bims-kimdis 2024-01-14 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒01‒14
nineteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketone bodies as chemical signals for the immune system.
Ketone ester supplementation of Atkins-type diet prolongs survival in an orthotopic xenograft model of glioblastoma.
Risks of the ketogenic diet in CKD - the con part.
Ketone Bodies in Cell Physiology and Cancer.
Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.
The Therapeutic Potential of Ketones in Cardiometabolic Disease: Impact on Heart and Skeletal Muscle.
Ketogenic diet preserves muscle mass and strength in a mouse model of type 2 diabetes.
Acute ingestion of a ketone monoester, whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of myofibrillar protein synthesis rates in young males: a double-blind randomized trial.
Pre-treatment with β-hydroxybutyrate mitigates cisplatin-induced acute kidney injury.
Ketogenic diet attenuates cognitive dysfunctions induced by hypoglycemia via inhibiting endoplasmic reticulum stress-dependent pathways.
Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.
Ketogenic Diet High in Saturated Fat Promotes Colonic Claudin Expression without Changes in Intestinal Permeability to Iohexol in Healthy Mice.
Circulating 3-hydroxy butyrate predicts mortality in patients with chronic heart failure with reduced ejection fraction.
Intermittent Fasting: Does It Affect Sports Performance? A Systematic Review.
The NLRP3 inflammasome: a vital player in inflammation and mediating the anti-inflammatory effect of CBD.
The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review.
Exogenous mitochondrial transfer increases energy expenditure and attenuates adiposity gains in mice with diet-induced obesity.
Defining "low-carb" in the scientific literature: A scoping review of clinical studies.
A century of exercise physiology: effects of muscle contraction and exercise on skeletal muscle Na+,K+-ATPase, Na+ and K+ ions, and on plasma K+ concentration-historical developments.

Am J Physiol Cell Physiol. 2024 Jan 08.

Ketone bodies as chemical signals for the immune system.

Michelangelo Bauwelz Gonzatti, Emily Goldberg.

  Ketone bodies are short chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding. Recent studies have highlighted important non-metabolic functions of the most abundant ketone body, β-hydroxybutyrate (BHB). Notably, many of these functions, including limiting certain sources of inflammation, histone deacetylase inhibition, NFκB inhibition, and GPCR stimulation, are particularly important to consider in immune cells. Likewise, dietary manipulations like caloric restriction or ketogenic diet feeding are associated with lowered inflammation, improved health outcomes, and improved host defense against infection, although the underlying mechanisms of the broad benefits of ketosis remain incompletely understood. In this perspective, we contextualize the current state of the field of non-metabolic functions of ketone bodies specifically in the immune system and speculate on the molecular explanations and broader physiological significance.

Keywords:  BHB; immune; inflammation; ketone bodies; metabolism

DOI:  https://doi.org/10.1152/ajpcell.00478.2023
Anat Cell Biol. 2024 Jan 09.

Ketone ester supplementation of Atkins-type diet prolongs survival in an orthotopic xenograft model of glioblastoma.

Hassan Azari, Angela Poff, Dominic D'Agostino, Brent Reynolds.

  Heavy reliance on glucose metabolism and a reduced capacity to use ketone bodies makes glioblastoma (GBM) a promising candidate for ketone-based therapies. Ketogenic diet (KD) is well-known for its promising effects in controlling tumor growth in GBM. Moreover, synthetic ketone ester (KE) has demonstrated to increase blood ketone levels and enhance animal survival in a metastatic VM-M3 murine tumor model. Here, we compared the efficacy of a KE-supplemented Atkins-type diet (ATD-KE) to a classic KD in controlling tumor progression and enhancing survival in a clinically relevant orthotopic patient-derived xenograft GBM model. Our findings demonstrate that ATD-KE preserves body weight (percent change from the baseline; 112±2.99 vs. 116.9±2.52 and 104.8±3.67), decreases blood glucose (80.55±0.86 vs. 118.6±9.51 and 52.35±3.89 mg/dl), and increases ketone bodies in blood (1.15±0.03 mM vs. 0.55±0.04 and 2.66±0.21 mM) and brain tumor tissue (3.35±0.30 mM vs. 2.04±0.3 and 4.25±0.25 mM) comparable to the KD (results presented for ATD-KE vs. standard diet [STD] and KD, respectively). Importantly, the ATD-KE treatment significantly enhanced survival compared to the STD and was indistinguishable from the KD (47 days in STD vs. 56 days in KD and ATD-KE), suggesting that a nutritionally balanced low carbohydrate ATD combined with KE may be as effective as the KD alone in reducing brain tumor progression. Overall, these data support the rationale for clinical testing of KE-supplemented low-carb diet as an adjunct treatment for brain tumor patients.

Keywords:  Glioblastoma; Ketone bodies; Ketone ester; Survival; Tumor progression

DOI:  https://doi.org/10.5115/acb.23.158
Clin Kidney J. 2024 Jan;17(1): sfad274

Risks of the ketogenic diet in CKD - the con part.

Shivam Joshi, Rachel Shi, Jason Patel.

  The ketogenic diet is a very low carbohydrate diet that has received a lot of attention for its role in the treatment of type 2 diabetes and obesity. For patients with chronic kidney disease, there is limited evidence on the risks and/or benefits of this diet. However, from the limited evidence that does exist, there are several inferences that can be drawn regarding this diet for patients with kidney disease. The ketogenic diet may not be better than comparator higher carbohydrate diets over the long term. The diet also has low adherence levels in studies lasting ≥12 months. The diet's emphasis on fat, which often comes from animal fat, increases the consumption of saturated fat, which may increase the risk of heart disease. It has the potential to worsen metabolic acidosis by increasing dietary acid load and endogenous acid production through the oxidation of fatty acids. In addition, the diet has been associated with an increased risk of kidney stones in patients using it for the treatment of refractory epilepsy. For these reasons, and for the lack of safety data on it, it is reasonable for patients with kidney disease to avoid utilizing the ketogenic diet as a first-line option given alternative dietary patterns (like the plant-dominant diet) with less theoretical risk for harm. For those adopting the ketogenic diet in kidney disease, a plant-based version of the ketogenic diet may mitigate some of the concerns with animal-based versions of the ketogenic diet.

Keywords:  ketogenic diet; kidney disease

DOI:  https://doi.org/10.1093/ckj/sfad274
Am J Physiol Cell Physiol. 2024 Jan 08.

Ketone Bodies in Cell Physiology and Cancer.

Giacomo Giuliani, Valter D Longo.

  Ketogenic diets (KDs), fasting, or prolonged physical activity elevate serum ketone bodies (KBs) levels, providing an alternative fuel source for the brain and other organs. However, KBs play pleiotropic roles that go beyond their role in energy production. KBs can act as signaling metabolites, influence gene expression, proteins' post-translational modifications (PTMs), inflammation, and oxidative stress. Here, we explore the impact of KBs on mammalian cell physiology, including aging and tissue regeneration. We also concentrate on KBs and cancer, given the extensive evidence that dietary approaches inducing ketosis, including Fasting Mimicking Diets (FMDs) and KDs, can prevent and affect tumor progression.

Keywords:  cancer; fasting mimicking diet; ketone bodies; tumor metabolism; ß-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00441.2023
Int J Mol Sci. 2023 Dec 21. pii: 124. [Epub ahead of print]25(1):

Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.

Jiwon Jang, Su Rim Kim, Jo Eun Lee, Seoyeon Lee, Hyeong Jig Son, Wonchae Choe, Kyung-Sik Yoon, Sung Soo Kim, Eui-Ju Yeo, Insug Kang.

  Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Keywords:  Alzheimer’s disease; Parkinson’s disease; cerebral ischemia; ketogenic diet; ketone bodies; mitochondrial dysfunction; neurodegenerative disease; neuroinflammation; oxidative stress; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/ijms25010124
Am J Physiol Cell Physiol. 2024 Jan 09.

The Therapeutic Potential of Ketones in Cardiometabolic Disease: Impact on Heart and Skeletal Muscle.

Shubham Soni, Seyed Amirhossein Tabatabaei Dakhili, John R Ussher, Jason R B Dyck.

  β-hydroxybutyrate (βOHB) is the major ketone in the body and it is recognized as a metabolic energy source and an important signaling molecule. While ketone oxidation is essential in the brain during prolonged fasting/starvation, other organs such as skeletal muscle and the heart also use ketones as metabolic substrates. Additionally, βOHB-mediated molecular signaling events occur in heart and skeletal muscle cells, and via metabolism and/or signaling, ketones may contribute to optimal skeletal muscle health and cardiac function. Of importance, when the use of ketones for ATP production and/or as signaling molecules becomes disturbed in the presence of underlying obesity, type 2 diabetes and/or cardiovascular diseases, these changes may contribute to cardiometabolic disease. As a result of these disturbances in cardiometabolic disease, multiple approaches have been used to elevate circulating ketones with the goal of improving either ketone metabolism or ketone-mediated signaling. These approaches have produced significant improvements in heart and skeletal muscle during cardiometabolic disease with a wide range of benefits that include improved metabolism, weight loss, better glycemic control, improved cardiac and vascular function, as well as reduced inflammation and oxidative stress. Herein, we present the evidence that indicates that ketone therapy could be used as an approach to help treat cardiometabolic diseases by targeting cardiac and skeletal muscle.

Keywords:  cardiovascular disease; diabetes; heart failure; ketone bodies; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00501.2023
PLoS One. 2024 ;19(1): e0296651

Ketogenic diet preserves muscle mass and strength in a mouse model of type 2 diabetes.

Sol Been Park, Soo Jin Yang.

Diabetes is often associated with reduced muscle mass and function. The ketogenic diet (KD) may improve muscle mass and function via the induction of nutritional ketosis. To test whether the KD is able to preserve muscle mass and strength in a mouse model of type 2 diabetes (T2DM), C57BL/6J mice were assigned to lean control, diabetes control, and KD groups. The mice were fed a standard diet (10% kcal from fat) or a high-fat diet (HFD) (60% kcal from fat). The diabetic condition was induced by a single injection of streptozotocin (STZ; 100 mg/kg) and nicotinamide (NAM; 120 mg/kg) into HFD-fed mice. After 8-week HFD feeding, the KD (90% kcal from fat) was fed to the KD group for the following 6 weeks. After the 14-week experimental period, an oral glucose tolerance test and grip strength test were conducted. Type 2 diabetic condition induced by HFD feeding and STZ/NAM injection resulted in reduced muscle mass and grip strength, and smaller muscle fiber areas. The KD nutritional intervention improved these effects. Additionally, the KD altered the gene expression of nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome- and endoplasmic reticulum (ER) stress-related markers in the muscles of diabetic mice. Collectively, KD improved muscle mass and function with alterations in NLRP3 inflammasome and ER stress.

DOI: https://doi.org/10.1371/journal.pone.0296651
Am J Clin Nutr. 2024 Jan 10. pii: S0002-9165(24)00004-2. [Epub ahead of print]

Acute ingestion of a ketone monoester, whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of myofibrillar protein synthesis rates in young males: a double-blind randomized trial.

Sarkis J Hannaian, Jamie Lov, Stephanie E Hawley, Manon Dargegen, Divine Malenda, Ari Gritsas, Gilles Gouspillou, José A Morais, Tyler A Churchward-Venne.

  BACKGROUND: Ketone bodies may have anabolic effects in skeletal muscle via their capacity to stimulate protein synthesis. Whether orally ingested exogenous ketones can stimulate postprandial myofibrillar protein synthesis (MyoPS) rates with and without dietary protein co-ingestion is unknown.OBJECTIVES: To evaluate the effects of ketone monoester intake and elevated blood β-hydroxybutyrate (β-OHB) concentration, with and without dietary protein co-ingestion, on postprandial MyoPS rates and mechanistic target of rapamycin complex 1 (mTORC1) pathway signalling.
METHODS: In a randomized, double-blind, parallel group design, 36 recreationally active healthy young males (age: 24.2±4.1 y; body fat: 20.9±5.8 %; BMI: 23.4±2 kg/m2) received a primed continuous infusion of L-[ring-2H5]-phenylalanine and ingested either: 1) the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KET), 2) 10 g whey protein (PRO), or 3) the combination of both (KET+PRO). Blood and muscle biopsy samples were collected during basal and postprandial (300 min) conditions to assess β-OHB, glucose, insulin, and amino acid concentrations, MyoPS rates, and mTORC1 pathway signalling.
RESULTS: Capillary blood β-OHB concentration increased similarly during postprandial conditions in KET and KET+PRO, with both being greater than PRO from 30-180 min (Treatment × Time Interaction: P<0.001). Postprandial plasma leucine and essential amino acid (EAA) incremental area under the curve (iAUC) over 300 min was greater (Treatment: both P<0.001) in KET+PRO vs. PRO and KET. KET, PRO, and KET+PRO stimulated postprandial MyoPS rates (0-300 min) above basal conditions (absolute change: 0.020%/h (95% CI: 0.013, 0.027%/h), 0.014%/h (95% CI: 0.009, 0.019%/h), 0.019%/h (95% CI: 0.014, 0.024%/h), respectively (Time: P<0.001), with no difference between treatments (Treatment: P=0.383) or treatment × time interaction (Interaction: P=0.245). mTORC1 pathway signalling responses did not differ between treatments (all P>0.05).
CONCLUSION: Acute oral intake of a ketone monoester, 10 g whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of postprandial MyoPS rates in healthy young males. This trial was registered at clinicaltrials.gov as NCT04565444. A direct link to the trial page is available here: https://clinicaltrials.gov/study/NCT04565444.

Keywords:  amino acids; exogenous ketosis; ketone bodies; myofibrillar protein synthesis; skeletal muscle; whey protein; young males; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.ajcnut.2024.01.004
Biochem Biophys Res Commun. 2024 Jan 05. pii: S0006-291X(24)00015-9. [Epub ahead of print]695 149482

Pre-treatment with β-hydroxybutyrate mitigates cisplatin-induced acute kidney injury.

Min Jeong Kim, Young Suk Kim, Seo Rin Kim, Dong Won Lee, Soo Bong Lee, Il Young Kim.

  β-Hydroxybutyrate (β-HB), the primary circulating ketone body, plays a dual role as both a metabolic fuel and an endogenous signaling molecule, offering diverse systemic benefits. Recent studies have highlighted the renoprotective effects of exogenous β-HB therapy in various animal models of kidney disease. In this investigation, our goal was to assess whether pre-treatment with exogenous β-HB could alleviate kidney damage in a mouse model of cisplatin-induced acute kidney injury (AKI). Prior to cisplatin administration, intraperitoneal administration of β-HB was carried out, and the groups were classified into four: Sham, β-HB, cisplatin, and β-HB + cisplatin. The tubular damage score and serum creatinine levels were significantly lower in the β-HB + cisplatin group compared to the cisplatin group. Furthermore, the expression of phosphorylated NF-κB, inflammatory cytokines, and the quantity of F4/80-positive macrophages in the β-HB + cisplatin group were reduced compared to those in the cisplatin group. Additionally, oxidative stress markers for DNA, protein, and lipid in the β-HB + cisplatin group were markedly diminished compared to those in the cisplatin group. The number of TUNEL-positive and cleaved caspase 3-positive tubular cells in the β-HB + cisplatin group was lower than in the cisplatin group. Pre-treating with exogenous β-HB effectively mitigated kidney damage by suppressing inflammation, oxidative stress, and tubular apoptosis in cisplatin-induced AKI. Therefore, exogenous β-HB as a pre-treatment emerges as a promising and novel strategy for preventing cisplatin-induced AKI.

Keywords:  Acute kidney injury; Cisplatin; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.bbrc.2024.149482
Food Funct. 2024 Jan 10.

Ketogenic diet attenuates cognitive dysfunctions induced by hypoglycemia via inhibiting endoplasmic reticulum stress-dependent pathways.

Cixia Li, Yue Ma, Xuejun Chai, Xiao Feng, Wenyu Feng, Yongkang Zhao, Chaochu Cui, Jianguo Wang, Shanting Zhao, Xiaoyan Zhu.

Hypoglycemia can potentially cause severe damage to the central nervous system. The ketogenic diet (KD), characterized by high-fat and extremely low-carbohydrate content, can modulate homeostasis and nutrient metabolism, thereby influencing body health. However, the effects and underlying mechanisms of KD on hypoglycemia-induced brain injury have not been thoroughly investigated. We aimed to explore the modulating effects of KD on cognitive functions and elucidate the underlying mechanisms. In this study, one-month-old mice were fed with KD for 2 weeks, and the changes in the gut microbiota were detected using the 16S rRNA gene amplicon sequencing method. The hypoglycemic model of mice was established using insulin, and the potential protective effect of KD on hypoglycemia-induced brain injury in mice was evaluated through immunofluorescence staining, western blotting, transmission electron microscopy, and Golgi staining. Our results showed that the intestinal flora of Dorea increased and Rikenella decreased in KD-fed mice. KD can not only alleviate anxiety-like behavior induced by hypoglycemia, but also increase the proportion of mushroom dendritic spines in the hippocampus by modulating changes in the gut microbiota. KD regulated synaptic plasticity by increasing the levels of SPN, PSD95, and SYP, which relieve cognitive impairment caused by hypoglycemia. Moreover, KD can promote the proliferation and survival of adult neural stem cells in the hippocampus, while reducing apoptosis by suppressing the activation of the IRE1-XBP1 and ATF6 endoplasmic reticulum stress pathways in mice with hypoglycemia. This study provides new evidence for demonstrating that KD may alleviate cognitive dysfunctions caused by hypoglycemia by modulating the gut microbiota.

DOI: https://doi.org/10.1039/d3fo04007k
Sci Rep. 2024 01 08. 14(1): 757

Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.

Jacob Marthinsen Seefeldt, Yaara Libai, Katrine Berg, Nichlas Riise Jespersen, Thomas Ravn Lassen, Frederik Flyvholm Dalsgaard, Pia Ryhammer, Michael Pedersen, Lars Bo Ilkjaer, Michiel A Hu, Michiel E Erasmus, Roni R Nielsen, Hans Erik Bøtker, Oren Caspi, Hans Eiskjær, Niels Moeslund.

Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia-reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer's acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.

DOI: https://doi.org/10.1038/s41598-024-51387-y
Nutrients. 2023 Dec 20. pii: 18. [Epub ahead of print]16(1):

Ketogenic Diet High in Saturated Fat Promotes Colonic Claudin Expression without Changes in Intestinal Permeability to Iohexol in Healthy Mice.

Lotta Luiskari, Hanna Launonen, Jere Lindén, Markku Lehto, Heikki Vapaatalo, Hanne Salmenkari, Riitta Korpela.

  Ketogenic diets (KDs) have been studied in preclinical models of intestinal diseases. However, little is known of how the fat source of these diets influences the intestinal barrier. Herein, we studied the impact of four-week feeding with KD high either in saturated fatty acids (SFA-KD) or polyunsaturated linoleic acid (LA-KD) on paracellular permeability of the intestine to iohexol in healthy male C57BL/6J mice. We investigated jejunal and colonic tight junction protein expression, histological changes, and inflammatory markers (Il1b, Il6, Tnf, and Lcn2), as well as the activity and expression of intestinal alkaline phosphatase (IAP) in feces and jejunal tissue, respectively, and plasma lipopolysaccharide. KDs did not change intestinal permeability to iohexol after two or twenty-six days of feeding regardless of fat quality. SFA-KD, but not LA-KD, upregulated the colonic expression of tight junction proteins claudin-1 and -4, as well as the activity of IAP. Both KDs resulted in increased epithelial vacuolation in jejunum, and this was pronounced in SFA-KD. Jejunal Il1β expression was lower and colonic Il6 expression higher in LA-KD compared to SFA-KD. In colon, Tnf mRNA was increased in LA-KD when compared to controls. Overall, the results suggest that KDs do not influence intestinal permeability to iohexol but elicit changes in colonic tight junction proteins and inflammatory markers in both jejunum and colon. Future research will show whether these changes become of importance upon proinflammatory insults.

Keywords:  dietary fat; intestinal permeability; ketogenic diet; tight junction proteins

DOI:  https://doi.org/10.3390/nu16010018
ESC Heart Fail. 2024 Jan 09.

Circulating 3-hydroxy butyrate predicts mortality in patients with chronic heart failure with reduced ejection fraction.

Kristian Hylleberg Christensen, Roni R Nielsen, Morten Schou, Ida Gustafsson, Anders Jorsal, Allan Flyvbjerg, Lise Tarnow, Hans Erik Bøtker, Caroline Kistorp, Mogens Johannsen, Niels Møller, Henrik Wiggers.

  AIMS: In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short-term treatment with the ketone body 3-hydroxy butyrate (3-OHB) has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3-OHB predicted all-cause mortality and sought to identify correlations between patient characteristics and circulating 3-OHB levels.METHODS AND RESULTS: We conducted a cohort study in 218 patients with HFrEF. Plasma 3-OHB levels were measured using high-performance liquid chromatography tandem mass spectrometry. Data on all-cause mortality were obtained by reviewing the patients' medical records, which are linked to the national 'Central Person Registry' that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35 ± 8.6%, mean age was 67 ± 10 years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow-up time was 7.3 (interquartile range 6.3-8.4) years. We observed large variations in 3-OHB levels between patients (median 59 μM, range: 14-694 μM). Patients with 3-OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio [HR]: 2.1 [95% confidence interval (CI): 1.3-3.5], P = 0.003}. In a multivariate analysis, 3-OHB predicted mortality independently of known chronic heart failure risk factors [HR: 1.004 (95% CI: 1.001-1.007), P = 0.02] and with a similar statistical strength as N-terminal pro-brain natriuretic peptide (NT-proBNP) [HR: 1.0005 (95% CI: 1.000-1.001), P = 0.02]. For every 100 μmol increase in plasma 3-OHB, the hazard of death increased by 49%. The following factors significantly predicted 3-OHB levels in the univariate analysis: free fatty acids (FFAs) [β: 238 (95% CI: 185-292), P < 0.0001], age [β: 2.43 (95% CI: 1.14-3.72), P < 0.0001], plasma insulin {β: -0.28 [95% CI: -0.54-(-0.02)], P = 0.036}, body mass index {β: -3.15 [95% CI: -5.26-(-0.05)], P = 0.046}, diabetes [β: 44.49 (95% CI: 14.84-74.14), P = 0.003], glycosylated haemoglobin [β: 1.92 (95% CI: 0.24-3.59), P = 0.025], New York Heart Association class [β: 26.86 (95% CI: 5.99-47.72), P = 0.012], and NT-proBNP [β: 0.03 (95% CI: 0.01-0.04), P = 0.001]. In a multivariate analysis, only FFAs predicted 3-OHB levels [β: 216 (95% CI: 165-268), P > 0.001].
CONCLUSIONS: In patients with HFrEF, circulating 3-OHB was a strong predictor of all-cause mortality independently of NT-proBNP. Circulating FFAs were the best predictor of 3-OHB levels.

Keywords:  3-Hydroxy butyrate; Heart failure; Ketone bodies; Metabolism; Prognosis

DOI:  https://doi.org/10.1002/ehf2.14476
Nutrients. 2024 Jan 04. pii: 168. [Epub ahead of print]16(1):

Intermittent Fasting: Does It Affect Sports Performance? A Systematic Review.

Javier Conde-Pipó, Agustín Mora-Fernandez, Manuel Martinez-Bebia, Nuria Gimenez-Blasi, Alejandro Lopez-Moro, José Antonio Latorre, Antonio Almendros-Ruiz, Bernardo Requena, Miguel Mariscal-Arcas.

  Intermittent fasting is one of the most popular types of diet at the moment because it is an effective nutritional strategy in terms of weight loss. The main objective of this review is to analyze the effects that intermittent fasting has on sports performance. We analyzed physical capacities: aerobic capacity, anaerobic capacity, strength, and power, as well as their effect on body composition. For this, a bibliographic search was carried out in several databases where 25 research articles were analyzed to clarify these objectives. Inclusion criteria: dates between 2013 and present, free full texts, studies conducted in adult human athletes, English and/or Spanish languages, and if it has been considered that intermittent fasting is mainly linked to sports practice and that this obtains a result in terms of performance or physical capacities. This review was registered in PROSPERO with code ref. 407024, and an evaluation of the quality or risk of bias was performed. After this analysis, results were obtained regarding the improvement of body composition and the maintenance of muscle mass. An influence of intermittent fasting on sports performance and body composition is observed. It can be concluded that intermittent fasting provides benefits in terms of body composition without reducing physical performance, maintenance of lean mass, and improvements in maximum power. But despite this, it is necessary to carry out new studies focusing on the sports field since the samples have been very varied. Additionally, the difference in hours of intermittent fasting should be studied, especially in the case of overnight fasting.

Keywords:  athletic performance; exercise; fasting strategies; sport nutrition

DOI:  https://doi.org/10.3390/nu16010168
Inflamm Res. 2024 Jan 08.

The NLRP3 inflammasome: a vital player in inflammation and mediating the anti-inflammatory effect of CBD.

Feng-Xin Chu, Xiao Wang, Bo Li, Li-Li Xu, Bin Di.

  BACKGROUND: The NLRP3 inflammasome is a vital player in the emergence of inflammation. The priming and activation of the NLRP3 inflammasome is a major trigger for inflammation which is a defense response against adverse stimuli. However, the excessive activation of the NLRP3 inflammasome can lead to the development of various inflammatory diseases. Cannabidiol, as the second-most abundant component in cannabis, has a variety of pharmacological properties, particularly anti-inflammation. Unlike tetrahydrocannabinol, cannabidiol has a lower affinity for cannabinoid receptors, which may be the reason why it is not psychoactive. Notably, the mechanism by which cannabidiol exerts its anti-inflammatory effect is still unclear.METHODS: We have performed a literature review based on published original and review articles encompassing the NLRP3 inflammasome and cannabidiol in inflammation from central databases, including PubMed and Web of Science.
RESULTS AND CONCLUSIONS: In this review, we first summarize the composition and activation process of the NLRP3 inflammasome. Then, we list possible molecular mechanisms of action of cannabidiol. Next, we explain the role of the NLRP3 inflammasome and the anti-inflammatory effect of cannabidiol in inflammatory disorders. Finally, we emphasize the capacity of cannabidiol to suppress inflammation by blocking the NLRP3 signaling pathway, which indicates that cannabidiol is a quite promising anti-inflammatory compound.

Keywords:  Cannabidiol; Inflammation; Inflammatory disease; NLRP3 inflammasome

DOI:  https://doi.org/10.1007/s00011-023-01831-y
Int J Mol Sci. 2024 Jan 03. pii: 626. [Epub ahead of print]25(1):

The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review.

Po-Ku Chen, Kuo-Tung Tang, Der-Yuan Chen.

  Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage and bone. RA is commonly accompanied by extra-articular comorbidities. The pathogenesis of RA and its comorbidities is complex and not completely elucidated. The assembly of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces the maturation of interleukin (IL)-1β and IL-18 and leads to the cleavage of gasdermin D with promoting pyroptosis. Accumulative evidence indicates the pathogenic role of NLRP3 inflammasome signaling in RA and its comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, and interstitial lung diseases. Although the available therapeutic agents are effective for RA treatment, their high cost and increased infection rate are causes for concern. Recent evidence revealed the components of the NLRP3 inflammasome as potential therapeutic targets in RA and its comorbidities. In this review, we searched the MEDLINE database using the PubMed interface and reviewed English-language literature on the NLRP3 inflammasome in RA and its comorbidities from 2000 to 2023. The current evidence reveals that the NLRP3 inflammasome contributes to the pathogenesis of RA and its comorbidities. Consequently, the components of the NLRP3 inflammasome signaling pathway represent promising therapeutic targets, and ongoing research might lead to the development of new, effective treatments for RA and its comorbidities.

Keywords:  NLRP3 inflammasome; comorbidities; pathogenic player; rheumatoid arthritis; therapeutic potential

DOI:  https://doi.org/10.3390/ijms25010626
bioRxiv. 2023 Dec 23. pii: 2023.12.23.573206. [Epub ahead of print]

Exogenous mitochondrial transfer increases energy expenditure and attenuates adiposity gains in mice with diet-induced obesity.

Maria Namwanje, Soumi Mazumdar, Amanda Stayton, Prisha S Patel, Christine Watkins, Catrina White, Chester Brown, James D Eason, Khyobeni Mozhui, Cem Kuscu, Navjot Pabla, Erin J Stephenson, Amandeep Bajwa.

Obesity is associated with chronic multi-system bioenergetic stress that may be improved by increasing the number of healthy mitochondria available across organ systems. However, treatments capable of increasing mitochondrial content are generally limited to endurance exercise training paradigms, which are not always sustainable long-term, let alone feasible for many patients with obesity. Recent studies have shown that local transfer of exogenous mitochondria from healthy donor tissues can improve bioenergetic outcomes and alleviate the effects of tissue injury in recipients with organ specific disease. Thus, the aim of this project was to determine the feasibility of systemic mitochondrial transfer for improving energy balance regulation in the setting of diet-induced obesity. We found that transplantation of mitochondria from lean mice into mice with diet-induced obesity attenuated adiposity gains by increasing energy expenditure and promoting the mobilization and oxidation of lipids. Additionally, mice that received exogenous mitochondria demonstrated improved glucose uptake, greater insulin responsiveness, and complete reversal of hepatic steatosis. These changes were, in part, driven by adaptations occurring in white adipose tissue. Together, these findings are proof-of-principle that mitochondrial transplantation is an effective therapeutic strategy for limiting the deleterious metabolic effects of diet-induced obesity in mice.

DOI: https://doi.org/10.1101/2023.12.23.573206
Crit Rev Food Sci Nutr. 2024 Jan 08. 1-10

Defining "low-carb" in the scientific literature: A scoping review of clinical studies.

Violeta Chacón, Kelly C Cara, Mei Chung, Taylor C Wallace.

  There remains a lack of scientific consensus on what level of carbohydrate intake constitutes low-carbohydrate diets. We conducted a scoping review to understand how low-carbohydrate diets were defined in the peer-reviewed literature. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement scoping review extension. Three electronic databases were searched for clinical studies in English. We identified 508 articles (317 randomized controlled, 99 cross-over, 33 before-and-after, 12 non-randomized, and 47 other clinical trials). Most examined effects of low-carbohydrate diets in healthy adults (62.4%), 40 to 59 years old (55.5%), with obesity or overweight (66.1%). The majority reported effects on weight or body composition (29.9%), diabetes (18.7%), or cardiovascular risk factors (12.9%) as primary outcomes. Most articles (56.9%) reported percent of energy from carbohydrates, and of those, 60.3% defined low-carbohydrate diets as being ≤30% of energy from carbohydrates. Some articles (22.9%) reported grams of carbohydrates per day, and of those, most defined low-carbohydrate diets as being under ∼100 grams of carbohydrates per day. Systematic reviews and dose-response meta-regressions utilizing patient-level data on carbohydrate intake, status markers (e.g., RQ/ketones), and health outcomes would be useful in informing consensus around a standardized definition.

Keywords:  Low-carbohydrate diets; dietary patterns; macronutrient

DOI:  https://doi.org/10.1080/10408398.2023.2300705
Eur J Appl Physiol. 2024 Jan 11.

A century of exercise physiology: effects of muscle contraction and exercise on skeletal muscle Na+,K+-ATPase, Na+ and K+ ions, and on plasma K+ concentration-historical developments.

Michael J McKenna, Jean-Marc Renaud, Niels Ørtenblad, Kristian Overgaard.

  This historical review traces key discoveries regarding K+ and Na+ ions in skeletal muscle at rest and with exercise, including contents and concentrations, Na+,K+-ATPase (NKA) and exercise effects on plasma [K+] in humans. Following initial measures in 1896 of muscle contents in various species, including humans, electrical stimulation of animal muscle showed K+ loss and gains in Na+, Cl- and H20, then subsequently bidirectional muscle K+ and Na+ fluxes. After NKA discovery in 1957, methods were developed to quantify muscle NKA activity via rates of ATP hydrolysis, Na+/K+ radioisotope fluxes, [3H]-ouabain binding and phosphatase activity. Since then, it became clear that NKA plays a central role in Na+/K+ homeostasis and that NKA content and activity are regulated by muscle contractions and numerous hormones. During intense exercise in humans, muscle intracellular [K+] falls by 21 mM (range - 13 to - 39 mM), interstitial [K+] increases to 12-13 mM, and plasma [K+] rises to 6-8 mM, whilst post-exercise plasma [K+] falls rapidly, reflecting increased muscle NKA activity. Contractions were shown to increase NKA activity in proportion to activation frequency in animal intact muscle preparations. In human muscle, [3H]-ouabain-binding content fully quantifies NKA content, whilst the method mainly detects α2 isoforms in rats. Acute or chronic exercise affects human muscle K+, NKA content, activity, isoforms and phospholemman (FXYD1). Numerous hormones, pharmacological and dietary interventions, altered acid-base or redox states, exercise training and physical inactivity modulate plasma [K+] during exercise. Finally, historical research approaches largely excluded female participants and typically used very small sample sizes.

Keywords:  Exercise; FXYD; Fatigue; Na+, K+-pump; Plasma; Potassium; Skeletal muscle; Sodium

DOI:  https://doi.org/10.1007/s00421-023-05335-9