bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023–06–04
thirteen papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins
  1. Ketone ester-what's in a name? Ambiguity begets uncertainty.
  2. A ketogenic diet containing medium-chain triglycerides reduces REM sleep duration without significant influence on mouse circadian phenotypes.
  3. Ketogenic diet in cancer management.
  4. Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D).
  5. Exogenous Ketosis Improves Sleep Efficiency and Counteracts the Decline in REM Sleep Following Strenuous Exercise.
  6. SGLT2 Inhibitor: an Emerging Pillar in Heart Failure Therapeutics?
  7. Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer's disease?
  8. Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction.
  9. Isolation of Mitochondria from Mouse Tissues for Functional Analysis.
  10. Preventive nutritional supplementation with furan fatty acid in a DIO mouse model increases muscle mass and reduces metabolic disorders.
  11. Live or death in cells: from micronutrition metabolism to cell fate.
  12. The Effects of Medium Chain Triglyceride for Alzheimer's Disease Related Cognitive Impairment: A Systematic Review and Meta-Analysis.
  13. Curcumin displays a potent caloric restriction mimetic effect in an accelerated senescent model of rat.
  1. Front Physiol. 2023 ;14 1197768
    Ketone ester-what's in a name? Ambiguity begets uncertainty.
    M Todd King.
      
    Keywords:  acetoacetate; beta-hydroxybutyrate; ketone bodies; ketone ester nomenclature; ketone esters
    DOI:  https://doi.org/10.3389/fphys.2023.1197768
  2. Food Res Int. 2023 07;pii: S0963-9969(23)00397-6. [Epub ahead of print]169 112852
    A ketogenic diet containing medium-chain triglycerides reduces REM sleep duration without significant influence on mouse circadian phenotypes.
    Haotong Zhuang, Yuri Fujikura, Naoki Ohkura, Sayaka Higo-Yamamoto, Taiga Mishima, Katsutaka Oishi.
      Ketogenic diets (KDs) affect the circadian rhythms of behavior and clock gene expression in experimental animals. However, these diets were designed to simulate a fasting state; thus, whether these effects are caused by diet-induced ketogenesis or persistent starvation is difficult to distinguish. The present study aimed to define the effects of a KD containing medium-chain triglycerides (MCT-KD) that increase blood ketone levels without inducing carbohydrate starvation, on circadian rhythms and sleep regulation. Mice were fed with a normal diet (CTRL) or MCT-KD for 2 weeks. Blood β-hydroxybutyrate levels were significantly increased up to 2 mM by the MCT-KD, whereas body weight gain and blood glucose levels were identical between the groups, suggesting that ketosis accumulated without carbohydrate starvation in the MCT-KD mice. Circadian rhythms of wheel-running activity and core body temperature were almost identical, although wheel-running was slightly reduced in the MCT-KD mice. The circadian expression of the core clock genes, Per1, Per2, Bmal1, and Dbp in the hypothalamus, heart, liver, epididymal adipose tissues, and skeletal muscle were almost identical between the CTRL and MCT-KD mice, whereas the amplitude of hepatic Per2 and adipose Per1 expression was increased in MCT-KD mice. The MCT-KD reduced the duration of rapid-eye-movement (REM) sleep without affecting the duration of non-REM sleep and the duration of wakefulness. These findings suggested that the impact of ketone bodies on circadian systems are limited, although they might reduce locomotor activity and REM sleep duration.
    Keywords:  Circadian rhythm; Clock gene; Ketogenic diet; Medium-chain triglyceride; Plasminogen activator inhibitor-1; Sleep
    DOI:  https://doi.org/10.1016/j.foodres.2023.112852
  3. Curr Opin Clin Nutr Metab Care. 2023 May 10.
    Ketogenic diet in cancer management.
    Wamidh H Talib, Anfal Al-Dalaeen, Asma Ismail Mahmod.
       PURPOSE OF REVIEW: This review presents details about types of ketogenic diet (KD), anticancer mechanisms, and the use of KD in experimental and clinical studies. Studies summarized in this review provide a solid ground for researchers to consider the use of KD to augment conventional treatments.
    RECENT FINDINGS: KD is a dietary pattern composed of high fat, moderate proteins, and very-low-carbohydrate. This diet was suggested to have an anticancer effect and to augment conventional anticancer therapies. KD can target cancer cell by interfering with its metabolism without harming normal cells.
    SUMMARY: Several experimental and clinical studies support the use of KD as adjuvant therapy to treat different cancers.
    DOI:  https://doi.org/10.1097/MCO.0000000000000944
  4. Sci Rep. 2023 Jun 02. 13(1): 8951
    Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D).
    Adrian Avila, Ignacio Málaga, Deepa Sirsi, Saima Kayani, Sharon Primeaux, Gauri A Kathote, Vikram Jakkamsetti, Raja Reddy Kallem, William C Putnam, Jason Y Park, Shlomo Shinnar, Juan M Pascual.
      Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet.ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017.
    DOI:  https://doi.org/10.1038/s41598-023-36001-x
  5. Med Sci Sports Exerc. 2023 Jun 01.
    Exogenous Ketosis Improves Sleep Efficiency and Counteracts the Decline in REM Sleep Following Strenuous Exercise.
    Ruben Robberechts, Geneviève Albouy, Peter Hespel, Chiel Poffè.
       INTRODUCTION: Available evidence indicates that ketone bodies may improve sleep quality. Therefore, we determined whether ketone ester (KE) intake could counteract sleep disruptions induced by strenuous exercise.
    METHODS: Ten well-trained cyclists with good sleep quality participated in a randomised crossover design consisting of two experimental sessions each involving a morning endurance training and an evening high-intensity interval training ending one hour before sleep, after which polysomnography was performed overnight. Post-exercise and 30 min before sleeping time, subjects received either 25 g KE (EXKE) or a placebo drink (EXCON). A third session without exercise, but with placebo supplements (RCON) was added to evaluate the effect of exercise per se on sleep.
    RESULTS: Blood D-β-hydroxybutyrate concentrations transiently increased to ~3 mM post-exercise and during the first part of the night in EXKE but not in EXCON or RCON. Exercise significantly reduced REM sleep by 26% (p = 0.001 vs. RCON) and increased wakefulness after sleep onset (WASO) by 95% (p = 0.004 vs. RCON). Interestingly, KE improved sleep efficiency by 3% (p = 0.040 vs. EXCON) and counteracted the exercise-induced decrease in REM sleep (p = 0.011 vs. EXCON) and the increase in WASO (p = 0.009 vs. EXCON). This was accompanied by a KE-induced increase in dopamine excretion (p = 0.033 vs. EXCON), which plays a pivotal role in sleep regulation. In addition, exercise increased sleep spindle density by 36% (p = 0.005 vs. RCON) suggesting an effect on neural plasticity processes during sleep.
    CONCLUSIONS: These data indicate that KE ingestion improves sleep efficiency and quality following high-intensity exercise. We provide preliminary evidence that this might result from KE-induced increases in dopamine signalling.
    DOI:  https://doi.org/10.1249/MSS.0000000000003231
  6. Maedica (Bucur). 2023 Mar;18(1): 102-110
    SGLT2 Inhibitor: an Emerging Pillar in Heart Failure Therapeutics?
    Madalina Andreea Munteanu, Surabhi Swarnkar, Razvan-Ionut Popescu, Anca Lungu, Lucia Ciobotaru, Camelia Nicolae, Emil Tufanoiu, Ioan Tiberiu Nanea.
      Heart failure (HF) is a worldwide pandemic that affects at least 26 million people and is becoming more prevalent. Heart failure health expenditures are substantial and will considerably increase with population aging. Newer medications for treating type 2 diabetes include sodium-glucose cotransporter-2 inhibitors (SGLT2). Recent clinical studies and research have shown the efficacy of this class in treating heart failure by lowering the risk of cardiovascular events, hospitalization, and mortality. In addition, there is undeniable evidence that SGLT2 inhibitors have a beneficial effect on metabolic function, even though the mechanisms responsible for these drugs' practical consequences have not been completely elucidated. In this narrative review, we discuss the effects of SGLT2 inhibitors on the provision of cardiac energy by ketone bodies, pathological remodeling of the ventricle, arterial stiffness, and inflammation in patients with HF.
    DOI:  https://doi.org/10.26574/maedica.2023.18.1.102
  7. Front Mol Neurosci. 2023 ;16 1166879
    Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer's disease?
    Oualid Sbai, Veronica Bazzani, Shreya Tapaswi, Joshua McHale, Carlo Vascotto, Lorena Perrone.
      Recent advances highlight that inflammation is critical to Alzheimer Disease (AD) pathogenesis. Indeed, several diseases characterized by inflammation are considered risk factors for AD, such as type 2 diabetes, obesity, hypertension, and traumatic brain injury. Moreover, allelic variations in genes involved in the inflammatory cascade are risk factors for AD. AD is also characterized by mitochondrial dysfunction, which affects the energy homeostasis of the brain. The role of mitochondrial dysfunction has been characterized mostly in neuronal cells. However, recent data are demonstrating that mitochondrial dysfunction occurs also in inflammatory cells, promoting inflammation and the secretion of pro-inflammatory cytokines, which in turn induce neurodegeneration. In this review, we summarize the recent finding supporting the hypothesis of the inflammatory-amyloid cascade in AD. Moreover, we describe the recent data that demonstrate the link between altered mitochondrial dysfunction and the inflammatory cascade. We focus in summarizing the role of Drp1, which is involved in mitochondrial fission, showing that altered Drp1 activation affects the mitochondrial homeostasis and leads to the activation of the NLRP3 inflammasome, promoting the inflammatory cascade, which in turn aggravates Amyloid beta (Ab) deposition and tau-induced neurodegeneration, showing the relevance of this pro-inflammatory pathway as an early event in AD.
    Keywords:  Alzheimer inflammation; DRP1; NLRP3; TXNIP; mitochondria
    DOI:  https://doi.org/10.3389/fnmol.2023.1166879
  8. Metabolism. 2023 May 31. pii: S0026-0495(23)00212-3. [Epub ahead of print] 155608
    Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction.
    Salva R Yurista, Robert A Eder, Aidan Welsh, William Jiang, Shi Chen, Anna N Foster, Adam Mauskapf, W H Wilson Tang, William J Hucker, Jaume Coll-Font, Anthony Rosenzweig, Christopher T Nguyen.
       BACKGROUND: Myocardial infarction (MI) is a major risk factor for the development of heart failure with reduce ejection fraction (HFrEF). While previous studies have focused on HFrEF, the cardiovascular effects of ketone bodies in acute MI are unclear. We examined the effects of oral ketone supplementation as a potential treatment strategy in a swine acute MI model.
    METHODS: Farm pigs underwent percutaneous balloon occlusion of the LAD for 80 min followed by 72 h reperfusion period. Oral ketone ester or vehicle was administered during reperfusion and continued during the follow-up period.
    RESULTS: Oral KE supplementation induced ketonemia 2-3 mmol/l within 30 min after ingestion. KE increased ketone (βHB) extraction in healthy hearts without affecting glucose and fatty acid (FA) consumption. During reperfusion, the MI hearts consumed less FA with no change in glucose consumption, whereas hearts from MI-KE-fed animals consumed more βHB and FA, as well as improved myocardial ATP production. A significant elevation of infarct T2 values indicative of inflammation was found only in untreated MI group compared to sham. Concordantly, cardiac expression of inflammatory markers, oxidative stress, and apoptosis were reduced by KE. RNA-seq analysis identified differentially expressed genes related to mitochondrial energy metabolism and inflammation.
    CONCLUSIONS: Oral KE supplementation induced ketosis and enhanced myocardial βHB extraction in both healthy and infarcted hearts. Acute oral supplementation with KE favorably altered cardiac substrate uptake and utilization, improved cardiac ATP levels, and reduced cardiac inflammation following MI.
    Keywords:  Inflammation; Ischemia reperfusion injury; Ketone; Ketone ester; Metabolism; Myocardial infarction
    DOI:  https://doi.org/10.1016/j.metabol.2023.155608
  9. Methods Mol Biol. 2023 ;2675 77-96
    Isolation of Mitochondria from Mouse Tissues for Functional Analysis.
    Rebeca Acín-Pérez, Katrina P Montales, Kaitlyn B Nguyen, Alexandra J Brownstein, Linsey Stiles, Ajit S Divakaruni.
      Methods for isolating mitochondria from different rodent tissues have been established for decades. Although the general principles for crude mitochondrial preparations are largely shared across tissues - tissue disruption followed by differential centrifugation - critical differences exist for isolation from different tissues to optimize mitochondrial yield and function. This protocol offers a unified resource for preparations of isolated mitochondria from mouse liver, kidney, heart, brain, skeletal muscle, and brown and white adipose tissue suitable for functional analysis.
    Keywords:  Bioenergetics; Brain; Brown adipose tissue; Heart; Kidney; Liver; Mitochondria; Oxidative phosphorylation; Skeletal muscle; White adipose tissue
    DOI:  https://doi.org/10.1007/978-1-0716-3247-5_7
  10. Biomed Pharmacother. 2023 May 30. pii: S0753-3322(23)00735-7. [Epub ahead of print]164 114945
    Preventive nutritional supplementation with furan fatty acid in a DIO mouse model increases muscle mass and reduces metabolic disorders.
    Laetitia Dore, Erwann Durand, Béatrice Bonafos, Jatuporn Chaiyut, Laurent Vaysse, Siriluck Liengprayoon, Sylvie Gaillet, Laurence Pessemesse, Karen Lambert, Christelle Bertrand-Gaday, Charles Coudray, Ariane Sultan, François Casas, Christine Feillet-Coudray.
      The increase in obesity has become a major global health problem and is associated with numerous metabolic dysfunctions. Furan fatty acids (FuFAs) are minor lipids present in our diet. Recently we showed that FuFA-F2 extracted from Hevea brasiliensis latex stimulates muscle anabolism in mice in vitro and in vivo, mimicking in part physical activity. While skeletal muscle is essential for energy metabolism and is the predominant site of insulin-mediated glucose uptake in the post prandial state, our results suggested that FuFA-F2 could have favorable effects against obesity. The aim of this work was therefore to study whether a preventive nutritional supplementation with FuFA-F2 (40 mg or 110 mg/day/kg of body weight) in a diet-induced obesity (DIO) mouse model may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. We showed that 12 weeks of FuFA-F2 supplementation in DIO mice decreased fat mass, increased lean mass and restored normal energy expenditure. In addition, we found that FuFA-F2 improved insulin sensitivity. We revealed that FuFA-F2 increased muscle mass but had no effect on mitochondrial function and oxidative stress in skeletal muscle. Furthermore, we observed that FuFA-F2 supplementation reduced liver steatosis without impact on mitochondrial function and oxidative stress in liver. Our findings demonstrated for the first time that a preventive nutritional supplementation with a furan fatty acid in DIO mice reduced metabolic disorders and was able to mimic partly the positive effects of physical activity. This study highlights that nutritional FuFA-F2 supplementation could be an effective approach to treat obesity and metabolic syndrome.
    Keywords:  Furan fatty acids; Insulin sensitivity; Liver; Mitochondria; Obesity; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.biopha.2023.114945
  11. Front Cell Dev Biol. 2023 ;11 1185989
    Live or death in cells: from micronutrition metabolism to cell fate.
    Yuting Wang, Wei Wu, Jianke Gong.
      Micronutrients and cell death have a strong relationship and both are essential for human to maintain good body health. Dysregulation of any micronutrients causes metabolic or chronic diseases, including obesity, cardiometabolic condition, neurodegeneration, and cancer. The nematode Caenorhabditis elegans is an ideal genetic organism for researching the mechanisms of micronutrients in metabolism, healthspan, and lifespan. For example, C. elegans is a haem auxotroph, and the research of this special haem trafficking pathway contributes important reference to mammal study. Also, C. elegans characteristics including anatomy simply, clear cell lineage, well-defined genetics, and easily differentiated cell forms make it a powerful tool for studying the mechanisms of cell death including apoptosis, necrosis, autophagy, and ferroptosis. Here, we describe the understanding of micronutrient metabolism currently and also sort out the fundamental mechanisms of different kinds of cell death. A thorough understanding of these physiological processes not only builds a foundation for developing better treatments for various micronutrient disorders but also provides key insights into human health and aging.
    Keywords:  Caenorhabditis elegans; cell death; metabolism disorder; nutrition; signal pathway
    DOI:  https://doi.org/10.3389/fcell.2023.1185989
  12. J Alzheimers Dis. 2023 May 23.
    The Effects of Medium Chain Triglyceride for Alzheimer's Disease Related Cognitive Impairment: A Systematic Review and Meta-Analysis.
    Lina Sun, Kaisy Xinhong Ye, Hoi Lin Kathleen Wong, Lingyan Wang, Su Lin Lim, Yin Xia Chao, Can Zhang, Kai Zhen Yap, Lei Feng.
       BACKGROUND: The current lack of effective drug therapies for Alzheimer's disease (AD) has prompted researchers to seek alternative nutritional therapies, such as medium chain triglycerides (MCTs). However, results are inconclusive.
    OBJECTIVE: This systematic review and meta-analysis aims to summarize current evidence on the effect of MCT on cognitive function in patients with mild cognitive impairment (MCI) or AD.
    METHODS: A systematic search was conducted up until December 16, 2022, to identify human interventions reporting the effects of MCT on cognitive functioning of MCI or AD patients. 995 non-duplicated publications were identified, of which nine (n = 10 studies) met the inclusion criteria.
    RESULTS: Meta-analysis showed cognitive improvements in general (SMD = 0.64; 95% CI [0.05, 1.24]), but not in memory, language, and attention domains after oral MCT administration, compared to placebo. The effect of MCT was greater among APOEɛ4 (-) subjects than APOEɛ4 (+) subjects (SMD = 1.87; 95% CI [0.35, 3.40]).
    CONCLUSION: This review provides some evidence that treatment with MCT could improve general cognitive function in APOEɛ4 (-) cognitive impaired patients. Better characterized clinical studies are warranted before making a definitive conclusion on the use of MCT for MCI and AD management.
    Keywords:  Alzheimer’s disease; cognitive impairment; medium chain triglyceride; mild cognitive impairment; systematic review
    DOI:  https://doi.org/10.3233/JAD-230406
  13. Biol Futur. 2023 May 29.
    Curcumin displays a potent caloric restriction mimetic effect in an accelerated senescent model of rat.
    Akanksha Singh, Parisha Srivastava, Avnish Kumar Verma, Jitendra Kumar Arya, Syed Ibrahim Rizvi.
      Curcumin, a strong natural compound with numerous health benefits, is extracted from the Curcuma longa. According to recent research findings, it also acts as a calorie restriction mimetic. We examined established aging biomarkers in erythrocytes and plasma and tested a persistent oral dietary dose of curcumin in young and D-galactose-induced accelerated rat aging models. For four weeks, D-gal (300 mg/kg b.w. subcutaneously) and curcumin (200 mg/kg b.w. oral) were administered simultaneously to test the protective effects of curcumin against D-galactose-induced accelerated aging and oxidative stress. In the accelerated senescent rat model, we discovered a significant rise in protein carbonyl, malonaldehyde (MDA), and advanced oxidation protein products. Increased levels of catalase, superoxide dismutase, ferric-reducing antioxidant potential, and reduced glutathione (GSH) were observed. Our findings reveal that curcumin has characteristics resembling a calorie restriction mimic and can successfully maintain redox equilibrium throughout the aging process in rat erythrocytes and plasma.
    Keywords:  Aging; Calorie restriction mimetics; Curcumin; D-galactose; Oxidative stress
    DOI:  https://doi.org/10.1007/s42977-023-00170-7
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