bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023‒09‒24
25 papers selected by
Matías Javier Monsalves Álvarez
  1. High-Fat Ketogenic Diets and Ketone Monoester Supplements Differentially Affect Substrate Metabolism during Aerobic Exercise.
  2. Ketogenic diet and metastasis: A critical review of the literature and possible mechanisms.
  3. Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.
  4. The impact and utility of very low-calorie diets: the role of exercise and protein in preserving skeletal muscle mass.
  5. Both moderate- and high-intensity exercise training increase intramyocellular lipid droplet abundance and modify myocellular distribution in adults with obesity.
  6. A circadian rhythm-restricted diet regulates autophagy to improve cognitive function and prolong lifespan.
  7. Mitochondrial protein and organelle quality control-Lessons from budding yeast.
  8. Exhaustive exercise alters native and site-specific H2O2 emission in red and white skeletal muscle mitochondria.
  9. Potassium effects on skeletal muscle contraction: are potassium-metabolic interactions required for fatigue?
  10. Advances in research on cell models for skeletal muscle atrophy.
  11. Stimulation of fat oxidation in rat muscle by unacylated ghrelin persists for 2-3 hours, but is independent of fatty acid transporter translocation.
  12. Mitophagy-dependent mitochondrial ROS mediates 2,5-hexanedione-induced NLRP3 inflammasome activation in BV2 microglia.
  13. Acyl-CoA synthetase expression in human skeletal muscle is reduced in obesity and insulin resistance.
  14. Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
  15. Fluctuations of serum fibroblast growth factor-21 levels in prolonged fasting in male adults.
  16. The role of estrogen in female skeletal muscle aging: A systematic review.
  17. Prescription for a healthy diet.
  18. An Update on Inflammation in Atherosclerosis: How to Effectively Treat Residual Risk.
  19. Glycogen Synthase Kinase-3β, NLRP3 Inflammasome, and Alzheimer's Disease.
  20. Low-Carbohydrate Diets in Children and Adolescents With or at Risk for Diabetes.
  21. SGLT2 Inhibitors and Iron: More Than Meets the Eye.
  22. Diving into cancer OXPHOS - The application of metabolic control analysis to cell and tissue research.
  23. Influence of the time of day in the effect of caffeine on maximal fat oxidation during exercise in women: a randomized, crossover, double-blind, and placebo-controlled study.
  24. Metabolic control of antitumor immunity.
  25. Myopathies of endocrine origin: A review for physicians.
  1. Am J Physiol Cell Physiol. 2023 Sep 18.
    High-Fat Ketogenic Diets and Ketone Monoester Supplements Differentially Affect Substrate Metabolism during Aerobic Exercise.
    Lee M Margolis, Stefan M Pasiakos, Emily E Howard.
      Chronically adhering to high-fat ketogenic diets or consuming ketone monoester supplements elicits ketosis. Resulting changes in substrate metabolism appear to be drastically different between ketogenic diets and ketone supplements. Consuming a ketogenic diet increases fatty acid oxidation with concomitant decreases in endogenous carbohydrate oxidation. Increased fat oxidation eventually results in an accumulation of circulating ketone bodies, which are metabolites of fatty acids that serve as an alternative source of fuel. Conversely, consuming ketone monoester supplements rapidly increases circulating ketone body concentrations that typically exceed those achieved by adhering to ketogenic diets. Rapid increases in ketone body concentrations with ketone monoester supplementation elicits a negative feedback inhibition that reduces fatty acid mobilization during aerobic exercise. Supplement-derived ketosis appears to have minimal impact on sparing of muscle glycogen or minimizing of carbohydrate oxidation during aerobic exercise. This review will discuss the substrate metabolic and associated aerobic performance responses to ketogenic diets and ketone supplements.
    Keywords:  Aerobic performance; endurance exercise; glycogen; high-fat, low-carbohydrate diet; β-hydroxybutyrate
    DOI:  https://doi.org/10.1152/ajpcell.00359.2023
  2. Clin Nutr ESPEN. 2023 Oct;pii: S2405-4577(23)00182-1. [Epub ahead of print]57 207-212
    Ketogenic diet and metastasis: A critical review of the literature and possible mechanisms.
    Lucas Soares Bezerra, Marcelo Antônio Oliveira Santos-Veloso.
      The ketogenic diet (KD) is a low-carb diet that has been indicated as a possible coadjuvant in cancer therapy, mainly due to its capacity to reduce glycolysis production, inflammation, and oxidative stress. However, KD's role in metastasis remains poorly explored. This study aims to provide a critical review of the literature about KD's efficacy in metastasis therapy and the possible molecular mechanisms behind it. Initially, general concepts on KD and metastasis are discussed. Then, it delves deeper into the main cancer mechanisms explored by KD experimental studies, discussing the central results obtained in metastasis research and their main limiting conditions. Following, there is a critical analysis of clinical trials, including those in the grey literature. In the end, there is a summary of the actual studies' limitations and barriers to future research. To date, it is possible to conclude that there is not enough evidence supporting the efficacy of KD in the treatment of metastasis.
    Keywords:  Carbohydrates; Ketogenic diet; Metastasis; Neoplasms
    DOI:  https://doi.org/10.1016/j.clnesp.2023.06.038
  3. J Epilepsy Res. 2023 Jun 30. 13(1): 1-6
    Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.
    Saman Hazany, Brittany DeClouette, Jessica Lowe, Darryl H Hwang, Paul E Kim, Stefan Bluml, Arthur Partikian.
      Background and Purpose: Ketogenic diet (KD) improves seizure control in patients with drug-resistant epilepsy. As increased mitochondrial levels of glutathione (GSH) might contribute to a change in seizure susceptibility, we quantified changes of absolute GSH levels in the brain by in vivo 1H magnetic resonance spectroscopy (1H MRS) and correlate that with degree of seizure control in patients on KD.Methods: Five cognitively normal adult patients with drug-resistant epilepsy were initially included and 2 completed the study. Each patient was evaluated by a neurologist and registered dietitian at baseline, 1, 3, and 6 months for seizure status and diet adherence after initiation of a modified atkins diet. Multiple metabolites including GSH were quantified using LCModel (version 6.3-1P; Stephen Provencher, Oakville, ON, CA) on a short echo time single-voxel 1H MRS in parieto/occipital grey matter and parietal white matter on a 3 Tesla General Electric magnet prior to starting the ketogenic diet and at 6 months.
    Results: Both patients (42-years-old male and 35-years-old female) demonstrated marked increases in absolute GSH level in both gray matter (0.12 to 1.40 and 0.10 to 0.70 international unit [IU]) and white matter (0.65 to 1.50 and 0.80 to 2.00 IU), as well as 50% improvements in seizure duration and frequency. Other metabolites including ketone bodies did not demonstrate consistent changes.
    Conclusions: Markedly increased levels of GSH (7-fold and 14-fold) were observed in longitudinal prospective study of two adult patients with intractable epilepsy with 50% seizure improvement after initiation of ketogenic diets. This pilot study supports the possible anticonvulsant role of GSH in the brain.
    Keywords:  1H MRS; Epilepsy; GSH; Glutathione; Ketogenic diet; MR spectroscopy
    DOI:  https://doi.org/10.14581/jer.23001
  4. Curr Opin Clin Nutr Metab Care. 2023 Sep 08.
    The impact and utility of very low-calorie diets: the role of exercise and protein in preserving skeletal muscle mass.
    Tom Anthonius Hubertus Janssen, Derrick W Van Every, Stuart M Phillips.
      PURPOSE OF REVIEW: Very low-calorie diets (VLCD) are used as a weight loss intervention, but concerns have been raised about their potential negative impact on lean mass. Here, we review the available evidence regarding the effects of VLCD on lean mass and explore their utility and strategies to mitigate reductions in skeletal muscle.RECENT FINDINGS: We observed that VLCD, despite their effects on lean mass, may be suitable in certain populations but have a risk in reducing lean mass. The extent of the reduction in lean mass may depend on various factors, such as the duration and degree of energy deficit of the diet, as well as the individual's starting weight and overall health.
    SUMMARY: VLCD may be a viable option in certain populations; however, priority needs to be given to resistance exercise training, and secondarily to adequate protein intake should be part of this dietary regime to mitigate losing muscle mass.
    DOI:  https://doi.org/10.1097/MCO.0000000000000980
  5. Am J Physiol Endocrinol Metab. 2023 Sep 20.
    Both moderate- and high-intensity exercise training increase intramyocellular lipid droplet abundance and modify myocellular distribution in adults with obesity.
    Michael W Schleh, Cheehoon Ahn, Benjamin J Ryan, Olivia K Chugh, Austin T Luker, Kathryn E Luker, Jenna B Gillen, Alison C Ludzki, Douglas W Van Pelt, Lisa M Pitchford, Tao Zhang, Thomas Rode, Suzette M Howton, Charles F Burant, Jeffrey F Horowitz.
      Exercise training modifies lipid metabolism in skeletal muscle, but the effect of exercise training on intramyocellular lipid droplet (LD) abundance, size, and intracellular distribution in adults with obesity remains elusive. This study compared high-intensity interval training (HIIT) with more conventional moderate-intensity continuous training (MICT) on intramyocellular lipid content, as well as LD characteristics (size and number) and abundance within the intramyofibrillar (IMF) and subsarcolemmal (SS) regions of type I and type II skeletal muscle fibers in adults with obesity. Thirty-six adults with obesity (BMI=33±3 kg/m2) completed 12 weeks (4d/week) of either HIIT (10x1 min, 90% HRmax + 1 min active recovery; n=19) or MICT (45 min steady-state exercise, 70% HRmax; n=17), while on a weight-maintaining diet throughout training. Skeletal muscle biopsies were collected from the vastus lateralis before and after training, and intramyocellular lipid content and intracellular LD distribution were measured by immunofluorescence microscopy. Both MICT and HIIT increased total intramyocellular lipid content by more than 50% (p<0.01), which was attributed to a greater LD number per µm2 in the IMF region of both type I and type II muscle fibers (p<0.01). Our findings also suggest that LD lipophagy (autophagy-mediated LD degradation) may be transiently upregulated the day after the last exercise training session (p<0.02 for both MICT and HIIT). In summary, exercise programs for adults with obesity involving either MICT or HIIT increased skeletal muscle LD abundance via a greater number of LDs in the IMF region of the myocyte, thereby providing more lipid in close proximity to the site of energy production during exercise.
    Keywords:  exercise; high-intensity interval training; lipid droplet; lipophagy; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00093.2023
  6. Biosci Trends. 2023 Sep 17.
    A circadian rhythm-restricted diet regulates autophagy to improve cognitive function and prolong lifespan.
    Xiqi Hu, Jun Peng, Wei Tang, Ying Xia, Peipei Song.
      Diet and circadian rhythms have been found to have a profound impact on health, disease, and aging. Skipping breakfast, eating late, and overeating have adverse effects on the body's metabolism and increase the risk of cardiovascular and metabolic diseases. Disturbance of circadian rhythms has been associated with increased risk of atherosclerosis, Alzheimer's disease, Parkinson's disease, and other diseases. Abnormal deposition of amyloid β (Aβ) and tau proteins in the brain and impaired synaptic function are linked to cognitive dysfunction. A restrictive diet following the circadian rhythm can affect the metabolism of lipids, glucose, and amino acids such as branched chain amino acids and cysteine. These metabolic changes contribute to autophagy through molecular mechanisms such as adenosine monophosphate-activated protein kinase (AMPK), rapamycin (mTOR), D-β-hydroxybutyrate (D-BHB), and neuropeptide Y (NPY). Autophagy, in turn, promotes the removal of abnormally deposited proteins and damaged organelles and improves cognitive function, ultimately prolonging lifespan. In addition, a diet restricted to the circadian rhythm induces increased expression of brain-derived neurotrophic factor (BDNF) in the forebrain region, regulating autophagy and increasing synaptic plasticity, thus enhancing cognitive function. Consequently, circadian rhythm-restricted diets could serve as a promising non-pharmacological treatment for preventing and improving cognitive dysfunction and prolonging lifespan.
    Keywords:  biological clock; intermittent fasting; metabolism; protein aggregation; quality control; sleep
    DOI:  https://doi.org/10.5582/bst.2023.01221
  7. IUBMB Life. 2023 Sep 20.
    Mitochondrial protein and organelle quality control-Lessons from budding yeast.
    Emily Jie-Ning Yang, Pin-Chao Liao, Liza Pon.
      Mitochondria are essential for normal cellular function and have emerged as key aging determinants. Indeed, defects in mitochondrial function have been linked to cardiovascular, skeletal muscle and neurodegenerative diseases, premature aging, and age-linked diseases. Here, we describe mechanisms for mitochondrial protein and organelle quality control. These surveillance mechanisms mediate repair or degradation of damaged or mistargeted mitochondrial proteins, segregate mitochondria based on their functional state during asymmetric cell division, and modulate cellular fitness, the response to stress, and lifespan control in yeast and other eukaryotes.
    Keywords:  ageing; mitochondria; mitochondrial reactive oxygen species; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1002/iub.2783
  8. Free Radic Biol Med. 2023 Sep 18. pii: S0891-5849(23)00642-1. [Epub ahead of print]
    Exhaustive exercise alters native and site-specific H2O2 emission in red and white skeletal muscle mitochondria.
    Collins Kamunde, Yashodya Wijayakulathilake, Chidozie Okoye, Nirmala Chinnappareddy, Zahra Kalvani, Michael van den Heuvel, Ravinder Sappal, Don Stevens.
      Mitochondrial reactive oxygen species (ROS) homeostasis is intricately linked to energy conversion reactions and entails regulation of the mechanisms of ROS production and removal. However, there is limited understanding of how energy demand modulates ROS balance. Skeletal muscle experiences a wide range of energy demand depending on the intensity and duration of exercise and therefore is an excellent model to probe the effect of altered energy demand on mitochondrial ROS production. Because in most fish skeletal muscle exists essentially as pure spatially distinct slow-twitch red oxidative and fast-twitch white glycolytic fibers, it provides a natural system for investigating how functional specialization affects ROS homeostasis. We tested the hypothesis that acute increase in energy demand imposed by exhaustive exercise will increase mitochondrial H2O2 emission to a greater extent in red muscle mitochondria (RMM) compared with white muscle mitochondria (WMM). We found that native H2O2 emission rates varied by up to 6-fold depending on the substrate being oxidized and muscle fiber type, with RMM emitting at higher rates with glutamate-malate and palmitoylcarnitine while WMM emitted at higher rates with succinate and glyceral-3-phosphate. Exhaustive exercise increased the native and site-specific H2O2 emission rates; however, the maximal emission rates depended on the substrate, fiber type and redox site. The H2O2 consumption capacity and activities of individual antioxidant enzymes including the glutathione- and thioredoxin-dependent peroxidases as well as catalase were higher in RMM compared with WMM indicating that the activity of antioxidant defense system does not explain the differences in H2O2 emission rates in RMM and WMM. Overall, our study suggests that substrate selection and oxidation may be the key factors determining the rates of ROS production in RMM and WMM following exhaustive exercise.
    Keywords:  Antioxidant capacity; Exhaustive exercise; H(2)O(2) emission and consumption; Mitochondria; Red and white skeletal muscle
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.018
  9. Eur J Appl Physiol. 2023 Sep 20.
    Potassium effects on skeletal muscle contraction: are potassium-metabolic interactions required for fatigue?
    Simeon P Cairns.
      
    DOI:  https://doi.org/10.1007/s00421-023-05313-1
  10. Biomed Pharmacother. 2023 Sep 20. pii: S0753-3322(23)01315-X. [Epub ahead of print]167 115517
    Advances in research on cell models for skeletal muscle atrophy.
    Liwei Li, Chunman Huang, Jingqun Pang, Yongbin Huang, Xinxin Chen, Guanghua Chen.
      Skeletal muscle, the largest organ in the human body, plays a crucial role in supporting and defending the body and is essential for movement. It also participates in regulating the processes of protein synthesis and degradation. Inhibition of protein synthesis and activation of degradation metabolism can both lead to the development of skeletal muscle atrophy, a pathological condition characterized by a decrease in muscle mass and fiber size. Many physiological and pathological conditions can cause a decline in muscle mass, but the underlying mechanisms of its pathogenesis remain incompletely understood, and the selection of treatment strategies and efficacy evaluations vary. Moreover, the early symptoms of this condition are often not apparent, making it easily overlooked in clinical practice. Therefore, it is necessary to develop and use cell models to understand the etiology and influencing factors of skeletal muscle atrophy. In this review, we summarize the methods used to construct skeletal muscle cell models, including hormone, inflammation, cachexia, genetic engineering, drug, and physicochemical models. We also analyze, compare, and evaluate the various construction and assessment methods.
    Keywords:  Cell models; Myotubes; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1016/j.biopha.2023.115517
  11. Physiol Rep. 2023 Sep;11(18): e15815
    Stimulation of fat oxidation in rat muscle by unacylated ghrelin persists for 2-3 hours, but is independent of fatty acid transporter translocation.
    Evan M Hoecht, Joshua M Budd, Nicole M Notaro, Graham P Holloway, David J Dyck.
      While a definitive mechanism-of-action remains to be identified, recent findings indicate that ghrelin, particularly the unacylated form (UnAG), stimulates skeletal muscle fatty acid oxidation. The biological importance of UnAG-mediated increases in fat oxidation remains unclear, as UnAG peaks in the circulation before mealtimes, and decreases rapidly during the postprandial situation before increases in postabsorptive circulating lipids. Therefore, we aimed to determine if the UnAG-mediated stimulation of fat oxidation would persist long enough to affect the oxidation of meal-derived fatty acids, and if UnAG stimulated the translocation of fatty acid transporters to the sarcolemma as a mechanism-of-action. In isolated soleus muscle strips from male rats, short-term pre-treatment with UnAG elicited a persisting stimulus on fatty acid oxidation 2 h after the removal of UnAG. UnAG also caused an immediate phosphorylation of AMPK, but not an increase in plasma membrane FAT/CD36 or FABPpm. There was also no increase in AMPK signaling or increased FAT/CD36 or FABPpm content at the plasma membrane at 2 h which might explain the sustained increase in fatty acid oxidation. These findings confirm UnAG as a stimulator of fatty acid oxidation and provide evidence that UnAG may influence the handling of postprandial lipids. The underlying mechanisms are not known.
    Keywords:  FABPpm; FAT/CD36; fatty acid oxidation; skeletal muscle; unacylated ghrelin
    DOI:  https://doi.org/10.14814/phy2.15815
  12. Neurotoxicology. 2023 Sep 16. pii: S0161-813X(23)00124-9. [Epub ahead of print]99 50-58
    Mitophagy-dependent mitochondrial ROS mediates 2,5-hexanedione-induced NLRP3 inflammasome activation in BV2 microglia.
    Wenqiong Wang, Rui Chang, Yan Wang, Liyan Hou, Qingshan Wang.
      We recently revealed a pivotal role of NLRP3 inflammasome in the neurotoxicity induced by n-hexane, owing to its activation and release of pro-inflammatory cytokines. However, the mechanisms of how the activation of NLRP3 inflammasome was triggered by 2,5-hexanedione (HD), the toxic product of n-hexane metabolism, remain to be explored. Here, we investigated whether mitochondrial reactive oxygen species (mtROS) was involved in HD-elicited NLRP3 inflammasome activation in microglia. We demonstrated that exposure to HD at 4 and 8 mM elevated production of mtROS in BV2 microglia. Scavenging mtROS by Mito-TEMPO, an mtROS scavenger, dramatically reduced HD-induced NLRP3 expression, caspase-1 activation and interleukin-1β production, pointing a crucial role of mtROS in NLRP3 inflammasome activation. Mechanistic study revealed that HD intoxication promoted activation of mitophagy. HD induced expression of Beclin-1, LC3II, and two mitophagy-related proteins, i.e., Pink1 and Parkin and simultaneously, reduced p62 expression in both whole cell and isolated mitochondria of microglia. Furthermore, inhibition of mitophagy by 3-methyladenine (3-MA) greatly reduced production of mtROS, expression of mitochondrial fission-related proteins, dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1) and activation of NLRP3 inflammasome in HD-intoxicated microglia. Blocking mitochondrial fission by Mdivi-1 also prevented HD-induced mtROS production and NLRP3 inflammasome activation in microglia. In conclusion, our data indicated that HD triggered activation of NLRP3 inflammasome through mitophagy-dependent mtROS production, offering an important insight for the immunopathogenesis of environmental toxins-induced neuroinflammation and neurotoxicity.
    Keywords:  Mitochondrial ROS; Mitochondrial fission; Mitophagy; N-Hexane; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.neuro.2023.09.008
  13. Physiol Rep. 2023 Sep;11(18): e15817
    Acyl-CoA synthetase expression in human skeletal muscle is reduced in obesity and insulin resistance.
    Margarete Poppelreuther, Anne-Marie Lundsgaard, Pernille Mensberg, Kim Sjøberg, Tina Vilsbøll, Bente Kiens, Joachim Füllekrug.
      Upon intramuscular entry, fatty acids are converted to amphiphatic fatty acyl-CoAs by action of the acyl-CoA synthetase (ACS) enzymes. While it has been reported that insulin resistant skeletal muscle shows an accumulation of fatty acyl-CoAs, the role of the enzymes which catalyze their synthesis is still sparsely studied in human muscle, in particular the influence of obesity, and insulin resistance. We analyzed muscle biopsies obtained from normal weight controls (n = 7, average BMI 24), males/females with obesity (n = 7, average BMI 31), and males/females with obesity and type 2 diabetes (T2D) (n = 7, average BMI 34), for relevant ACS (long-chain acyl-CoA synthetase 1 (ACSL1), -3 (ACSL3) and - 4 (ACSL4), fatty acid transport protein 1 (FATP1) and - 4 (FATP4)). The mRNA expression was determined by real-time PCR, and total oleoyl-CoA synthetase activity was measured. In the males/females with obesity and T2D, the response to 16 weeks of exercise training with minor weight loss was evaluated. ACSL1 is the dominantly expressed ACS isoform in human skeletal muscle. The content of total ACS mRNA, as well as ACSL1 mRNA, were lower in muscle of males/females with obesity and T2D. Exercise training in the males/females with obesity and T2D increased the total ACS enzyme activity, along with a lowering of the HOMA-IR index. The capacity for synthesis of fatty acyl-CoAs is lower in skeletal muscle of obese males/females with T2D. This suggests a decreased ability to convert fatty acids to fatty acyl-CoAs, which in turn may affect their entry into storage or metabolic pathways in muscle. Thus, the accumulation of fatty acyl-CoAs in the obese or insulin resistant state that has been shown in previous reports is not likely to result from increased fatty acid acylation. The upregulation of ACS activity by exercise training appears beneficial and occurred concomitantly with increased insulin sensitivity.
    Keywords:  ACSL1; fatty acyl-CoA synthetase activity; human skeletal muscle; insulin resistance; type 2 diabetes
    DOI:  https://doi.org/10.14814/phy2.15817
  14. Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00280-5. [Epub ahead of print]
    Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
    Kiran Kurmi, Dan Liang, Robert van de Ven, Peter Georgiev, Brandon Mark Gassaway, SeongJun Han, Giulia Notarangelo, Isaac S Harris, Cong-Hui Yao, Joon Seok Park, Song-Hua Hu, Jingyu Peng, Jefte M Drijvers, Sarah Boswell, Artem Sokolov, Stephanie K Dougan, Peter K Sorger, Steven P Gygi, Arlene H Sharpe, Marcia C Haigis.
      Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.
    Keywords:  CD4(+) T cells; T cell differentiation; high-throughput metabolic screen; mitochondrial biogenesis; pyruvate oxidation; pyrvinium pamoate
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.008
  15. Clin Nutr ESPEN. 2023 Oct;pii: S2405-4577(23)00168-7. [Epub ahead of print]57 144-150
    Fluctuations of serum fibroblast growth factor-21 levels in prolonged fasting in male adults.
    Aslıhan Ağaçdiken, Zeynep Göktaş.
      BACKGROUND & AIMS: Fibroblast Growth Factor-21 (FGF21) is a significant protein in the process of adaptation to fasting. The aim of this cross-sectional study to examine the effects of fasting on serum FGF21 levels, nutritional status, and anthropometric measurements of adult males during prolonged Ramadan fasting.METHODS: This study included a total of 12 healthy individuals with normal body mass index, between the ages of 18-35. All individuals fasted for 16 h each day for 29 days of Ramadan. A questionnaire was administered to determine individuals' general characteristics and nutritional habits. Anthropometric measurements, 24-h dietary recall, and physical activities were recorded, and blood samples were collected four times in the following periods: before Ramadan, 1st week of Ramadan, 3rd week of Ramadan and 4 weeks after Ramadan.
    RESULTS: It was observed that serum FGF21 levels increased until the 1st week of fasting. Remarkably, FGF21 levels declined in most subjects during the late phase of fasting and continued to decrease until 4 weeks after fasting. There was a positive correlation between serum FGF21 levels and protein intake at the 3rd week of fasting. Individuals' PAL and energy expenditure increased during fasting and continued to increase until 4 weeks after fasting. Energy intake, on the other hand, decreased from baseline until 4 weeks after fasting.
    CONCLUSION: FGF21 serum levels may show an increase during fasting, however in long-term fasting periods like Ramadan it may decrease back to the beginning levels, therefore, FGF21 serum levels must be evaluated carefully.
    Keywords:  Adaptation to fasting; Body composition; Fibroblast growth factor-21; Nutritional status; Prolonged fasting
    DOI:  https://doi.org/10.1016/j.clnesp.2023.06.024
  16. Maturitas. 2023 Sep 07. pii: S0378-5122(23)00450-4. [Epub ahead of print]178 107844
    The role of estrogen in female skeletal muscle aging: A systematic review.
    Annabel J Critchlow, Danielle Hiam, Ross Williams, David Scott, Séverine Lamon.
      Aging is associated with a loss of skeletal muscle mass and function that negatively impacts the independence and quality of life of older individuals. Females demonstrate a distinct pattern of muscle aging compared to males, potentially due to menopause, when the production of endogenous sex hormones declines. This systematic review aims to investigate the current knowledge about the role of estrogen in female skeletal muscle aging. A systematic search of MEDLINE Complete, Global Health, Embase, PubMed, SPORTDiscus, and CINHAL was conducted. Studies were considered eligible if they compared a state of estrogen deficiency (e.g. postmenopausal females) or supplementation (e.g. estrogen therapy) to normal estrogen conditions (e.g. premenopausal females or no supplementation). Outcome variables of interest included measures of skeletal muscle mass, function, damage/repair, and energy metabolism. Quality assessment was completed with the relevant Johanna Briggs critical appraisal tool, and data were synthesized in a narrative manner. Thirty-two studies were included in the review. Compared to premenopausal women, postmenopausal women had reduced muscle mass and strength, but the effect of menopause on markers of muscle damage and expression of the genes involved in metabolic signaling pathways remains unclear. Some studies suggest a beneficial effect of estrogen therapy on muscle size and strength, but evidence is largely conflicting and inconclusive, potentially due to large variations in the reporting and status of exposure and outcomes. The findings from this review point toward a potential negative effect of estrogen deficiency on aging skeletal muscle, but further mechanistic evidence is needed to clarify its role.
    Keywords:  Aging; Menopause; Ovarian hormones; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.maturitas.2023.107844
  17. Nat Med. 2023 Sep 21.
    Prescription for a healthy diet.
    Karen O'Leary.
      
    Keywords:  Cardiovascular diseases; Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41591-023-00082-y
  18. Clin Ther. 2023 Sep 14. pii: S0149-2918(23)00320-X. [Epub ahead of print]
    An Update on Inflammation in Atherosclerosis: How to Effectively Treat Residual Risk.
    N Mohammadnia, T S J Opstal, S El Messaoudi, W A Bax, J H Cornel.
      PURPOSE: This study reviewed the contribution of inflammation to atherosclerotic cardiovascular disease (ASCVD), which has gained widespread recognition in recent years.METHODS: This critical review evaluated how recent publications and ongoing clinical trials in atherosclerotic inflammation will affect clinical care.
    FINDINGS: Key trials, including CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) with canakinumab (interleukin-1β inhibition), and COLCOT (Colchicine Cardiovascular Outcomes Trial) and LoDoCo2 (Low Dose Colchicine 2) with colchicine, have shown that suppressing inflammation can improve outcomes in ASCVD. Cholesterol crystals play an important role in activating the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome and subsequent cytokine cascade. Inflammation contributes to significant residual risk after optimal lipid-lowering therapy. High-sensitivity C-reactive protein is a recognized biomarker of residual risk, and newer biomarkers such as the neutrophil to lymphocyte ratio may add additional information. The role of lipoprotein(a) as a proinflammatory agent or possible inflammatory biomarker is under investigation. The contribution of clonal hematopoiesis of indeterminate potential and trained immunity are in the early stages of investigation. Ongoing clinical trials of suppressing inflammation with NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome inhibition (colchicine) and alternative approaches with downstream interleukin-6 ligand inhibition (ziltivekimab) will expand the evidence base for the use of anti-inflammatory agents in ASCVD.
    IMPLICATIONS: Based on current evidence and ongoing clinical trials, targeting inflammation alongside optimal lipid lowering is likely to be central to the future treatment of ASCVD. (Clin Ther. 2023;45:XXX-XXX) © 2023 Elsevier HS Journals, Inc.
    Keywords:  Atherosclerotic Cardiovascular Disease; Disease Prevention; Inflammation; Residual Risk
    DOI:  https://doi.org/10.1016/j.clinthera.2023.08.016
  19. Curr Med Sci. 2023 Sep 18.
    Glycogen Synthase Kinase-3β, NLRP3 Inflammasome, and Alzheimer's Disease.
    Yue-Ran Jia, Zi-Qing Guo, Qian Guo, Xiao-Chuan Wang.
      Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide. Because of the progressive neurodegeneration, individual cognitive and behavioral functions are impaired, affecting the quality of life of millions of people. Although the exact pathogenesis of AD has not been fully elucidated, amyloid plaques, neurofibrillary tangles (NFTs), and sustaining neuroinflammation dominate its characteristics. As one of the major tau kinases leading to hyperphosphorylation and aggregation of tau, glycogen synthase kinase-3β (GSK-3β) has been drawing great attention in various AD studies. Another research focus of AD in recent years is the inflammasome, a multiprotein complex acting as a regulator in immunological reactions to exogenous and endogenous danger signals, of which the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome has been studied mostly in AD and proven to play a significant role in AD development by its activation and downstream effects such as caspase-1 maturation and interleukin (IL)-1β release. Studies have shown that the NLRP3 inflammasome is activated in a GSK-3β-dependent way and that inhibition of the NLRP3 inflammasome downregulates GSK-3β, suggesting that these two important proteins are closely related. This article reviews the respective roles of GSK-3β and the NLRP3 inflammasome in AD as well as their relationship and interaction.
    Keywords:  Alzheimer’s disease; NLRP3 inflammasome; glycogen synthase kinase-3β
    DOI:  https://doi.org/10.1007/s11596-023-2788-4
  20. Pediatrics. 2023 Sep 18. pii: e2023063755. [Epub ahead of print]
    Low-Carbohydrate Diets in Children and Adolescents With or at Risk for Diabetes.
    COMMITTEE ON NUTRITION
      Carbohydrate restriction is increasingly popular as a weight loss strategy and for achieving better glycemic control in people with diabetes, including type 1 and type 2 diabetes. However, evidence to support low-carbohydrate diets in youth (children and adolescents 2-18 years of age) with obesity or diabetes is limited. There are no guidelines for restricting dietary carbohydrate consumption to reduce risk for diabetes or improve diabetes outcomes in youth. Thus, there is a need to provide practical recommendations for pediatricians regarding the use of low-carbohydrate diets in patients who elect to follow these diets, including those with type 1 diabetes and for patients with obesity, prediabetes, and type 2 diabetes. This clinical report will:Provide background on current dietary patterns in youth, describe how moderate-, low-, and very low-carbohydrate diets differ, and review safety concerns associated with the use of these dietary patternsReview the physiologic rationale for carbohydrate reduction in youth with type 1 diabetes and for youth with obesity, prediabetes, and type 2 diabetesReview the evidence for low-carbohydrate diets in the management of youth with type 1 diabetesReview the evidence for low-carbohydrate diets in the management of youth with obesity, prediabetes, and type 2 diabetesProvide practical information for pediatricians counseling families and youth on carbohydrate recommendations for type 1 diabetes and for obesity, prediabetes, and type 2 diabetes.
    DOI:  https://doi.org/10.1542/peds.2023-063755
  21. JACC Heart Fail. 2023 Sep 11. pii: S2213-1779(23)00540-1. [Epub ahead of print]
    SGLT2 Inhibitors and Iron: More Than Meets the Eye.
    Kieran F Docherty.
      
    Keywords:  SGLT2 inhibitors; heart failure; iron
    DOI:  https://doi.org/10.1016/j.jchf.2023.08.013
  22. Biosystems. 2023 Sep 20. pii: S0303-2647(23)00207-1. [Epub ahead of print] 105032
    Diving into cancer OXPHOS - The application of metabolic control analysis to cell and tissue research.
    Marju Puurand, Kersti Tepp, Tuuli Käämbre.
      Knowing how the oxidative phosphorylation (OXPHOS) system in cancer cells operates differently from that of normal cells would help find compounds that specifically paralyze the energy metabolism of cancer cells. The first experiments in the study of mitochondrial respiration using the metabolic control analysis (MCA) method were done with isolated liver mitochondria in the early 80s of the last century. Subsequent studies have shown that the regulation of mitochondrial respiration by ADP in isolated mitochondria differs significantly from a model of mitochondria in situ, where the contacts with components in the cytoplasm are largely preserved. The method of selective permeabilization of the outer membrane of the cells allows the application of MCA to evaluate the contribution of different components of the OXPHOS system to its functioning while mitochondria are in a natural state. In this review, we summarize the use of MCA to study OXPHOS in cancer using permeabilized cells and tissues. In addition, we give examples of how this data fits into cancer research with a completely different approach and methodology.
    Keywords:  Cancer; Metabolic control analysis; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.biosystems.2023.105032
  23. Eur J Appl Physiol. 2023 Sep 20.
    Influence of the time of day in the effect of caffeine on maximal fat oxidation during exercise in women: a randomized, crossover, double-blind, and placebo-controlled study.
    Alejandro Muñoz, Millán Aguilar-Navarro, Carlos Ruiz-Moreno, David Varillas-Delgado, Francisco J Amaro-Gahete, Jorge Gutiérrez-Hellín, Juan Del Coso, Álvaro López-Samanes.
      PURPOSE: Caffeine is a stimulant with well-recognized performance and metabolic benefits, however, there is a lack of studies investigating the time-of-day influence in the properties of caffeine to enhance fat oxidation in women. Thus, the aim of the present study was to evaluate the influence of the time of the day on the effect of caffeine on the maximal rate of fat oxidation during aerobic exercise in trained women.METHODS: Fourteen female athletes (25.5 ± 7.1 years) took part in a randomized, crossover, double-blind study. All participants undertook four different experimental trials combining the ingestion of 3 mg/kg caffeine and a placebo either in the morning (8.00-10.00 h) and in the evening (17.00-19.00 h) realizing an incremental test on a cycle ergometer with 3 min stages at workloads from 30 to 70% of maximal oxygen uptake (VO2max). Substrate oxidation rates were measured by indirect calorimetry. In each trial, the maximum rate of fat oxidation (MFO) and the intensity that elicited MFO (Fatmax) were measured.
    RESULTS: In comparison to placebo, MFO was significantly higher with caffeine both in the morning (0.24 ± 0.13 vs 0.30 ± 0.14 g/min; p < 0.001; ES = 0.79) and in the evening (0.21 ± 0.08 vs 0.28 ± 0.10 g/min; p = 0.002; ES = 0.72). No time-of-day effect on the capacity of caffeine to increase MFO was found (all p = 0.336) CONCLUSION: The intake of 3 mg/kg of caffeine increased the use of fat as a fuel during exercise independently of the time-of-day in trained women.
    TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov with the following ID: NCT05880186 by 15 May 2023.
    Keywords:  Circadian rhythms; Fat oxidation; Fatmax; MFO; Sports nutrition; Substrate oxidation
    DOI:  https://doi.org/10.1007/s00421-023-05312-2
  24. Science. 2023 Sep 22. 381(6664): 1287-1288
    Metabolic control of antitumor immunity.
    Andromachi Pouikli, Christian Frezza.
      Mitochondrial metabolite reduces melanoma growth by boosting antigen presentation.
    DOI:  https://doi.org/10.1126/science.adk1785
  25. Dis Mon. 2023 Sep 15. pii: S0011-5029(23)00108-6. [Epub ahead of print] 101628
    Myopathies of endocrine origin: A review for physicians.
    Devarsh N Shah, Harshal Prakash Chorya, N Nishitha Ramesh, Sulochana Gnanasekaram, Neil Patel, Yashendra Sethi, Nirja Kaka.
      Myopathies are a common manifestation of endocrine disorders. Endocrine myopathies are often overlooked while considering differential diagnoses in patients with musculoskeletal symptoms. The hindrance to mobility and the musculoskeletal discomfort owing to these myopathies are important causes of disability and depreciated quality of life in these patients. Endocrine myopathies occur due to the effects of endogenous or iatrogenic hormonal imbalance on skeletal muscle protein and glucose metabolism, disrupting the excitation-contraction coupling. Abnormalities of the pituitary, thyroid, parathyroid, adrenal, and gonadal hormones have all been associated with myopathies and musculoskeletal symptoms. Endocrine myopathies can either be the complication of a secondary endocrine disorder or a presenting symptom of a missed underlying disorder. Therefore, an underlying endocrine abnormality must always be excluded in all patients with musculoskeletal symptoms. This review presents a compilation of various endocrine myopathies, their etiopathogenesis, clinical presentation, diagnostic modalities, and treatment protocols.
    Keywords:  Creatine kinase; Endocrine; Hormones; Muscle dystrophy; Myopathy
    DOI:  https://doi.org/10.1016/j.disamonth.2023.101628
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