bims-kimdis 2023-07-02 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–07–02
twenty-six papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Ketogenic diet in cancer: insufficient stress response?
Ketogenic Diet and Ketone Bodies as Clinical Support for the Treatment of SARS-CoV-2-Review of the Evidence.
Ketosis and migraine: a systematic review of the literature and meta-analysis.
The Impact of a Very-Low-Calorie Ketogenic Diet in the Gut Microbiota Composition in Obesity.
Unrestricted Ketogenic Diet Feeding Enhances Epithelial Ovarian Cancer Growth In Vivo.
Posttranslational modifications of NLRP3 and their regulatory roles in inflammasome activation.
Oral 3-hydroxybuturate ingestion acutely lowers circulating testosterone concentrations in healthy young males.
The effect of dietary approaches to stop hypertension and ketogenic diets intervention on serum uric acid concentration: a systematic review and meta-analysis of randomized controlled trials.
Intermittent Fasting Sustainably Improves Glucose Tolerance in Normal Weight Male Mice Through Histone Hyperacetylation.
Ketogenic therapy in childhood and adolescence: recommendations of the Brazilian experts group.
The Lipogenic Enzyme Acetoacetyl-Coenzyme A Synthetase and Ketone Body Utilization for Denovo Lipid Synthesis, a Review.
Sodium butyrate promotes gastrointestinal development of preweaning bull calves via inhibiting inflammation, balancing nutrient metabolism, and optimizing microbial community functions.
Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension.
The NLRP3 inflammasome: contributions to inflammation-related diseases.
Case report: KETOLAND the psychoeducation program for ketogenic diet.
mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.
Effect of an acute long-duration exercise bout on skeletal muscle lipid droplet morphology, GLUT 4 protein, and perilipin protein expression.
Sodium butyrate facilitates CRHR2 expression to alleviate HPA axis hyperactivity in autism-like rats induced by prenatal lipopolysaccharides through histone deacetylase inhibition.
Improving Mitochondrial Function in Skeletal Muscle Contributes to the Amelioration of Insulin Resistance by Nicotinamide Riboside.
The Effect of Astaxanthin on Mitochondrial Dynamics in Rat Heart Mitochondria under ISO-Induced Injury.
Inflammatory Mediators of Endothelial Dysfunction.
Circadian mechanisms in adipose tissue bioenergetics and plasticity.
NLRP3 Inflammasome as Therapeutic Targets in Inflammatory Diseases.
How does exercise affect energy metabolism? An in silico approach for cardiac muscle.
Dietary Medium-Chain Fatty Acids Reduce Food Intake via the GDF15-GFRAL Axis in Mice.
Butyrate Protects Barrier Integrity and Suppresses Immune Activation in a Caco-2/PBMC Co-Culture Model While HDAC Inhibition Mimics Butyrate in Restoring Cytokine-Induced Barrier Disruption.

Nat Rev Endocrinol. 2023 Jun 30.

Ketogenic diet in cancer: insufficient stress response?

Shimona Starling.

DOI: https://doi.org/10.1038/s41574-023-00869-6
Viruses. 2023 05 27. pii: 1262. [Epub ahead of print]15(6):

Ketogenic Diet and Ketone Bodies as Clinical Support for the Treatment of SARS-CoV-2-Review of the Evidence.

Izabela Bolesławska, Magdalena Kowalówka, Natasza Bolesławska-Król, Juliusz Przysławski.

  One of the proposed nutritional therapies to support drug therapy in COVID-19 is the use of a ketogenic diet (KD) or ketone bodies. In this review, we summarized the evidence from tissue, animal, and human models and looked at the mechanisms of action of KD/ketone bodies against COVID-19. KD/ketone bodies were shown to be effective at the stage of virus entry into the host cell. The use of β-hydroxybutyrate (BHB), by preventing the metabolic reprogramming associated with COVID-19 infection and improving mitochondrial function, reduced glycolysis in CD4+ lymphocytes and improved respiratory chain function, and could provide an alternative carbon source for oxidative phosphorylation (OXPHOS). Through multiple mechanisms, the use of KD/ketone bodies supported the host immune response. In animal models, KD resulted in protection against weight loss and hypoxemia, faster recovery, reduced lung injury, and resulted in better survival of young mice. In humans, KD increased survival, reduced the need for hospitalization for COVID-19, and showed a protective role against metabolic abnormalities after COVID-19. It appears that the use of KD and ketone bodies may be considered as a clinical nutritional intervention to assist in the treatment of COVID-19, despite the fact that numerous studies indicate that SARS-CoV-2 infection alone may induce ketoacidosis. However, the use of such an intervention requires strong scientific validation.

Keywords:  COVID-19; SARS-CoV-2; ketogenic diet; ketone bodies

DOI:  https://doi.org/10.3390/v15061262
Front Nutr. 2023 ;10 1204700

Ketosis and migraine: a systematic review of the literature and meta-analysis.

Lenycia de Cassya Lopes Neri, Cinzia Ferraris, Guido Catalano, Monica Guglielmetti, Ludovica Pasca, Elena Pezzotti, Adriana Carpani, Anna Tagliabue.

   Introduction: Headaches are a prevalent disorder worldwide, and there is compelling evidence that certain dietary interventions could provide relief from attacks. One promising approach is ketogenic therapy, which replaces the brain's glucose fuel source with ketone bodies, potentially reducing the frequency or severity of headaches.
Aim: This study aims to conduct a systematic review of the scientific literature on the impact of ketosis on migraine, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method.
Results: After a careful selection process and bias evaluation, 10 articles were included in the review, primarily from Italy. The bias assessment indicated that 50% of the selected articles had a low risk of bias in all domains, with the randomization process being the most problematic domain. Unfortunately, the evaluation of ketosis was inconsistent between articles, with some assessing ketonuria, some assessing ketonemia, and some not assessing ketosis levels at all. Therefore, no association could be made between the level of ketosis and the prevention or reduction of migraine attacks. The ketogenic therapies tested in migraine treatments included the very low-calorie ketogenic diet (VLCKD, n = 4), modified Atkins diet (MAD, n = 3), classic ketogenic diet (cKDT, n = 2), and the administration of an exogenous source of beta-hydroxybutyrate (BHB). The meta-analysis, despite reporting high heterogeneity, found that all interventions had an overall significant effect (Z = 9.07, p < 0.00001; subgroup differences, Chi2 = 9.19, dif = 3, p = 0.03; I2, 67.4%), regardless of the type of endogenous or exogenous induction of ketosis.
Conclusion: The initial findings of this study suggest that metabolic ketogenic therapy may provide some benefit in treating migraines and encourage further studies, especially randomized clinical trials with appropriate and standardized methodologies. The review strongly recommends the use of the adequate measurement of ketone levels during ketogenic therapy to monitor adherence to the treatment and improve knowledge of the relationship between ketone bodies and efficacy.
Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022330626.

Keywords:  ketogenic diet; ketosis; meta-analysis; migraine disorders; systematic review

DOI:  https://doi.org/10.3389/fnut.2023.1204700
Nutrients. 2023 Jun 13. pii: 2728. [Epub ahead of print]15(12):

The Impact of a Very-Low-Calorie Ketogenic Diet in the Gut Microbiota Composition in Obesity.

Ana Karina Zambrano, Santiago Cadena-Ullauri, Patricia Guevara-Ramírez, Evelyn Frias-Toral, Viviana A Ruiz-Pozo, Elius Paz-Cruz, Rafael Tamayo-Trujillo, Sebastián Chapela, Martha Montalván, Gerardo Sarno, Claudia V Guerra, Daniel Simancas-Racines.

  The very-low-calorie KD (VLCKD) is characterized by a caloric intake of under 800 kcal/day divided into less than 50 g/day of carbohydrate (13%) and 1 to 1.5 g of protein/kg of body weight (44%) and 43% of fat. This low carbohydrate intake changes the energy source from glucose to ketone bodies. Moreover, clinical trials have consistently shown a beneficial effect of VLCKD in several diseases, such as heart failure, schizophrenia, multiple sclerosis, Parkinson's, and obesity, among others. The gut microbiota has been associated with the metabolic conditions of a person and is regulated by diet interactions; furthermore, it has been shown that the microbiota has a role in body weight homeostasis by regulating metabolism, appetite, and energy. Currently, there is increasing evidence of an association between gut microbiota dysbiosis and the pathophysiology of obesity. In addition, the molecular pathways, the role of metabolites, and how microbiota modulation could be beneficial remain unclear, and more research is needed. The objective of the present article is to contribute with an overview of the impact that VLCKD has on the intestinal microbiota composition of individuals with obesity through a literature review describing the latest research regarding the topic and highlighting which bacteria phyla are associated with obesity and VLCKD.

Keywords:  nutrition; obesity; very-low-calorie ketogenic diet; weight loss

DOI:  https://doi.org/10.3390/nu15122728
Nutrients. 2023 Jun 13. pii: 2730. [Epub ahead of print]15(12):

Unrestricted Ketogenic Diet Feeding Enhances Epithelial Ovarian Cancer Growth In Vivo.

Mariam M AlHilli, Emily E Rhoades, Danielle Chau, Surabhi Tewari, Adrian Reich, Alex Myers, Daniel J Lindner, Justin D Lathia, Renliang Zhang, Belinda Willard, Gail Cresci, Nathan A Berger, Ofer Reizes.

  The ketogenic diet (KD) is hypothesized to impact tumor progression by altering tumor metabolism. In this study, we assessed the impact of an unrestricted KD on epithelial ovarian cancer (EOC) tumor growth, gene expression, and metabolite concentration in a mouse model. ID8 EOC cells, which were syngeneic with C57Bl/6J mouse strain and transfected with luciferase (ID8-luc), were injectedand monitored for tumor development. Female mice were fed either a strict KD, a high fat/low carbohydrate (HF/LC) diet, or a low fat/high carbohydrate (LF/HC) diet (n = 10 mice per group) ad libitum. EOC tumor growth was monitored weekly, and tumor burden was determined based on luciferase fluorescence (photons/second). At the endpoint (42 days), tumors were collected and processed for RNA sequencing. Plasma and tumor metabolites were evaluated using LC-MS. The KD-fed mice exhibited a statistically significant increase in tumor progression in comparison to the HF/LC- and LF/HC-fed groups (9.1 vs. 2.0 vs. 3.1-fold, respectively, p < 0.001). The EOC tumors of the KD-fed mice exhibited significant enrichment of the peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid metabolism pathways based on the RNA sequencing analysis when compared to the LF/HC- and HF/LC-fed mice. Thus, unrestricted KD diet enhanced tumor progression in our mouse EOC model. KD was associated with the upregulation of fatty acid metabolism and regulation pathways, as well as enrichment of fatty acid and glutamine metabolites.

Keywords:  RNA sequencing; dietary intervention; high fat diet; ketone bodies; mice; ovarian cancer; tumor metabolism; tumor progression

DOI:  https://doi.org/10.3390/nu15122730
Eur J Immunol. 2023 Jun 29. e2350382

Posttranslational modifications of NLRP3 and their regulatory roles in inflammasome activation.

Ying Qin, Wei Zhao.

  The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is a multimolecular complex that plays a fundamental role in inflammation. Optimal activation of NLRP3 inflammasome is crucial for host defense against pathogens and the maintenance of immune homeostasis. Aberrant NLRP3 inflammasome activity has been implicated in various inflammatory diseases. Posttranslational modifications (PTMs) of NLRP3, a key inflammasome sensor, play critical roles in directing inflammasome activation and controlling the severity of inflammation and inflammatory diseases, such as arthritis, peritonitis, inflammatory bowel disease, atherosclerosis, and Parkinson's disease. Various NLRP3 PTMs, including phosphorylation, ubiquitination, and SUMOylation, could direct inflammasome activation and control inflammation severity by affecting the protein stability, ATPase activity, subcellular localization, and oligomerization of NLRP3 as well as the association between NLRP3 and other inflammasome components. Here, we provide an overview of the PTMs of NLRP3 and their roles in controlling inflammation and summarize potential anti-inflammatory drugs targeting NLRP3 PTMs.

Keywords:  NLRP3; inflammasome; inflammation; posttranslational modifications; ubiquitination

DOI:  https://doi.org/10.1002/eji.202350382
Scand J Med Sci Sports. 2023 Jun 28.

Oral 3-hydroxybuturate ingestion acutely lowers circulating testosterone concentrations in healthy young males.

Mads Svart, Mette Mølby Nielsen, Nikolaj Rittig, Mette Hansen, Niels Møller, Claus H Gravholt.

  Ketone bodies, such as 3-hydroxybutyrate (3-OHB), have been frequently used by endurance athletes, such as cyclists, to enhance performance and recovery and are recognized for their health benefits and therapeutic effects for decades. Testosterone is a potent regulator of red blood cell production. Evidence suggests that ketone bodies can increase the production of erythropoietin, which stimulates red blood cell production. Therefore, we investigated whether an acute increase in 3-OHB levels affects testosterone levels in healthy young men. We studied six healthy, young male participants who fasted overnight and were tested twice: (i) after drinking 37.5 g of Na-D/L-3-OHB dissolved in 500 mL of distilled water (KET), and (ii) after drinking 500 mL of placebo saline water (0.9% NaCl) (CTR). During the KET trial, 3-OHB levels increased to approximately 2.5 mM. Testosterone levels decreased significantly by 20% during KET compared to 3% during CTR. A simultaneous increase in luteinizing hormone was observed in KET. We observed no changes in other adrenal androgens, such as androstenedione and 11-keto androgens. In conclusion, an acute increase in 3-OHB levels decreases testosterone levels. Concomitantly, an increase in luteinizing hormone was observed. This suggests that 3-OHB may counteract some of the beneficial effects of endurance training. Further studies, involving larger sample sizes and performance outcomes, are required to fully understand this phenomenon.

Keywords:  3-hydroxybuturate; ketone bodies; muscle protein synthesis; testosterone; training

DOI:  https://doi.org/10.1111/sms.14441
Sci Rep. 2023 06 28. 13(1): 10492

The effect of dietary approaches to stop hypertension and ketogenic diets intervention on serum uric acid concentration: a systematic review and meta-analysis of randomized controlled trials.

Sepehr Gohari, Saeed Ghobadi, Alireza Jafari, Hassan Ahangar, Sheida Gohari, Mahsa Mahjani.

Hyperuricemia as a risk factor for metabolic diseases is proved to be profoundly modified by dietary approaches. This systematic review and meta-analysis of randomized control trials (RCT) was conducted to investigate the effect of two nutritional interventions; dietary approaches to stop hypertension (DASH) diet and ketogenic diet (KD) on serum uric acid (UA) concentrations. Our systematic search was for RCTs in which KD or DASH diet were assigned to adults for at least 2 weeks or more. Until March 2023 in Embase, Web of Science, PubMed, and Scopus databases, 10 eligible RCTs that intervened with DASH diet (n = 4) or KD (n = 6) and had provided laboratory data on serum UA were found. Summary effect was calculated by random-effects model. Results from the meta-analysis of the 4 DASH diet RCTs with a total of 590 participants revealed significant decrease in serum UA after at least 4 weeks of interventions (mean difference (MD) = ‒0.25; 95% CI ‒0.4 to ‒0.1 mg/dL; p < 0.01; I2 = 0%). The pooled meta-analysis of the 6 included RCTs of KD reporting data of 267 participants showed no significant changes in serum UA (MD = 0.26; 95% CI ‒0.47 to 0.98 mg/dL, I2 = 95.32%). However, a non-significant reduction of UA in the subgroup analysis of very low-calorie KD (VLCKD) studies (MD = ‒0.04; 95% CI ‒0.29 to 0.22, I2 = 0%) was obtained. DASH diet has an ameliorating effect on serum UA and may be recommended for hyperuricemia states such as gout. In addition, we have shown that serum UA level following KD remained unchanged. Although, in view of the heterogeneity across the studies, further investigations are needed to determine the effect of KD and VLKD on serum UA concentrations.

DOI: https://doi.org/10.1038/s41598-023-37672-2
J Endocr Soc. 2023 Jun 05. 7(7): bvad082

Intermittent Fasting Sustainably Improves Glucose Tolerance in Normal Weight Male Mice Through Histone Hyperacetylation.

Sho Endo, Asuka Uto, Kazutoshi Miyashita, Masaaki Sato, Hiroyuki Inoue, Kentaro Fujii, Aika Hagiwara, Masaki Ryuzaki, Takuma Oshida, Kenichiro Kinouchi, Hiroshi Itoh.

  To explore the mechanism by which intermittent fasting (IF) exerts prolonged effects after discontinuation, we examined mice that had been subjected to 4 cycles of fasting for 72 hours and ad libitum feeding for 96 hours per week (72hIF), followed by 4 weeks of ad libitum feeding, focusing on expression of genes for lipid metabolism in the skeletal muscle and histone acetylation in the promoter region. The 72hIF regimen resulted in metabolic remodeling, characterized by enhanced lipid utilization and mitochondrial activation in the muscle. This long-term IF (72hIF) caused stronger metabolic effects than alternate day fasting (24hIF) wherein fasting and refeeding are repeated every 24 hours. Upregulation of lipid oxidation genes and an increase in oxygen utilization were sustained even at 4 weeks after discontinuation of 72hIF, associated with histone hyperacetylation of the promoter region of uncoupling protein 3 (Ucp3) and carnitine palmitoyl transferase 1b (Cpt1b) genes. An increase in leucine owing to fasting-induced muscle degradation was suggested to lead to the histone acetylation. These findings support the previously unappreciated notion that sustainable promotion of histone acetylation in lipid oxidation genes of the muscle and adipose tissues during and after IF may contribute to sustained metabolic effects of IF.

Keywords:  exercise endurance; glucose tolerance; histone acetylation; intermittent fasting; lipid oxidation; mitochondria

DOI:  https://doi.org/10.1210/jendso/bvad082
Arq Neuropsiquiatr. 2023 06;81(6): 597-606

Ketogenic therapy in childhood and adolescence: recommendations of the Brazilian experts group.

Letícia Pereira de Brito Sampaio, Adélia Maria de Miranda Henriques-Souza, Katia Lin, Lenycia de Cassya Lopes Neri, Luciana Midori Inuzuka, Ludmila Inácio de Lima Uchôa, Marcela Marques de Oliveira Gregório, Laura Maria Guilhoto, Maria Augusta Montenegro, Mariana Lunardi, Marielza Veiga, Patricia Azevedo de Lima, Vera Braatz.

Ketogenic dietary therapies (KDTs) are a safe and effective treatment for pharmacoresistant epilepsy in children. There are four principal types of KDTs: the classic KD, the modified Atkins diet (MAD), the medium-chain triglyceride (MCT) diet, and the low glycemic index diet (LGID). The International Ketogenic Diet Study Group recommends managing KDTs in children with epilepsy. However, there are no guidelines that address the specific needs of the Brazilian population. Thus, the Brazilian Child Neurology Association elaborated on these recommendations with the goal of stimulating and expanding the use of the KD in Brazil.

DOI: https://doi.org/10.1055/s-0043-1768676
J Lipid Res. 2023 Jun 23. pii: S0022-2275(23)00080-9. [Epub ahead of print] 100407

The Lipogenic Enzyme Acetoacetyl-Coenzyme A Synthetase and Ketone Body Utilization for Denovo Lipid Synthesis, a Review.

James D Bergstrom.

  Acetoacetyl-CoA synthetase (AACS) is the key enzyme in the anabolic utilization of ketone bodies (KBs) for denovo lipid synthesis, a process that bypasses citrate and ATP citrate lyase. This review shows that AACS is a highly regulated, cytosolic and lipogenic enzyme and that many tissues can readily use KBs for denovo lipid synthesis. AACS has a low, micromolar Km for acetoacetate (AcAc) and supply of AcAc should not limit its activity in the fed state. In many tissues AACS appears to be regulated in conjunction with the need for cholesterol, but in adipose tissue it seems tied to fatty acid synthesis. KBs are readily utilized as substrates for lipid synthesis in lipogenic tissues including liver, adipose tissue, lactating mammary gland, skin, intestinal mucosa, adrenals and developing brain. In numerous studied cases, KBs served several-fold better than glucose as substrates for lipid synthesis and when present, KBs suppressed the utilization of glucose for lipid synthesis. Here it is hypothesized that a physiological role for the utilization of KBs for lipid synthesis is a metabolic process of lipid interconversion. Fatty acids are converted to KBs in liver and then the KBs are utilized to synthesize cholesterol and other long-chainfatty acids in liver and non-hepatic tissues. The conversion of fatty acids to cholesterol via the KBs may be a particularly important example of lipid interconversion. Utilizing KBs for lipid synthesis is glucose sparing and probably is important with low carbohydrate diets. Metabolic situations and tissues where lipid interconversion may be important are discussed.

Keywords:  ATP citrate lyase; Acetoacetate; Denovo lipid synthesis; anabolic role for ketone bodies; cholesterol synthesis; glucose sparing; lipid interconversion

DOI:  https://doi.org/10.1016/j.jlr.2023.100407
Anim Nutr. 2023 Sep;14 88-100

Sodium butyrate promotes gastrointestinal development of preweaning bull calves via inhibiting inflammation, balancing nutrient metabolism, and optimizing microbial community functions.

Huiyue Zhong, Wenjing Yu, Min Wang, Bo Lin, Xuezhao Sun, Nan Zheng, Jiaqi Wang, Shengguo Zhao.

  Butyrate promotes the growth and gastrointestinal development of calves. But, the mechanisms behind its effects on signaling pathways of the gastrointestinal tract and rumen microbiome is unclear. This study aimed to reveal transcriptomic pathways of gastrointestinal epithelium and microbial community in response to butyrate supplementation in calves fed a high fiber starter. Fourteen Holstein bull calves (39.9 ± 3.7 kg, 14 d of age) were assigned to 2 groups (sodium butyrate group, SB; control group, Ctrl). The SB group received 0.5% SB supplementation. At d 51, the calves were slaughtered to obtain samples for analysis of the transcriptome of the rumen and jejunum epithelium as well as ruminal microbial metagenome. Sodium butyrate supplementation resulted in a higher performance in average daily gain and development of jejunum and rumen papillae. In both the rumen and jejunum epithelium, SB down-regulated pathways related to inflammation including NF-κB (PPKCB, CXCL8, CXCL12), interleukin-17 (IL17A, IL17B, MMP9), and chemokine (CXCL12, CCL4, CCL8) and up-regulated immune pathways including the intestinal immune network for immunoglobulin A (IgA) production (CD28). Meanwhile, in the jejunum epithelium, SB regulated pathways related to nutritional metabolism including nitrogen metabolism (CA1, CA2, CA3), synthesis and degradation of ketone bodies (HMGCS2, BDH1, LOC100295719), fat digestion and absorption (PLA2G2F, APOA1, APOA4), and the PPAR signaling pathway (FABP4, FABP6, CYP4A11). The metagenome showed that SB greatly increased the relative abundance of Bacillus subtilis and Eubacterium limosum, activated ruminal microbial carbohydrate metabolism pathways and increased the abundance of carbohydrate hydrolysis enzymes. In conclusion, butyrate exhibited promoting effects on growth and gastrointestinal development by inhibiting inflammation, enhancing immunity and energy harvesting, and activating microbial carbohydrate metabolism. These findings provide new insights into the potential mechanisms behind the beneficial effects of butyrate in calf nutrition.

Keywords:  Calf; Gastrointestinal development; Inflammation; Microbiome; Sodium butyrate; Transcriptomics

DOI:  https://doi.org/10.1016/j.aninu.2023.04.004
Geroscience. 2023 Jun 30.

Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension.

Tomoya Shintani, Hideya Shintani, Masashi Sato, Hisashi Ashida.

  Calorie restriction (CR) can prolong human lifespan, but enforcing long-term CR is difficult. Thus, a drug that reproduces the effects of CR without CR is required. More than 10 drugs have been listed as CR mimetics (CRM), and some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, whereas the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Intriguingly, recent reports have revealed the beneficial effects of CRMs on the body such as improving the host body condition via intestinal bacteria and their metabolites. This beneficial effect of gut microbiota may lead to lifespan extension. Thus, CRMs may have a dual effect on longevity. However, no reports have collectively discussed them as CRMs; hence, our knowledge about CRM and its physiological effects on the host remains fragmentary. This study is the first to present and collectively discuss the accumulative evidence of CRMs improving the gut environments for healthy lifespan extension, after enumerating the latest scientific findings related to the gut microbiome and CR. The conclusion drawn from this discussion is that CRM may partially extend the lifespan through its effect on the gut microbiota. CRMs increase beneficial bacteria abundance by decreasing harmful bacteria rather than increasing the diversity of the microbiome. Thus, the effect of CRMs on the gut could be different from that of conventional prebiotics and seemed similar to that of next-generation prebiotics.

Keywords:  Acarbose; Anti-aging; Calorie restriction mimetics; Glucosamine; Microbiome

DOI:  https://doi.org/10.1007/s11357-023-00851-0
Cell Mol Biol Lett. 2023 Jun 27. 28(1): 51

The NLRP3 inflammasome: contributions to inflammation-related diseases.

Ying Chen, Xingyan Ye, Germaine Escames, Wangrui Lei, Xin Zhang, Meng Li, Tong Jing, Yu Yao, Zhenye Qiu, Zheng Wang, Darío Acuña-Castroviejo, Yang Yang.

  The NOD-like receptor protein 3 (NLRP3) inflammasome is a protein complex that regulates innate immune responses by activating caspase-1 and the inflammatory cytokines interleukin (IL)-1β and IL-18. Multiple studies have demonstrated the importance of the NLRP3 inflammasome in the development of immune and inflammation-related diseases, including arthritis, Alzheimer's disease, inflammatory bowel disease, and other autoimmune and autoinflammatory diseases. This review first explains the activation and regulatory mechanism of the NLRP3 inflammasome. Secondly, we focus on the role of the NLRP3 inflammasome in various inflammation-related diseases. Finally, we look forward to new methods for targeting the NLRP3 inflammasome to treat inflammation-related diseases, and provide new ideas for clinical treatment.

Keywords:  Inflammatory disease; Innate immunity; NLRP3 inflammasome

DOI:  https://doi.org/10.1186/s11658-023-00462-9
Front Psychiatry. 2023 ;14 1155717

Case report: KETOLAND the psychoeducation program for ketogenic diet.

Martina Paola Zanaboni, Ludovica Pasca, Maria Angela Geraci, Costanza Varesio, Monica Guglielmetti, Anna Tagliabue, Serena Grumi, Valentina De Giorgis.

  Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare neurological disorder characterized by a wide spectrum of symptoms: epilepsy, movement disorders and neurocognitive impairment. The gold standard treatment for GLUT1DS are ketogenic dietary therapies (KDTs), specifically classical ketogenic diet (CKD). Despite the benefits, CKD often represents a challenge for patients and their families since meal preparation is extremely demanding and deviates a lot from normal diet. To assure an optimal compliance to CKD a psychological support for parents and patients with GLUT1DS is highly recommended. Specifically, a psychoeducational intervention that ameliorates the knowledge about the illness and its therapy improves treatment' s adherence and efficacy. The aim of this case report is to investigate the effectiveness of a psychoeducational program, partially implemented through telepsychology, based on the theoretical model of Cognitive Behavioral Play Therapy (CBPT) to support KDT knowledge and adherence in a patient with GLUT1DS who presented a worsening of her clinical picture due to a sparse knowledge of KDTs principles which determined a low adherence. Thus, with this case report we propose a model of intervention with psychoeducation in a patient with a complex chronic disease.

Keywords:  Cognitive Behavioral Play Therapy; chronic disease; glut1 deficiency syndrome (GLUT1DS); ketogenic diet therapy; psychoeducation; therapeutic storytelling

DOI:  https://doi.org/10.3389/fpsyt.2023.1155717
Nat Cell Biol. 2023 Jun 29.

mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.

Nuria Martinez-Lopez, Pamela Mattar, Miriam Toledo, Henrietta Bains, Manu Kalyani, Marie Louise Aoun, Mridul Sharma, Laura Beth J McIntire, Leslie Gunther-Cummins, Frank P Macaluso, Jennifer T Aguilan, Simone Sidoli, Mathieu Bourdenx, Rajat Singh.

Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.

DOI: https://doi.org/10.1038/s41556-023-01163-3
Eur J Appl Physiol. 2023 Jun 27.

Effect of an acute long-duration exercise bout on skeletal muscle lipid droplet morphology, GLUT 4 protein, and perilipin protein expression.

Sudip Bajpeyi, Jehu N Apaflo, Victoria Rosas, Keisha Sepulveda-Rivera, Armando Varela-Ramirez, Jeffrey D Covington, Jose E Galgani, Eric Ravussin.

   PURPOSE: Smaller lipid droplet morphology and GLUT 4 protein expression have been associated with greater muscle oxidative capacity and glucose uptake, respectively. The main purpose of this study was to determine the effect of an acute long-duration exercise bout on skeletal muscle lipid droplet morphology, GLUT4, perilipin 3, and perilipin 5 expressions.
METHODS: Twenty healthy men (age 24.0 ± 1.0 years, BMI 23.6 ± 0.4 kg/m2) were recruited for the study. The participants were subjected to an acute bout of exercise on a cycle ergometer at 50% VO2max until they reached a total energy expenditure of 650 kcal. The study was conducted after an overnight fast. Vastus lateralis muscle biopsies were obtained before and immediately after exercise for immunohistochemical analysis to determine lipid, perilipin 3, perilipin 5, and GLUT4 protein contents while GLUT 4 mRNA was quantified using RT-qPCR.
RESULTS: Lipid droplet size decreased whereas total intramyocellular lipid content tended to reduce (p = 0.07) after an acute bout of endurance exercise. The density of smaller lipid droplets in the peripheral sarcoplasmic region significantly increased (0.584 ± 0.04 to 0.638 ± 0.08 AU; p = 0.01) while larger lipid droplets significantly decreased (p < 0.05). GLUT4 mRNA tended to increase (p = 0.05). There were no significant changes in GLUT 4, perilipin 3, and perilipin 5 protein levels.
CONCLUSION: The study demonstrates that exercise may impact metabolism by enhancing the quantity of smaller lipid droplets over larger lipid droplets.

Keywords:  Fat; Glucose; Intramyocellular; Lipid; PLIN; Triglycerides

DOI:  https://doi.org/10.1007/s00421-023-05266-5
mSystems. 2023 Jun 26. e0041523

Sodium butyrate facilitates CRHR2 expression to alleviate HPA axis hyperactivity in autism-like rats induced by prenatal lipopolysaccharides through histone deacetylase inhibition.

Xinyuan Wang, Zhujun Sun, Ting Yang, Fang Lin, Shasha Ye, Junyan Yan, Tingyu Li, Jie Chen.

  Short-chain fatty acids (SCFAs, especially butyric acid) have been demonstrated to play a promising role in the development of autism spectrum disorders (ASD). Recently, the hypothalamic-pituitary-adrenal (HPA) axis is also suggested to increase the risk of ASD. However, the mechanism underlying SCFAs and HPA axis in ASD development remains unknown. Here, we show that children with ASD exhibited lower SCFA concentrations and higher cortisol levels, which were recaptured in prenatal lipopolysaccharide (LPS)-exposed rat model of ASD. These offspring also showed decreased SCFA-producing bacteria and histone acetylation activity as well as impaired corticotropin-releasing hormone receptor 2 (CRHR2) expression. Sodium butyrate (NaB), which can act as histone deacetylases inhibitors, significantly increased histone acetylation at the CRHR2 promoter in vitro and normalized the corticosterone as well as CRHR2 expression level in vivo. Behavioral assays indicated ameliorative effects of NaB on anxiety and social deficit in LPS-exposed offspring. Our results imply that NaB treatment can improve ASD-like symptoms via epigenetic regulation of the HPA axis in offspring; thus, it may provide new insight into the SCFA treatment of neurodevelopmental disorders like ASD. IMPORTANCE Growing evidence suggests that microbiota can affect brain function and behavior through the "microbiome-gut-brain'' axis, but its mechanism remains poorly understood. Here, we show that both children with autism and LPS-exposed rat model of autism exhibited lower SCFA concentrations and overactivation of HPA axis. SCFA-producing bacteria, Lactobacillus, might be the key differential microbiota between the control and LPS-exposed offspring. Interestingly, NaB treatment contributed to the regulation of HPA axis (such as corticosterone as well as CRHR2) and improvement of anxiety and social deficit behaviors in LPS-exposed offspring. The potential underlying mechanism of the ameliorative effect of NaB may be mediated via increasing histone acetylation to the CRHR2 promoter. These results enhance our understanding of the relationship between the SCFAs and the HPA axis in the development of ASD. And gut microbiota-derived SCFAs may serve as a potential therapeutic agent to neurodevelopmental disorders like ASD.

Keywords:  HPA axis; autism; glucocorticoid; histone deacetylases; short chain fatty acids; social behavior

DOI:  https://doi.org/10.1128/msystems.00415-23
Int J Mol Sci. 2023 Jun 12. pii: 10015. [Epub ahead of print]24(12):

Improving Mitochondrial Function in Skeletal Muscle Contributes to the Amelioration of Insulin Resistance by Nicotinamide Riboside.

Qiuyan Li, Xuye Jiang, Yujia Zhou, Yingying Gu, Yijie Ding, Jing Luo, Nengzhi Pang, Yan Sun, Lei Pei, Jie Pan, Mengqi Gao, Sixi Ma, Ying Xiao, De Hu, Feilong Wu, Lili Yang.

  High-fat diet (HFD)-induced insulin resistance (IR) in skeletal muscle is often accompanied by mitochondrial dysfunction and oxidative stress. Boosting nicotinamide adenine dinucleotide (NAD) using nicotinamide riboside (NR) can effectively decrease oxidative stress and increase mitochondrial function. However, whether NR can ameliorate IR in skeletal muscle is still inconclusive. We fed male C57BL/6J mice with an HFD (60% fat) ± 400 mg/kg·bw NR for 24 weeks. C2C12 myotube cells were treated with 0.25 mM palmitic acid (PA) ± 0.5 mM NR for 24 h. Indicators for IR and mitochondrial dysfunction were analyzed. NR treatment alleviated IR in HFD-fed mice with regard to improved glucose tolerance and a remarkable decrease in the levels of fasting blood glucose, fasting insulin and HOMA-IR index. NR-treated HFD-fed mice also showed improved metabolic status regarding a significant reduction in body weight and lipid contents in serum and the liver. NR activated AMPK in the skeletal muscle of HFD-fed mice and PA-treated C2C12 myotube cells and upregulated the expression of mitochondria-related transcriptional factors and coactivators, thereby improving mitochondrial function and alleviating oxidative stress. Upon inhibiting AMPK using Compound C, NR lost its ability in enhancing mitochondrial function and protection against IR induced by PA. In summary, improving mitochondrial function through the activation of AMPK pathway in skeletal muscle may play an important role in the amelioration of IR using NR.

Keywords:  AMPK activation; NAD; insulin resistance; mitochondrial dysfunction; nicotinamide riboside (NR); oxidative stress

DOI:  https://doi.org/10.3390/ijms241210015
Antioxidants (Basel). 2023 Jun 09. pii: 1247. [Epub ahead of print]12(6):

The Effect of Astaxanthin on Mitochondrial Dynamics in Rat Heart Mitochondria under ISO-Induced Injury.

Roman Krestinin, Yulia Baburina, Irina Odinokova, Alexey Kruglov, Linda Sotnikova, Olga Krestinina.

  Mitochondria are dynamic organelles that produce ATP in the cell and are sensitive to oxidative damage that impairs mitochondrial function in pathological conditions. Mitochondria are involved not only in a healthy heart but also in the development of heart disease. Therefore, attempts should be made to enhance the body's defense response against oxidative stress with the help of various antioxidants in order to decrease mitochondrial damage and reduce mitochondrial dysfunction. Mitochondrial fission and fusion play an important role in the quality control and maintenance of mitochondria. The ketocarotenoid astaxanthin (AX) is an antioxidant able to maintain mitochondrial integrity and prevent oxidative stress. In the present study, we investigated the effect of the protective effect of AX on the functioning of rat heart mitochondria (RHM). Changes in the content of proteins responsible for mitochondrial dynamics, prohibitin 2 (PHB2) as a protein that performs the function of quality control of mitochondrial proteins and participates in the stabilization of mitophagy, and changes in the content of cardiolipin (CL) in rat heart mitochondria after isoproterenol (ISO)-induced damage were examined. AX improved the respiratory control index (RCI), enhanced mitochondrial fusion, and inhibited mitochondrial fission in RHM after ISO injury. Rat heart mitochondria (RHM) were more susceptible to Ca2+-induced mitochondrial permeability pore (mPTP) opening after ISO injection, while AX abolished the effect of ISO. AX is able to perform a protective function in mitochondria, improving their efficiency. Therefore, AX can be considered an important ingredient in the diet for the prevention of cardiovascular disease. Therefore, AX can be examined as an important component of the diet for the prevention of heart disease.

Keywords:  ISO-induced damage; fission; fusion; mytophagy; oxidative stress; rat heart mitochondria

DOI:  https://doi.org/10.3390/antiox12061247
Life (Basel). 2023 Jun 20. pii: 1420. [Epub ahead of print]13(6):

Inflammatory Mediators of Endothelial Dysfunction.

Eirini Dri, Evangelos Lampas, George Lazaros, Emilia Lazarou, Panagiotis Theofilis, Costas Tsioufis, Dimitris Tousoulis.

  Endothelial dysfunction (ED) is characterized by imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species (ROS), and inflammatory factors, as well as deficiency of nitric oxide (NO) bioavailability. It has been reported that the maintenance of endothelial cell integrity serves a significant role in human health and disease due to the involvement of the endothelium in several processes, such as regulation of vascular tone, regulation of hemostasis and thrombosis, cell adhesion, smooth muscle cell proliferation, and vascular inflammation. Inflammatory modulators/biomarkers, such as IL-1α, IL-1β, IL-6, IL-12, IL-15, IL-18, and tumor necrosis factor α, or alternative anti-inflammatory cytokine IL-10, and adhesion molecules (ICAM-1, VCAM-1), involved in atherosclerosis progression have been shown to predict cardiovascular diseases. Furthermore, several signaling pathways, such as NLRP3 inflammasome, that are associated with the inflammatory response and the disrupted H2S bioavailability are postulated to be new indicators for endothelial cell inflammation and its associated endothelial dysfunction. In this review, we summarize the knowledge of a plethora of reviews, research articles, and clinical trials concerning the key inflammatory modulators and signaling pathways in atherosclerosis due to endothelial dysfunction.

Keywords:  H2S gasotransmitter; NLRP3 inflammasome; atherosclerosis; endothelial dysfunction; inflammatory modulators

DOI:  https://doi.org/10.3390/life13061420
Genes Dev. 2023 Jun 26.

Circadian mechanisms in adipose tissue bioenergetics and plasticity.

Chelsea Hepler, Joseph Bass.

  The circadian clock plays an essential role in coordinating feeding and metabolic rhythms with the light/dark cycle. Disruption of clocks is associated with increased adiposity and metabolic disorders, whereas aligning feeding time with cell-autonomous rhythms in metabolism improves health. Here, we provide a comprehensive overview of recent literature in adipose tissue biology as well as our understanding of molecular mechanisms underlying the circadian regulation of transcription, metabolism, and inflammation in adipose tissue. We highlight recent efforts to uncover the mechanistic links between clocks and adipocyte metabolism, as well as its application to dietary and behavioral interventions to improve health and mitigate obesity.

Keywords:  adipocyte; adipose tissue; circadian clock; circadian rhythms; inflammation; metabolism; plasticity; thermogenesis; transcription

DOI:  https://doi.org/10.1101/gad.350759.123
Biomol Ther (Seoul). 2023 Jul 01. 31(4): 395-401

NLRP3 Inflammasome as Therapeutic Targets in Inflammatory Diseases.

Annamneedi Venkata Prakash, Il-Ho Park, Jun Woo Park, Jae Pil Bae, Geum Seon Lee, Tae Jin Kang.

  Innate immunity is a first line defence system in the body which is for sensing signals of danger such as pathogenic microbes or host-derived signals of cellular stress. Pattern recognition receptors (PRR's), which present in the cell memebrane, are suspect the infection through pathogen-associated molecular patterns (PAMP), and activate innate immunity with response to promote inflammation via inflammatory cells such as macrophages and neutrophils, and cytokines. Inflammasome are protein complexes which are part of innate immunity in inflammation to remove pathogens and repair damaged tissues. What is the important role of inflammation in disease? In this review, we are focused on the action mechanism of NLRP3 inflammasome in inflammatory diseases such as asthma, atopic dermatitis, and sepsis.

Keywords:  Asthma; Atopic dermatitis; Inflammasome; Sepsis

DOI:  https://doi.org/10.4062/biomolther.2023.099
Heliyon. 2023 Jun;9(6): e17164

How does exercise affect energy metabolism? An in silico approach for cardiac muscle.

Bahar Hazal Yalçınkaya, Seda Genc, Bayram Yılmaz, Mustafa Özilgen.

  We explored an in silico model of muscle energy metabolism and demonstrated its theoretical plausibility. Results indicate that energy metabolism triggered by activation can capture the muscle condition, rest, or exercise, and can respond accordingly adjusting the rates of their respiration and energy utilization for efficient use of the nutrients. Our study demonstrated during exercise higher respiratory activity causes a substantial increase in exergy release with an increase in exergy destruction, and entropy generation rate. The thermodynamic analysis showed that at the resting state when the exergy destruction rate was 0.66 W/kg and the respiratory metabolism energetic efficiency was 36% and exergetic efficiency was 32%; whereas, when the exergy destroyed was 1.24 W/kg, the energetic efficiency was 58% and exergetic efficiency was 50% during exercise. The efficiency results suggest the ability of the system to regulate itself in response to higher work demand and become more efficient in terms of converting energy coming from nutrients to useable energy when the circulating medium has sufficient energy precursor.

Keywords:  Entropy generation; Exergy destruction; Kinetic and thermodynamic analyses; Mitochondrial bioenergetics; Muscle work performance efficiency

DOI:  https://doi.org/10.1016/j.heliyon.2023.e17164
Mol Metab. 2023 Jun 23. pii: S2212-8778(23)00094-7. [Epub ahead of print] 101760

Dietary Medium-Chain Fatty Acids Reduce Food Intake via the GDF15-GFRAL Axis in Mice.

Josephine M Kanta, Luisa Deisen, Kornelia Johann, Stephanie Holm, Annemarie Lundsgaard, Jens Lund, Markus Jähnert, Annette Schürmann, Christoffer Clemmensen, Bente Kiens, Andreas M Fritzen, Maximilian Kleinert.

   OBJECTIVE: Medium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8 to 12 carbon atoms, have been shown to reduce food intake in rodents and humans, but the underlying mechanisms are unknown. Unlike most other fatty acids, MCFAs are absorbed from the intestine into the portal vein and enter first the liver. We thus hypothesized that MCFAs trigger the release of hepatic factors that reduce appetite.
METHODS: The liver transcriptome in mice that were orally administered MCFAs as C8:0 triacylglycerol (TG) was analyzed. Circulating growth/differentiation factor 15 (GDF15), tissue Gdf15 mRNA and food intake were investigated after acute oral gavage of MCFAs as C8:0 or C10:0 TG in mice. Effects of acute and subchronic administration of MCFAs as C8:0 TG on food intake and body weight were determined in mice lacking either the receptor for GDF15, GDNF Family Receptor Alpha Like (GFRAL), or GDF15.
RESULTS: Hepatic and small intestinal expression of Gdf15 and circulating GDF15 increased after MCFAs ingestion, while intake of typical dietary long-chain fatty acids (LCFAs) had no effect. Plasma GDF15 levels also increased in the portal vein with MCFA intake, indicating that in addition to the liver, the small intestine contributes to the rise in circulating GDF15. Acute oral provision of MCFAs decreased food intake over 24 hours compared with a LCFA-containing bolus, and this anorectic effect required the GDF15 receptor, GFRAL. Moreover, subchronic oral administration of MCFAs reduced body weight over 7 days, an effect that was blunted in mice lacking either GDF15 or GFRAL.
CONCLUSIONS: We have identified ingestion of MCFAs as a novel nutritional approach that increases circulating GDF15 in mice and have revealed that the GDF15-GFRAL axis is required for the full anorectic effect of MCFAs.

Keywords:  Food intake; Growth/differentiation factor 15; Hepatokine; Lipid Metabolism; Medium-chain fatty acids; Satiety

DOI:  https://doi.org/10.1016/j.molmet.2023.101760
Nutrients. 2023 Jun 15. pii: 2760. [Epub ahead of print]15(12):

Butyrate Protects Barrier Integrity and Suppresses Immune Activation in a Caco-2/PBMC Co-Culture Model While HDAC Inhibition Mimics Butyrate in Restoring Cytokine-Induced Barrier Disruption.

Sandra G P J Korsten, Herman Vromans, Johan Garssen, Linette E M Willemsen.

  Low-grade inflammation and barrier disruption are increasingly acknowledged for their association with non-communicable diseases (NCDs). Short chain fatty acids (SCFAs), especially butyrate, could be a potential treatment because of their combined anti-inflammatory and barrier- protective capacities, but more insight into their mechanism of action is needed. In the present study, non-activated, lipopolysaccharide-activated and αCD3/CD28-activated peripheral blood mononuclear cells (PBMCs) with and without intestinal epithelial cells (IEC) Caco-2 were used to study the effect of butyrate on barrier function, cytokine release and immune cell phenotype. A Caco-2 model was used to compare the capacities of butyrate, propionate and acetate and study their mechanism of action, while investigating the contribution of lipoxygenase (LOX), cyclooxygenase (COX) and histone deacetylase (HDAC) inhibition. Butyrate protected against inflammatory-induced barrier disruption while modulating inflammatory cytokine release by activated PBMCs (interleukin-1 beta↑, tumor necrosis factor alpha↓, interleukin-17a↓, interferon gamma↓, interleukin-10↓) and immune cell phenotype (regulatory T-cells↓, T helper 17 cells↓, T helper 1 cells↓) in the PBMC/Caco-2 co-culture model. Similar suppression of immune activation was shown in absence of IEC. Butyrate, propionate and acetate reduced inflammatory cytokine-induced IEC activation and, in particular, butyrate was capable of fully protecting against cytokine-induced epithelial permeability for a prolonged period. Different HDAC inhibitors could mimic this barrier-protective effect, showing HDAC might be involved in the mechanism of action of butyrate, whereas LOX and COX did not show involvement. These results show the importance of sufficient butyrate levels to maintain intestinal homeostasis.

Keywords:  PBMCs; butyrate; in vitro models; intestinal epithelial cells; mucosal immunity; short chain fatty acids

DOI:  https://doi.org/10.3390/nu15122760