearly show the influence of lifestyles on the development and prevention of cancer. An incorrect diet, composed mainly of saturated fats and processed products, resulting in increased body weight, combined with physical inactivity, alcohol consumption, and smoking, has induced an increase in the incidence of all three types of cancer under study. Given the importance of adopting correct and healthy lifestyles to prevent cancer, global institutions should develop strategies and environments that encourage individuals to adopt healthy and regular behaviors.

Keywords:  breast cancer; cancer prevention recommendations; cancer risk; colorectal cancer; healthy lifestyle; modifiable risk factors; prostate cancer

DOI:  https://doi.org/10.3390/nu16060800
Camb Prism Precis Med. 2024 ;2 e2

Heterogeneity in precision oncology.

Bartłomiej Tomasik, Filip Garbicz, Marcin Braun, Michał Bieńkowski, Jacek Jassem.

  Precision oncology is a rapidly evolving concept that holds great promise in cancer treatment. However, a cancer complexity attributed to genomic and acquired tumour heterogeneity limits treatment effectiveness and increases toxicity. These limitations refer to both systemic therapies and radiotherapy, which are two mainstays of non-invasive cancer treatment. By understanding cancer heterogeneity and utilising advanced tools to personalise treatment strategies, precision oncology has the potential to revolutionise cancer care. In this article, we review the current status of precision oncology in solid tumours, specifically focusing on the impact of tumour heterogeneity and genomic patient features on systemic therapies and radiation. We also discuss the implementation of novel tools, such as next-generation sequencing and liquid biopsies, to overcome this problem.

Keywords:  cancer; genomics; precision oncology; proteomics; tumour heterogeneity

DOI:  https://doi.org/10.1017/pcm.2023.23
Front Nutr. 2024 ;11 1347724

Artificially sweetened beverages consumption and risk of obesity-related cancers: a wide-angled Mendelian randomization study.

Xing Jin, Mengyue Wu, Shuangshuang Dong, Hui Liu, Haochuan Ma.

  Background: The impact of artificially sweetened beverages (ASBs) consumption on obesity-related cancers (ORCs) risk remains controversial. To address this challenging issue, this study employed wide-angle mendelian randomization (MR) analyses to explore the genetic causality between ASB consumption and the risk of ORCs, thereby effectively minimizing the impact of external confounders.Methods: We conducted a suite of analyses encompassing univariable, multivariable, and two-step MR to evaluate causal associations between ASB consumption (samples = 85,852) and risk of ORCs (total samples = 2,974,770) using summary statistics from genome-wide association studies (GWAS). Total, direct, and intermediary effects were derived by performing inverse-variance weighted (IVW), MR-Egger, weighted mode, weighted median, and lasso method. Additionally, we performed an extensive range of sensitivity analyses to counteract the potential effects of confounders, heterogeneity, and pleiotropy, enhancing the robustness and reliability of the findings.
Results: Genetically predicted ASB consumption was positively associated with the risk of colorectal cancer (CRC, p = 0.011; OR: 6.879; 95% CI: 1.551, 30.512 by IVW) and breast cancer (p = 0.022; OR: 3.881; 95% CI: 2.023, 9.776 by IVW). Multivariable analysis yielded similar results. The results of the two-step MR unveiled that body mass index (BMI) assumes a pivotal role in mediating the association between ASB consumption and CRC risk (intermediary effect = 0.068, p = 0.024).
Conclusion: No causal connection exists between ASB consumption and the majority of ORCs, in addition to CRC and breast cancer. Additionally, our findings suggest that BMI might be a potential mediator in the association between ASB consumption and CRC.

Keywords:  BMI; Mendelian randomization; artificially sweetened beverages; cancer risk; obesity; sugar

DOI:  https://doi.org/10.3389/fnut.2024.1347724
Cancers (Basel). 2024 Mar 08. pii: 1091. [Epub ahead of print]16(6):

Venetoclax Resistance in Acute Myeloid Leukemia.

Sylvain Garciaz, Marie-Anne Hospital, Yves Collette, Norbert Vey.

  Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, VEN-AZA showed a 65% overall response rate and 14.7 months overall survival in comparison with 22% and 8 months in the azacitidine monotherapy control arm. Despite these promising results, relapses and primary resistance to venetoclax are frequent and remain an unmet clinical need. Clinical and preclinical studies have been conducted to identify factors driving resistance. Among them, the most documented are molecular alterations including IDH, FLT3, TP53, and the newly described BAX mutations. Several non-genetic factors are also described such as metabolic plasticity, changes in anti-apoptotic protein expression, and dependencies, as well as monocytic differentiation status. Strategies to overcome venetoclax resistance are being developed in clinical trials, including triplet therapies with targeted agents targeting IDH, FLT3, as well as the recently developed menin inhibitors or immunotherapies such as antibody-drug conjugated or monoclonal antibodies. A better understanding of the molecular factors driving venetoclax resistance by single-cell analyses will help the discovery of new therapeutic strategies in the future.

Keywords:  acute myeloid leukemia; apoptosis; venetoclax

DOI:  https://doi.org/10.3390/cancers16061091
Cell Rep Med. 2024 Mar 22. pii: S2666-3791(24)00128-9. [Epub ahead of print] 101482

Real-time glioblastoma tumor microenvironment assessment by SpiderMass for improved patient management.

Yanis Zirem, Léa Ledoux, Lucas Roussel, Claude Alain Maurage, Pierre Tirilly, Émilie Le Rhun, Bertrand Meresse, Gargey Yagnik, Mark J Lim, Kenneth J Rothschild, Marie Duhamel, Michel Salzet, Isabelle Fournier.

  Glioblastoma is a highly heterogeneous and infiltrative form of brain cancer associated with a poor outcome and limited therapeutic effectiveness. The extent of the surgery is related to survival. Reaching an accurate diagnosis and prognosis assessment by the time of the initial surgery is therefore paramount in the management of glioblastoma. To this end, we are studying the performance of SpiderMass, an ambient ionization mass spectrometry technology that can be used in vivo without invasiveness, coupled to our recently established artificial intelligence pipeline. We demonstrate that we can both stratify isocitrate dehydrogenase (IDH)-wild-type glioblastoma patients into molecular sub-groups and achieve an accurate diagnosis with over 90% accuracy after cross-validation. Interestingly, the developed method offers the same accuracy for prognosis. In addition, we are testing the potential of an immunoscoring strategy based on SpiderMass fingerprints, showing the association between prognosis and immune cell infiltration, to predict patient outcome.

Keywords:  MALDI-IHC; SpiderMass; diagnosis; glioblastoma; imaging; immunoscore; lipids; machine learning; mass spectrometry; prognosis

DOI:  https://doi.org/10.1016/j.xcrm.2024.101482
Biomolecules. 2024 Mar 04. pii: 303. [Epub ahead of print]14(3):

Solute Transport through Mitochondrial Porins In Vitro and In Vivo.

Roland Benz.

  Mitochondria are most likely descendants of strictly aerobic prokaryotes from the class Alphaproteobacteria. The mitochondrial matrix is surrounded by two membranes according to its relationship with Gram-negative bacteria. Similar to the bacterial outer membrane, the mitochondrial outer membrane acts as a molecular sieve because it also contains diffusion pores. However, it is more actively involved in mitochondrial metabolism because it plays a functional role, whereas the bacterial outer membrane has only passive sieving properties. Mitochondrial porins, also known as eukaryotic porins or voltage-dependent anion-selective channels (VDACs) control the permeability properties of the mitochondrial outer membrane. They contrast with most bacterial porins because they are voltage-dependent. They switch at relatively small transmembrane potentials of 20 to 30 mV in closed states that exhibit different permeability properties than the open state. Whereas the open state is preferentially permeable to anionic metabolites of mitochondrial metabolism, the closed states prefer cationic solutes, in particular, calcium ions. Mitochondrial porins are encoded in the nucleus, synthesized at cytoplasmatic ribosomes, and post-translationally imported through special transport systems into mitochondria. Nineteen beta strands form the beta-barrel cylinders of mitochondrial and related porins. The pores contain in addition an α-helical structure at the N-terminal end of the protein that serves as a gate for the voltage-dependence. Similarly, they bind peripheral proteins that are involved in mitochondrial function and compartment formation. This means that mitochondrial porins are localized in a strategic position to control mitochondrial metabolism. The special features of the role of mitochondrial porins in apoptosis and cancer will also be discussed in this article.

Keywords:  VDAC; apoptosis; cancer; lipid bilayer; mitochondrial metabolism; mitochondrial porin; peripheral kinases; pore structure; voltage dependence

DOI:  https://doi.org/10.3390/biom14030303
Methods Cell Biol. 2024 ;pii: S0091-679X(23)00114-0. [Epub ahead of print]183 317-333

Humanized mouse models for anti-cancer therapy.

Maria Francesca Baietti, Eleonora Leucci.

  Patient-derived xenograft (PDX) models are the golden standard for preclinical oncology as they can recapitulate the genotypic and phenotypic complexity of human tumors, thus enabling the development of effective therapeutic strategies. PDX models are typically established in immunocompromised animals that allow efficient growth of the xenografted tumor. Given the recent success of immune therapies in different tumors however, the establishment of humanized PDX models is critical to evaluate immune oncology drugs and/or combinations thereof. Here, we describe the detailed methods to obtain humanized PDX models for anti-cancer therapy testing.

Keywords:  Humanization; Immunotherapy; In vivo; PDX; Tumor models; Xenografts

DOI:  https://doi.org/10.1016/bs.mcb.2023.06.002