bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024–10–13
25 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello



  1. Cureus. 2024 Sep;16(9): e68697
      The ketogenic diet (KD) has gained a lot of attraction in the management of neurological disorders. KD therapies are high-fat, low-carbohydrate diets intended to shift energy consumption and metabolism from carbohydrates to fat in ketogenesis. The oxidative phosphorylation of ketone bodies generates energy packets for body cells, especially the central nervous system, replacing the role of glucose. KD can benefit multiple neurologic disorders like migraine, motor neuron disease, autism, multiple sclerosis, neuro-oncology, drug-resistant epilepsy, and neurotrauma. KD can provide significant adjuncts to limited conventional therapies, highlighting the feasibility, safety, and potential efficacy in neurology and neurosurgical disease management.
    Keywords:  brain; cancer; epilepsy; fat; keto diet; ketogenic; migraine; spine; traumatic brain injury; tumor
    DOI:  https://doi.org/10.7759/cureus.68697
  2. Int J Obes (Lond). 2024 Oct 05.
      We have long known that subjects with obesity who fast for several weeks survive. Calculations that assume the brain can only use glucose indicated that all carbohydrate and protein sources would be consumed by the brain within several weeks yet subjects with obesity who fasted for several weeks survived. This anomaly led to the determination of the metabolic role of ketone bodies. Subsequent studies transformed our understanding of ketone bodies and illustrated the value of challenging the norm and adapting theory to evidence. Although prolonged fasting is no longer a treatment for obesity, the early studies of starvation provided valuable insights about macronutrient metabolism and ketone body adaptations that fasting elicits. Intermittent fasting and its variants such as time-restricted eating are fasting models that are far less regimented than starvation and severe calorie restriction; yet they produce metabolic benefits. The mechanisms that produce the metabolic changes that intermittent fasting elicits are relatively unknown. In this article, we review the physiology of starvation, starvation adaptation diets, diet-induced ketosis, and intermittent fasting. Understanding the premise and physiology that these regimens induce is necessary to draw parallels and provoke thoughts on the mechanisms underlying the metabolic benefits of intermittent fasting and its variants.
    DOI:  https://doi.org/10.1038/s41366-024-01641-0
  3. Brain Behav Immun. 2024 Oct 06. pii: S0889-1591(24)00645-7. [Epub ahead of print]
      The ketogenic diet (KD) has been shown to be effective in treating various brain pathologies. In this study, we conducted detailed transcriptomic and metabolomic profiling of rat brains after KD and ischemic stroke in order to investigate the effects of KD and its underlying mechanisms. We evaluated the effect of a two-month KD on gene expression in intact brain tissue and after middle cerebral artery occlusion (MCAO). We analyzed the effects of KD on gut microbiome composition and blood metabolic profile as well as investigated the correlation between severity of neurological deficits and KD-induced changes. We found transcriptional reprogramming in the brain after stroke and KD treatment. The KD altered the expression of genes involved in the regulation of glucose and fatty acid metabolism, mitochondrial function, the immune response, Wnt-associated signaling, stem cell development, and neurotransmission, both in intact rats and after MCAO. The KD led to a significant change in the composition of gut microbiome and the levels of amino acids, acylcarnitines, polyunsaturated fatty acids, and oxylipins in the blood. However, the KD slightly worsened the neurological functions after MCAO, so that the therapeutic effect of the diet remained unproven.
    Keywords:  Intestine microbiota; Ketogenic diet; Metabolism; Neurologic deficit; RNA sequencing; Stroke
    DOI:  https://doi.org/10.1016/j.bbi.2024.10.004
  4. medRxiv. 2024 Sep 18. pii: 2024.09.17.24313811. [Epub ahead of print]
       Background: Ketone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on the inflammatory and metabolic aging pathways underpinning frailty in in vivo models. Ketone esters (KEs) are compounds that induce hyperketonemia without dietary changes and that may impact physical and cognitive function in young adults. The functional effects of KEs have not been studied in older adults.
    Objectives: Our long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults. Here, we report the exploratory functional and quality-of-life outcome measures collected during a 12-week safety and tolerability study of KE ( NCT05585762 ).
    Design: Randomized, placebo-controlled, double-blinded, parallel-group, pilot trial of 12-weeks of daily KE ingestion.
    Setting: The Clinical Research Unit at the Buck Institute for Research on Aging, California. Participants: Community-dwelling older adults (≥ 65 years), independent in activities of daily living, with no unstable acute medical conditions (n = 30).
    Intervention: Subjects were randomly allocated (1:1) to consume 25 g daily of either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil.
    Measurements: Longitudinal change in physical function, cognitive function and quality of life were assessed as exploratory outcomes in n = 23 completers (n = 11 PLA, n = 12 KE). A composite functional outcome to describe the vigor-frailty continuum was calculated. Heart rate and activity was measured throughout the study using digital wearables.
    Results: There were no statistically significant longitudinal differences between groups in exploratory functional, activity-based or quality of life outcomes.
    Conclusion: Daily ingestion of 25 g of KE did not affect exploratory functional or quality-of-life end points in this pilot cohort of healthy older adults. Future work will address these endpoints as primary and secondary outcomes in a larger trial of pre-frail older adults.
    DOI:  https://doi.org/10.1101/2024.09.17.24313811
  5. EJNMMI Res. 2024 Oct 08. 14(1): 92
       BACKGROUND: Inadequate myocardial glucose metabolism suppression (GMS) can hamper interpretation of cardiac [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET/CT). Use of β-hydroxybutyrate (BHB) measurement before [18F]FDG injection has been proposed for predicting adequate GMS. However, limited information is available on BHB measurement in guiding preparations for [18F]FDG-PET/CT. The purpose of this study was to evaluate if point-of-care measured BHB is useful in guiding heparin premedication for cardiac [18F]FDG-PET/CT.
    RESULTS: 155 patients (82 male) had followed a high-fat, low-carbohydrate diet and fasted for at least twelve hours. For the first 63 patients, BHB was measured, but it was not used to guide premedication. For the subsequent 92 patients, heparin 50 IU/kg was injected intravenously 15-20 min before [18F]FDG injection if the BHB level was low (< 0.35 mmol/l). Cardiac [18F]FDG uptake pattern was evaluated visually and [18F]FDG uptake in the myocardium and blood pool were measured. Median BHB level was 0.4 (range 0.1-5.8) mmol/l. Eighty-eight patients (57%) reached a BHB level higher than 0.35 mmol/l. 112 patients (72%) had adequate GMS. In the high BHB group, 74 patients (84%) had adequate GMS, whereas of those with low BHB, only 38 (57%) had adequate GMS (p < 0.001). In the low BHB group, the prevalence of inadequate GMS was comparable in patients with and without heparin (44% vs. 42%, p = 0.875).
    CONCLUSIONS: While high BHB predicts adequate GMS, unfractionated heparin does not improve GMS in patients with low BHB.
    Keywords:  BHB; Beta-hydroxybutyrate; FDG-PET; Glucose metabolism; Heparin; Myocardial inflammation; Myocardium
    DOI:  https://doi.org/10.1186/s13550-024-01153-y
  6. Radiol Case Rep. 2024 Dec;19(12): 6292-6296
      Short-chain enoyl-CoA hydratase, encoded by ECHS1, plays a major role in the valine catabolic pathway and mitochondrial fatty acid β-oxidation. Deficiency of this enzyme causes Leigh syndrome. Herein, we report a case of ECHS1-related Leigh syndrome with a prominent ketone body spectrum on magnetic resonance spectroscopy during acute exacerbation. A 6-month-old boy with mild motor developmental delay presented with disturbances of consciousness and hypercapnia without prior infection or feeding failure. Upon admission, investigations revealed prominent ketosis and elevated 2,3-dihydroxy-2-methylbutyric acid excretion. Brain magnetic resonance imaging revealed symmetrical T2 prolongation with restricted diffusion in the basal ganglia. Magnetic resonance spectroscopy showed a prominent ketone body spectrum in the cerebral white matter, and prominent ketone bodies, elevated lactate and markedly decreased N-acetylaspartate levels in the basal ganglia. Genetic analysis identified compound heterozygous variants of ECHS1. Short-chain enoyl-CoA hydratase deficiency is a disease for which a valine-restricted diet is reported to be beneficial, and early diagnosis is desirable. Severe ketosis and the ketone body magnetic resonance spectroscopy spectrum during acute exacerbation may aid in the diagnosis of this disease.
    Keywords:  ECHS1; Ketosis; Leigh syndrome; Magnetic resonance spectroscopy; Metabolic encephalopathies
    DOI:  https://doi.org/10.1016/j.radcr.2024.08.164
  7. Epilepsy Behav. 2024 Oct 10. pii: S1525-5050(24)00453-0. [Epub ahead of print]160 110071
       INTRODUCTION: The ketogenic diet is a valuable nonpharmacologic therapy for the treatment of refractory epilepsy in children and adults. It can be time-intensive for ketogenic teams, typically comprised of a physician and dietitian at a minimum. Challenges and barriers to providing ketogenic diet services to patients by members of these teams has not been studied extensively.
    METHODS: A survey was created and distributed to attendees at a ketogenic diet training conference (KetoCollegeAdvance™) held 21-23 May 2024 in United Kingdom. Questions included Likert scales and fill-in responses. Surveys were provided by 63 attendees (mostly dietitians) from 17 countries.
    RESULTS: Respondents were mostly dietitians (45/63, 71 %) and from the United Kingdom. In regards to perceived interest levels in KD in general in their countries, dietitians were perceived as 80 % very or extremely interested, parents (66 %), and neurologists (45 %). The majority of teams included a dietitian (79 %) and physician (78 %). The majority, 43 (68 %) of respondents, assumed care of all aspects of epilepsy care once the KD was started. Common barriers to starting KD services included a long waiting list, lack of adult KD services, funding dietitians, and low referrals. Barriers to continuing KD services included poor patient compliance, a lack of financial resources for some families to afford foods, and a need for more pre-made ketogenic foods including bread, pizza, pasta, potato fries, and chocolates.
    CONCLUSIONS: These results from a conference of international ketogenic dietitians and physicians highlights common difficulties in providing the ketogenic diet successfully. Addressing these barriers may help expand the usage of this therapy for more patients with epilepsy.
    Keywords:  Diet; Dietitian; Finances; Ggoals; Ketogenic; Research
    DOI:  https://doi.org/10.1016/j.yebeh.2024.110071
  8. JACC Adv. 2024 Aug;3(8): 101109
       Background: Increases in low-density lipoprotein cholesterol (LDL-C) can occur on carbohydrate restricted ketogenic diets. Lean metabolically healthy individuals with a low triglyceride-to-high-density lipoprotein cholesterol ratio appear particularly susceptible, giving rise to the novel "lean mass hyper-responder" (LMHR) phenotype.
    Objectives: The purpose of the study was to assess coronary plaque burden in LMHR and near-LMHR individuals with LDL-C ≥190 mg/dL (ketogenic diet [KETO]) compared to matched controls with lower LDL-C from the Miami Heart (MiHeart) cohort.
    Methods: There were 80 KETO individuals with carbohydrate restriction-induced LDL-C ≥190 mg/dL, high-density lipoprotein cholesterol ≥60 mg/dL, and triglyceride levels ≤80 mg/dL, without familial hypercholesterolemia, matched 1:1 with MiHeart subjects for age, gender, race, hyperlipidemia, hypertension, and smoking status. Coronary artery calcium and coronary computed tomography angiography (CCTA) were used to compare coronary plaque between groups and correlate LDL-C to plaque levels.
    Results: The matched mean age was 55.5 years, with a mean LDL-C of 272 (maximum LDL-C of 591) mg/dl and a mean 4.7-year duration on a KETO. There was no significant difference in coronary plaque burden in the KETO group as compared to MiHeart controls (mean LDL 123 mg/dL): coronary artery calcium score (median 0 [IQR: 0-56]) vs (1 [IQR: 0-49]) (P = 0.520) CCTA total plaque score (0 [IQR: 0-2] vs [IQR: 0-4]) (P = 0.357). There was also no correlation between LDL-C level and CCTA coronary plaque.
    Conclusions: Coronary plaque in metabolically healthy individuals with carbohydrate restriction-induced LDL-C ≥190 mg/dL on KETO for a mean of 4.7 years is not greater than a matched cohort with 149 mg/dL lower average LDL-C. There is no association between LDL-C and plaque burden in either cohort. (Diet-induced Elevations in LDL-C and Progression of Atherosclerosis [Keto-CTA]; NCT057333255).
    Keywords:  LDL cholesterol; atherosclerosis; coronary CT angiography; ketogenic diet; lean mass hyper-responder; plaque
    DOI:  https://doi.org/10.1016/j.jacadv.2024.101109
  9. Res Q Exerc Sport. 2024 Oct 10. 1-7
      Calisthenics is a form of bodyweight exercise that involves dynamic and rhythmic exercises. The physiological responses during and after calisthenics remain unclear. This study examined whether a bout of full-body calisthenics, a form of circuit resistance exercise that involves bodyweight movements, yields greater excess post-exercise oxygen consumption (EPOC) than steady-state exercise (SSE) at matched oxygen consumption. Twenty-two young adults (age = 22.1 ± 2.4 years; four females) participated in two separate, oxygen consumption (V˙O2) matched exercise sessions: full-body calisthenics (nine body weight exercises, 15 reps × 4 sets) and SSE (running on a treadmill at 60-90% of V˙O2max). Energy expenditure, substrate utilization, and EPOC were measured during exercise and 60 min of recovery. SSE showed higher peak V˙O2 and heart rate during exercise than those during calisthenics. However, the post-exercise V˙O2 and energy expenditure above baseline level during the first 10 min of recovery were significantly higher with calisthenics than with SSE (0-5 min: 1.7 ± 0.5 vs. 1.0 ± 0.6; 6-10 min: 0.5 ± 0.4 vs. 0.1 ± 0.2 kcal/min; 31-60 min recovery: -0.1 ± 0.3 vs. -0.2 ± 0.2; all p < .05). During calisthenics, participants utilized a significantly higher proportion of energy from carbohydrates (85 vs. 73%; p < .01) but after exercise, they used a greater proportion of fat as the energy source (71 vs. 50%; p < .01) compared to SSE. Full-body calisthenics, a circuit-style bodyweight exercise, may be more effective than V˙O2 matched SSE in triggering greater EPOC and fat metabolism. Further efforts are warranted to demonstrate whether different amounts of skeletal muscle mass groups indeed lead to varying EPOC responses and energy use.
    Keywords:  Bodyweight exercise; calisthenics; excess post-exercise oxygen consumption; high-intensity interval training; oxygen debt; substrate utilization
    DOI:  https://doi.org/10.1080/02701367.2024.2410394
  10. Sports Med. 2024 Oct 10.
       BACKGROUND: Skeletal muscle mitochondria and capillaries are crucial for aerobic fitness, and suppressed levels are associated with chronic and age-related diseases. Currently, evidence-based exercise training recommendations to enhance these characteristics are limited. It is essential to explore how factors, such as fitness level, age, sex, and disease affect mitochondrial and capillary adaptations to different exercise stimuli.
    OBJECTIVES: The main aim of this study was to compare the effects of low- or moderate intensity continuous endurance training (ET), high-intensity interval or continuous training (HIT), and sprint interval training (SIT) on changes in skeletal muscle mitochondrial content and capillarization. Secondarily, the effects on maximal oxygen consumption (VO2max), muscle fiber cross-sectional area, and fiber type proportion were investigated.
    METHODS: A systematic literature search was conducted in PubMed, Web of Science, and SPORTDiscus databases, with no data restrictions, up to 2 February 2022. Exercise training intervention studies of ET, HIT, and SIT were included if they had baseline and follow-up measures of at least one marker of mitochondrial content or capillarization. In total, data from 5973 participants in 353 and 131 research articles were included for the mitochondrial and capillary quantitative synthesis of this review, respectively. Additionally, measures of VO2max, muscle fiber cross-sectional area, and fiber type proportion were extracted from these studies.
    RESULTS: After adjusting for relevant covariates, such as training frequency, number of intervention weeks, and initial fitness level, percentage increases in mitochondrial content in response to exercise training increased to a similar extent with ET (23 ± 5%), HIT (27 ± 5%), and SIT (27 ± 7%) (P > 0.138), and were not influenced by age, sex, menopause, disease, or the amount of muscle mass engaged. Higher training frequencies (6 > 4 > 2 sessions/week) were associated with larger increases in mitochondrial content. Per total hour of exercise, SIT was ~ 2.3 times more efficient in increasing mitochondrial content than HIT and ~ 3.9 times more efficient than ET, while HIT was ~ 1.7 times more efficient than ET. Capillaries per fiber increased similarly with ET (15 ± 3%), HIT (13 ± 4%) and SIT (10 ± 11%) (P = 0.556) after adjustments for number of intervention weeks and initial fitness level. Capillaries per mm2 only increased after ET (13 ± 3%) and HIT (7 ± 4%), with increases being larger after ET compared with HIT and SIT (P < 0.05). This difference coincided with increases in fiber cross-sectional area after ET (6.5 ± 3.5%), HIT (8.9 ± 4.9%), and SIT (11.9 ± 15.1%). Gains in capillarization occurred primarily in the early stages of training (< 4 weeks) and were only observed in untrained to moderately trained participants. The proportion of type I muscle fibers remained unaltered by exercise training (P > 0.116), but ET and SIT exhibited opposing effects (P = 0.041). VO2max increased similarly with ET, HIT, and SIT, although HIT showed a tendency for greater improvement compared with both ET and SIT (P = 0.082), while SIT displayed the largest increase per hour of exercise. Higher training frequencies (6 > 4 > 2 sessions/week) were associated with larger increases in VO2max. Women displayed greater percentage gains in VO2max compared with men (P = 0.008). Generally, lower initial fitness levels were associated with greater percentage improvements in mitochondrial content, capillarization, and VO2max. SIT was particularly effective in improving mitochondrial content and VO2max in the early stages of training, while ET and HIT showed slower but steady improvements over a greater number of training weeks.
    CONCLUSIONS: The magnitude of change in mitochondrial content, capillarization, and VO2max to exercise training is largely determined by the initial fitness level, with greater changes observed in individuals with lower initial fitness. The ability to adapt to exercise training is maintained throughout life, irrespective of sex and presence of disease. While training load (volume × intensity) is a suitable predictor of changes in mitochondrial content and VO2max, this relationship is less clear for capillary adaptations.
    DOI:  https://doi.org/10.1007/s40279-024-02120-2
  11. Phytomedicine. 2024 Oct 02. pii: S0944-7113(24)00709-8. [Epub ahead of print]135 156052
       BACKGROUND: Chondrocyte senescence and inflammation are hallmarks of osteoarthritis (OA). Forsythiaside A (FTA), a phenylethanol glycoside isolated from air-dried fruits of Forsythia, has been reported to have significant anti-inflammatory and antioxidant properties. However, its protective effects against OA have not been elucidated.
    PURPOSE: We explored the therapeutic efficacy of FTA in inhibiting chondrocyte senescence and inflammation during OA, as well as the potential underlying mechanisms.
    STUDY DESIGN: This study aimed to investigate the novel mechanism of FTA in alleviating OA in both cell and animal models.
    METHODS: The protective effect of FTA against tert‑butyl hydroperoxide-induced chondrocyte damage was assessed, and the effects of FTA on cartilage aging and OA progression were evaluated using a medial meniscus (DMM)-induced knee OA mouse model. The regulatory effects of FTA on the NLRP3 Inflammasome, mitophagy, and the PKC/Nrf2 pathway were also explored.
    RESULTS: In vitro, FTA improved mitochondrial function, enhanced mitophagy, suppressed NLRP3 inflammasome activation, and inhibited chondrocyte senescence; however, these chondroprotective effects were partially reversed after mitophagy inhibition, NLRP3 inflammasome activation, and Nrf2 pathway inhibition. Furthermore, we found that FTA directly interacts with Nrf2 and enhances its phosphorylation by protein kinase C (PKC). In vivo, FTA attenuated the pathological signs of knee OA in a DMM-model mouse model, which was partially reversed by ML385.
    CONCLUSION: FTA inhibited chondrocyte senescence and OA progression by activating the PKC-Nrf2 pathway. Thus, FTA is a potential novel therapeutic agent for OA.
    Keywords:  Forsythiaside A; Nrf2; inflammasome; mitophagy; osteoarthritis; senescence
    DOI:  https://doi.org/10.1016/j.phymed.2024.156052
  12. Sci Adv. 2024 Oct 11. 10(41): eadl4374
      Type 2 diabetes (T2D) and obesity are strongly associated with low natriuretic peptide (NP) plasma levels and a down-regulation of NP guanylyl cyclase receptor-A (GCA) in skeletal muscle and adipose tissue. However, no study has so far provided evidence for a causal link between atrial NP (ANP)/GCA deficiency and T2D pathogenesis. Here, we show that both systemic and skeletal muscle ANP/GCA deficiencies in mice promote metabolic disturbances and prediabetes. Skeletal muscle insulin resistance is further associated with altered mitochondrial function and impaired endurance running capacity. ANP/GCA-deficient mice exhibit increased proton leak and reduced content of mitochondrial oxidative phosphorylation proteins. We further show that GCA is related to several metabolic traits in T2D and positively correlates with markers of oxidative capacity in human skeletal muscle. Together, these results indicate that ANP/GCA signaling controls muscle mitochondrial integrity and oxidative capacity in vivo and plays a causal role in the development of prediabetes.
    DOI:  https://doi.org/10.1126/sciadv.adl4374
  13. Front Med (Lausanne). 2024 ;11 1421962
      The relationship between exercise and obesity has attracted increasing attention from researchers worldwide in recent years. The aim of the present study was to analyze the current knowledge and scientific trends of research into myokines and exercise in the context of obesity and provide ideas for future research strategies to prevent obesity. The study conducted a comprehensive bibliometric analysis of 300 scientific publications related to myokines, exercise, and obesity from 2004 to 2024. Applying the VOSviewer tool, the analysis revealed a significant increase over time in the number of publications on these topics, with a total of 1,142 related keywords identified. Key themes identified in the analysis included molecular processes, new organokines, skeletal muscle research, model organism studies, and human studies based on sex and age differences. The study highlighted the growing interest in the molecular mechanisms of obesity and role of myokines. Results showed a substantial increase in publications from 2014 to 2024, with a focus on new organokines (myokines, adipokines) and animal models. The analysis underscored the importance of myokines in modulating metabolic processes and their potential therapeutic implications in managing non-communicable diseases such as obesity. Furthermore, the study revealed the close relationship between exercise, myokine production, and regulation of metabolism, stress response, and inflammation. In conclusion, over the last years, increasing research interest has been focused on the molecular mechanisms of obesity and benefits of exercise, and probably will be focused on a set of myokines released during muscle contraction. A newly identified myokines has emerged as a promising marker for the prevention and control of obesity.
    Keywords:  VOSviewer; bibliometric analysis; myokines; obesity; physical activity
    DOI:  https://doi.org/10.3389/fmed.2024.1421962
  14. Immunometabolism (Cobham). 2024 Oct;6(4): e00048
      Hematopoietic stem cells (HSCs) are the multipotent progenitors of all immune cells. During aging, their regenerative capacity decreases for reasons that are not well understood. Recently, Song et al investigated the roles of two metabolic proteins in age-related HSC dysfunction: CD38 (a membrane-bound NADase) and the mitochondrial calcium uniporter that transports calcium into the mitochondrial matrix. They found that the interplay between these proteins is deranged in aged HSCs, contributing to their diminished renewal capacity. These findings implicate compromised nicotinamide adenine dinucleotide metabolism as underlying HSC dysfunction in aging.
    Keywords:  CD38; aging; hematopoiesis; mitochondria; mitochondrial calcium uniporter; nicotinamide adenine dinucleotide metabolism
    DOI:  https://doi.org/10.1097/IN9.0000000000000048
  15. Front Nutr. 2024 ;11 1321198
       Introduction: The prevalence of diet-related non-communicable diseases has increased. A low-carbohydrate diet (LCDs) is one of the most popular interventions. Several systematic reviews and meta-analyses of randomised clinical trials (RCTs) and non-RCTs have linked LCDs to the management of obesity, diabetes, cardiovascular disease, epilepsy, and cancer. However, there has been limited appraisal of the strength and quality of this evidence.
    Objective: To systematically appraise existing meta-analyses and systematic reviews of RCTs and non-RCTs on the effects of LCDs on different health conditions. To understand their potential efficacy, we summarised the studies' findings and assessed the strength of the evidence.
    Methods: A search was conducted using the PubMed database from inception to October 2021 for systematic reviews and meta-analyses of RCTs and non-RCTs investigating the association between LCDs and multiple health outcomes in humans. The Academy of Nutrition and Dietetics Quality Criteria was used for the quality assessment. In addition, the evolution of heterogeneity, strength of the included studies, and effect sizes were extracted from each systematic review and meta-analysis.
    Results: Ten systematic reviews and meta-analyses were included. Of the included reviews, 70% were of positive quality, 30% were neutral, and none were negative. The majority of the studies included strength in each systematic review, and the meta-analyses were of low to medium strength. The existing literature indicates that LCDs may help promote weight reduction in adults who are obese or overweight. This conclusion is supported by the findings of studies included in the analysis, which were of low to moderate strength. Furthermore, compelling data indicates a significant association between low-carbohydrate diets (LCDs) and a reduction in haemoglobin A1c levels among those diagnosed with type 2 diabetes mellitus. In contrast, there was a lack of evidence of this correlation in type 1 diabetes mellitus patients or those with cardiovascular diseases. Additionally, there was limited evidence regarding the effectiveness of LCDs in epilepsy and adult cancer patients.
    Conclusion: This review thoroughly examines the current body of information on how LCDs affect various health outcomes. Studies have presented evidence to support the idea that incorporating LCDs can positively influence weight management and HbA1c levels. However, there is a lack of information regarding the association between LCDs and individuals with Type 1 diabetes mellitus and cardiovascular diseases. Additionally, there is limited empirical evidence to substantiate the effectiveness of LCDs in the treatment of epilepsy and adult cancer patients. The long-term effects of LCDs on mortality and other chronic diseases that account for different carbohydrate subtypes is unclear. Further longitudinal cohort studies are required to reach definitive conclusions.
    Keywords:  health; ketogenic diet; low-carbohydrate diet; nutrition; umbrella review
    DOI:  https://doi.org/10.3389/fnut.2024.1321198
  16. Nature. 2024 Oct 09.
      
    Keywords:  Ageing; Immunology; Metabolism; Nutrition
    DOI:  https://doi.org/10.1038/d41586-024-03055-4
  17. Arch Physiol Biochem. 2024 Oct 09. 1-13
      Background: Diabetes patients' quality of life can be severely impacted by diabetic muscle atrophy.Aim: This study aimed to explore the impact of high-intensity exercise (HIE) alongside insulin treatment on muscle atrophy in a rat model of type 1 diabetes mellitus (T1DM).Methodology: Fifty rats were allocated into five groups; Group 1, control sedentary (CS), T1DM was elicited in the rest of the groups by giving them Streptozotocin (STZ) (60 mg/kg), where group 2 (DS) remained sedentary, while groups 3,4,5 were treated with insulin after induction of diabetes. Group 4 (DI+MIE) and 5 (DI+ HIE) underwent moderate and high-intensity exercise, respectively.Results: HIE for 14 days combined with insulin treatment significantly restored muscle strength and mass with a significant modification in the mitophagy-related proteins and fibroblast growth factor 21 (FGF 21) compared to other treated groups.Conclusion: This study concluded that there is a therapeutic role for HIE with insulin against T1DM-induced muscle atrophy.
    Keywords:  FGF 21; Type 1 DM; high-intensity exercise; mitophagy; muscle atrophy
    DOI:  https://doi.org/10.1080/13813455.2024.2410791
  18. Kidney Res Clin Pract. 2024 Sep 11.
       Background: The current study was initiated to evaluate renal nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway activation and macrophage subtype distribution and their clinicopathological significance in a cohort of oxalate-induced acute kidney injury.
    Methods: Twelve patients with biopsy-proven acute oxalate nephropathy (AON) from January 2016 to October 2022 were retrospectively enrolled, with estimated glomerular filtration rate (eGFR)-matched 24 patients with acute tubulointerstitial nephritis (ATIN) as disease control. Pathological lesions as well as markers of NLRP3 inflammasome pathway and macrophage phenotype detected by immunohistochemistry staining were semi-quantitatively analyzed.
    Results: Oxalate depositions were found in 5% to 20% of tubules with a positive correlation with Sirius Red staining in AON specimens (rp = 0.668, p = 0.02). Disruption of tubular basement membrane and inflammatory cell reaction was more prominent in specimens of AON (both p < 0.05) as compared with ATIN specimens. The expressions of NLRP3, caspase-1, and gasdermin D were significantly increased in AON specimens as well (all p < 0.05). Patients with M1/M2 macrophage ratio <1 were found with more chronic tubulointerstitial lesions and presented with lower eGFR at the last follow-up (24.8  10.6 mL/min/1.73 m2 vs. 55.1  21.2 mL/min/1.73 m2, p = 0.02) in the AON group.
    Conclusion: The NLRP3 inflammasome pathway was activated in the kidneys of AON patients, and the ratio of M1 and M2 macrophages was associated with chronicity of pathological changes, which needs further exploration.
    Keywords:  Crystals; Macrophages; NLRP3 inflammasome; Oxalate nephropathy
    DOI:  https://doi.org/10.23876/j.krcp.23.266
  19. J Sport Health Sci. 2024 Oct 04. pii: S2095-2546(24)00151-0. [Epub ahead of print] 100994
      Exercise is a therapeutic approach in cancer treatment, providing several benefits. Moreover, exercise is associated with a reduced risk for developing a range of cancers and for their recurrence, as well as with improving survival, even though the underlying mechanisms remain unclear. Preclinical and clinical evidence shows that the acute effects of a single exercise session can suppress the growth of various cancer cell lines in vitro. This suppression is potentially due to altered concentrations of hormones (e.g., insulin) and cytokines (e.g., tumor necrosis factor alpha and interleukin 6) after exercise. These factors, known to be involved in tumorigenesis, may explain why exercise is associated with reduced cancer incidence, recurrence, and mortality. However, the effects of short- (<8 weeks) and long-term (≥8 weeks) exercise programs on cancer cells have been reported with mixed results. Although more research is needed, it appears that interventions incorporating both exercise and diet seem to have greater inhibitory effects on cancer cell growth in both apparently healthy subjects as well as in cancer patients. Although speculative, these suppressive effects on cancer cells may be driven by changes in body weight and composition as well as by a reduction in low-grade inflammation often associated with sedentary behavior, low muscle mass, and excess fat mass in cancer patients. Taken together, such interventions could alter the systemic levels of suppressive circulating factors, leading to a less favorable environment for tumorigenesis. While regular exercise and a healthy diet may establish a more cancer-suppressive environment, each acute bout of exercise provides a further "dose" of anti-cancer medicine. Therefore, integrating regular exercise could potentially play a significant role in cancer management, highlighting the need for future investigations in this promising area of research.
    Keywords:  Aerobic training; Cancer cells; Cytokines; Hormones; Resistance training
    DOI:  https://doi.org/10.1016/j.jshs.2024.100994
  20. J Physiol. 2024 Oct 07.
      Prolonged passive heat treatment (PHT) has been suggested to trigger skeletal muscle adaptations that may improve muscle maintenance in older individuals. To assess the effects of PHT on skeletal muscle tissue capillarization, perfusion capacity, protein synthesis rates, hypertrophy and leg strength, 14 older adults (9 males, 5 females; 73 ± 6 years) underwent 8 weeks of PHT (infrared sauna: 3× per week, 45 min at ∼60°C). Before and after PHT we collected muscle biopsies to assess skeletal muscle capillarization and fibre cross-sectional area (CSA). Basal and postprandial muscle tissue perfusion kinetics and protein synthesis rates were assessed using contrast-enhanced ultrasound and primed continuous l-[ring-13C6]phenylalanine infusions, respectively. One-repetition maximum (1RM) leg strength and vastus lateralis muscle CSA were assessed. Type I and type II muscle fibre capillarization strongly increased following PHT (capillary-to-fibre perimeter exchange index: +31 ± 18 and +33 ± 30%, respectively; P < 0.001). No changes were observed in basal (0.24 ± 0.27 vs. 0.18 ± 0.11 AU; P = 0.266) or postprandial (0.20 ± 0.12 vs. 0.18 ± 0.14 AU; P = 0.717) microvascular blood flow following PHT. Basal (0.048 ± 0.014 vs. 0.051 ± 0.019%/h; P = 0.630) and postprandial (0.041 ± 0.012 vs. 0.051 ± 0.024%/h; P = 0.199) muscle protein synthesis rates did not change in response to prolonged PHT. Furthermore, no changes in vastus lateralis muscle CSA (15.3 ± 4.6 vs. 15.2 ± 4.6 cm2; P = 0.768) or 1RM leg strength (46 ± 12 vs. 47 ± 12 kg; P = 0.087) were observed over time. In conclusion, prolonged PHT increases muscle tissue capillarization but this does not improve muscle microvascular blood flow or increase muscle protein synthesis rates in healthy, older adults. Prolonged PHT does not induce skeletal muscle hypertrophy or increase leg strength in healthy, older adults. KEY POINTS: Repeated exposure to heat has been suggested to trigger skeletal muscle adaptive responses. We investigated the effect of 8 weeks of whole-body passive heat treatment (PHT; infrared sauna: 3× per week for 45 min at ∼60°C) on skeletal muscle tissue capillarization, perfusion capacity, basal, and postprandial muscle protein synthesis rates, muscle (fibre) hypertrophy, and leg strength in healthy, older adults. Prolonged PHT increases muscle tissue capillarization, but this does not improve muscle microvascular blood flow or increase muscle protein synthesis rates. Despite increases in muscle tissue capillarization, prolonged PHT does not suffice to induce skeletal muscle hypertrophy or increase leg strength in healthy, older adults.
    Keywords:  adaptation; ageing; blood pressure; glucose metabolism; heat stress; hypertrophy; mitochondrial content; mitochondrial function; stable isotope tracers; vascular conductance
    DOI:  https://doi.org/10.1113/JP286986
  21. Front Cell Dev Biol. 2024 ;12 1464815
      Nicotinamide adenine dinucleotide (NAD+) is crucial for cellular energy production, serving as a coenzyme in oxidation-reduction reactions. It also supports enzymes involved in processes such as DNA repair, aging, and immune responses. Lower NAD+ levels have been associated with various diseases, highlighting the importance of replenishing NAD+. Nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role in the NAD+ salvage pathway, which helps sustain NAD+ levels, particularly in high-energy tissues like skeletal muscle.This review explores how the NAMPT-driven NAD+ salvage pathway influences skeletal muscle health and functionality in aging, type 2 diabetes mellitus (T2DM), and skeletal muscle injury. The review offers insights into enhancing the salvage pathway through exercise and NAD+ boosters as strategies to improve muscle performance. The findings suggest significant potential for using this pathway in the diagnosis, monitoring, and treatment of skeletal muscle conditions.
    Keywords:  NAD+; NAMPT; T2DM; aging; skelelal muscle
    DOI:  https://doi.org/10.3389/fcell.2024.1464815
  22. Am J Physiol Cell Physiol. 2024 Oct 07.
      Human studies examining the cellular mechanisms behind sarcopenia, or age-related loss of skeletal muscle mass and function, have produced inconsistent results. A systematic review and meta-analysis were performed to determine the aging effects on protein expression, size and distribution of fibers with various myosin heavy chain (MyHC) isoforms. Study eligibility included MyHC comparisons between young (18-49 years) and older (≥ 60 years) adults, with 27 studies identified. Relative protein expression was higher with age for the slow-contracting MyHC I fibers, with correspondingly lower fast-contracting MyHC II and IIA values. Fiber sizes were similar with age for MyHC I, while smaller for MyHC II and IIA. Fiber distributions were similar with age. When separated by sex, the few studies that examined females showed atrophy of MyHC II and IIA fibers with age, but no change in MyHC protein expression. Additional analyses by measurement technique, physical activity, and muscle biopsied provided important insights. In summary, age-related atrophy in fast-contracting fibers lead to more of the slow-contracting, lower force-producing isoform in older male muscles, which helps explain their age-related loss in whole muscle force, velocity, and power. Exercise or pharmacological interventions that shift MyHC expression towards faster isoforms and/or increase fast-contracting fiber size should decrease the prevalence of sarcopenia. Our findings also indicate that future studies need to include or focus solely on females, measure MyHC IIA and IIX isoforms separately, examine fiber type distribution, sample additional muscles to the vastus lateralis, and incorporate an objective measurement of physical activity.
    Keywords:  MHC; aging; physical activity; sarcopenia; sex
    DOI:  https://doi.org/10.1152/ajpcell.00347.2024
  23. Front Aging Neurosci. 2024 ;16 1459134
       Background: Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer's disease (AD), alongside ß-amyloid deposition and the formation of neurofibrillary tangles. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, part of the innate immune system, has been implicated in the neuropathology of both preclinical amyloid and tau transgenic models. Activation of the NLRP3 pathway involves an initial priming step, which increases the expression of Nlrp3 and interleukin (IL)-1β, followed by the assembly of the NLRP3 inflammasome complex, comprising NLRP3, ASC, and caspase-1. This assembly leads to the proteolytic maturation of the pro-inflammatory cytokines IL-1β and IL-18. Additionally, the NLRP3 inflammasome induces Gasdermin D (GSDMD) cleavage, forming membrane pores through which IL-1β and IL-18 are secreted. Inhibition of NLRP3 has been shown to enhance plaque clearance by modulating microglial activation. Furthermore, blocking NLRP3 in tau transgenic mice has been found to reduce tau phosphorylation by affecting the activity of certain tau kinases and phosphatases.
    Methods: In this study, organotypic brain slice cultures from P301S transgenic mice were treated with lipopolysaccharide (LPS) plus nigericin as a positive control or exposed to tau seeds (K18) to evaluate NLRP3 inflammasome activation. The effect of tau seeding on NLRP3 activity was further examined using Meso Scale Discovery (MSD) assays to measure IL1β secretion levels in the presence and absence of NLRP3 inhibitors. The role of NLRP3 activity was investigated in full-body Nlrp3 knockout mice crossbred with the tau transgenic P301S model. Additionally, full-body and microglia-selective Gsdmd knockout mice were crossbred with P301S mice, and tau pathology and neurodegeneration were evaluated at early and late stages of the disease using immunohistochemistry and biochemical assays.
    Results: Activation of the NLRP3 pathway was observed in the mouse organotypic slice culture (OSC) model following stimulation with LPS and nigericin or exposure to tau seeds. However, Nlrp3 deficiency did not mitigate tauopathy or neurodegeneration in P301S mice in vivo, showing only a minor effect on plasma neurofilament (NF-L) levels. Consistently, Gsdmd deficiency did not alter tau pathology in P301S mice. Furthermore, neither full-body nor microglia-selective Gsdmd deletion had an impact on neuronal pathology or the release of pro-inflammatory cytokines.
    Conclusion: The absence of key components of the NLRP3 inflammasome pathway did not yield a beneficial effect on tau pathology or neurodegeneration in the preclinical Tau-P301S mouse model of AD. Nonetheless, organotypic slice cultures could serve as a valuable ex vivo mechanistic model for evaluating NLRP3 pathway activation and pharmacological inhibitors.
    Keywords:  GSDMD; NLRP3; OSCs; P301S; neurodegeneration and tau pathology
    DOI:  https://doi.org/10.3389/fnagi.2024.1459134
  24. Brain Nerve. 2024 Oct;76(10): 1127-1135
      Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by a mitochondrial DNA mutation that leads to defective taurine modification of the leucine tRNA anticodon, with consequent impaired translation of the UUG codon. This defect reduces synthesis of respiratory chain complexes, which causes energy failure. Taurine supplementation improved mitochondrial function in MELAS model cells. A physician-initiated clinical trial reported that high-dose taurine supplementation therapy suppressed stroke-like episodes and improved taurine modification rates in leukocytes.
    DOI:  https://doi.org/10.11477/mf.1416202748
  25. BMJ Open Sport Exerc Med. 2024 ;10(4): e001878
       Objectives: This study aimed to evaluate the effects of a novel, low-volume combined high-intensity interval training (HIIT) and progressive resistance training (PRT) in overweight/obese adults.
    Methods: This randomised control trial compared the effect of regular supervised HIIT combined with PRT (Exercise) with an unsupervised stretching intervention (Control), in previously inactive adults with either normal glucose (NG), pre-diabetes or type 2 diabetes (T2DM) with body mass index of >25 kg/m2. Participants were randomly allocated (1:1) to receive low-volume exercise or control by an online randomisation tool. The primary outcome was the difference in change of hepatic steatosis between Exercise and Control. A prespecified sensitivity analysis was undertaken for weight stable participants (<5% change in bodyweight from baseline). Secondary outcomes were change in hepatic steatosis within the glucose groups, glycaemic control, cardiorespiratory fitness, muscle strength and body composition.
    Results: Between June 2018 and May 2021, 162 participants were randomly assigned (NG: 76, pre-diabetes: 60, T2DM: 26) and 144 were included in the final analysis. Mean absolute change in hepatic steatosis was -1.4% (4.9) in Exercise (n=73) and -0.1% (7.2) in Control (n=71)(p=0.25). By preplanned sensitivity analysis, the mean change in hepatic steatosis with Exercise (n=70) was -1.5% (5) compared with 0.7% (4.6) with Control (n=61) (p=0.017). Subgroup analysis within the glucose groups showed that exercise reduced hepatic steatosis in those with pre-diabetes but not NG or T2DM (pre-diabetes: -1.2% (4.4) in Exercise and 1.75% (5.7) in Control, p=0.019).
    Conclusion: These findings show that low-volume HIIT with PRT yields improvements in muscle strength and cardiorespiratory fitness and may have a small effect on hepatic steatosis.
    Trial registration number: The trial was prospectively registered with the ANZCTR (ACTRN12617000552381).
    Keywords:  Diabetes; Exercise; Liver; Obesity
    DOI:  https://doi.org/10.1136/bmjsem-2023-001878