bims-kimdis 2023-01-15 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒01‒15
thirty-one papers selected by
Matías Javier Monsalves Álvarez

Effects of Hypocaloric Low-Fat, Ketogenic and Ketogenic & Ketone Supplement diets on Aldosterone and Renin.
Intractable Seizures in Children With Type 1 Diabetes: Implications of the Ketogenic Diet.
Ketogenic Diet Combined with Moderate Aerobic Exercise Training Ameliorates White Adipose Tissue Mass, Serum Biomarkers, and Hepatic Lipid Metabolism in High-Fat Diet-Induced Obese Mice.
Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis.
Muscle fiber type grouping does not change in response to prolonged resistance exercise training in healthy older men.
Impact of ketogenic diet therapy on growth in children with epilepsy.
Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.
SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.
Mitochondrial signalling and homeostasis: from cell biology to neurological disease.
NLRP3 Inflammasome: From Pathophysiology to Therapeutic Target in Major Depressive Disorder.
FAT/CD36 Participation in Human Skeletal Muscle Lipid Metabolism: A Systematic Review.
A Skeletal Muscle-Centric View on Time-Restricted Feeding and Obesity under Various Metabolic Challenges in Humans and Animals.
Inflammation and oxidative stress in salt sensitive hypertension; The role of the NLRP3 inflammasome.
Fasting for 20 h does not affect exercise-induced increases in circulating BDNF in humans.
Role of microbiome and its metabolite, short chain fatty acid in prostate cancer.
Sleep deprivation and NLRP3 inflammasome: Is there a causal relationship?
How to adjust muscle mass while defining sarcopenia component of sarcopenic obesity: is body weight sufficient enough to represent body size?
Remarks on Mitochondrial Myopathies.
Carnosine increases insulin-stimulated glucose uptake and reduces methylglyoxal-modified proteins in type-2 diabetic human skeletal muscle cells.
Chronic kidney disease and NLRP3 inflammasome: Pathogenesis, development and targeted therapeutic strategies.
High fiber diet attenuate the inflammation and adverse remodeling of myocardial infarction via modulation of gut microbiota and metabolites.
Update on Anti-Inflammatory Molecular Mechanisms Induced by Oleic Acid.
Intramuscular mitochondrial and lipid metabolic changes of rats after regular high-intensity interval training (HIIT) of different training periods.
Long-Chain and Medium-Chain Fatty Acids in Energy Metabolism of Murine Kidney Mitochondria.
Integrative Proteome Analysis Revels 3-Hydroxybutyrate Exerts Neuroprotective Effect by Influencing Chromatin Bivalency.
Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization.
Canonical and non-canonical functions of NLRP3.
Exercise blood-drop metabolic profiling links metabolism with perceived exertion.
Pyroptosis, inflammasome, and gasdermins in tumor immunity.
Effects of Resveratrol on Muscle Inflammation, Energy Utilisation, and Exercise Performance in an Eccentric Contraction Exercise Mouse Model.
Mitochondrial dysfunction in a rat model and the related risk of metabolic disorders.

J Clin Endocrinol Metab. 2023 Jan 11. pii: dgad009. [Epub ahead of print]

Effects of Hypocaloric Low-Fat, Ketogenic and Ketogenic & Ketone Supplement diets on Aldosterone and Renin.

Paul Belany, Madison L Kackley, Songzhu Zhao, Bjorn Kluwe, Alex Buga, Chris Crabtree, Divya Nedungadi, David Kline, Guy Brock, Orlando P Simonetti, Jeff S Volek, Joshua J Joseph.

  CONTEXT: Ketogenic diets (KDs) and low-fat diets (LFD) result in similar weight loss, but differential cardiometabolic effects on lipids and insulin. Generally, weight loss decreases renin-angiotensin-aldosterone system (RAAS) activity.OBJECTIVE: Investigate the effects of KDs with varying sodium content versus LFD on RAAS in overweight and obese adults.
DESIGN: Twenty-eight participants were randomized 1:1 to KD + ketone salt supplement (KD + KS) or a KD + placebo (KD + PL) arms with prepared hypocaloric meals. Twelve participants were enrolled in a post-hoc LFD arm. Serum renin, aldosterone, anthropometric and metabolic biomarkers, were assessed at 0, 2, 4, and 6 weeks. Linear mixed models with random intercepts were used to compare between group differences controlling for sex and body mass index.
RESULTS: Participants had a median age of 33 years, 51% female, weighed 91.3 kg, with body mass index 30.6 kg/m2. At 6 weeks, weight decreased by 6, 8, and 7 kg on average in the KD + KS, KD + PL, and LFD groups, respectively (p < 0.05). Aldosterone increased by 88% and 144% in the KD + PL and KD + KS groups, respectively, but did not change in the LFD after 6 weeks while renin decreased across groups. Systolic and diastolic blood pressure did not change in the KD + PL and KD + KS groups. Log-ketones were positively associated with aldosterone (p < 0.001). Aldosterone was not associated with cardiovascular measures including blood pressure and ejection fraction (p > 0.05).
CONCLUSION: KD reduced weight and increased aldosterone without worsening cardiometabolic risk factors. Future KD studies are needed to elucidate mechanistic connections between ketones and aldosterone.

Keywords:  Adiposity; Aldosterone; Ketogenic Diet; Ketones; Renin

DOI:  https://doi.org/10.1210/clinem/dgad009
WMJ. 2022 Dec;121(4): 292-296

Intractable Seizures in Children With Type 1 Diabetes: Implications of the Ketogenic Diet.

Kimberly K Vidmar, Allison J Pollock.

INTRODUCTION: The ketogenic diet is prescribed for seizures in some children with epilepsy. Children with type 1 diabetes are at risk for diabetic ketoacidosis caused by ketosis due to decreased insulin effect. Currently there are no clinical guidelines regarding the safety and efficacy of the ketogenic diet in patients with concurrent epilepsy and type 1 diabetes.OBJECTIVES: This review examines the current literature regarding the association between TID and epilepsy, proposed mechanisms for the observed relationship, risks and benefits of the ketogenic diet, and clinical applications of the ketogenic diet in the context of type 1 diabetes and epilepsy.
METHODS: PubMed was used to identify relevant articles. Key search terms included, "type 1 diabetes," "ketogenic diet," "seizure," "epilepsy," and "autoimmunity."
RESULTS: There is an observed association between type 1 diabetes and epilepsy, with proposed mechanisms including genetic predisposition, anti-glutamic acid decarboxylase (GAD) antibodies, metabolic derangements and cerebrovascular damages. Case reports describe the use of the ketogenic diet for epilepsy management in children with diabetes with mixed results; however, there are no large, randomized controlled trials to evaluate the broader application of these findings.
CONCLUSIONS: In summary, there is inadequate evidence to support the use of the ketogenic diet in patients with coexisting epilepsy and type 1 diabetes in clinical practice. Further research is needed to determine the effectiveness, safety, and monitoring parameters of the ketogenic diet for these patients. The risks and benefits of the ketogenic diet as medical nutrition therapy for patients with both type 1 diabetes and epilepsy should be considered on an individualized basis.
Nutrients. 2023 Jan 03. pii: 251. [Epub ahead of print]15(1):

Ketogenic Diet Combined with Moderate Aerobic Exercise Training Ameliorates White Adipose Tissue Mass, Serum Biomarkers, and Hepatic Lipid Metabolism in High-Fat Diet-Induced Obese Mice.

Jiabao Yan, Cuiru Ren, Yunlong Dong, Jibran A Wali, Hongjie Song, Ying Zhang, Hengrui Zhang, Guangning Kou, David Raubenheimer, Zhenwei Cui.

  Obesity is a serious public health issue worldwide. Growing evidence demonstrates the efficacy of the ketogenic diet (KD) for weight loss, but there may be some adverse side effects such as dyslipidemia and hepatic steatosis. Aerobic exercise is a widely recognized approach for improving these metabolic markers. Here we explored the combined impacts of KD and moderate aerobic exercise for an 8-week intervention on body weight and fat loss, serum biomarkers, and hepatic lipid metabolism in a mouse model of high-fat diet-induced obesity. Both KD and KD combined with exercise significantly reduced body weight and fat mass. No significant adverse effects of KD were observed in serum biomarkers or hepatic lipid storage, except for an increase in circulating triglyceride level. However, aerobic exercise lowered serum triglyceride levels, and further ameliorated serum parameters, and hepatic steatosis in KD-fed mice. Moreover, gene and protein expression analysis indicated that KD combined with exercise was associated with increased expression of lipolysis-related genes and protein levels, and reduced expression of lipogenic genes relative to KD without exercise. Overall, our findings for mice indicate that further work on humans might reveal that KD combined with moderate aerobic exercise could be a promising therapeutic strategy for obesity.

Keywords:  aerobic exercise; ketogenic diet; lipid metabolism; obesity

DOI:  https://doi.org/10.3390/nu15010251
Nutr Rev. 2023 Jan 12. pii: nuac104. [Epub ahead of print]

Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis.

Carolina B Castro, Cintia B Dias, Heidi Hillebrandt, Hamid R Sohrabi, Pratishtha Chatterjee, Tejal M Shah, Stephanie J Fuller, Manohar L Garg, Ralph N Martins.

  CONTEXT: In preclinical Alzheimer's disease (AD), the brain gradually becomes insulin resistant. As a result, brain glucose utilization is compromised, causing a cellular energy deficit that leads to the accumulation of free radicals, which increases inflammation and damages neurons. When glucose utilization is impaired, ketone bodies offer an alternative energy source. Ketone bodies are synthesized from fats, obtained from either the diet or adipose tissue. Dietary medium-chain fatty acids (MCFAs), which are preferentially metabolized into ketone bodies, have the potential to supply the insulin-resistant brain with energy.OBJECTIVE: This systematic review and meta-analysis aims to review the effect of MCFA supplements on circulating ketone bodies and cognition in individuals with subjective cognitive decline, mild cognitive impairment, and AD.
DATA SOURCES: A comprehensive search of electronic databases was performed on August 12, 2019, to retrieve all publications meeting the inclusion criteria. Alerts were then set to identify any publications after the search date up until January 31, 2021.
DATA EXTRACTION: Data were extracted by 2 authors and assessed by a third. In total, 410 publications were identified, of which 16 (n = 17 studies) met the inclusion criteria.
DATA ANALYSIS: All studies assessing change in levels of blood ketone bodies due to MCFA supplementation (n = 12) reported a significant increase. Cognition outcomes (measured in 13 studies), however, varied, ranging from no improvement (n = 4 studies) to improvement (n = 8 studies) or improvement only in apolipoprotein E allele 4 (APOE ε4) noncarriers (n = 2 studies). One study reported an increase in regional cerebral blood flow in APOE ε4 noncarriers and another reported an increase in energy metabolism in the brain.
CONCLUSION: MCFA supplementation increases circulating ketone body levels, resulting in increased brain energy metabolism. Further research is required to determine whether this MCFA-mediated increase in brain energy metabolism improves cognition.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42019146967.

Keywords:  Alzheimer’s; MCT oil; coconut oil; dementia; medium-chain fatty acids; nutrition; prevention

DOI:  https://doi.org/10.1093/nutrit/nuac104
Exp Gerontol. 2023 Jan 05. pii: S0531-5565(23)00004-9. [Epub ahead of print] 112083

Muscle fiber type grouping does not change in response to prolonged resistance exercise training in healthy older men.

Dominika Kraková, Andrew M Holwerda, Milan W Betz, Kaleen M Lavin, Marcas M Bamman, Luc J C van Loon, Lex B Verdijk, Tim Snijders.

  BACKGROUND: Ageing of skeletal muscle is characterized in some by muscle fiber type grouping due to denervation-reinnervation cycles, but the severity of fiber type grouping varies widely across individuals of the same chronological age. It remains unknown whether fiber type grouping is associated with lower muscle mass and/or reduced physical function in elderly. Therefore, we assessed the relationship between fiber type grouping and indices of muscle mass and physical function in older adults. In addition, we assessed whether fiber type grouping is affected by prolonged resistance training in older adults.METHODS: Twenty young (21 ± 2 y) and twenty older (70 ± 4 y) healthy men participated in the present study. Body composition (DXA-scan), quadriceps cross-sectional area (CT-scan) and muscle strength (1RM) were assessed at baseline (young and old) and following 12 weeks of resistance training (old only). Percutaneous skeletal muscle biopsies from the vastus lateralis were collected at baseline (young and old) and following exercise training (old only). Immunohistochemical analyses were performed to evaluate type I and type II muscle fiber distribution, size, myonuclear content and grouping.
RESULTS: At baseline, type II fibers were significantly (P < 0.05) smaller in older compared with young adults (5366 ± 1288 vs 6705 ± 1168 μm2). Whereas no differences were observed in type I, type II fiber grouping was significantly (P < 0.05) lower in older (18 ± 18 %) compared with young (32 ± 25 %) men. No significant correlations were observed between fiber type grouping and muscle mass or physical function. Prolonged resistance training in old men resulted in a significant increase (P < 0.05) in type II fiber size (from 5366 ± 1288 to 6165 ± 1484 μm2) with no significant changes in the proportion of type I muscle fibers found grouped.
CONCLUSION: Muscle fiber type grouping is not associated with lower body strength or muscle mass in healthy, older men. In addition, twelve weeks of resistance exercise training results in type II muscle fiber specific hypertrophy but does not affect fiber type grouping.

Keywords:  Hypertrophy; Morphology; Myosin heavy chain; Sarcopenia

DOI:  https://doi.org/10.1016/j.exger.2023.112083
Epilepsy Res. 2023 Jan 06. pii: S0920-1211(23)00001-3. [Epub ahead of print]190 107076

Impact of ketogenic diet therapy on growth in children with epilepsy.

Serena Lu, Helena Champion, Nicole Mills, Zoe Simpson, Victoria J Whiteley, Natasha E Schoeler.

  RATIONALE: Ketogenic diet therapy (KDT) is an effective treatment for drug-resistant epilepsy in children. There is conflicting evidence regarding the impact of KDT on growth. We aimed to determine whether linear growth and weight were affected in children who followed KDT in the UK, and to explore potential associations with clinical or demographic factors with impacted growth.METHODS: A retrospective review of medical records of children with epilepsy following KDT at 3 UK centres was conducted. Height and weight measurements taken as part of routine clinical management were recorded at baseline, 1-8 years on diet, and 1-year post-diet. Measurements were converted into z-scores, and the differences from baseline analysed using Wilcoxon Signed Rank tests. Potential associations of impacted growth with feeding method, ambulatory status, diet type, age at diet onset and average daily protein intake were investigated using Mann-Whitney, Kruskal-Wallis tests or Spearman's Rank correlation.
RESULTS: 265 individuals were included, of which 84 had post-diet data available. Median height z-score significantly decreased at 1- (n = 139, p = .018), 2- (n = 86, p < .0005) and 3 years (n = 27, p = .001) on diet. There was no significant change to height or weight z-score 1-year post-diet discontinuation. Median weight z-score significantly decreased from baseline at 4 years (n = 15, p = .020), and 6 years (n = 8, p = .025) on diet, but not at other time points. There was greater height z-score decrease in non-ambulatory children at 2 years (p = .009), in those following a classical diet compared with the modified ketogenic diet at 2 years (p = .006) and amongst younger children at 2 years (n = 86, p < .005) and 3 years (n = 27, p = .008) on diet. No significant differences were found in weight z-score change across any subgroup, following Bonferroni correction for multiple testing.
CONCLUSIONS: Median linear growth was significantly adversely affected for the first 3 years on KDT but catch-up growth post diet discontinuation was observed. Non-ambulatory children, younger children, and individuals following a classical diet may be more vulnerable to impacted growth when on KDT, although this was not consistent across all time points. The potential short-term impact on linear growth should be discussed with individuals considering KDT, and monitored closely.

Keywords:  Height; High fat; Low carbohydrate; Seizures; Weight

DOI:  https://doi.org/10.1016/j.eplepsyres.2023.107076
Cell Rep. 2023 Jan 09. pii: S2211-1247(22)01842-3. [Epub ahead of print]42(1): 111941

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.

Allison K Meyers, Zhan Wang, Wenzheng Han, Qingxia Zhao, Manal Zabalawi, Likun Duan, Juan Liu, Qianyi Zhang, Rajesh K Manne, Felipe Lorenzo, Matthew A Quinn, Qianqian Song, Daping Fan, Hui-Kuan Lin, Cristina M Furdui, Jason W Locasale, Charles E McCall, Xuewei Zhu.

  Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and interleukin-1β (IL-1β) secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves crista ultrastructure, and attenuates mitochondrial reactive oxygen species (ROS) production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. Our study suggestsa non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation.

Keywords:  CP: Immunology; NLRP3 inflammasome; autophagy; cristae; immunometabolism; macrophages; metabolic flux; mitochondria; mitochondrial fission and fusion; pyruvate dehydrogenase kinase; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2022.111941
Nat Rev Cardiol. 2023 Jan 06.

SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.

Milton Packer.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.

DOI: https://doi.org/10.1038/s41569-022-00824-4
Trends Neurosci. 2023 Jan 10. pii: S0166-2236(22)00239-9. [Epub ahead of print]

Mitochondrial signalling and homeostasis: from cell biology to neurological disease.

Jack J Collier, Monika Oláhová, Thomas G McWilliams, Robert W Taylor.

  Efforts to understand how mitochondrial dysfunction contributes to neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress in understanding the etiological nature of emerging mitochondrial functions has yielded new ideas about the mitochondrial basis of neurological disease. Studies aimed at deciphering how mitochondria signal through interorganellar contacts, vesicular trafficking, and metabolic transmission have revealed that mitochondrial regulation of immunometabolism, cell death, organelle dynamics, and neuroimmune interplay are critical determinants of neural health. Moreover, the homeostatic mechanisms that exist to protect mitochondrial health through turnover via nanoscale proteostasis and lysosomal degradation have become integrated within mitochondrial signalling pathways to support metabolic plasticity and stress responses in the nervous system. This review highlights how these distinct mitochondrial pathways converge to influence neurological health and contribute to disease pathology.

Keywords:  immunity; inflammation; metabolism; mitochondrial-derived vesicles; mitochondria–lysosome axis; quality control

DOI:  https://doi.org/10.1016/j.tins.2022.12.001
Int J Mol Sci. 2022 Dec 21. pii: 133. [Epub ahead of print]24(1):

NLRP3 Inflammasome: From Pathophysiology to Therapeutic Target in Major Depressive Disorder.

Bruna R Kouba, Joana Gil-Mohapel, Ana Lúcia S Rodrigues.

  Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, whose pathophysiology has been linked to the neuroinflammatory process. The increased activity of the Nod-like receptor pyrin containing protein 3 (NLRP3) inflammasome, an intracellular multiprotein complex, is intrinsically implicated in neuroinflammation by promoting the maturation and release of proinflammatory cytokines such as interleukin (IL)-1β and IL-18. Interestingly, individuals suffering from MDD have higher expression of NLRP3 inflammasome components and proinflammatory cytokines when compared to healthy individuals. In part, intense activation of the inflammasome may be related to autophagic impairment. Noteworthy, some conventional antidepressants induce autophagy, resulting in less activation of the NLRP3 inflammasome. In addition, the fast-acting antidepressant ketamine, some bioactive compounds and physical exercise have also been shown to have anti-inflammatory properties via inflammasome inhibition. Therefore, it is suggested that modulation of inflammasome-driven pathways may have an antidepressant effect. Here, we review the role of the NLRP3 inflammasome in the pathogenesis of MDD, highlighting that pathways related to its priming and activation are potential therapeutic targets for the treatment of MDD.

Keywords:  NLRP3 complex; antidepressants; bioactive compounds; depression; neuroinflammation; physical exercise

DOI:  https://doi.org/10.3390/ijms24010133
J Clin Med. 2022 Dec 31. pii: 318. [Epub ahead of print]12(1):

FAT/CD36 Participation in Human Skeletal Muscle Lipid Metabolism: A Systematic Review.

Arnulfo Ramos-Jiménez, Ruth A Zavala-Lira, Verónica Moreno-Brito, Everardo González-Rodríguez.

  Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs), leptin, and insulin. The principal function of FAT/CD36 is to facilitate the transport of long-chain fatty acids through cell membranes such as myocytes, adipocytes, heart, and liver. Under high-energy expenditure, the different isoforms of FAT/CD36 in the plasma membrane and mitochondria bind to the mobilization and oxidation of FAs. Furthermore, FAT/CD36 is released in its soluble form and becomes a marker of metabolic dysfunction. Studies with healthy animals and humans show that physical exercise and a high-lipid diet increase FAT/CD36 expression and caloric expenditure. However, several aspects such as obesity, diabetes, Single Nucleotide polymorphisms (SNPs), and oxidative stress affect the normal FAs metabolism and function of FAT/CD36, inducing metabolic disease. Through a comprehensive systematic review of primary studies, this work aimed to document molecular mechanisms related to FAT/CD36 in FAs oxidation and trafficking in skeletal muscle under basal conditions, physical exercise, and diet in healthy individuals.

Keywords:  adenosine monophosphate activating protein; fat oxidation; fatty acid-binding protein; mitochondria; muscle contraction; nutrients; sarcolemmal; scavenger receptor type B2

DOI:  https://doi.org/10.3390/jcm12010318
Int J Mol Sci. 2022 Dec 27. pii: 422. [Epub ahead of print]24(1):

A Skeletal Muscle-Centric View on Time-Restricted Feeding and Obesity under Various Metabolic Challenges in Humans and Animals.

Christopher Livelo, Yiming Guo, Girish C Melkani.

  Nearly 50% of adults will suffer from obesity in the U.S. by 2030. High obesity rates can lead to high economic and healthcare burdens in addition to elevated mortality rates and reduced health span in patients. Emerging data demonstrate that obesity is a multifactorial complex disease with various etiologies including aging, a lifestyle of chronic high-fat diets (HFD), genetic predispositions, and circadian disruption. Time-restricted feeding/eating (TRF; TRE in humans) is an intervention demonstrated by studies to show promise as an effective alternative therapy for ameliorating the effects of obesity and metabolic disease. New studies have recently suggested that TRF/TRE modulates the skeletal muscle which plays a crucial role in metabolism historically observed to be impaired under obesity. Here we discuss recent findings regarding potential mechanisms underlying TRF's modulation of skeletal muscle function, metabolism, and structure which may shed light on future research related to TRF as a solution to obesity.

Keywords:  energy metabolism; insulin resistance; obesity; skeletal muscle disorders/aging; time-restricted feeding/feeding

DOI:  https://doi.org/10.3390/ijms24010422
Front Physiol. 2022 ;13 1096296

Inflammation and oxidative stress in salt sensitive hypertension; The role of the NLRP3 inflammasome.

Lale A Ertuglu, Ashley Pitzer Mutchler, Justin Yu, Annet Kirabo.

  Salt-sensitivity of blood pressure is an independent risk factor for cardiovascular disease and affects approximately half of the hypertensive population. While the precise mechanisms of salt-sensitivity remain unclear, recent findings on body sodium homeostasis and salt-induced immune cell activation provide new insights into the relationship between high salt intake, inflammation, and hypertension. The immune system, specifically antigen-presenting cells (APCs) and T cells, are directly implicated in salt-induced renal and vascular injury and hypertension. Emerging evidence suggests that oxidative stress and activation of the NLRP3 inflammasome drive high sodium-mediated activation of APCs and T cells and contribute to the development of renal and vascular inflammation and hypertension. In this review, we summarize the recent insights into our understanding of the mechanisms of salt-sensitive hypertension and discuss the role of inflammasome activation as a potential therapeutic target.

Keywords:  hypertension; immunity; inflammasome; inflammation; salt sensitivity

DOI:  https://doi.org/10.3389/fphys.2022.1096296
J Physiol. 2023 Jan 11.

Fasting for 20 h does not affect exercise-induced increases in circulating BDNF in humans.

Travis D Gibbons, James D Cotter, Philip N Ainslie, Wickliffe C Abraham, Bruce G Mockett, Holly A Campbell, Emma M W Jones, Elliott J Jenkins, Kate N Thomas.

  Intermittent fasting and exercise provide neuroprotection from age-related cognitive decline. A link between these two seemingly distinct stressors is their capability to steer the brain away from exclusively glucose metabolism. This cerebral substrate switch has been implicated in upregulating brain-derived neurotrophic factor (BDNF), a protein involved in neuroplasticity, learning and memory, and may underlie some of these neuroprotective effects. We examined the isolated and interactive effects of (1) 20-h fasting, (2) 90-min light exercise, and (3) high-intensity exercise on peripheral venous BDNF in 12 human volunteers. A follow-up study isolated the influence of cerebrovascular shear stress on circulating BDNF. Fasting for 20 h decreased glucose and increased ketones (P ≤ 0.0157) but had no effect on BDNF (P ≥ 0.4637). Light cycling at 25% of peak oxygen uptake ( V̇O2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ ) increased serum BDNF by 6 ± 8% (independent of being fed or fasted) and was mediated by a 7 ± 6% increase in platelets (P < 0.0001). Plasma BDNF was increased from 336 pg l-1 [46,626] to 390 pg l-1 [127,653] by 90-min of light cycling (P = 0.0128). Six 40-s intervals at 100% of V̇O2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ increased plasma and serum BDNF, as well as the BDNF-per-platelet ratio 4- to 5-fold more than light exercise did (P ≤ 0.0044). Plasma BDNF was correlated with circulating lactate during the high-intensity intervals (r = 0.47, P = 0.0057), but not during light exercise (P = 0.7407). Changes in cerebral shear stress - whether occurring naturally during exercise or induced experimentally with inspired CO2 - did not correspond with changes in BDNF (P ≥ 0.2730). BDNF responses to low-intensity exercise are mediated by increased circulating platelets, and increasing either exercise duration or particularly intensity is required to liberate free BDNF. KEY POINTS: Intermittent fasting and exercise both have potent neuroprotective effects and an acute upregulation of brain-derived neurotrophic factor (BDNF) appears to be a common mechanistic link. Switching the brain's fuel source from glucose to either ketone bodies or lactate, i.e. a cerebral substrate switch, has been shown to promote BDNF production in the rodent brain. Fasting for 20 h caused a 9-fold increase in ketone body delivery to the brain but had no effect on any metric of BDNF in peripheral circulation at rest. Prolonged (90 min) light cycling exercise increased plasma- and serum-derived BDNF irrespective of being fed or fasted and seemed to be independent of changes in cerebral shear stress. Six minutes of high-intensity cycling intervals increased every metric of circulating BDNF by 4 to 5 times more than prolonged low-intensity cycling; the increase in plasma-derived BDNF was correlated with a 6-fold increase in circulating lactate irrespective of feeding or fasting. Compared to 1 day of fasting with or without prolonged light exercise, high-intensity exercise is a much more efficient means to increase BDNF in circulation.

Keywords:  BDNF; brain; exercise; fasting; ketones; lactate; substrate switch

DOI:  https://doi.org/10.1113/JP283582
Investig Clin Urol. 2023 Jan;64(1): 3-12

Role of microbiome and its metabolite, short chain fatty acid in prostate cancer.

Hee Jo Yang, Jae Heon Kim.

  The microbiome which is an assembly of all microbes living inside our bodies performs a major role in maintaining human health and wellness. It has been found that the imbalance of the microbiome can cause various diseases in humans. Similarly, there is growing evidence that the microbiome largely affects a person's chance of contracting certain cancers and how the disease develops and progresses. Studies have shown that about 15% to 20% of all cancers are caused by microbial pathogens. The prevalence of prostate cancer, which is increasing rapidly in Korea, is related to lifestyle including diet. These diets can alter the gut microbial composition, and the effect of the microbiome on prostate cancer development can be estimated. However, the microbiome associated with prostate cancer has been reported differently according to race. This means that the metabolite rather than the specific microbiome will be important. Short chain fatty acids, metabolites of the microbiome, plays an important role in the action mechanism of the microbiome. Short chain fatty acids play roles such as immunomodulation and inhibition of histone deacetylase. Here, we examined the most up-to-date literature featuring the effects of the microbiome on the risk and pathogenesis of prostate cancer.

Keywords:  Microbiome; Prostate cancer; Short chain fatty acid

DOI:  https://doi.org/10.4111/icu.20220370
Front Neurosci. 2022 ;16 1018628

Sleep deprivation and NLRP3 inflammasome: Is there a causal relationship?

Mohammad Amini, Zahra Yousefi, Sayed Soran Ghafori, Gholamreza Hassanzadeh.

  In the modern era, sleep deprivation (SD) is one of the most common health problems that has a profound influence on an individual's quality of life and overall health. Studies have identified the possibility that lack of sleep can stimulate inflammatory responses. NLRP3 inflammasome, a key component of the innate immune responses, initiates inflammatory responses by enhancing proinflammatory cytokine release and caspase-1-mediated pyroptosis. In this study, NLRP3 modification, its proinflammatory role, and potential targeted therapies were reviewed with regard to SD-induced outcomes. A growing body of evidence has showed the importance of the mechanistic connections between NLRP3 and the detrimental consequences of SD, but there is a need for more clinically relevant data. In animal research, (i) some animals show differential vulnerability to the effects of SD compared to humans. (ii) Additionally, the effects of sleep differ depending on the SD technique employed and the length of SD. Moreover, paying attention to the crosstalk of all the driving factors of NLRP3 inflammasome activation such as inflammatory responses, autonomic control, oxidative stress, and endothelial function is highly recommended. In conclusion, targeting NLRP3 inflammasome or its downstream pathways for therapy could be complicated due to the reciprocal and complex relationship of SD with NLRP3 inflammasome activation. However, additional research is required to support such a causal claim.

Keywords:  inflammasome; inflammation; neuroinflammation; sleep; sleep deprivation

DOI:  https://doi.org/10.3389/fnins.2022.1018628
Aging Clin Exp Res. 2023 Jan 09.

How to adjust muscle mass while defining sarcopenia component of sarcopenic obesity: is body weight sufficient enough to represent body size?

Gulistan Bahat, Serdar Ozkok.



Keywords:  Body mass index; Body weight; Obesity; Sarcopenia; Sarcopenic obesity

DOI:  https://doi.org/10.1007/s40520-022-02326-2
Int J Mol Sci. 2022 Dec 21. pii: 124. [Epub ahead of print]24(1):

Remarks on Mitochondrial Myopathies.

Patrizia Bottoni, Giulia Gionta, Roberto Scatena.

  Mitochondrial myopathies represent a heterogeneous group of diseases caused mainly by genetic mutations to proteins that are related to mitochondrial oxidative metabolism. Meanwhile, a similar etiopathogenetic mechanism (i.e., a deranged oxidative phosphorylation and a dramatic reduction of ATP synthesis) reveals that the evolution of these myopathies show significant differences. However, some physiological and pathophysiological aspects of mitochondria often reveal other potential molecular mechanisms that could have a significant pathogenetic role in the clinical evolution of these disorders, such as: i. a deranged ROS production both in term of signaling and in terms of damaging molecules; ii. the severe modifications of nicotinamide adenine dinucleotide (NAD)+/NADH, pyruvate/lactate, and α-ketoglutarate (α-KG)/2- hydroxyglutarate (2-HG) ratios. A better definition of the molecular mechanisms at the basis of their pathogenesis could improve not only the clinical approach in terms of diagnosis, prognosis, and therapy of these myopathies but also deepen the knowledge of mitochondrial medicine in general.

Keywords:  electron respiratory chain; mitochondria; mitochondrial DNA; mutations; oxidative metabolism; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms24010124
Amino Acids. 2023 Jan 13.

Carnosine increases insulin-stimulated glucose uptake and reduces methylglyoxal-modified proteins in type-2 diabetic human skeletal muscle cells.

Joseph J Matthews, Mark D Turner, Livia Santos, Kirsty J Elliott-Sale, Craig Sale.

  Type-2 diabetes (T2D) is characterised by a dysregulation of metabolism, including skeletal muscle insulin resistance, mitochondrial dysfunction, and oxidative stress. Reactive species, such as methylglyoxal (MGO) and 4-hydroxynonenal (4-HNE), positively associate with T2D disease severity and can directly interfere with insulin signalling and glucose uptake in skeletal muscle by modifying cellular proteins. The multifunctional dipeptide carnosine, and its rate-limiting precursor β-alanine, have recently been shown to improve glycaemic control in humans and rodents with diabetes. However, the precise mechanisms are unclear and research in human skeletal muscle is limited. Herein, we present novel findings in primary human T2D and lean healthy control (LHC) skeletal muscle cells. Cells were differentiated to myotubes, and treated with 10 mM carnosine, 10 mM β-alanine, or control for 4-days. T2D cells had reduced ATP-linked and maximal respiration compared with LHC cells (p = 0.016 and p = 0.005). Treatment with 10 mM carnosine significantly increased insulin-stimulated glucose uptake in T2D cells (p = 0.047); with no effect in LHC cells. Insulin-stimulation increased MGO-modified proteins in T2D cells by 47%; treatment with carnosine attenuated this increase to 9.7% (p = 0.011). There was no effect treatment on cell viability or expression of other proteins. These findings suggest that the beneficial effects of carnosine on glycaemic control may be explained by its scavenging actions in human skeletal muscle.

Keywords:  Diabetes; Glycaemia; Metabolism; Prediabetes; Therapeutics

DOI:  https://doi.org/10.1007/s00726-022-03230-9
Biochem Biophys Rep. 2023 Mar;33 101417

Chronic kidney disease and NLRP3 inflammasome: Pathogenesis, development and targeted therapeutic strategies.

Gengzhen Huang, Yaodan Zhang, Yingying Zhang, Yuerong Ma.

  Chronic kidney disease (CKD) is a global health concern and public health priority. The condition often involves inflammation due to the accumulation of toxins and the reduced clearance of inflammatory cytokines, leading to gradual loss of kidney function. Because of the tremendous burden of CKD, finding effective treatment strategies against inflammation is crucial. Substantial evidence suggests an association between kidney disease and the inflammasome. As a well-known multiprotein signaling complex, the NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in inducing renal inflammation and fibrosis. Small molecule inhibitors targeting the NLRP3 inflammasome are potential agents for the treatment of CKD.The NLRP3 inflammasome activation amplifies the inflammation response, promoting pyroptotic cell death. Thus, it may contribute to the onset and progression of CKD, but the mechanism behind inflammasome activation in CKD remains obscure.In this review, we summarized recent findings on the role of the NLRP3 inflammasome in CKD and new strategies targeting the NLRP3 inflammasome.

Keywords:  ,IL-18, Interleukin-18; ASC, apoptosis-associated speck-like protein; Ang II, Angiotensin II; CKD, Chronic kidney disease; Chronic kidney disease; DAMPs, damage-associated molecular patterns; ESRD, End-stage renal disease; GFR, glomerular filtration rate; HK-2, renal tubular epithelial cells; IL-1β, Interleukin-1β; Inflammasome; Kidney function; LRR, leucine-rich repeat; NEK7, NIMA-related kinase 7; NF-kB, nuclear factor kappa-B; NLRP3, NLR family pyrin domain containing 3; NOD-like receptor; PAMPs, Pathogen-associated molecular patterns; ROS, reactive oxygen species; TXNIP, thioredoxin-interacting protein

DOI:  https://doi.org/10.1016/j.bbrep.2022.101417
Front Microbiol. 2022 ;13 1046912

High fiber diet attenuate the inflammation and adverse remodeling of myocardial infarction via modulation of gut microbiota and metabolites.

Jinxuan Zhao, Wei Cheng, He Lu, Anqi Shan, Qi Zhang, Xuan Sun, Lina Kang, Jun Xie, Biao Xu.

  Introduction: High intake of dietary fiber is associated with lower incidence of cardiovascular diseases. Dietary fiber, functions as a prebiotic, has a significant impact on intestinal bacteria composition and diversity. The intestinal flora and metabolites generated by fermentation of dietary fiber not only affect the health of intestine but also play a role in many extra-intestinal diseases, such as obesity, diabetes and atherosclerosis. However, the role and the mechanism by which a high fiber diet contributes to the development of myocardial infarction is still unclear.Methods and results: Here we used an in vivo mouse model to investigate whether dietary fiber intake could protect against myocardial infarction. Our study demonstrated high fiber diet significantly improved cardiac function, reduced infarct size and prevented adverse remodeling following myocardial infarction. The protective effects of high fiber diet had a strong relation with its attenuation of inflammation. Moreover, we observed that high fiber diet could modulate the composition of intestinal flora and differentially impacted metabolites production, including the biosynthesis of bile acids and linoleic acid metabolism.
Conclusion: Overall, the findings of this study provided mechanistic insights into the curative effect of dietary fiber on myocardial infarction with a specific emphasis on the potential role of microbiota-metabolism-immunity interactions.

Keywords:  fibrosis; gut microbiota; high fiber diet; inflammation; metabolomics; myocardial infarction

DOI:  https://doi.org/10.3389/fmicb.2022.1046912
Nutrients. 2023 Jan 01. pii: 224. [Epub ahead of print]15(1):

Update on Anti-Inflammatory Molecular Mechanisms Induced by Oleic Acid.

Consuelo Santa-María, Soledad López-Enríquez, Sergio Montserrat-de la Paz, Isabel Geniz, María Edith Reyes-Quiroz, Manuela Moreno, Francisca Palomares, Francisco Sobrino, Gonzalo Alba.

  In 2010, the Mediterranean diet was recognized by UNESCO as an Intangible Cultural Heritage of Humanity. Olive oil is the most characteristic food of this diet due to its high nutraceutical value. The positive effects of olive oil have often been attributed to its minor components; however, its oleic acid (OA) content (70-80%) is responsible for its many health properties. OA is an effective biomolecule, although the mechanism by which OA mediates beneficial physiological effects is not fully understood. OA influences cell membrane fluidity, receptors, intracellular signaling pathways, and gene expression. OA may directly regulate both the synthesis and activities of antioxidant enzymes. The anti-inflammatory effect may be related to the inhibition of proinflammatory cytokines and the activation of anti-inflammatory ones. The best-characterized mechanism highlights OA as a natural activator of sirtuin 1 (SIRT1). Oleoylethanolamide (OEA), derived from OA, is an endogenous ligand of the peroxisome proliferator-activated receptor alpha (PPARα) nuclear receptor. OEA regulates dietary fat intake and energy homeostasis and has therefore been suggested to be a potential therapeutic agent for the treatment of obesity. OEA has anti-inflammatory and antioxidant effects. The beneficial effects of olive oil may be related to the actions of OEA. New evidence suggests that oleic acid may influence epigenetic mechanisms, opening a new avenue in the exploration of therapies based on these mechanisms. OA can exert beneficial anti-inflammatory effects by regulating microRNA expression. In this review, we examine the cellular reactions and intracellular processes triggered by OA in T cells, macrophages, and neutrophils in order to better understand the immune modulation exerted by OA.

Keywords:  T cells; macrophages; neutrophils; oleic acid; oleoylethanolamide

DOI:  https://doi.org/10.3390/nu15010224
Mol Biol Rep. 2023 Jan 10.

Intramuscular mitochondrial and lipid metabolic changes of rats after regular high-intensity interval training (HIIT) of different training periods.

Ruonan Shangguan, Zhiqiang Hu, Yuzhen Luo, Min Chen, Xiangdeng Lai, Jingquan Sun, Siyu Chen.

  BACKGROUND: High-intensity Interval Training (HIIT) is a time-efficient form of exercise and has gained popularity in recent years. However, at molecular level, the understanding about the effects of HIIT is not comprehensive, and even less is elucidated about HIIT of different training duration cycles, although different durations always lead to different post-training consequences.METHOD: In this study, by training SD rats using HIIT protocols lasting for different training duration cycles, we investigated the adaptive response of intramuscular triglyceride abundance as well as mitochondrial and lipid metabolic changes after HIIT training (2, 4, 6, 8, and 10 weeks). We selected 72 h after the last session of training as the time point of sacrifice.
RESULTS: The suppressed activation of the cAMP-PKA pathway indicates that skeletal muscle was in the recovery phase at this time point. Intramuscular triglyceride abundance was significantly elevated after 2, 4, and 10 weeks of HIIT. However, the lipid metabolism-related proteins inconsistently changed in a chaotic trend (see Table 1). The expression levels of PGC1-α and COX IV decreased after 2 and 4 weeks of training and raised after 6 and 8 weeks of training. The expression level of citrate synthase (CS) decreased after 2, 4, 8, and 10 weeks of training, and showed an upward trend after 6 weeks of training. While the activity of CS decreased after 2 and 8 weeks of training and showed an upward trend after 6 weeks of HIIT.
CONCLUSION: Given the abovementioned changing trends, we propose two speculations: (A) the damaged mitochondria oxidation capacity might be one of the causes of IMTG accumulation observed after 2 and 4 weeks of HIIT. This phase might be similar to the condition of type 2 diabetes. (B) after 6-week HIIT, mitochondria function and biogenesis might be improved and the IMTG contents declined to baseline. This might be explained as: mitochondrial enhancement increased the capacity of lipid oxidation and then offset the increase in IMTG achieved during the first 4 weeks. For HIIT Rat Modelling, if the aim is to observe HIIT-induced positive effects, caution should be exercised when considering 2 and 4 weeks of training under our HIIT frame. Also, implementing six-week training is at least effective for mitochondrial enhancement when using similar HIIT frame of this study.

Keywords:  Exercise; Exercise training period; Lipid metabolism; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1007/s11033-022-08205-3
Int J Mol Sci. 2022 Dec 26. pii: 379. [Epub ahead of print]24(1):

Long-Chain and Medium-Chain Fatty Acids in Energy Metabolism of Murine Kidney Mitochondria.

Alexander V Panov, Vladimir I Mayorov, Anna E Dikalova, Sergey I Dikalov.

  Scientists have long established that fatty acids are the primary substrates for kidney mitochondria. However, to date we still do not know how long-chain and middle-chain fatty acids are oxidized at the mitochondrial level. Our previous research has shown that mitochondria from the heart, brain, and kidney oxidize palmitoylcarnitine at a high rate only in the presence of succinate, glutamate, or pyruvate. In this paper, we report properties of the isolated kidney mitochondria and how malate and succinate affect the oxidation of C16 and C8 acylcarnitines. The isolated kidney mitochondria contain very few endogenous substrates and require malate to oxidize pyruvate, glutamate, and C16 or C8 acylcarnitines. We discovered that with 10 µM of C16 or C8 acylcarnitines, low concentrations of malate (0.2 mM) or succinate (0.5 mM) enhance the States 4 and 3 respiratory rates several times. The highest respiration rates were observed with C16 or C8 acylcarnitines and 5 mM succinate mixtures. Results show that kidney mitochondria, unlike the heart and brain mitochondria, lack the intrinsic inhibition of succinate dehydrogenase. Additionally, results show that the oxidation of fatty acid by the small respirasome's supercomplex generates a high level of CoQH2, and this makes SDH in the presence of succinate reverse the flow of electrons from CoQH2 to reduce fumarate to succinate. Finally, we report evidence that succinate dehydrogenase is a key mitochondrial enzyme that allows fast oxidation of fatty acids and turns the TCA cycle function from the catabolic to the anabolic and anaplerotic metabolic pathways.

Keywords:  beta-oxidation; fatty acids; kidney; kidney mitochondria; octanoylcarnitine; oxidative phosphorylation; palmitoylcarnitine; respirasome; respiration; succinate; succinate dehydrogenase

DOI:  https://doi.org/10.3390/ijms24010379
Int J Mol Sci. 2023 Jan 03. pii: 868. [Epub ahead of print]24(1):

Integrative Proteome Analysis Revels 3-Hydroxybutyrate Exerts Neuroprotective Effect by Influencing Chromatin Bivalency.

Xin-Liang Zhu, Huan Du, Lei-Lei Wang, Er-Ling Hu, Ning Li, Hai-Xia Lu, Guo-Qiang Chen, Xiao-Yun Lu.

  3-hydroxybutyrate (3OHB) has been proved to act as a neuroprotective molecule in multiple neurodegenerative diseases. Here, we employed a quantitative proteomics approach to assess the changes of the global protein expression pattern of neural cells upon 3OHB administration. In combination with a disease-related, protein-protein interaction network we pinpointed a hub marker, histone lysine 27 trimethylation, which is one of the key epigenetic markers in multiple neurodegenerative diseases. Integrative analysis of transcriptomic and epigenomic datasets highlighted the involvement of bivalent transcription factors in 3OHB-mediated disease protection and its alteration of neuronal development processes. Transcriptomic profiling revealed that 3OHB impaired the fate decision process of neural precursor cells by repressing differentiation and promoting proliferation. Our study provides a new mechanism of 3OHB's neuroprotective effect, in which chromatin bivalency is sensitive to 3OHB alteration and drives its neuroprotective function both in neurodegenerative diseases and in neural development processes.

Keywords:  3-hydroxybutyrate; chromatin bivalency; neuroprotection; proteomics; transcriptomics

DOI:  https://doi.org/10.3390/ijms24010868
Int J Mol Sci. 2023 Jan 03. pii: 886. [Epub ahead of print]24(1):

Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization.

Andrey V Kuznetsov, Michael J Ausserlechner.

Mitochondria have been recognized as the energy (in the form of ATP)-producing cell organelles, required for cell viability, survival and normal cell function [...].

DOI: https://doi.org/10.3390/ijms24010886
J Adv Res. 2023 Jan 04. pii: S2090-1232(23)00001-2. [Epub ahead of print]

Canonical and non-canonical functions of NLRP3.

Théo Accogli, Christophe Hibos, Frédérique Vegran.

  BACKGROUND: Since its discovery, NLRP3 is almost never separated from its major role in the protein complex it forms with ASC, NEK7 and Caspase-1, the inflammasome. This key component of the innate immune response mediates the secretion of proinflammatory cytokines IL-1β and IL-18 involved in immune response to microbial infection and cellular damage. However, NLRP3 has also other functions that do not involve the inflammasome assembly nor the innate immune response. These non-canonical functions have been poorly studied. Nevertheless, NLRP3 is associated with different kind of diseases probably through its inflammasome dependent function as through its inflammasome independent functions.AIM OF THE REVIEW: The study and understanding of the canonical and non-canonical functions of NLRP3 can help to better understand its involvement in various pathologies. In parallel, the description of the mechanisms of action and regulation of its various functions, can allow the identification of new therapeutic strategies.
KEY SCIENTIFIC CONCEPTS OF THE REVIEW: NLRP3 functions have mainly been studied in the context of the inflammasome, in myeloid cells and in totally deficient transgenic mice. However, for several year, the work of different teams has proven that NLRP3 is also expressed in other cell types where it has functions that are independent of the inflammasome. If these studies suggest that NLRP3 could play different roles in the cytoplasm or the nucleus of the cells, the mechanisms underlying NLRP3 non-canonical functions remain unclear. This is why we propose in this review an inventory of the canonical and non-canonical functions of NLRP3 and their impact in different pathologies.

Keywords:  Inflammasome; Myeloid cells; NLRP3; Uncanonical functions

DOI:  https://doi.org/10.1016/j.jare.2023.01.001
Front Mol Biosci. 2022 ;9 1042231

Exercise blood-drop metabolic profiling links metabolism with perceived exertion.

Tobias Opialla, Benjamin Gollasch, Peter H J L Kuich, Lars Klug, Gabriele Rahn, Andreas Busjahn, Simone Spuler, Michael Boschmann, Jennifer A Kirwan, Friedrich C Luft, Stefan Kempa.

  Background: Assessing detailed metabolism in exercising persons minute-to-minute has not been possible. We developed a "drop-of-blood" platform to fulfill that need. Our study aimed not only to demonstrate the utility of our methodology, but also to give insights into unknown mechanisms and new directions. Methods: We developed a platform, based on gas chromatography and mass spectrometry, to assess metabolism from a blood-drop. We first observed a single volunteer who ran 13 km in 60 min. We particularly monitored relative perceived exertion (RPE). We observed that 2,3-bisphosphoglycerate peaked at RPE in this subject. We next expanded these findings to women and men volunteers who performed an RPE-based exercise protocol to RPE at Fi O 2 20.9% or Fi O 2 14.5% in random order. Results: At 6 km, our subject reached his maximum relative perceived exertion (RPE); however, he continued running, felt better, and finished his run. Lactate levels had stably increased by 2 km, ketoacids increased gradually until the run's end, while the hypoxia marker, 2,3 bisphosphoglycerate, peaked at maximum relative perceived exertion. In our normal volunteers, the changes in lactate, pyruvate, ß hydroxybutyrate and a hydroxybutyrate were not identical, but similar to our model proband runner. Conclusion: Glucose availability was not the limiting factor, as glucose availability increased towards exercise end in highly exerted subjects. Instead, the tricarboxylic acid→oxphos pathway, lactate clearance, and thus and the oxidative capacity appeared to be the defining elements in confronting maximal exertion. These ideas must be tested further in more definitive studies. Our preliminary work suggests that our single-drop methodology could be of great utility in studying exercise physiology.

Keywords:  blood drop sampling; gas chromatography; hypoxia; metabolomics; relative perceived exertion

DOI:  https://doi.org/10.3389/fmolb.2022.1042231
Innate Immun. 2023 Jan 11. 17534259221143216

Pyroptosis, inflammasome, and gasdermins in tumor immunity.

Xiaohu Ouyang, Junfen Zhou, Lan Lin, Zili Zhang, Shanshan Luo, Desheng Hu.

  The gasdermins (GSDM), a family of pore-forming proteins, consist of gasdermin A (GSDMA), gasdermin B (GSDMB), gasdermin C (GSDMC), gasdermin D (GSDMD), gasdermin E (GSDME) and DFNB59 (Pejvakin (PJVK)) in humans. These proteins play an important role in pyroptosis. Among them, GSDMD is the most extensively studied protein and is identified as the executioner of pyroptosis. Other family members have also been implicated in certain cancers. As a unique form of programmed cell death, pyroptosis is closely related to tumor progression, and the inflammasome, an innate immune mechanism that induces inflammation and pyroptosis. In this review, we explore the current developments of pyroptosis, the inflammasome, and especially we review the gasdermin family members and their role in inducing pyroptosis and the possible therapeutic values in antitumor effects.

Keywords:  Gasdermin A; anti-tumor immunity; gasdermin B; gasdermin C; gasdermin D; gasdermin E; inflammasome; pyroptosis

DOI:  https://doi.org/10.1177/17534259221143216
Nutrients. 2023 Jan 03. pii: 249. [Epub ahead of print]15(1):

Effects of Resveratrol on Muscle Inflammation, Energy Utilisation, and Exercise Performance in an Eccentric Contraction Exercise Mouse Model.

Liang-Yu Su, Wen-Ching Huang, Nai-Wen Kan, Te-Hsuan Tung, Linh Ba Phuong Huynh, Shih-Yi Huang.

  Eccentric contraction can easily cause muscle damage and an inflammatory response, which reduces the efficiency of muscle contraction. Resveratrol causes anti-inflammatory effects in muscles, accelerates muscle repair, and promotes exercise performance after contusion recovery. However, whether resveratrol provides the same benefits for sports injuries caused by eccentric contraction is unknown. Thus, we explored the effects of resveratrol on inflammation and energy metabolism. In this study, mice were divided into four groups: a control group, an exercise group (EX), an exercise with low-dose resveratrol group (EX + RES25), and an exercise with high-dose resveratrol group (EX + RES150). The results of an exhaustion test showed that the time before exhaustion of the EX + RES150 group was greater than that of the EX group. Tumour necrosis factor-α (Tnfα) mRNA expression was lower in the EX + RES150 group than in the EX group. The energy utilisation of the EX + RES150 group was greater than that of the EX + RES25 group in different muscles. High-dose resveratrol intervention decreased Tnfα mRNA expression and enhanced the mRNA expressions of sirtuin 1, glucose transporter 4, AMP-activated protein kinase α1, and AMP-activated protein kinase α2 in muscles. These results revealed that high-dose resveratrol supplementation can reduce inflammation and oxidation and improve energy utilisation during short-duration high-intensity exercise.

Keywords:  anti-inflammation; downhill running; eccentric contraction; energy utilization; resveratrol

DOI:  https://doi.org/10.3390/nu15010249
J Tradit Chin Med. 2023 Feb;43(1): 95-104

Mitochondrial dysfunction in a rat model and the related risk of metabolic disorders.

L I Han, Huang Xiaomin, Cai Haiyang, Herok George, H E Jing, S U Yixun, L I Weihong, Y I Chenju, Oliver Brian G, Chen Hui.

  OBJECTIVE: To explore whether kidney deficiency (KYD) is prone to metabolic disorders may be linked to impaired mitochondrial function in thermogenesis and metabolic tissues.METHODS: A rat model of KYD was used, which was established using Sprague Dawley rat dams with warm preference subjected to herbal treatment that can improve kidney . The human relevance was confirmed by reduced serum corticosterone levels, and increased preference for warm location.
RESULTS: KYD Rats were underdeveloped. Adenosine-triphosphate (ATP) production was reduced in the brown fat, but increased in the muscle. However, oxidative phosphorylated complexes to generate ATP and mitochondrial biogenesis marker were reduced in both tissues. When the second insult of high-fat diet (HFD) was introduced, KYD rats gained less weight yet developed more severe lipid and glucose metabolic disorders. This may be driven by disregulated liver gluconeogenesis marker forkhead box protein O1 and lipid metabolic regulator cholesterol 7 alpha-hydroxylase.
CONCLUSION: KYD rats exhibited reduced mito-chondrial function in the brown fat, but were partially compensated by skeletal muscle, associated with the phenotype of warm preference and metabolic disorder, which was further exacerbated by additional HFD consumption. Future studies can focus on treatment targetting mitochondria function to reverse this phenotype.

Keywords:  DNA, mitochondrial; adenosine triphosphate; kidney deficiency; peroxisome proliferator-activated receptor gamma coactivator 1-alpha; thermogenesis

DOI:  https://doi.org/10.19852/j.cnki.jtcm.20221017.001