bims-kimdis 2022-10-30 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–10–30
thirty papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults.
Mediterranean Diet versus Very Low-Calorie Ketogenic Diet: Effects of Reaching 5% Body Weight Loss on Body Composition in Subjects with Overweight and with Obesity-A Cohort Study.
Italian Ketogenic Mediterranean Diet in Overweight and Obese Patients with Prediabetes or Type 2 Diabetes.
Acetoacetate and β-hydroxybutyrate reduce mouse embryo viability via differential metabolic and epigenetic mechanisms.
Differential Effects of Beta-Hydroxybutyrate Enantiomers on Induced Pluripotent Stem Derived Cardiac Myocyte Electrophysiology.
Medium-chain triglycerides may improve memory in non-demented older adults: a systematic review of randomized controlled trials.
Corilagin Restrains NLRP3 Inflammasome Activation and Pyroptosis through the ROS/TXNIP/NLRP3 Pathway to Prevent Inflammation.
Effects of SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes on skeletal muscle cellular metabolism.
Body Composition, Fasting Blood Glucose and Lipidemic Indices Are Not Primarily Determined by the Nutritional Intake of Middle-Aged Endurance Trained Men-Another "Athletes' Paradox"?
Mitochondrial adaptations to calorie restriction and bariatric surgery in human skeletal muscle: a systematic review with meta-analysis.
Targeting Mitochondrial Function with Chemoptogenetics.
Consuming an All-Meat Ketogenic Diet for the Long-Term Management of Candida Vulvovaginitis and Vaginal Hidradenitis Suppurativa: A 47-Month Follow-Up Case Report.
Ketogenic diet therapy in children with epilepsy caused by SLC2A1 mutations: a single-center single-arm retrospective study.
Effects of a Low-Carbohydrate Dietary Intervention on Hemoglobin A1c: A Randomized Clinical Trial.
Beneficial effects of butyrate on brain functions: A view of epigenetic.
Chicken or Egg? Mitochondrial Phospholipids and Oxidative Stress in Disuse-induced Skeletal Muscle Atrophy.
Mitophagy in the aging nervous system.
Role of mitochondria-associated endoplasmic reticulum membranes in insulin sensitivity, energy metabolism, and contraction of skeletal muscle.
The time is now: Regular exercise maintains vascular health in aging women.
Ketone Ester Supplementation Improves Some Aspects of Cognitive Function during a Simulated Soccer Match after Induced Mental Fatigue.
AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism.
The Effects of Exercise Training on Mitochondrial Function in Cardiovascular Diseases: A Systematic Review and Meta-Analysis.
The thioredoxin system: balancing redox responses in immune cells and tumors.
Inhibition of Dectin-1 Alleviates Neuroinflammatory Injury by Attenuating NLRP3 Inflammasome-Mediated Pyroptosis After Intracerebral Hemorrhage in Mice: Preliminary Study Results.
Autophagy-inducing nutritional interventions in experimental and clinical oncology.
Neutrophil Extracellular Vesicles: A Delicate Balance between Pro-Inflammatory Responses and Anti-Inflammatory Therapies.
Mitochondrial Dysfunction, Mitophagy and Their Correlation with Perinatal Complications: Preeclampsia and Low Birth Weight.
Fasting and cancer: from yeast to mammals.
The Complex Interplay between Mitochondria, ROS and Entire Cellular Metabolism.
NLRP3-mediated pyroptosis in diabetic nephropathy.

J Am Nutr Assoc. 2022 Oct 24. 1-8

A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults.

Kristin M Nieman, Joshua C Anthony, Brianna J Stubbs.

  Objective: Growing interest in the metabolic state of ketosis has driven development of exogenous ketone products to induce ketosis without dietary changes. Bis hexanoyl (R)-1,3-butanediol (BH-BD) is a novel ketone ester which, when consumed, increases blood beta-hydroxybutyrate (BHB) concentrations. BH-BD is formulated as a powder or ready-to-drink (RTD) beverage; the relative efficacy of these formulations is unknown, but hypothesized to be equivalent.Methods: This randomized, observer-blinded, controlled, crossover decentralized study in healthy adults (n = 15, mean age = 33.7 years, mean BMI = 23.6 kg/m2) aimed to elucidate blood BHB and glucose concentrations before and 15, 30, 45, 60, 90 and 120 minutes following two serving sizes of reconstituted BH-BD powder (POW 25 g, POW 12.5 g), compared to a RTD BH-BD beverage (RTD 12.5 g), and a non-ketogenic control, all taken with a standard meal.Results: All BH-BD products were well tolerated and increased BHB, inducing nutritional ketosis (BHB ≥0.5 mM) after ∼15 minutes, relative to the control. BHB remained elevated 2 h post-consumption. The control did not increase BHB. Ketosis was dose responsive; peak BHB concentration and area under the curve (AUC) were two-fold greater with POW 25 g compared to POW 12.5 g and RTD 12.5 g. There were no differences in peak BHB and AUC between matched powder and RTD formulas. Blood glucose increased in all conditions following the meal but there were neither significant differences in lowest observed concentrations, nor consistent differences at each time point between conditions. These results demonstrate that both powdered and RTD BH-BD formulations similarly induce ketosis with no differences in glucose concentrations in healthy adults.

Keywords:  Ketones; beta-hydroxybutyrate; exogenous ketone; ketone di-ester; ketone ester

DOI:  https://doi.org/10.1080/27697061.2022.2117743
Int J Environ Res Public Health. 2022 Oct 11. pii: 13040. [Epub ahead of print]19(20):

Mediterranean Diet versus Very Low-Calorie Ketogenic Diet: Effects of Reaching 5% Body Weight Loss on Body Composition in Subjects with Overweight and with Obesity-A Cohort Study.

Claudia Di Rosa, Greta Lattanzi, Chiara Spiezia, Elena Imperia, Sara Piccirilli, Ivan Beato, Gianluigi Gaspa, Vanessa Micheli, Federica De Joannon, Noemi Vallecorsa, Massimo Ciccozzi, Giuseppe Defeudis, Silvia Manfrini, Yeganeh Manon Khazrai.

  The best nutritional strategy to fight the rise in obesity remains a debated issue. The Mediterranean diet (MD) and the Very Low-Calorie Ketogenic diet (VLCKD) are effective at helping people lose body weight (BW) and fat mass (FM) while preserving fat-free mass (FFM). This study aimed to evaluate the time these two diets took to reach a loss of 5% of the initial BW and how body composition was affected. We randomized 268 subjects with obesity or overweight in two arms, MD and VLCKD, for a maximum of 3 months or until they reached 5% BW loss. This result was achieved after one month of VLCKD and 3 months of MD. Both diets were effective in terms of BW (p < 0.0001) and FM loss (p < 0.0001), but the MD reached a higher reduction in both waist circumference (p = 0.0010) and FM (p = 0.0006) and a greater increase in total body water (p = 0.0017) and FFM (p = 0.0373) than VLCKD. The population was also stratified according to gender, age, and BMI. These two nutritional protocols are both effective in improving anthropometrical parameters and body composition, but they take different time spans to reach the goal. Therefore, professionals should evaluate which is the most suitable according to each patient's health status.

Keywords:  5% weight loss; Mediterranean diet; ketogenic diet

DOI:  https://doi.org/10.3390/ijerph192013040
Nutrients. 2022 Oct 18. pii: 4361. [Epub ahead of print]14(20):

Italian Ketogenic Mediterranean Diet in Overweight and Obese Patients with Prediabetes or Type 2 Diabetes.

Cincione Raffaele Ivan, Antonietta Messina, Giuseppe Cibelli, Giovanni Messina, Rita Polito, Francesca Losavio, Ester La Torre, Vincenzo Monda, Marcellino Monda, Stefano Quiete, Elias Casula, Nicola Napoli, Giuseppe Defeudis.

  Obesity is a multifactorial disease strongly associated with insulin resistance and/or type 2 diabetes mellitus. Correct nutrition represents a valid strategy to fight these dysmetabolic pathologies responsible for numerous diseases, including inflammatory and cardiovascular ones. Medical nutrition therapy, including a Mediterranean diet (MD) and a very low-calorie ketogenic diet (VLKCD), is the first-line treatment for prediabetes/diabetes and overweight/obesity. Eighty patients (forty women and forty men) affected by overweight/obesity and type 2 diabetes mellitus or impaired glucose tolerance or impaired fasting glucose (51 (ys) ± 1.75; BMI (kg/m2) 33.08 ± 1.93; HA1c (%): 6.8% ± 0.25) were enrolled at the University Service of Diet Therapy, Diabetology and Metabolic Diseases, Policlinico Riuniti Hospital of Foggia, and subjected to a very-low-calorie Mediterranean diet and a very-low-calorie ketogenic Mediterranean diet for thirty days. Both diets result in a marked decrease in body weight (kg) and BMI (kg/m2). At the same time, only the very-low-calories ketogenic Mediterranean diet reduced waist and hip circumferences. Both diets helped reduce fat mass, but a major loss was achieved in a very low-calorie ketogenic Mediterranean diet. Among gluco-metabolic parameters, only the very-low-calorie ketogenic Mediterranean diet group showed a significant decrease in fasting blood glucose and HbA1c, insulin, C-peptide total cholesterol, LDL, and triglycerides. The results of our study seem to show that the very-low-calorie ketogenic Mediterranean diet is a good strategy to improve rapidly metabolic, anthropometric, and body composition parameters in patients with prediabetes or diabetes and overweight/obesity.

Keywords:  Mediterranean diet; VLCD_MED; VLCKD_MED; obesity; overweight; prediabetes; type 2 diabetes

DOI:  https://doi.org/10.3390/nu14204361
Reprod Biomed Online. 2022 Sep 25. pii: S1472-6483(22)00712-X. [Epub ahead of print]

Acetoacetate and β-hydroxybutyrate reduce mouse embryo viability via differential metabolic and epigenetic mechanisms.

Emma G Whatley, Thi T Truong, Alexandra J Harvey, David K Gardner.

   RESEARCH QUESTION: Does the ketone acetoacetate (AcAc) alone, or combined with β-hydroxybutyrate (βOHB), impact mouse embryo development, metabolism, histone acetylation and viability?
DESIGN: Pronucleate mouse oocytes were cultured in vitro in G1/G2 media supplemented with ketones (AcAc or AcAc + βOHB) at concentrations representing those in maternal serum during pregnancy (0.04 mmol/l AcAc, 0.1 mmol/l βOHB), standard diet consumption (0.1 mmol/l AcAc, 0.25 mmol/l βOHB), ketogenic diet consumption (0.8 mmol/l AcAc, 2 mmol/l βOHB) and diabetic ketoacidosis (2 mmol/l AcAc, 4 mmol/l βOHB). Day 5 blastocysts were assessed for cell allocation, glucose metabolism and histone acetylation. Day 4 blastocysts exposed to 0.8 mmol/l AcAc + 2 mmol/l βOHB were transferred to standard-fed recipient females, and E14.5 fetal and placental development assessed.
RESULTS: Exposure to 2 mmol/l AcAc or 0.8 mmol/l AcAc + 2 mmol/l βOHB did not impair blastocyst development, but significantly increased glucose consumption (P = 0.001 each), lowered glycolytic flux (P = 0.01, P < 0.001) and elevated trophectoderm (TE) histone 3 lysine 27 acetylation (H3K27ac; P < 0.001 each) compared with unexposed controls. Preimplantation AcAc + βOHB exposure reduced post-implantation fetal development by 25% (P = 0.037), and delayed female-specific fetal limb development (P = 0.019) and estimated fetal age (P = 0.019) compared with controls.
CONCLUSION: Preimplantation exposure to ketones affects underlying metabolism and histone acetylation in blastocysts that are associated with persistent, female-specific perturbations in fetal development. A periconceptional diet that elevates ketone concentrations may impair human embryonic viability.

Keywords:  Acetylation; Blastocyst; Development; Ketogenic diet; Ketone; Nutrient

DOI:  https://doi.org/10.1016/j.rbmo.2022.09.018
Biomolecules. 2022 Oct 17. pii: 1500. [Epub ahead of print]12(10):

Differential Effects of Beta-Hydroxybutyrate Enantiomers on Induced Pluripotent Stem Derived Cardiac Myocyte Electrophysiology.

Matthew L Klos, Wanqing Hou, Bernard Nsengimana, Shiwang Weng, Chuyun Yan, Suowen Xu, Eric Devaney, Shuxin Han.

  Beta-hydroxybutyrate (βOHB), along with acetoacetate and acetone, are liver-produced ketone bodies that are increased after fasting or prolonged exercise as an alternative fuel source to glucose. βOHB, as the main circulating ketone body, is not only a G-protein coupled receptor ligand but also a histone deacetylases inhibitor, prompting the reexamination of its role in health and disease. In this study, we compared the effects of two commercial βOHB formulations an enantiomer R βOHB and a racemic mixture ±βOHB on induced pluripotent stem cell cardiac myocytes (iPS-CMs) electrophysiology. Cardiac myocytes were cultured in R βOHB or ±βOHB for at least ten days after lactate selection. Flouvolt or Fluo-4 was used to assay iPS-CMs electrophysiology. We found that while both formulations increased the optical potential amplitude, R βOHB prolonged the action potential duration but ±βOHB shortened the action potential duration. Moreover, ±βOHB increased the peak calcium transient but R βOHB reduced the peak calcium transient. Co-culturing with glucose or fatty acids did not ameliorate the effects, suggesting that βOHB was more than a fuel source. The effect of βOHB on iPS-CMs electrophysiology is most likely stereoselective, and care must be taken to evaluate the role of exogenous βOHB in health and disease.

Keywords:  beta-hydroxybutyrate (βOHB); electrophysiology; enantiomer; induced pluripotent stem cell-derived cardiac myocytes (iPS-CMs); racemic mixture

DOI:  https://doi.org/10.3390/biom12101500
BMC Geriatr. 2022 Oct 23. 22(1): 817

Medium-chain triglycerides may improve memory in non-demented older adults: a systematic review of randomized controlled trials.

Panagiotis Giannos, Konstantinos Prokopidis, Irene Lidoriki, Konstantinos K Triantafyllidis, Konstantinos S Kechagias, Kamil Celoch, Darren G Candow, Sergej M Ostojic, Scott C Forbes.

   BACKGROUND: Ketosis has been exploited for its neuroprotective impact and treatment of neurological conditions via ketone production. Exogenous medium-chain triglyceride (MCT) supplementation may induce nutritional ketosis. The aim of this systematic review is to explore the effects of MCTs on memory function in older adults without cognitive impairment.
METHODS: A systematic literature search of PubMed, Cochrane Library, Scopus, and Web of Science was employed from inception until April 2022 for randomized controlled trials (RCTs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, investigating the impact of MCT oils on components of memory. Risk of bias (RoB2) tool was utilized for quality assessment.
RESULTS: Six trials were included for qualitative synthesis, in which two studies examined the effect of MCTs through a ketogenic meal. MCT supplementation compared to controls was associated with improved indices of memory function in 4 out of 6 studies, particularly working memory. A meta-analysis was not employed due to the low number of studies, therefore, a true effect measure of MCT supplementation was not explored.
CONCLUSIONS: MCT supplementation may enhance working memory in non-demented older adults. These effects may be more prominent in individuals with lower baseline scores, from short and long-term supplementation. Further studies are warranted to confirm these findings in terms of optimal dose and MCTs composition, which may protect from memory decline during aging.

Keywords:  Cognitive function; Medium-chain triglycerides; Memory; Non-demented; Nutritional ketosis

DOI:  https://doi.org/10.1186/s12877-022-03521-6
Oxid Med Cell Longev. 2022 ;2022 1652244

Corilagin Restrains NLRP3 Inflammasome Activation and Pyroptosis through the ROS/TXNIP/NLRP3 Pathway to Prevent Inflammation.

Tianyu Luo, Xiaoyi Zhou, Minyan Qin, Yuqing Lin, Jiefen Lin, Guangpei Chen, Aijun Liu, Dongyun Ouyang, Dongfeng Chen, Hao Pan.

Corilagin, a gallotannin, shows excellent antioxidant and anti-inflammatory effects. The NLRP3 inflammasome dysfunction has been implicated in a variety of inflammation diseases. However, it remains unclear how corilagin regulates the NLRP3 inflammasome to relieve gouty arthritis. In this study, bone marrow-derived macrophages (BMDMs) were pretreated with lipopolysaccharide (LPS) and then incubated with NLRP3 inflammasome agonists, such as adenine nucleoside triphosphate (ATP), nigericin, and monosodium urate (MSU) crystals. The MSU crystals were intra-articular injected to induce acute gouty arthritis. Here we showed that corilagin reduced lactate dehydrogenase (LDH) secretion and the proportion of propidium iodide- (PI-)stained cells. Corilagin suppressed the expression of N-terminal of the pyroptosis executive protein gasdermin D (GSDMD-NT). Corilagin restricted caspase-1 p20 and interleukin (IL)-1β release. Meanwhile, corilagin attenuated ASC oligomerization and speck formation. Our findings confirmed that corilagin diminished NLRP3 inflammasome activation and macrophage pyroptosis. We further discovered that corilagin limited the mitochondrial reactive oxygen species (ROS) production and prevented the interaction between TXNIP and NLRP3, but ROS activator imiquimod could antagonize the inhibitory function of corilagin on NLRP3 inflammasome and macrophage pyroptosis. Additionally, corilagin ameliorated MSU crystals induced joint swelling, inhibited IL-1β production, and abated macrophage and neutrophil migration into the joint capsule. Collectively, these results demonstrated that corilagin suppressed the ROS/TXNIP/NLRP3 pathway to repress inflammasome activation and pyroptosis and suggest its potential antioxidative role in alleviating NLRP3-dependent gouty arthritis.

DOI: https://doi.org/10.1155/2022/1652244
Mol Metab. 2022 Oct 21. pii: S2212-8778(22)00189-2. [Epub ahead of print] 101620

Effects of SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes on skeletal muscle cellular metabolism.

Yvo J M Op den Kamp, Anne Gemmink, Marlies de Ligt, Bas Dautzenberg, Esther Kornips, Johanna A Jorgensen, Gert Schaart, Russell Esterline, Diego A Pava, Joris Hoeks, Vera B Schrauwen-Hinderling, Sander Kersten, Bas Havekes, Timothy R Koves, Deborah M Muoio, Matthijs K C Hesselink, Jan Oscarsson, Esther Phielix, Patrick Schrauwen.

   OBJECTIVE: SGLT2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may be metabolic adaptations due to urinary glucose loss. Here, we investigated the cellular and molecular effects of 5 weeks of dapagliflozin treatment on skeletal muscle metabolism in type 2 diabetes patients.
METHODS: Twenty-six type 2 diabetes mellitus patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. Skeletal muscle acetylcarnitine levels, intramyocellular lipid (IMCL) content and phosphocreatine (PCr) recovery rate were measured by magnetic resonance spectroscopy (MRS). Ex vivo mitochondrial respiration was measured in skeletal muscle fibers using high resolution respirometry. Intramyocellular lipid droplet and mitochondrial network dynamics were investigated using confocal microscopy. Skeletal muscle levels of acylcarnitines, amino acids and TCA cycle intermediates were measured. Expression of genes involved in fatty acid metabolism were investigated.
RESULTS: Mitochondrial function, mitochondrial network integrity and citrate synthase and carnitine acetyltransferase activities in skeletal muscle were unaltered after dapagliflozin treatment. Dapagliflozin treatment increased intramyocellular lipid content (0.060 (0.011, 0.110) %, p=0.019). Myocellular lipid droplets increased in size (0.03 μm2 (0.01-0.06), p<0.05) and number (0.003 μm-2 (-0.001-0.007), p=0.09) upon dapagliflozin treatment. CPT1A, CPT1B and malonyl CoA-decarboxylase mRNA expression was increased by dapagliflozin. Fasting acylcarnitine species and C4-OH carnitine levels (0.4704 (0.1246, 0.8162) pmoles*mg tissue-1, p<0.001) in skeletal muscle were higher after dapagliflozin treatment, while acetylcarnitine levels were lower (-40.0774 (-64.4766, -15.6782) pmoles*mg tissue-1, p<0.001). Fasting levels of several amino acids, succinate, alpha-ketoglutarate and lactate in skeletal muscle were significantly lower after dapagliflozin treatment.
CONCLUSION: Dapagliflozin treatment for 5 weeks leads to adaptive changes in skeletal muscle substrate metabolism favoring metabolism of fatty acid and ketone bodies and reduced glycolytic flux. The trial is registered with ClinicalTrials.gov, number NCT03338855.

Keywords:  Acylcarnitines; Dapagliflozin; Mitochondrial function; Myocellular lipid metabolism; SGLT2i; TCA cycle intermediates

DOI:  https://doi.org/10.1016/j.molmet.2022.101620
J Clin Med. 2022 Oct 13. pii: 6057. [Epub ahead of print]11(20):

Body Composition, Fasting Blood Glucose and Lipidemic Indices Are Not Primarily Determined by the Nutritional Intake of Middle-Aged Endurance Trained Men-Another "Athletes' Paradox"?

Spyridon Methenitis, Konstantinos Feidantsis, Athina Kaprara, Apostolos Hatzitolios, Petros Skepastianos, Sousana K Papadopoulou, George Panayiotou.

  Systematic, regular high-volume endurance training induces significant metabolic adaptations in glucose and lipids metabolism, which seems to affect the negative impact of unhealthy nutrition, at least in animal models. The present study aimed to investigate the main determinants of body composition, blood glucose and lipids concentrations between middle-aged sedentary individuals (Sed) and well-trained endurance athletes (Run), both following an unhealthy high-fat diet. In thirty-five Sed (Age: 54.0 ± 6.6 yrs, Body Mass: 77.1 ± 10.5 kg, BMI: 31.3 ± 6.0 kg·m-2) and thirty-six Run (Age: 51.6 ± 5.2 yrs, Body Mass: 85.8 ± 3.4 kg, BMI: 23.2 ± 1.8 kg·m-2), body composition, nutritional intake, energy expenditure, resting metabolic rate (RMR), respiratory exchange ratio (RER), and blood glucose and lipids concentrations were evaluated. Multiple linear regression analyses revealed that body composition, blood glucose and lipids' concentrations in the Run group were primarily determined by the energy expenditure (B: -0.879 to -1.254), while in the Sed group, by their energy intake (B:-0.754 to 0.724). In conclusion, it seems that in well-trained endurance middle-aged athletes, body composition, blood glucose, and lipids concentrations seem to be determined by their training-induced daily energy expenditure and not by their nutritional intake per se. At the same time, nutrition is the primary determinant in aged-matched sedentary individuals, even if they both follow high-fat diets.

Keywords:  body fat; cardiovascular risk factors; energy balance; energy expenditure; lean body mass; oxidative metabolism; runners

DOI:  https://doi.org/10.3390/jcm11206057
Metabolism. 2022 Oct 24. pii: S0026-0495(22)00214-1. [Epub ahead of print] 155336

Mitochondrial adaptations to calorie restriction and bariatric surgery in human skeletal muscle: a systematic review with meta-analysis.

Miguel Pérez-Rodríguez, Jesús R Huertas, José M Villalba, Rafael A Casuso.

   OBJECTIVE: We performed a meta-analysis to determine the changes induced by calorie restriction (CR) and bariatric surgery on human skeletal muscle mitochondria.
METHODS: A systematic search of Medline and Web of Science was conducted. Controlled trials exploring CR (≥14 days) and mitochondrial function and/or content assessment were included. Moreover, studies analyzing weight loss following gastric surgery were included for comparison purposes. Human muscle data from 28 studies assessing CR (520 muscle samples) and from 10 studies assessing bariatric surgery (155 muscle samples) were analyzed in a random effect meta-analysis with three a priori chosen covariates.
MAIN RESULTS: We report a decrease (p < 0.05) (mean (95 % CI)) in maximal mitochondrial state 3 respiration in response to CR (-0.44 (-0.85, -0.03)) but not in response to surgery (-0.33 (-1.18, 0.52)). No changes in mitochondrial content were reported after CR (-0.05 (-0.12, 0.13)) or in response to surgery (0.23 (-0.05, 0.52)). Moreover, data from CR subjects showed a reduction in complex IV (CIV) activity (-0.29 (-0.56, -0.03)) but not in CIV content (-0.21 (-0.63, 0.22)). Similar results were obtained when the length of the protocol, the initial body mass index, and the estimated energy deficit were included in the model as covariates.
CONCLUSION: The observation of reduced maximal mitochondrial state 3, uncoupled respiration, and CIV activity without altering mitochondrial content suggests that, in human skeletal muscle, CR mainly modulates intrinsic mitochondrial function.

Keywords:  Energy restriction; Muscle metabolism; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.metabol.2022.155336
Biomedicines. 2022 Oct 01. pii: 2459. [Epub ahead of print]10(10):

Targeting Mitochondrial Function with Chemoptogenetics.

Amy Romesberg, Bennett Van Houten.

  Mitochondria are ATP-generating organelles in eukaryotic cells that produce reactive oxygen species (ROS) during oxidative phosphorylation (OXPHOS). Mitochondrial DNA (mtDNA) is packaged within nucleoids and, due to its close proximity to ROS production, endures oxidative base damage. This damage can be repaired by base excision repair (BER) within the mitochondria, or it can be degraded via exonucleases or mitophagy. Persistent mtDNA damage may drive the production of dysfunctional OXPHOS components that generate increased ROS, or OXPHOS components may be directly damaged by ROS, which then can cause more mtDNA damage and create a vicious cycle of ROS production and mitochondrial dysfunction. If mtDNA damage is left unrepaired, mtDNA mutations including deletions can result. The accumulation of mtDNA mutations has been associated with conditions ranging from the aging process to cancer and neurodegenerative conditions, but the sequence of events leading to mtDNA mutations and deletions is yet unknown. Researchers have utilized many systems and agents for generating ROS in mitochondria to observe the downstream effects on mtDNA, ROS, and mitochondrial function; yet, there are various drawbacks to these methodologies that limit their precision. Here, we describe a novel chemoptogenetic approach to target oxidative damage to mitochondria and mtDNA with a high spatial and temporal resolution so that the downstream effects of ROS-induced damage can be measured with a high precision in order to better understand the mechanism of mitochondrial dysfunction in aging, cancer, and neurodegenerative diseases.

Keywords:  base excision repair; chemoptogenetics; mitochondria; mitochondrial DNA; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.3390/biomedicines10102459
Cureus. 2022 Oct;14(10): e30510

Consuming an All-Meat Ketogenic Diet for the Long-Term Management of Candida Vulvovaginitis and Vaginal Hidradenitis Suppurativa: A 47-Month Follow-Up Case Report.

Nadia Yar, Lawrance T Mukona, Kim Nguyen, Linette Nalbandyan, Lorraine Mukona, Guinda St Fleur, Norman L Lamberty, Kyle Zullo, Adam Le, Alex Van, Brandon Allen.

  This case report describes long-term therapeutic management in a 33-year-old diagnosed with Candida vulvovaginitis and vulvar hidradenitis suppurativa 47 months previously. Candida spp. yeasts are part of many women's normal vaginal microflora, and the development of vulvovaginal candidiasis is typically a result of a disturbance in the patient's microbial ecosystem, which manifests itself by intense pruritus, erythema, swelling, and thick white vaginal discharge. Hidradenitis suppurativa is a chronic auto-inflammatory skin condition that causes painful weeping lesions in areas of dense apocrine glands. Although certain mechanisms underlying the pathogenesis of Hidradenitis Suppurativa (e.g., risk factors include smoking, obesity, and family history) have been investigated, a definitive explanation remains elusive. Nutritional intervention in the form of an all-meat ketogenic diet may be considered therapy in the management of both diseases, as successfully seen in this case report. The patient refused standard of care with oral fluconazole for Candida vulvovaginitis and surgical removal for Hidradenitis suppurativa, and instead consumed a zero-carbohydrate all-meat ketogenic diet mostly of beef with strict adherence to the diet for 43 days in which symptoms ceased.

Keywords:  a case report; candida infection; candida vulvovaginitis; classic ketogenic diet; hiradenitis suppurativa

DOI:  https://doi.org/10.7759/cureus.30510
World J Pediatr. 2022 Oct 27.

Ketogenic diet therapy in children with epilepsy caused by SLC2A1 mutations: a single-center single-arm retrospective study.

Ying-Yan Wang, Yun-Qing Zhou, Li-Juan Luo, Cui-Jin Wang, Nan Shen, Hao Li, Ji-Wen Wang.

   BACKGROUND: This retrospective study assessed the efficacy and safety of ketogenic diet therapies in children with epilepsy caused by SLC2A1 genetic mutations and glucose transporter type 1 deficiency syndrome.
METHODS: Pediatric patients with epilepsy symptoms admitted to our medical center between January 2017 and October 2021 were included if they presented with an SLC2A1 genetic mutation on whole-exome sequencing. We analyzed the patients' convulsions and treatment with antiepileptic drugs. The patients were followed up at different time periods after ketogenic diet therapies.
RESULTS: Six patients with SLC2A1 mutations were included in this study. The patients had seizures of different types and frequencies, and they took antiepileptic drugs to relieve their symptoms. They were then treated with a ketogenic diet for at least four months. We analyzed epilepsy control rates at 1, 2, 3, 6, and 12 months after ketogenic diet treatment. All patients were seizure-free within a month of receiving the diet therapy. All patients were followed up for six months, three were followed up for 12 months after the treatment, and there was no recurrence of epilepsy during this period. After antiepileptic drug withdrawal, none of the patients experienced seizure relapse when receiving ketogenic diet treatment alone. No severe adverse events occurred during the therapy.
CONCLUSIONS: Ketogenic diet therapy is very effective and safe for the treatment of epilepsy caused by SLC2A1 mutations. Therefore, patients with glucose transporter type 1 deficiency syndrome caused by SLC2A1 mutations should begin ketogenic diet treatment as soon as possible.

Keywords:  Epilepsy; Glucose transporter type 1; Ketogenic diet; SLC2A1

DOI:  https://doi.org/10.1007/s12519-022-00620-7
JAMA Netw Open. 2022 Oct 03. 5(10): e2238645

Effects of a Low-Carbohydrate Dietary Intervention on Hemoglobin A1c: A Randomized Clinical Trial.

Kirsten S Dorans, Lydia A Bazzano, Lu Qi, Hua He, Jing Chen, Lawrence J Appel, Chung-Shiuan Chen, Ming-Hui Hsieh, Frank B Hu, Katherine T Mills, Bernadette T Nguyen, Matthew J O'Brien, Jonathan M Samet, Gabriel I Uwaifo, Jiang He.

Importance: Low-carbohydrate diets decrease hemoglobin A1c (HbA1c) among patients with type 2 diabetes at least as much as low-fat diets. However, evidence on the effects of low-carbohydrate diets on HbA1c among individuals with HbA1c in the range of prediabetes to diabetes not treated by diabetes medications is limited.
Objective: To study the effect of a behavioral intervention promoting a low-carbohydrate diet compared with usual diet on 6-month changes in HbA1c among individuals with elevated untreated HbA1c.
Design, Setting, and Participants: This 6-month randomized clinical trial with 2 parallel groups was conducted from September 2018 to June 2021 at an academic medical center in New Orleans, Louisiana. Laboratory analysts were blinded to assignment. Participants were aged 40 to 70 years with untreated HbA1c of 6.0% to 6.9% (42-52 mmol/mol). Data analysis was performed from November 2021 to September 2022.
Interventions: Participants were randomized to a low-carbohydrate diet intervention (target <40 net grams of carbohydrates during the first 3 months; <60 net grams for months 3 to 6) or usual diet. The low-carbohydrate diet group received dietary counseling.
Main Outcomes and Measures: Six-month change in HbA1c was the primary outcome. Outcomes were measured at 0, 3, and 6 months.
Results: Of 2722 prescreened participants, 962 underwent screening, and 150 were enrolled (mean [SD] age, 58.9 [7.9] years; 108 women [72%]; 88 Black participants [59%]) and randomized to either the low-carbohydrate diet intervention (75 participants) or usual diet (75 participants) group. Six-month data were collected on 142 participants (95%). Mean (SD) HbA1c was 6.16% (0.30%) at baseline. Compared with the usual diet group, the low-carbohydrate diet intervention group had significantly greater 6-month reductions in HbA1c (net difference, -0.23%; 95% CI, -0.32% to -0.14%; P < .001), fasting plasma glucose (-10.3 mg/dL; 95% CI, -15.6 to -4.9 mg/dL; P < .001), and body weight (-5.9 kg; 95% CI, -7.4 to -4.4 kg; P < .001).
Conclusions and Relevance: In this randomized clinical trial, a low-carbohydrate dietary intervention led to improvements in glycemia in individuals with elevated HbA1c not taking glucose-lowering medication, but the study was unable to evaluate its effects independently of weight loss. This diet, if sustained, might be a useful dietary approach for preventing and treating type 2 diabetes, but more research is needed.
Trial Registration: ClinicalTrials.gov Identifier: NCT03675360.

DOI: https://doi.org/10.1001/jamanetworkopen.2022.38645
Crit Rev Food Sci Nutr. 2022 Oct 26. 1-10

Beneficial effects of butyrate on brain functions: A view of epigenetic.

Gabriela de Cássia Ávila Alpino, Gabriela Amorim Pereira-Sol, Mariana de Moura E Dias, Aline Silva de Aguiar, Maria do Carmo Gouveia Peluzio.

  Brain functions are influenced by the presence, activity, and metabolism of the gut microbiota through the gut-microbiota-brain (GMB) axis. The consumption of a fiber-rich diet increases the content of short-chain fatty acids (SCFAs) from bacterial fermentation in the colon. Among SCFAs, butyrate stands out because of its wide array of biological functions, such as ability to influence brain functions. Pharmacologically, sodium butyrate (NaB) regulates gene expression in the brain, where it has several beneficial effects ranging from neurodegenerative diseases to behavioral disorders through inhibitors of histone deacetylases (HDACis). In this context, we review the mechanisms of action of the two types of butyrate on brain functions, with an emphasis on the epigenetic approach. Both types of butyrate are potentially interesting for the prevention and adjuvant therapy of neurological and psychological disorders due to their neuroprotective functions. However, further studies are needed to investigate the possible neuroepigenetic effects of butyrate derived from bacterial fermentation.

Keywords:  Butyrate; brain disorders; epigenetics; gut-microbiota-brain axis; high-fiber diet

DOI:  https://doi.org/10.1080/10408398.2022.2137776
Antioxid Redox Signal. 2022 Oct 27.

Chicken or Egg? Mitochondrial Phospholipids and Oxidative Stress in Disuse-induced Skeletal Muscle Atrophy.

Edwin R Miranda, Justin L Shahtout, Katsuhiko Funai.

SIGNIFICANCE: Accumulation of reactive oxygen species (ROS) is known to promote cellular damage in multiple cell-types. In skeletal muscle, ROS has been implicated in disuse-induced muscle atrophy. However, the molecular origin and mechanism of how disuse promotes ROS and muscle dysfunction remains unclear.
RECENT ADVANCES: Recently, we implicated membrane lipids of mitochondria to be a potential source of ROS to promote muscle atrophy.
CRITICAL ISSUES: In this review, we discuss evidence that changes in mitochondrial lipids represent a physiologically-relevant process by which disuse promotes mitochondrial electron leak and oxidative stress.
FUTURE DIRECTIONS: We further discuss lipid hydroperoxides (LOOH) as a potential downstream mediator of ROS to induce muscle atrophy.

DOI: https://doi.org/10.1089/ars.2022.0151
Front Cell Dev Biol. 2022 ;10 978142

Mitophagy in the aging nervous system.

Anna Rappe, Thomas G McWilliams.

  Aging is characterised by the progressive accumulation of cellular dysfunction, stress, and inflammation. A large body of evidence implicates mitochondrial dysfunction as a cause or consequence of age-related diseases including metabolic disorders, neuropathies, various forms of cancer and neurodegenerative diseases. Because neurons have high metabolic demands and cannot divide, they are especially vulnerable to mitochondrial dysfunction which promotes cell dysfunction and cytotoxicity. Mitophagy neutralises mitochondrial dysfunction, providing an adaptive quality control strategy that sustains metabolic homeostasis. Mitophagy has been extensively studied as an inducible stress response in cultured cells and short-lived model organisms. In contrast, our understanding of physiological mitophagy in mammalian aging remains extremely limited, particularly in the nervous system. The recent profiling of mitophagy reporter mice has revealed variegated vistas of steady-state mitochondrial destruction across different tissues. The discovery of patients with congenital autophagy deficiency provokes further intrigue into the mechanisms that underpin neural integrity. These dimensions have considerable implications for targeting mitophagy and other degradative pathways in age-related neurological disease.

Keywords:  aging; autophagy; brain; disease; longevity; mitochondria; mitophagy

DOI:  https://doi.org/10.3389/fcell.2022.978142
Front Mol Biosci. 2022 ;9 959844

Role of mitochondria-associated endoplasmic reticulum membranes in insulin sensitivity, energy metabolism, and contraction of skeletal muscle.

Bianca Nieblas, Perla Pérez-Treviño, Noemí García.

  Skeletal muscle has a critical role in the regulation of the energy balance of the organism, particularly as the principal tissue responsible for insulin-stimulated glucose disposal and as the major site of peripheral insulin resistance (IR), which has been related to accumulation of lipid intermediates, reduced oxidative capacity of mitochondria and endoplasmic reticulum (ER) stress. These organelles form contact sites, known as mitochondria-associated ER membranes (MAMs). This interconnection seems to be involved in various cellular processes, including Ca2+ transport and energy metabolism; therefore, MAMs could play an important role in maintaining cellular homeostasis. Evidence suggests that alterations in MAMs may contribute to IR. However, the evidence does not refer to a specific subcellular location, which is of interest due to the fact that skeletal muscle is constituted by oxidative and glycolytic fibers as well as different mitochondrial populations that appear to respond differently to stimuli and pathological conditions. In this review, we show the available evidence of possible differential responses in the formation of MAMs in skeletal muscle as well as its role in insulin signaling and the beneficial effect it could have in the regulation of energetic metabolism and muscular contraction.

Keywords:  insulin resistance; mitochondria-associated ER membranes (MAMs); mitochondrial dysfunction; mitochondrial skeletal muscle; mitochondrial subpopulations; obesity

DOI:  https://doi.org/10.3389/fmolb.2022.959844
J Physiol. 2022 Oct 27.

The time is now: Regular exercise maintains vascular health in aging women.

Andrea Tamariz-Ellemann, Kate Aiko Wickham, L B Nørregaard, Lasse Gliemann, Ylva Hellsten.

  Although aging impairs cardiovascular health in both men and women, the timeline is different between the sexes. This is at least partially attributed to the loss of estrogen in women at midlife, in connection with menopause. Estrogen has protective effects on the cardiovascular system, and menopause consequently leads to a rapid and significant decline in cardiovascular health. Notably, estrogen interacts with its nuclear and membrane receptors leading to changes in proteins of importance for cardiovascular health. Skeletal muscle activity, which affects the expression of many of the same proteins as estrogen, could potentially counteract the loss of 8estrogen at menopause. The hypothesis that exercise can counteract the loss of estrogen has been explored in several recent studies. It has been found that regular physical activity opposes the detrimental effects not only of aging, but also the menopausal transition, on cardiovascular health. Although, vascular benefits can be gained at all ages, initiating physical activity at or soon after menopause may be more effective than at a later time point in life. Intuitively, it is easier to prevent decrements than attempting to regain lost vascular health. This idea is supported by evidence at the molecular level, suggesting that exercise-induced activation of the estrogen-related receptor alpha pathway is more effective soon after menopause compared to later. Together, although a decline in cardiovascular health due to chronological aging cannot be completely prevented, a physically active lifestyle mitigates age-related cardiovascular impairments. Importantly, regular physical activity through life should always be addressed as the biological norm. Abstract figure legend Compared to a physically inactive lifestyle, lifelong participation in physical activity protects against the development of vascular disease. However, aging and menopause, irrespective of physical activity status, have inevitable, negative effects on vascular health. Importantly, if regular exercise is initiated around the menopausal transition, the vascular consequences of aging and menopause can be, at least partially, mitigated. This article is protected by copyright. All rights reserved.

Keywords:  aging; exercise; menopause; vascular health

DOI:  https://doi.org/10.1113/JP282896
Nutrients. 2022 Oct 19. pii: 4376. [Epub ahead of print]14(20):

Ketone Ester Supplementation Improves Some Aspects of Cognitive Function during a Simulated Soccer Match after Induced Mental Fatigue.

Manuel D Quinones, Peter W R Lemon.

  Ketone supplementation has been proposed to enhance cognition during exercise. To assess whether any benefits are due to reduced cognitive fatigue during the latter portions of typical sport game action, we induced cognitive fatigue, provided a ketone monoester supplement (KME) vs. a non-caloric placebo (PLAC), and assessed cognitive performance during a simulated soccer match (SSM). In a double-blind, balanced, crossover design, nine recreationally active men (174.3 ± 4.2 cm, 76.6 ± 7.4 kg, 30 ± 3 y, 14.2 ± 5.5 % body fat, V˙O2 max = 55 ± 5 mL·kg BM-1·min-1; mean ± SD) completed a 45-min SSM (3 blocks of intermittent, variable intensity exercise) consuming either KME (25 g) or PLAC, after a 40-min mental fatiguing task. Cognitive function (Stroop and Choice Reaction Task [CRT]) and blood metabolites were measured throughout the match. KME reduced concentrations of both blood glucose (block 2: 4.6 vs. 5.2 mM, p = 0.02; block 3: 4.7 vs. 5.3 mM, p = 0.01) and blood lactate (block 1: 4.7 vs. 5.4 mM, p = 0.05; block 2: 4.9 vs. 5.9 mM, p = 0.01) during the SSM vs. PLAC, perhaps indicating a CHO sparing effect. Both treatments resulted in impaired CRT performance during the SSM relative to baseline, but KME displayed a reduced (p < 0.05) performance decrease compared to PLAC (1.3 vs. 3.4% reduction in correct answers, p = 0.02). No other differences in cognitive function were seen. These data suggest that KME supplementation attenuated decrements in CRT during repeated, high intensity, intermittent exercise. More study is warranted to assess fully the potential cognitive/physical benefits of KME for athletes.

Keywords:  cognition; exogenous ketones; intermittent exercise; ketosis; soccer

DOI:  https://doi.org/10.3390/nu14204376
Heliyon. 2022 Oct;8(10): e11091

AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism.

Ryan M Esquejo, Bina Albuquerque, Anna Sher, Matthew Blatnik, Kyle Wald, Matthew Peloquin, Jake Delmore, Erick Kindt, Wenlin Li, Jamey D Young, Kim Cameron, Russell A Miller.

  The AMP-activated protein kinase (AMPK) is a cellular sensor of energetics and when activated in skeletal muscle during contraction can impart changes in skeletal muscle metabolism. Therapeutics that selectively activate AMPK have been developed to lower glucose levels through increased glucose disposal rates as an approach to abrogate the hyperglycemic state of diabetes; however, the metabolic fate of glucose following AMPK activation remains unclear. We have used a combination of in vivo evaluation of glucose homeostasis and ex vivo skeletal muscle incubation to systematically evaluate metabolism following pharmacological activation of AMPK with PF-739, comparing this with AMPK activation through sustained intermittent electrical stimulation of contraction. These methods to activate AMPK result in increased glucose uptake but divergent metabolism of glucose: pharmacological activation results in increased glycogen accumulation while contraction-induced glucose uptake results in increased lactate formation and glucose oxidation. These results provide additional evidence to support a role for AMPK in control of skeletal muscle metabolism and additional insight into the potential for AMPK stimulation with small molecule direct activators.

Keywords:  AMPK; Metabolism; Pharmacology; Skeletal muscle

DOI:  https://doi.org/10.1016/j.heliyon.2022.e11091
Int J Mol Sci. 2022 Oct 19. pii: 12559. [Epub ahead of print]23(20):

The Effects of Exercise Training on Mitochondrial Function in Cardiovascular Diseases: A Systematic Review and Meta-Analysis.

Ai Yin Lim, Yi-Ching Chen, Chih-Chin Hsu, Tieh-Cheng Fu, Jong-Shyan Wang.

  Mitochondria dysfunction is implicated in the pathogenesis of cardiovascular diseases (CVD). Exercise training is potentially an effective non-pharmacological strategy to restore mitochondrial health in CVD. However, how exercise modifies mitochondrial functionality is inconclusive. We conducted a systematic review using the PubMed; Scopus and Web of Science databases to investigate the effect of exercise training on mitochondrial function in CVD patients. Search terms included "mitochondria", "exercise", "aerobic capacity", and "cardiovascular disease" in varied combination. The search yielded 821 records for abstract screening, of which 20 articles met the inclusion criteria. We summarized the effect of exercise training on mitochondrial morphology, biogenesis, dynamics, oxidative capacity, antioxidant capacity, and quality. Amongst these parameters, only oxidative capacity was suitable for a meta-analysis, which demonstrated a significant effect size of exercise in improving mitochondrial oxidative capacity in CVD patients (SMD = 4.78; CI = 2.99 to 6.57; p < 0.01), but with high heterogeneity among the studies (I2 = 75%, p = 0.003). Notably, aerobic exercise enhanced succinate-involved oxidative phosphorylation. The majority of the results suggested that exercise improves morphology and biogenesis, whereas findings on dynamic, antioxidant capacity, and quality, were inadequate or inconclusive. A further randomized controlled trial is clearly required to explain how exercise modifies the pathway of mitochondrial quantity and quality in CVD patients.

Keywords:  cardiovascular system; exercise; mitochondrial function; oxidative capacity

DOI:  https://doi.org/10.3390/ijms232012559
Eur J Immunol. 2022 Oct 25.

The thioredoxin system: balancing redox responses in immune cells and tumors.

Jonathan Muri, Manfred Kopf.

  The thioredoxin (TRX) system is an important contributor to cellular redox balance and regulates cell growth, apoptosis, gene expression, and antioxidant defense in nearly all living cells. Oxidative stress, the imbalance between reactive oxygen species (ROS) and antioxidants, can lead cell death and tissue damage, thereby contributing to ageing and to the development of several diseases, including cardiovascular and allergic diseases, diabetes, and neurological disorders. Targeting its activity is also considered as a promising strategy in the treatment of cancer. Over the past years, immunologists have established an essential function of TRX for activation, proliferation, and responses in T cells, B cells, and macrophages. Upon activation, immune cells rearrange their redox system and activate the TRX pathway to promote proliferation through sustainment of nucleotide biosynthesis and to support inflammatory responses in myeloid cells by allowing NF-κB and NLRP3 inflammasome responses. Consequently, targeting the TRX system may therapeutically be exploited to inhibit immune responses in inflammatory conditions. In this review, we summarize recent insights revealing key roles of the TRX pathway in immune cells in health and disease, and lessons learnt for cancer therapy. This article is protected by copyright. All rights reserved.

Keywords:  TRX system ⋅ Immunoregulation ⋅ ROS ⋅ Cancer ⋅ Cellular redox

DOI:  https://doi.org/10.1002/eji.202249948
J Inflamm Res. 2022 ;15 5917-5933

Inhibition of Dectin-1 Alleviates Neuroinflammatory Injury by Attenuating NLRP3 Inflammasome-Mediated Pyroptosis After Intracerebral Hemorrhage in Mice: Preliminary Study Results.

Zhiquan Ding, Zhenzhong Zhong, Jun Wang, Run Zhang, Jinlian Shao, Yulong Li, Guiwei Wu, Huiru Tu, Wen Yuan, Haitao Sun, Qinghua Wang.

   Background: Neuroinflammation plays an important role following intracerebral hemorrhage (ICH). NLRP3 inflammasome-mediated pyroptosis contributes to the mechanism of neuroinflammation. It has been reported that dendritic cell-associated C-type lectin-1 (Dectin-1) activation triggers inflammation in neurological diseases. However, the role of Dectin-1 on NLRP3 inflammasome-mediated pyroptosis after ICH remains unclear. Here, we aimed to explore the effect of Dectin-1 on NLRP3 inflammasome-mediated pyroptosis and neuroinflammation after ICH.
Methods: Adult male C57BL/6 mice were used to establish the ICH model. Laminarin, an inhibitor of Dectin-1, was administered for intervention. Expression of Dectin-1 was evaluated by Western blot and immunofluorescence. Brain water content and neurobehavioral function were tested to assess brain edema and neurological performance. Western blot was conducted to evaluate the level of GSDMD-N. ELISA kits were used to measure the levels of IL-1β and IL-18. qRT-PCR and Western blot were performed to evaluate the expressions of NLRP3 inflammasome, IL-1β, and IL-18.
Results: The expression of Dectin-1 increased following ICH, and Dectin-1 was expressed on microglia. In addition, inhibition of Dectin-1 by laminarin decreased brain edema and neurological impairment after ICH. Moreover, inhibition of Dectin-1 decreased the expression of pyroptosis-related protein, GSDMD-N, and inflammatory cytokines (IL-1β and IL-18). Mechanistically, Dectin-1 blockade inhibits NLRP3 inflammasome activation, thereby alleviating neuroinflammatory injury by attenuating NLRP3 inflammasome-mediated pyroptosis both in vivo and in vitro.
Conclusion: Our study indicates that the inhibition of Dectin-1 alleviates neuroinflammation by attenuating NLRP3 inflammasome-mediated pyroptosis after ICH.

Keywords:  Dectin-1; NLRP3 inflammasome; intracerebral hemorrhage; microglia; pyroptosis

DOI:  https://doi.org/10.2147/JIR.S384020
Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00111-3. [Epub ahead of print]373 125-158

Autophagy-inducing nutritional interventions in experimental and clinical oncology.

Sebastian J Hofer, Guido Kroemer, Oliver Kepp.

  Numerous pro-autophagic dietary interventions are being investigated for their potential cancer-preventive or therapeutic effects. This applies to different fasting regimens, methionine restriction and ketogenic diets. In addition, the supplementation of specific micronutrients such as nicotinamide (vitamin B3) or spermidine induces autophagy. In humans, leanness, plant-based diets (that may lead to partial methionine restriction) and high dietary uptake of spermidine are associated with a low incidence of cancers. Moreover, clinical trials have demonstrated the capacity of nicotinamide to prevent non-melanoma skin carcinogenesis. Multiple interventional trials are evaluating the capacity of autophagy-inducing regimens to improve the outcome of chemotherapy and immunotherapy. Here, we discuss the mechanistic underpinnings of autophagy induction by nutritional interventions, as well as the mechanisms through which autophagy induction in malignant or immune cells improves anticancer immunosurveillance.

Keywords:  Checkpoint blockade; Dietary restriction; Immunogenic cell death; Immunotherapy

DOI:  https://doi.org/10.1016/bs.ircmb.2022.08.003
Cells. 2022 Oct 21. pii: 3318. [Epub ahead of print]11(20):

Neutrophil Extracellular Vesicles: A Delicate Balance between Pro-Inflammatory Responses and Anti-Inflammatory Therapies.

Yang Zhou, Sabrina Bréchard.

  Extracellular vesicles (EVs) are released in the extracellular environment during cell activation or apoptosis. Working as signal transducers, EVs are important mediators of intercellular communication through the convoying of proteins, nucleic acids, lipids, and metabolites. Neutrophil extracellular vesicles (nEVs) contain molecules acting as key modulators of inflammation and immune responses. Due to their potential as therapeutic tools, studies about nEVs have been increasing in recent years. However, our knowledge about nEVs is still in its infancy. In this review, we summarize the current understanding of the role of nEVs in the framework of neutrophil inflammation functions and disease development. The therapeutic potential of nEVs as clinical treatment strategies is deeply discussed. Moreover, the promising research landscape of nEVs in the near future is also examined.

Keywords:  extracellular vesicles; inflammation; neutrophils; therapy

DOI:  https://doi.org/10.3390/cells11203318
Biomedicines. 2022 Oct 12. pii: 2539. [Epub ahead of print]10(10):

Mitochondrial Dysfunction, Mitophagy and Their Correlation with Perinatal Complications: Preeclampsia and Low Birth Weight.

Raziye Melike Yildirim, Yagmur Ergun, Murat Basar.

  Mitochondria are essential organelles and crucial for cellular survival. Mitochondrial biogenesis and mitophagy are dynamic features that are essential for both maintaining the health of the mitochondrial network and cellular demands. The accumulation of damaged mitochondria has been shown to be related to a wide range of pathologies ranging from neurological to musculoskeletal. Mitophagy is the selective autophagy of mitochondria, eliminating dysfunctional mitochondria in cells by engulfment within double-membraned vesicles. Preeclampsia and low birth weight constitute prenatal complications during pregnancy and are leading causes of maternal and fetal mortality and morbidity. Both placental implantation and fetal growth require a large amount of energy, and a defect in the mitochondrial quality control mechanism may be responsible for the pathophysiology of these diseases. In this review, we compiled current studies investigating the role of BNIP3, DRAM1, and FUNDC1, mediators of receptor-mediated mitophagy, in the progression of preeclampsia and the role of mitophagy pathways in the pathophysiology of low birth weight. Recent studies have indicated that mitochondrial dysfunction and accumulation of reactive oxygen species are related to preeclampsia and low birth weight. However, due to the lack of studies in this field, the results are controversial. Therefore, mitophagy-related pathways associated with these pathologies still need to be elucidated. Mitophagy-related pathways are among the promising study targets that can reveal the pathophysiology behind preeclampsia and low birth weight.

Keywords:  fetal growth restriction; low birth weight; mitochondria; mitophagy; perinatal complications; preeclampsia

DOI:  https://doi.org/10.3390/biomedicines10102539
Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00010-7. [Epub ahead of print]373 81-106

Fasting and cancer: from yeast to mammals.

Maira Di Tano, Valter D Longo.

  Fasting and fasting mimicking diets extend lifespan and healthspan in mouse models and decrease risk factors for cancer and other age-related pathologies in humans. Normal cells respond to fasting and the consequent decrease in nutrients by down-regulating proto-oncogene pathways to enter a stress-resistant mode, which protects them from different cancer therapies. In contrast, oncogene mutations and the constitutive activation of pathways including RAS, AKT, and PKA allow cancer cells to disobey fasting-dependent anti-growth signal. Importantly, in different tumor types, fasting potentiates the toxicity of various therapies by increasing reactive oxygen species and oxidative stress, which ultimately leads to DNA damage and cell death. This effect is not limited to chemotherapy, since periodic fasting/FMD cycles potentiate the effects of tyrosine kinase inhibitors, hormone therapy, radiotherapy, and pharmacological doses of vitamin C. In addition, the anticancer effects of fasting/FMD can also be tumor-independent and involve an immunotherapy-like activation of T cell-dependent attack of tumor cells. Supported by a range of pre-clinical studies, clinical trials are beginning to confirm the safety and efficacy of fasting/FMD cycles in improving the potential of different cancer therapies, while decreasing side effects to healthy cells and tissues.

Keywords:  Cancer; Differential stress resistance; Differential-stress sensitization; Fasting-mimicking diet; Longevity

DOI:  https://doi.org/10.1016/bs.ircmb.2022.02.005
Antioxidants (Basel). 2022 Oct 08. pii: 1995. [Epub ahead of print]11(10):

The Complex Interplay between Mitochondria, ROS and Entire Cellular Metabolism.

Andrey V Kuznetsov, Raimund Margreiter, Michael J Ausserlechner, Judith Hagenbuchner.

  Besides their main function for energy production in form of ATP in processes of oxidative phosphorylation (OxPhos), mitochondria perform many other important cellular functions and participate in various physiological processes that are congregated. For example, mitochondria are considered to be one of the main sources of reactive oxygen species (ROS) and therefore they actively participate in the regulation of cellular redox and ROS signaling. These organelles also play a crucial role in Ca2+ signaling and homeostasis. The mitochondrial OxPhos and their cellular functions are strongly cell/tissue specific and can be heterogeneous even within the same cell, due to the existence of mitochondrial subpopulations with distinct functional and structural properties. However, the interplay between different functions of mitochondria is not fully understood. The mitochondrial functions may change as a response to the changes in the cellular metabolism (signaling in). On the other hand, several factors and feedback signals from mitochondria may influence the entire cell physiology (signaling out). Numerous interactions between mitochondria and the rest of cell, various cytoskeletal proteins, endoplasmic reticulum (ER) and other cellular elements have been demonstrated, and these interactions could actively participate in the regulation of mitochondrial and cellular metabolism. This review highlights the important role of the interplay between mitochondrial and entire cell physiology, including signaling from and to mitochondria.

Keywords:  ROS; calcium; cellular metabolism; mitochondria; mitochondrial function/morphology; mitochondrial interactions; redox state; signaling

DOI:  https://doi.org/10.3390/antiox11101995
Front Pharmacol. 2022 ;13 998574

NLRP3-mediated pyroptosis in diabetic nephropathy.

Jiayi Wan, Dongwei Liu, Shaokang Pan, Sijie Zhou, Zhangsuo Liu.

  Diabetic nephropathy (DN) is the main cause of end-stage renal disease (ESRD), which is characterized by a series of abnormal changes such as glomerulosclerosis, podocyte loss, renal tubular atrophy and excessive deposition of extracellular matrix. Simultaneously, the occurrence of inflammatory reaction can promote the aggravation of DN-induced kidney injury. The most important processes in the canonical inflammasome pathway are inflammasome activation and membrane pore formation mediated by gasdermin family. Converging studies shows that pyroptosis can occur in renal intrinsic cells and participate in the development of DN, and its activation mechanism involves a variety of signaling pathways. Meanwhile, the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome can not only lead to the occurrence of inflammatory response, but also induce pyroptosis. In addition, a number of drugs targeting pyroptosis-associated proteins have been shown to have potential for treating DN. Consequently, the pathogenesis of pyroptosis and several possible activation pathways of NLRP3 inflammasome were reviewed, and the potential drugs used to treat pyroptosis in DN were summarized in this review. Although relevant studies are still not thorough and comprehensive, these findings still have certain reference value for the understanding, treatment and prognosis of DN.

Keywords:  diabetic nephropathy; drugs; pathogenesis; pyroptosis; signaling pathways

DOI:  https://doi.org/10.3389/fphar.2022.998574