bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024‒04‒21
24 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

  1. Front Physiol. 2024 ;15 1404454
    Keywords:  butanediol; exogenous ketone; ketogenic diet; ketone ester; ketone infusion; ketosis
  2. Front Endocrinol (Lausanne). 2024 ;15 1400206
    Keywords:  adverse (side) effects; animal model; betahydroxybutyrate (BHB); fatty acids (FA); ketogenic diet (KD); ketogenic diets; ketones
  3. Aging (Albany NY). 2024 Apr 12. 16
      Studies suggest that ketogenic diets (KD) may improve memory in mouse models of aging and Alzheimer's disease (AD). This study determined whether a continuous or intermittent KD (IKD) enhanced cognitive behavior in the TgF344-AD rat model of AD. At 6 months-old, TgF344-AD and wild-type (WT) littermates were placed on a control (CD), KD, or IKD (morning CD and afternoon KD) provided as two meals per day for 2 or 6 months. Cognitive and motor behavior and circulating β-hydroxybutyrate (BHB), AD biomarkers and blood lipids were assessed. Animals on a KD diet had elevated circulating BHB, with IKD levels intermediate to CD and KD. TgF344-AD rats displayed impaired spatial learning memory in the Barnes maze at 8 and 12 months of age and impaired motor coordination at 12 months of age. Neither KD nor IKD improved performance compared to CD. At 12 months of age, TgF344-AD animals had elevated blood lipids. IKD reduced lipids to WT levels with KD further reducing cholesterol below WT levels. This study shows that at 8 or 12 months of age, KD or IKD intervention did not improve measures of cognitive or motor behavior in TgF344-AD rats; however, both IKD and KD positively impacted circulating lipids.
    Keywords:  Alzheimer’s disease; cognitive behavior; ketogenic diet; lipids; motor function
  4. BMJ Nutr Prev Health. 2023 ;6(2): 122-126
      Beta-hydroxybutyrate (D-BHB) is a metabolite with intrinsic signalling activity that has gained attention as a potentially clinically useful supplement. There are available supplements for inducing ketosis: ketone salts, ketone esters and medium-chain triglycerides. Even when all of them raise D-BHB in the blood and all are safe and well tolerated, they significantly differ in their safety profile, their palatability and their price. A fourth and potentially interesting option is to use biologically identical D-BHB, which it is already commercially available in the USA (American Ketone) and Greater China (MedPHA). However, its safety and tolerability had not yet been documented in the scientific literature. We evaluated the safety and tolerability of orally administered free D-BHB in a gender and age-balanced sample of 24 asymptomatic and overtly healthy adults. No participant showed acid-base abnormalities or electrolyte abnormalities. Secondary symptoms were reported after only 6.2% of all drink takes and none of the reports described the symptom as 'severe'. The most frequently reported secondary effects (19/720 or 2.6%) were gastrointestinal discomfort, headache (7/720 or 1%) and loss of appetite (7/720 or 1%). No correlation between weight-adjusted dose and frequency of secondary symptoms was observed. Free D-BHB was a safe and well-tolerated intervention for inducing sustained exogenous ketosis. Being bioidentical, salt-free and lacking intermediate metabolites, this form of supplementation could have a larger safety spectrum than salt or alcohol-based exogenous ketones. More research is warranted to assess its clinical efficacy in those clinical scenarios in which achieving ketosis rapidly could be beneficial.
    Keywords:  nutritional treatment
  5. Mol Aspects Med. 2024 Apr 15. pii: S0098-2997(24)00031-1. [Epub ahead of print]97 101272
      Ageing is associated with widespread physiological changes prominent within all tissues, including skeletal muscle and the brain, which lead to a decline in physical function. To tackle the growing health and economic burdens associated with an ageing population, the concept of healthy ageing has become a major research priority. Changes in skeletal muscle mitochondrial characteristics have been suggested to make an important contribution to the reductions in skeletal muscle function with age, and age-related changes in mitochondrial content, respiratory function, morphology, and mitochondrial DNA have previously been reported. However, not all studies report changes in mitochondrial characteristics with ageing, and there is increasing evidence to suggest that physical activity (or inactivity) throughout life is a confounding factor when interpreting age-associated changes. Given that physical activity is a potent stimulus for inducing beneficial adaptations to mitochondrial characteristics, delineating the influence of physical activity on the changes in skeletal muscle that occur with age is complicated. This review aims to summarise our current understanding and knowledge gaps regarding age-related changes to mitochondrial characteristics within skeletal muscle, as well as to provide some novel insights into brain mitochondria, and to propose avenues of future research and targeted interventions. Furthermore, where possible, we incorporate discussions of the modifying effects of physical activity, exercise, and training status, to purported age-related changes in mitochondrial characteristics.
  6. Nutr Res. 2024 Mar 21. pii: S0271-5317(24)00041-1. [Epub ahead of print]126 67-87
      Treatment adherence, defined as the degree to which the patient actively follows the plan of care, is very difficult for subjects undergoing ketogenic dietary therapies (KDTs). This is a relevant issue because adherence to dietary therapies is considered 1 of the primary determinants of the treatment's success. This paper aimed to review the literature evidence about KDT adherence according to age and diagnosis of patients. Performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method, this systematic review included clinical trials and observational studies. The risk of bias was assessed by the RoB 2.0 Cochrane tool and the quality of evidence according to the Mixed Methods Appraisal Tool system. Twenty-two articles were included, with more than half (n = 12) having average quality (2-3 stars). The studies' heterogeneity in measuring adherence and diagnosis made it difficult to compare results. Mean adherence rates were 71.5%, 66%, and 63.9% for children, adolescents, and adults, respectively. Adherence and compliance rates varied according to the follow-up period (79.7%, 66.7%, and 37.7% at 6, 24, and 36 months, respectively). The most frequent reasons for low adherence were linked to inefficacy in seizure control, adverse effects, food refusal, difficulty in preparing KDT meals or diet restrictiveness, lack of motivation, poor parental compliance, or cost of the diet. To conclude, there is a lack of standardized tools to measure adherence. Several studies highlighted the families' challenges in adhering to KDTs. These factors should be considered when creating strategies and resources on family education.
    Keywords:  Adherence; Compliance; Ketogenic diet; Ketosis; Systematic review; Treatment adherence
  7. Biochemistry (Mosc). 2024 Feb;89(2): 279-298
      An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process ("the mitochondrial hypothesis of aging"). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower - not higher - than in wildtype, thus apparently invalidating the "mitochondrial hypothesis of aging". We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wildtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + carnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly, even during active oxidative phosphorylation (as would be ongoing physiologically), higher ROS rates were seen in the mtDNA-mutator mitochondria than in wildtype. Thus, when examined under physiological conditions, mitochondrial ROS production rates are indeed increased in mtDNA-mutator mitochondria. While this does not prove the validity of the mitochondrial hypothesis of aging, it may no longer be said to be negated in this respect. This paper is dedicated to the memory of Professor Vladimir P. Skulachev.
    Keywords:  ROS production; aging; membrane potential; mtDNA mutator mice; oxidative phosphorylation; succinate
  8. Ann Nutr Metab. 2024 Apr 17.
      BACKGROUND: A major risk factor for neurodegenerative disorders is old age. Nutritional interventions that delay aging, such as calorie restriction (CR) and intermittent fasting (IF), as well as pharmaceuticals that affect the pathways linking nutrition and aging processes, have been developed in recent decades and have been shown to alleviate the effects of aging on the brain.SUMMARY: CR is accomplished by alternating periods of ad libitum feeding and fasting. In animal models, IF has been shown to increase lifespan and slow the progression and severity of age-related pathologies such as cardiovascular and neurodegenerative diseases and cancer. According to recent research, dietary changes can help older people with dementia retain brain function. However, the mechanisms underlying the neuroprotective effect of IF on the aging brain and related questions in this area of study (i.e., the potential of IF to treat neurodegenerative disorders) remain to be examined.
    KEY MESSAGES: This review addresses the hypothesis that IF may have translational potential in protecting the aged brain while summarizing the research supporting the putative neuroprotective mechanisms of IF in animal models. Additionally, given the emerging understanding of the connection between aging and dementia, our investigations may offer a fresh perspective on the use of dietary interventions for enhancing brain function and preventing dementia in elderly individuals. Finally, the absence of guidelines regarding the application of IF in patients hampers its broad utilization in clinical practice, and further studies are needed to improve our knowledge of the long-term effects of IF on dementia before it can be widely prescribed. In conclusion, IF may be an ancillary intervention for preserving memory and cognition in elderly individuals.
  9. Biochim Biophys Acta Mol Basis Dis. 2024 Apr 15. pii: S0925-4439(24)00161-3. [Epub ahead of print] 167172
      The skeletal muscle is a metabolically heterogeneous tissue that plays a key role in maintaining whole-body glucose homeostasis. It is well known that muscle insulin resistance (IR) precedes the development of type 2 diabetes. There is a consensus that the accumulation of specific lipid species in the tissue can drive IR. However, the role of the mitochondrial fatty-acid β-oxidation in IR and, consequently, in the control of glucose uptake remains paradoxical: interventions that either inhibit or activate fatty-acid β-oxidation have been shown to prevent IR. We here discuss the current theories and evidence for the interplay between β-oxidation and glucose uptake in IR. To address the underlying intricacies, we (1) dive into the control of glucose uptake fluxes into muscle tissues using the framework of Metabolic Control Analysis, and (2) disentangle concepts of flux and catalytic capacities taking into account skeletal muscle heterogeneity. Finally, we speculate about hitherto unexplored mechanisms that could bring contrasting evidence together. Elucidating how β-oxidation is connected to muscle IR and the underlying role of muscle heterogeneity enhances disease understanding and paves the way for new treatments for type 2 diabetes.
    Keywords:  Diabetes; Fatty-acid β-oxidation; Glucose metabolism; Insulin resistance; Mitochondria
  10. JACC Heart Fail. 2024 Apr 03. pii: S2213-1779(24)00182-3. [Epub ahead of print]
    PRESERVED-HF Investigators
      BACKGROUND: Although sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF.OBJECTIVES: The goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF.
    METHODS: Targeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed.
    RESULTS: The mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro-B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro-B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction.
    CONCLUSIONS: Leveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235).
    Keywords:  SGLT2i; acylcarnitine; branched-chain amino acids; heart failure with preserved ejection fraction; ketone bodies; metabolomics
  11. Neurochem Int. 2024 Apr 17. pii: S0197-0186(24)00072-X. [Epub ahead of print] 105745
      Maintaining an optimum microbial community within the gastrointestinal tract is intricately linked to human metabolic, immune and brain health. Disturbance to these microbial populations perturbs the production of vital bioactive compounds synthesised by the gut microbiome, such as short-chain fatty acids (SCFAs). Of the SCFAs, butyrate is known to be a major source of energy for colonocytes and has valuable effects on the maintenance of intestinal epithelium and blood brain barrier integrity, gut motility and transit, anti-inflammatory effects, and autophagy induction. Inducing endogenous butyrate production is likely to be beneficial for gut-brain homeostasis and for optimal neuronal function. For these reasons, butyrate has gained interest as a potential therapy for not only metabolic and immunological disorders, but also conditions related to the brain, including neurodegenerative diseases. While direct and indirect sources of butyrate, including prebiotics, probiotics, butyrate pro-drugs and glucosidase inhibitors, offer a promising therapeutic avenue, their efficacy and dosage in neurodegenerative conditions remain largely unknown. Here, we review current literature on effects of butyrate relevant to neuronal function, the impact of butyrate in a range of neurodegenerative diseases and related treatments that may have potential for the treatment of neurodegenerative diseases.
    Keywords:  butyrate; gut microbiome; neurodegenerative disease; prebiotic; probiotic; short-chain fatty acids
  12. Curr Nutr Rep. 2024 Apr 16.
      PURPOSE OF REVIEW: Time-restricted eating (TRE), a form of intermittent fasting, restricts feeding time across the day, imposing a daily 'eating window'. The time of day when the eating window occurs could result in differential metabolic effects. Here, we describe recent intervention studies in humans assessing the metabolic consequences of an early- (i.e., eating window starting in the early morning) vs. late (i.e., eating window starting after midday)-TRE protocol.RECENT FINDINGS: Well-controlled studies indicate that both TRE protocols effectively reduce body weight and improve altered glucose metabolism, lipid profile, inflammation, or blood pressure levels. An early-TRE (e-TRE) might have a further positive impact on improving blood glucose, insulin levels, and insulin resistance. However, the studies directly assessing the metabolic consequences of an early- vs. late-TRE have shown dissimilar findings, and more well-controlled clinical trials are needed on the metabolic benefits of these two types of TRE. Evidence suggests that an e-TRE might have enhanced metabolic results, particularly regarding glucose homeostasis. More long-term studies, including larger sample sizes, are needed to assess the metabolic, circadian, and adherence benefits, together with socio-cultural acceptance of both TRE approaches.
    Keywords:  Early time-restricted eating; Glucose homeostasis; Intermittent fasting; Late time-restricted eating; Obesity; Weight loss
  13. J Int Soc Sports Nutr. 2024 Dec;21(1): 2341903
      Protein supplementation often refers to increasing the intake of this particular macronutrient through dietary supplements in the form of powders, ready-to-drink shakes, and bars. The primary purpose of protein supplementation is to augment dietary protein intake, aiding individuals in meeting their protein requirements, especially when it may be challenging to do so through regular food (i.e. chicken, beef, fish, pork, etc.) sources alone. A large body of evidence shows that protein has an important role in exercising and sedentary individuals. A PubMed search of "protein and exercise performance" reveals thousands of publications. Despite the considerable volume of evidence, it is somewhat surprising that several persistent questions and misconceptions about protein exist. The following are addressed: 1) Is protein harmful to your kidneys? 2) Does consuming "excess" protein increase fat mass? 3) Can dietary protein have a harmful effect on bone health? 4) Can vegans and vegetarians consume enough protein to support training adaptations? 5) Is cheese or peanut butter a good protein source? 6) Does consuming meat (i.e., animal protein) cause unfavorable health outcomes? 7) Do you need protein if you are not physically active? 8) Do you need to consume protein ≤ 1 hour following resistance training sessions to create an anabolic environment in skeletal muscle? 9) Do endurance athletes need additional protein? 10) Does one need protein supplements to meet the daily requirements of exercise-trained individuals? 11) Is there a limit to how much protein one can consume in a single meal? To address these questions, we have conducted a thorough scientific assessment of the literature concerning protein supplementation.
    Keywords:  Erogenic aid; exercise; performance; supplement
  14. BMC Cardiovasc Disord. 2024 Apr 16. 24(1): 210
      BACKGROUND: Cardiovascular disease continues to be a leading cause of mortality worldwide, highlighting the need to explore innovative approaches to improve cardiovascular health outcomes. Time-restricted fasting (TRF) is a dietary intervention that involves limiting the time window for food consumption. It has gained attention for its potential benefits on metabolic health and weight management. This study aims to investigate the impact of TRF on key risk factors, including body weight, glucose metabolism, blood pressure, and lipid profile.METHODS: We conducted a systematic search in five databases (Scopus, Embase, PubMed, Cochrane, and Web of Science) for relevant studies up to January 2023. After applying inclusion criteria, 12 studies were eligible for analysis. Quality assessment was conducted using the ROB-2.0 tool and ROBINS-I. Risk of bias was mapped using Revman 5.3, and data analysis included Hartung-Knapp adjustment using R 4.2.2.
    RESULTS: The group that underwent the TRF intervention exhibited a significant decrease in body weight (SMD: -0.22; 95%CI: -0.41, -0.04; P < 0.05) and fat mass (SMD: -0.19; 95%CI: -0.36, -0.02; P < 0.05), while maintaining lean mass (SMD: -0.09; 95%CI: -0.08, 0.26; P > 0.05).
    CONCLUSION: TRF has shown potential as a treatment strategy for reducing total body weight by targeting adipose tissue, with potential improvements in cardiometabolic function.
    Keywords:  Cardiovascular disease; Meta-analysis; Rhythm; Time-restricted fasting; Weight loss
  15. Cardiovasc Res. 2024 Apr 16. pii: cvae071. [Epub ahead of print]
      AIM: The activation of Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in endothelial cells (ECs) contributes to vascular inflammation in atherosclerosis. Considering the high glycolytic rate of ECs, we delineated whether and how glycolysis determines endothelial NLRP3 inflammasome activation in atherosclerosis.METHODS AND RESULTS: Our results demonstrated a significant upregulation of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), a key regulator of glycolysis, in human and mouse atherosclerotic endothelium, which positively correlated with NLRP3 levels. Atherosclerotic stimuli upregulated endothelial PFKFB3 expression via sterol regulatory element binding protein 2 (SREBP2) transactivation. EC-selective haplodeficiency of Pfkfb3 in Apoe-/- mice resulted in reduced endothelial NLRP3 inflammasome activation and attenuation of atherogenesis. Mechanistic investigations revealed that PFKFB3-driven glycolysis increased the NADH content and induced oligomerization of C-terminal binding protein 1 (CtBP1), an NADH-sensitive transcriptional co-repressor. The monomer form, but not the oligomer form, of CtBP1 was found to associate with the transcriptional repressor Forkhead box P1 (FOXP1) and acted as a transrepressor of inflammasome components, including NLRP3, caspase-1, and interleukin-1β (IL-1β). Interfering with NADH-induced CtBP1 oligomerization restored its binding to FOXP1 and inhibited the glycolysis-dependent upregulation of NLRP3, Caspase-1, and IL-1β. Additionally, EC-specific overexpression of NADH-insensitive CtBP1 alleviates atherosclerosis.
    CONCLUSIONS: Our findings highlight the existence of a glycolysis-dependent NADH/CtBP/FOXP1-transrepression pathway that regulates endothelial NLRP3 inflammasome activation in atherogenesis. This pathway represents a potential target for selective PFKFB3 inhibitors or strategies aimed at disrupting CtBP1 oligomerization to modulate atherosclerosis.
    Keywords:  FOXP1; NLRP3 inflammasome; PFKFB3; endothelial cell; glycolysis
  16. Compr Rev Food Sci Food Saf. 2024 May;23(3): e13342
      Mitochondrial dysfunction increasingly becomes a target for promoting healthy aging and longevity. The dysfunction of mitochondria with age ultimately leads to a decline in physical functions. Among them, biogenesis dysfunction and the imbalances in the metabolism of reactive oxygen species and mitochondria as signaling organelles in the aging process have aroused our attention. Dietary intervention in mitochondrial dysfunction and physical decline during aging processes is essential, and greater attention should be directed toward healthful legume intake. Legumes are constantly under investigation for their nutritional and bioactive properties, and their consumption may yield antiaging and mitochondria-protecting benefits. This review summarizes mitochondrial dysfunction with age, discusses the benefits of legumes on mitochondrial function, and introduces the potential role of legumes in managing aging-related physical decline. Additionally, it reveals the benefits of legume intake for the elderly and offers a viable approach to developing legume-based functional food.
    Keywords:  aging; bioactive; legumes; mitochondria; nutrition
  17. Biosci Rep. 2024 Apr 16. pii: BSR20231918. [Epub ahead of print]
      Parasitic diseases are a serious global health concern, causing many common and severe infections, including Chagas disease, leishmaniasis,and schistosomiasis. The NLRP3 inflammasome belongs to the NLR (nucleotide-binding domain leucine-rich-repeat-containing proteins) family, which are cytosolic proteins playing key roles in the detection of pathogens. NLRP3 inflammasomes are activated in immune responses to Plasmodium,Leishmania, Toxoplasma gondii, Entamoeba histolytica,Trypanosoma cruzi and other parasites. The role of NLRP3 is not fully understood, but it is a crucial component of the innate immune response to parasitic infections and its functions as a sensor triggering the inflammatory response to the invasive parasites. However, while this response can limit the parasites' growth, it can also result in potentially catastrophic host pathology. This makes it essential to understand how NLRP3 interacts with parasites to initiate the inflammatory response. Plasmodium hemozoin, Leishmania glycoconjugate lipophosphoglycan (LPG) and E. histolytica Gal/GalNAc lectin can stimulate NLRP3 activation, while the dense granule protein 9 (GRA9) of T. gondii has been shown to suppress it. Several other parasitic products also have diverse effects on NLRP3 activation. Understanding the mechanism of NLRP3 interaction with these products will help to develop advanced therapeutic approaches to treat parasitic diseases. This review summarizes current knowledge of the NLRP3 inflammasome's action on the immune response to parasitic infections and aims to determine the mechanisms through which parasitic molecules either activate or inhibit its action.
    Keywords:  Helminths; NLRP3 Inflammasomes; Plasmodium; T. gondii; Trypanosome cruzi
  18. J Appl Physiol (1985). 2024 Apr 18.
      Chronic testosterone (T) substitution and short-term T administration positively affect protein metabolism, however, data on acute effects in humans are sparse. This study aimed to investigate T's acute effects on whole-body protein metabolism in hypogonadal and eugonadal conditions. We designed a randomized, double-blind, placebo-controlled, crossover study, including twelve healthy young males. Whole-body protein metabolism was evaluated during 1) eugonadism, and after medically-induced hypogonadism, with application of a gel on each trial day containing either 2) placebo, 3) T 50 mg, or 4) T 150 mg; under basal (5h basal period) and insulin-stimulated conditions (3h clamp). The main outcome measure was change in net protein balance. The net protein loss was 62% larger in the placebo-treated hypogonadal state compared with the eugonadal state during the basal period (-5.5 ±3.5 µmol/kg/h versus -3.4 ± 1.2 µmol/kg/h, p=0.038), but not during the clamp (p=0.06). Also, hypogonadism resulted in a 25% increase in whole-body urea flux (p=0.006). However, T did not result in any significant changes in protein breakdown, synthesis, or net balance during either the basal period or clamp (all p > 0.05). Protein breakdown was reduced during clamp compared to the basal period regardless of gonadal status or T exposure (all p≤0.001). In conclusion, the application of transdermal T did not counteract the negative effects of hypogonadism with no effects on protein metabolism within five hours of administration. Insulin (during clamp) mitigated the effects of hypogonadism. This study is the first to investigate acute protein-metabolic effects of T in hypogonadal men.
    Keywords:  Hypogonadism; Protein Metabolism; Randomized Controlled Trial; Testosterone
  19. J Cardiothorac Surg. 2024 Apr 15. 19(1): 208
      BACKGROUND: Cardiac fibroblasts (CFs) are activated after initial injury, and then differentiate into myofibroblasts (MFs), which play a pivotal role as the primary mediator cells in pathological remodeling. Sodium butyrate (NaB), being a metabolite of gut microbiota, exhibits anti-inflammatory property in local therapies on sites other than the intestine. Thus, this study aimed to probe the mechanism by which NaB regulates CFs transdifferentiation through the NLRP3/Caspase-1 pyroptosis pathway.METHODS: CFs were cultured in vitro and induced into MFs by TGFβ1. CFs were identified by immunofluorescence labelling technique of vimentin and α-SMA, followed by treatment with NaB or NLRP3 inflammasome inhibitor (CY-09) and its activator [nigericin sodium salt (NSS)]. The expression levels of α-SMA, GSDMD-N/NLRP3/cleaved Caspase-1 proteins, and inflammatory factors IL-1β/IL-18/IL-6/IL-10 were determined using immunofluorescence, Western blot and ELISA. Cell proliferation and migration were evaluated using the CCK-8 assay and the cell scratch test, respectively.
    RESULTS: Following the induction of TGFβ1, CFs exhibited increased expression levels of α-SMA proteins and IL-6/IL-10, as well as cell proliferative and migratory abilities. TGFβ1 induced CFs to differentiate into MFs, while NaB inhibited this differentiation. NaB inactivated the NLRP3/Caspase-1 pyroptosis pathway. CY-09 demonstrated inhibitory effects on the NLRP3/Caspase-1 pyroptosis pathway, leading to a reduction in TGFβ1-induced CFs transdifferentiation. NSS activated the NLRP3/Caspase-1 pyroptosis pathway, and thus partially counteracting the inhibitory effect of intestinal microbiota metabolite NaB on CFs transdifferentiation.
    CONCLUSION: NaB, a metabolite of the gut microbiota, inhibited the activation of the NLRP3/Caspase-1 pyroptosis pathway in TGFβ1-induced CFs, repressed the transdifferentiation of CFs into MFs.
    Keywords:  Cardiac fibroblasts; Caspase-1; Cell pyroptosis; Gut microbiota metabolite sodium butyrate; Myofibroblasts; NLRP3 inflammasomes; TGFβ1; α-SMA
  20. Neuropharmacology. 2024 Apr 16. pii: S0028-3908(24)00119-9. [Epub ahead of print]252 109950
      Effective therapeutic interventions for elderly patients are lacking, despite advances in pharmacotherapy. Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases.
    Keywords:  Aging; Cognitive function; Mitochondrial function; NLRP3; Neuroinflammation; mUro A
  21. Life Sci. 2024 Apr 11. pii: S0024-3205(24)00217-0. [Epub ahead of print] 122627
      A high mortality rate makes hepatocellular carcinoma (HCC) a difficult cancer to treat. When surgery is not possible, liver cancer patients are treated with chemotherapy. However, HCC management and treatment are difficult. Sorafenib, which is a first-line treatment for hepatocellular carcinoma, initially slows disease progression. However, sorafenib resistance limits patient survival. Recent studies have linked HCC to programmed cell death, which has increased researcher interest in therapies targeting cell death. Pyroptosis, which is an inflammatory mode of programmed cell death, may be targeted to treat HCC. Pyroptosis pathways, executors, and effects are examined in this paper. This review summarizes how pyroptosis affects the tumor microenvironment (TME) in HCC, including the role of cytokines such as IL-1β and IL-18 in regulating immune responses. The use of chemotherapies and their ability to induce cancer cell pyroptosis as alternative treatments and combining them with other drugs to reduce side effects is also discussed. In conclusion, we highlight the potential of inducing pyroptosis to treat HCC and suggest ways to improve patient outcomes. Studies on cancer cell pyroptosis may lead to new HCC treatments.
    Keywords:  Hepatocellular carcinoma (HCC); Pyroptosis; Tumor microenvironment (TME)
  22. Free Radic Res. 2024 Apr 17. 1-18
      Calorie restriction is a nutritional intervention that reproducibly protects against the maladaptive consequences of cardiovascular diseases. Pathological cardiac hypertrophy leads to cellular growth, dysfunction (with mitochondrial dysregulation), and oxidative stress. The mechanisms behind the cardiovascular protective effects of calorie restriction are still under investigation. In this study, we show that this dietetic intervention prevents cardiac protein elevation, avoids fetal gene reprogramming (atrial natriuretic peptide), and blocks the increase in heart weight per tibia length index (HW/TL) seen in isoproterenol-induced cardiac hypertrophy. Our findings suggest that calorie restriction inhibits cardiac pathological growth while also lowering mitochondrial reverse electron transport-induced hydrogen peroxide formation and improving mitochondrial content. Calorie restriction also attenuated the opening of the Ca2+-induced mitochondrial permeability transition pore. We also found that calorie restriction blocked the negative correlation of antioxidant enzymes (superoxide dimutase and glutatione peroxidase activity) and HW/TL, leading to the maintenance of protein sulphydryls and glutathione levels. Given the nature of isoproterenol-induced cardiac hypertrophy, we investigated whether calorie restriction could alter cardiac beta-adrenergic sensitivity. Using isolated rat hearts in a Langendorff system, we found that calorie restricted hearts have preserved beta-adrenergic signaling. In contrast, hypertrophic hearts (treated for seven days with isoproterenol) were insensitive to beta-adrenergic activation using isoproterenol (50 nM). Despite protecting against cardiac hypertrophy, calorie restriction did not alter the lack of responsiveness to isoproterenol in isolated hearts harvested from isoproterenol-treated rats. These results suggest (through a series of mitochondrial, oxidative stress, and cardiac hemodynamic studies) that calorie restriction possesses beneficial effects against hypertrophic cardiomyopathy.
    Keywords:  Mitochondria; adrenergic signaling; calorie restriction; cardiac hypertrophy; oxidative stress
  23. Immun Inflamm Dis. 2024 Apr;12(4): e1241
      BACKGROUND: Inflammation in adipose tissue, resulting from imbalanced caloric intake and energy expenditure, contributes to the metabolic dysregulation observed in obesity. The production of inflammatory cytokines, such as IL-1β and IL-18, plays a key role in this process. While IL-1β promotes insulin resistance and diabetes, IL-18 regulates energy expenditure and food intake. Previous studies have suggested that caspase-1, activated by the Nlrp3 inflammasome in response to lipid excess, mediates IL-1β production, whereas activated by the Nlrp1b inflammasome in response to energy excess, mediates IL-18 production. However, this has not been formally tested.METHODS: Wild-type and caspase-1-deficient Balb/c mice, carrying the Nlrp1b1 allele, were fed with regular chow or a high-fat diet for twelve weeks. Food intake and mass gain were recorded weekly. At the end of the twelve weeks, glucose tolerance and insulin resistance were evaluated. Mature IL-18 protein levels and the inflammatory process in the adipose tissue were determined. Fasting lipid and cytokine levels were quantified in the sera of the different experimental groups.
    RESULTS: We found that IL-18 production in adipose tissue is independent of caspase-1 activity, regardless of the metabolic state, while Nlrp3-mediated IL-1β production remains caspase-1 dependent. Additionally, caspase-1 null Balb/c mice did not develop metabolic abnormalities in response to energy excess from the high-fat diet.
    CONCLUSION: Our findings suggest that IL-18 production in the adipose tissue is independent of Nlrp3 inflammasome and caspase-1 activation, regardless of caloric food intake. In contrast, Nlrp3-mediated IL-1β production is caspase-1 dependent. These results provide new insights into the mechanisms underlying cytokine production in the adipose tissue during both homeostatic conditions and metabolic stress, highlighting the distinct roles of caspase-1 and the Nlrp inflammasomes in regulating inflammatory responses.
    Keywords:  adipose tissue; animals; cytokines; diabetes; inflammation; macrophage; molecules