bims-kimdis 2022-11-13 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022‒11‒13
29 papers selected by
Matías Javier Monsalves Álvarez

Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders.
Effects of the ketogenic diet on cognition: a systematic review.
A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice.
Ketone Body Exposure of Cardiomyocytes Impairs Insulin Sensitivity and Contractile Function through Vacuolar-Type H+-ATPase Disassembly-Rescue by Specific Amino Acid Supplementation.
Correction to: Gardner et al. Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interventional Keto-Med randomized crossover trial.
Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function.
Obesogenic versus ketogenic diets in the regulation of the renin-angiotensin system in rat white and brown adipose tissues.
Dynamics of Gut Microbiota and Clinical Variables after Ketogenic and Mediterranean Diets in Drug-Naïve Patients with Type 2 Diabetes Mellitus and Obesity.
Small extracellular vesicles in plasma reveal molecular effects of modified Mediterranean-ketogenic diet in participants with mild cognitive impairment.
Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer's Disease.
Diverging in vitro inflammatory responses toward Streptococcus uberis in mouse macrophages either preconditioned or continuously treated with β-hydroxybutyrate.
Diet-Related Changes of Short-Chain Fatty Acids in Blood and Feces in Obesity and Metabolic Syndrome.
Elevated LDL-cholesterol levels among lean mass hyper-responders on low-carbohydrate ketogenic diets deserve urgent clinical attention and further research.
Clinical Benefits of Sodium-Glucose Cotransporter 2 Inhibitors and the Mechanisms Underlying Their Cardiovascular Effects.
Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed.
The NLRP3 inflammasome: activation and regulation.
Mitochondrial dysfunction, aging, and the mitochondrial unfolded protein response in Caenorhabditis elegans.
Effects of dietary butyrate supplementation and oral nonsteroidal antiinflammatory drug administration on uterine inflammation and interval to first ovulation in postpartum dairy cows.
Butyrate: Connecting the gut-lung axis to the management of pulmonary disorders.
The Anti-Inflammatory Effect of Novel Antidiabetic Agents.
The Role of Crosstalk between Adipose Cells and Myocytes in the Pathogenesis of Sarcopenic Obesity in the Elderly.
Ketone-derived 2,3-dihydroquinazolinones in N-heteroarene C-H alkylation via C-C bond scission under oxidative metal catalysis.
Energy metabolism and frailty: The potential role of exercise-induced myokines - A narrative review.
Euglycemic diabetic ketoacidosis: A rare but serious side effect of sodium-glucose co-transporter 2 inhibitors.
Short-time recovery skeletal muscle from dexamethasone-induced atrophy and weakness in old female rats.
The effects of fasting diets on nonalcoholic fatty liver disease.
Can sodium-glucose cotransporter 2 inhibitors 'spin the thread of life'?
Benefits of SGLT2 inhibitors in arrhythmias.
Hunting down NLRP3 inflammasome: An executioner of radiation-induced injury.

Front Endocrinol (Lausanne). 2022 ;13 972890

Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders.

Valentina Spigoni, Gloria Cinquegrani, Nicolas Thomas Iannozzi, Giulia Frigeri, Giulia Maggiolo, Marta Maggi, Vanessa Parello, Alessandra Dei Cas.

 Ketogenesis takes place in hepatocyte mitochondria where acetyl-CoA derived from fatty acid catabolism is converted to ketone bodies (KB), namely β-hydroxybutyrate (β-OHB), acetoacetate and acetone. KB represent important alternative energy sources under metabolic stress conditions. Ketogenic diets (KDs) are low-carbohydrate, fat-rich eating strategies which have been widely proposed as valid nutritional interventions in several metabolic disorders due to its substantial efficacy in weight loss achievement. Carbohydrate restriction during KD forces the use of FFA, which are subsequently transformed into KB in hepatocytes to provide energy, leading to a significant increase in ketone levels known as "nutritional ketosis". The recent discovery of KB as ligands of G protein-coupled receptors (GPCR) - cellular transducers implicated in a wide range of body functions - has aroused a great interest in understanding whether some of the clinical effects associated to KD consumption might be mediated by the ketone/GPCR axis. Specifically, anti-inflammatory effects associated to KD regimen are presumably due to GPR109A-mediated inhibition of NLRP3 inflammasome by β-OHB, whilst lipid profile amelioration by KDs could be ascribed to the actions of acetoacetate via GPR43 and of β-OHB via GPR109A on lipolysis. Thus, this review will focus on the effects of KD-induced nutritional ketosis potentially mediated by specific GPCRs in metabolic and endocrinological disorders. To discriminate the effects of ketone bodies per se, independently of weight loss, only studies comparing ketogenic vs isocaloric non-ketogenic diets will be considered as well as short-term tolerability and safety of KDs.

Keywords: GPCR (G protein coupled receptors); ketogenic diet; ketone bodies; metabolic disorder; very low carbohydrate ketogenic diet

DOI: https://doi.org/10.3389/fendo.2022.972890
Nutr Neurosci. 2022 Nov 10. 1-21

Effects of the ketogenic diet on cognition: a systematic review.

Arun Chinna-Meyyappan, Fabiano Alves Gomes, Elena Koning, Jennifer Fabe, Vitor Breda, Elisa Brietzke.

  INTRODUCTION: Ketogenic diet (KD) therapy has been used as a dietary intervention in drug-resistant epilepsy for several years. Research currently suggests that KD therapy may carry neuroprotective and cognition enhancing effects for individuals with non-epileptic conditions as well as for healthy individuals. Therefore, KD may have potential as a non-invasive, nutritional treatment approach for difficult to manage conditions such as neurodegenerative illnesses or mood disorders. The aim of this review is to summarize the available evidence on ketogenic interventions and the resulting cognitive outcomes.MATERIALS AND METHODS: The paper was based on PRISMA 2020 guidelines. The search was conducted in June 2021 on the following databases: CENTRAL, PubMed, EMBASE, PsycInfo, Web of Science. The search yielded 2014 studies, of which 49 were included.
RESULTS: There were 22 animal studies assessing murine models and 27 studies on humans. The primary indications in these studies were epileptic conditions, neurodegenerative disorders, cognitive impairment, and healthy populations.
DISCUSSION: Administration of KD seems to confer cognitive-enhancing effects in areas such as working memory, reference memory and attention. Studies found that KD treatment in animals has the potential to alleviate age-related cognitive decline. Over 80% of the 27 human studies reported a favourable effect of intervention, and none reported a detrimental effect of KD. While these findings suggest that KD may improve the functioning of certain cognitive domains, definitive conclusions were limited by studies with small sample sizes, the absence of controls and randomization, and the lack of objective measures of cognition.

Keywords:  Ketosis; attention; cognition; executive function; ketogenic diet; low-carbohydrate; nutrition; working memory

DOI:  https://doi.org/10.1080/1028415X.2022.2143609
Metabolites. 2022 Oct 25. pii: 1019. [Epub ahead of print]12(11):

A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice.

Erin R Saito, Cali E Warren, Cameron M Hanegan, John G Larsen, Johannes D du Randt, Mio Cannon, Jeremy Y Saito, Rachel J Campbell, Colin M Kemberling, Gavin S Miller, Jeffrey G Edwards, Benjamin T Bikman.

  Mitochondrial dysfunction and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as nonpathological aging. Ketones have been suggested as therapeutic for their efficacy in epilepsy and other brain pathologies such as Alzheimer's disease and major depressive disorder. However, their effects on cognitive function in healthy individuals is less established. Here, we explored the mitochondrial and performative outcomes of a novel eight-week ketone-supplemented ketogenic (KETO) diet in healthy adult male and female mice. In a novel object recognition test, KETO mice spent more time with the novel, compared to familiar, object, indicating an improvement in recognition memory. High-resolution respirometry on permeabilized hippocampal tissue returned significant reductions in mitochondrial O2 consumption. No changes in ATP production were observed, yielding a significantly higher ATP:O2 ratio, a measure of mitochondrial efficiency. Together, these findings demonstrate the KETO diet improves hippocampal mitochondrial efficiency. They add to a growing body of evidence that suggests ketones and ketogenic diets are neuroprotective and metabolically and cognitively relevant, even in healthy adults. They also suggest that ketogenic lifestyle changes may be effective strategies for protecting against cognitive decline associated with aging and disease.

Keywords:  hippocampus; ketogenic diet; metabolism; mitochondrial efficiency; recognition memory

DOI:  https://doi.org/10.3390/metabo12111019
Int J Mol Sci. 2022 Oct 26. pii: 12909. [Epub ahead of print]23(21):

Ketone Body Exposure of Cardiomyocytes Impairs Insulin Sensitivity and Contractile Function through Vacuolar-Type H+-ATPase Disassembly-Rescue by Specific Amino Acid Supplementation.

Shujin Wang, Dietbert Neumann, B Daan Westenbrink, Francesco Schianchi, Li-Yen Wong, Aomin Sun, Agnieszka Strzelecka, Jan F C Glatz, Joost J F P Luiken, Miranda Nabben.

  The heart is metabolically flexible. Under physiological conditions, it mainly uses lipids and glucose as energy substrates. In uncontrolled diabetes, the heart switches towards predominant lipid utilization, which over time is detrimental to cardiac function. Additionally, diabetes is accompanied by high plasma ketone levels and increased utilization of energy provision. The administration of exogenous ketones is currently being investigated for the treatment of cardiovascular disease. Yet, it remains unclear whether increased cardiac ketone utilization is beneficial or detrimental to cardiac functioning. The mechanism of lipid-induced cardiac dysfunction includes disassembly of the endosomal proton pump (named vacuolar-type H+-ATPase; v-ATPase) as the main early onset event, followed by endosomal de-acidification/dysfunction. The de-acidified endosomes can no longer serve as a storage compartment for lipid transporter CD36, which then translocates to the sarcolemma to induce lipid accumulation, insulin resistance, and contractile dysfunction. Lipid-induced v-ATPase disassembly is counteracted by the supply of specific amino acids. Here, we tested the effect of ketone bodies on v-ATPase assembly status and regulation of lipid uptake in rodent/human cardiomyocytes. 3-β-hydroxybutyrate (3HB) exposure induced v-ATPase disassembly and the entire cascade of events leading to contractile dysfunction and insulin resistance, similar to conditions of lipid oversupply. Acetoacetate addition did not induce v-ATPase dysfunction. The negative effects of 3HB could be prevented by addition of specific amino acids. Hence, in sedentary/prediabetic subjects ketone bodies should be used with caution because of possible aggravation of cardiac insulin resistance and further loss of cardiac function. When these latter maladaptive conditions would occur, specific amino acids could potentially be a treatment option.

Keywords:  contractile function; diabetic heart; endosomal CD36; ketone bodies; lipid-induced insulin resistance; vacuolar-type H+-ATPase

DOI:  https://doi.org/10.3390/ijms232112909
Am J Clin Nutr. 2022 Nov 09. pii: nqac279. [Epub ahead of print]

Correction to: Gardner et al. Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interventional Keto-Med randomized crossover trial.

DOI: https://doi.org/10.1093/ajcn/nqac279
Front Pharmacol. 2022 ;13 947387

Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function.

Yan Yan, Ming Li, Jie Lin, Yanan Ji, Kexin Wang, Dajun Yan, Yuntian Shen, Wei Wang, Zhongwei Huang, Haiyan Jiang, Hualin Sun, Lei Qi.

  Skeletal muscle is one of the largest organs in the body and the largest protein repository. Mitochondria are the main energy-producing organelles in cells and play an important role in skeletal muscle health and function. They participate in several biological processes related to skeletal muscle metabolism, growth, and regeneration. Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor and regulator of systemic energy balance. AMPK is involved in the control of energy metabolism by regulating many downstream targets. In this review, we propose that AMPK directly controls several facets of mitochondrial function, which in turn controls skeletal muscle metabolism and health. This review is divided into four parts. First, we summarize the properties of AMPK signal transduction and its upstream activators. Second, we discuss the role of mitochondria in myogenesis, muscle atrophy, regeneration post-injury of skeletal muscle cells. Third, we elaborate the effects of AMPK on mitochondrial biogenesis, fusion, fission and mitochondrial autophagy, and discuss how AMPK regulates the metabolism of skeletal muscle by regulating mitochondrial function. Finally, we discuss the effects of AMPK activators on muscle disease status. This review thus represents a foundation for understanding this biological process of mitochondrial dynamics regulated by AMPK in the metabolism of skeletal muscle. A better understanding of the role of AMPK on mitochondrial dynamic is essential to improve mitochondrial function, and hence promote skeletal muscle health and function.

Keywords:  AMPK; mitochondria; muscle atrophy; muscle regeneration; skeletal muscle

DOI:  https://doi.org/10.3389/fphar.2022.947387
Nutrition. 2022 Oct 10. pii: S0899-9007(22)00275-1. [Epub ahead of print]105 111862

Obesogenic versus ketogenic diets in the regulation of the renin-angiotensin system in rat white and brown adipose tissues.

Daniel Da Eira, Shailee Jani, Mateja Stefanovic, Rolando B Ceddia.

  OBJECTIVE: The ketogenic diet (KD) has been reported to reverse metabolic dysfunction in obesity. However, it remains unknown how the KD affects the balance between the classical and counterregulatory renin-angiotensin system (RAS) arms in adipose tissue, which carries important implications for metabolic function in adipocytes. The aim of this study was to compare the effects of the obesogenic diet and the KD on RAS balance in white and brown fat.METHODS: Nine male Wistar rats were fed a standard chow (SC), 11 fed a high-fat sucrose-enriched (HFS) obesogenic diet, and 12 a KD. At the end of the 8-wk feeding period, subcutaneous inguinal (Sc Ing), epididymal (Epid), and interscapular brown adipose tissue (iBAT) fat depots were extracted and subsequently used for the measurement of RAS proteins and MasR gene expression.
RESULTS: In SC-fed rats, the Sc Ing fat displayed the highest levels of angiotensin-converting enzyme (ACE)1, but very low levels of angiotensin II types 1 and 2 receptors (AT1R and AT2R) and ACE2. Conversely, the highest levels of ACE2, AT1R, and AT2R were found in iBAT. The HFS diet increased AT1R protein in Sc Ing fat and iBAT, whereas the KD maintained low AT1R levels in these fat depots. However, in Sc Ing and Epid fat depots, the KD elevated AT2R levels and significantly reduced Epid ACE1 levels.
CONCLUSION: Despite fat depot-specific differences in RAS components, the obesogenic diet promoted the classical RAS arm, whereas the KD attenuated it and enhanced the counterregulatory arm.

Keywords:  ACE2; AT(1)R; ERK; MasR; Obesity; Subcutaneous fat; Visceral fat

DOI:  https://doi.org/10.1016/j.nut.2022.111862
Metabolites. 2022 Nov 10. pii: 1092. [Epub ahead of print]12(11):

Dynamics of Gut Microbiota and Clinical Variables after Ketogenic and Mediterranean Diets in Drug-Naïve Patients with Type 2 Diabetes Mellitus and Obesity.

Andrea Deledda, Vanessa Palmas, Vitor Heidrich, Michele Fosci, Mauro Lombardo, Giulia Cambarau, Alessio Lai, Marietta Melis, Elisabetta Loi, Andrea Loviselli, Aldo Manzin, Fernanda Velluzzi.

  Type 2 diabetes mellitus (T2DM), the most common form of diabetes, is a progressive chronic metabolic disease that has increasingly spread worldwide, enhancing the mortality rate, particularly from cardiovascular diseases (CVD). Lifestyle improvement through diet and physical activity is, together with drug treatment, the cornerstone of T2DM management. The Mediterranean diet (MD), which favors a prevalence of unprocessed vegetable foods and a reduction in red meats and industrial foods, without excluding any food category, is usually recommended. Recently, scientific societies have promoted a very low-calorie ketogenic diet (VLCKD), a multiphasic protocol that limits carbohydrates and then gradually re-introduces them, with a favorable outcome on body weight and metabolic parameters. Indeed, gut microbiota (GM) modifications have been linked to overweight/obesity and metabolic alterations typical of T2DM. Diet is known to affect GM largely, but only a few studies have investigated the effects of VLCKD on GM, especially in T2DM. In this study, we have compared anthropometric, biochemical, lifestyle parameters, the quality of life, and the GM of eleven patients with recently diagnosed T2DM and overweight or obesity, randomly assigned to two groups of six and five patients who followed the VLCKD (KETO) or hypocaloric MD (MEDI) respectively; parameters were recorded at baseline (T0) and after two (T2) and three months (T3). The results showed that VLCKD had more significant beneficial effects than MD on anthropometric parameters, while biochemical improvements did not statistically differ. As for the GM, despite the lack of significant results regarding the alpha and beta diversity, and the Firmicutes/Bacteroidota ratio between the two groups, in the KETO group, a significant increase in beneficial microbial taxa such as Verrucomicrobiota phylum with its members Verrucomicrobiae, Verrucomicrobiales, Akkermansiaceae, and Akkermansia, Christensenellaceae family, Eubacterium spp., and a reduction in microbial taxa previously associated with obesity (Firmicutes and Actinobacteriota) or other diseases (Alistipes) was observed both at T2 and T3. With regards to the MEDI group, variations were limited to a significant increase in Actinobacteroidota phylum at T2 and T3 and Firmicutes phylum at T3. Moreover, a metagenomic alteration linked to some metabolic pathways was found exclusively in the KETO group. In conclusion, both dietary approaches allowed patients to improve their state of health, but VLCKD has shown better results on body composition as well as on GM profile.

Keywords:  16S rRNA; Mediterranean diet; body composition; glycometabolic status; gut microbiota; ketogenic diet; obesity; physical activity; quality of life; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/metabo12111092
Brain Commun. 2022 ;4(6): fcac262

Small extracellular vesicles in plasma reveal molecular effects of modified Mediterranean-ketogenic diet in participants with mild cognitive impairment.

Ashish Kumar, Mitu Sharma, Yixin Su, Sangeeta Singh, Fang-Chi Hsu, Bryan J Neth, Thomas C Register, Kaj Blennow, Henrik Zetterberg, Suzanne Craft, Gagan Deep.

 Extracellular vesicles have emerged as a less-invasive nano-tool for discovering biomarkers of Alzheimer's disease and related dementia. Here, we analysed different neuron-enriched extracellular vesicles from plasma to predict response and molecular mechanisms of ketogenic diet's efficacy in mild cognitive impairment participants. The study was a randomized crossover design in which cognitively normal and mild cognitive impairment participants consumed a modified Mediterranean-ketogenic diet or American Heart Association diet for 6 weeks, followed by other diet after washout. L1 cell adhesion molecule, synaptophysin and neural cell adhesion molecule surface markers were used to enrich for neuron-secreted small extracellular vesicles (sEVL1CAM, sEVSYP and sEVNCAM). For the first time, we have presented multiple evidences, including immunogold labelling/transmission electron microscopy, clusters of differentiation 63-ELISA-based assay, confocal microscopy fluorescent images and flow cytometry data confirming the presence of L1 cell adhesion molecule on the surface of sEVL1CAM, validating purity and relative abundance of sEVL1CAM in the plasma. Cargo analysis of sEVL1CAM showed that modified Mediterranean-ketogenic diet intervention reduces amyloid beta 1-42 (50.3%, P = 0.011), p181-tau (34.9%, P = 0.033) and neurofilament light (54.2%, P = 0.020) in mild cognitive impairment participants. Moreover, sEVL1CAMshowed better sensitivity compared with CSF in analysing increased glutamate (6-folds, P < 0.0001) from mild cognitive impairment participants following modified Mediterranean-ketogenic diet intervention. sEVL1CAM characterization also suggested that modified Mediterranean-ketogenic diet differentially targets the expression of various glutamate receptors-glutamate receptor ionotropic NMDA1, glutamate receptor ionotropic NMDA2A, glutamate receptor ionotropic NMDA2B and glutamate receptor ionotropic AMPA type subunit 1. Importantly, these sEVL1CAM measures strongly correlated with corresponding clinical CSF biomarkers (neurogranin, amyloid beta 1-42, neurofilament light and tau). Furthermore, sEVL1CAM were loaded with less advanced glycation endproducts and exhibited anti-inflammatory activity following modified Mediterranean-ketogenic diet intervention. Most importantly, the expression of monocarboxylate transporter 2 on the surface of sEVL1CAM predicted the amyloid beta 1-42 response to modified Mediterranean-ketogenic diet intervention (area under the curve = 0.87, P = 0.0044) and offered a novel screening tool to identify participants responsive to this dietary intervention. Finally, sEVL1CAM, sEVSYP and sEVNCAM showed significantly high concordance in analysing amyloid beta 1-42 (Pearson correlation coefficient ≥ 0.63, P < 0.01) and neurofilament light (Pearson correlation coefficient ≥ 0.49, P < 0.05). Together, small extracellular vesicles in plasma offers promise in assessing the efficacy of dietary/therapeutic intervention against mild cognitive impairment/Alzheimer's disease.

Keywords: amyloid β; extracellular vesicles; glutamate receptor; ketogenic diet; mild cognitive impairment

DOI: https://doi.org/10.1093/braincomms/fcac262
Biomedicines. 2022 Nov 01. pii: 2778. [Epub ahead of print]10(11):

Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer's Disease.

Aishat O Ameen, Kristine Freude, Blanca I Aldana.

  Characterising Alzheimer's disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major metabolic disorders. Therefore, metabolic interventions have been explored as a strategy for brain energetic rescue. Amongst these, medium-chain fatty acid (MCFA) supplementations have been reported to rescue the energetic failure in brain cells as well as the cognitive decline in patients. Short-chain fatty acids (SCFA) have also been implicated in AD pathology. Due to the increasing therapeutic interest in metabolic interventions and brain energetic rescue in neurodegenerative disorders, in this review, we first summarise the role of SCFAs and MCFAs in AD. We provide a comparison of the main findings regarding these lipid species in established AD animal models and recently developed human cell-based models of this devastating disorder.

Keywords:  butyrate; decanoic acid; energy metabolism; hiPSC; neurodegeneration; octanoic acid

DOI:  https://doi.org/10.3390/biomedicines10112778
JDS Commun. 2021 May;2(3): 142-147

Diverging in vitro inflammatory responses toward Streptococcus uberis in mouse macrophages either preconditioned or continuously treated with β-hydroxybutyrate.

T H Swartz, B J Bradford, L K Mamedova.

Hyperketonemia is a common condition in early-lactation dairy cows that has been associated with an increase in the risk of infectious disease. Recent mouse studies have elucidated an anti-inflammatory effect of the ketone body β-hydroxybutyrate (BHB). Therefore, the objective of this study was to determine whether BHB altered inflammatory responses in macrophages challenged with the common mastitis pathogen Streptococcus uberis. A secondary objective was to determine whether the inflammatory response to the S. uberis challenge was dependent on whether BHB was present in the medium during the challenge (i.e., preconditioned vs. continuous treatment). Two cell culture experiments were conducted. In the first experiment, mouse macrophages (RAW 264.7 line) were preconditioned with BHB (0, 0.6, 1.2, and 1.8 mM) for 24 h; the medium was then replaced with a standard cell culture medium, and the cells were challenged or not with S. uberis for an additional 6 h. In the second experiment, a similar protocol was used; however, cells were preconditioned with BHB (0, 0.6, 1.2, and 1.8 mM) for 24 h, the medium was replaced with fresh medium containing the same concentration of BHB, and cells were either challenged or not with S. uberis for 6 h. In both experiments, relative transcript abundance of cell membrane receptors (Tlr2 and Gpr109a), cytokines (Il1b, Il10, Tnf, and Tgfb1), and chemokines (Cxcl2 and Ccl5) were determined using quantitative real-time PCR and normalized against the geometric mean of Hprt and B2m. Data were analyzed using a linear mixed model, and orthogonal contrasts were conducted to examine the effect of S. uberis challenge and BHB treatment. Streptococcus uberis activated the macrophages, noted by greater transcript abundance of analyzed genes. Intriguingly, in both experiments, the S. uberis challenge increased expression of Gpr109a, which encodes a receptor that is ligated by BHB. Paradoxically, preconditioning macrophages with BHB increased transcript abundance of the immunosuppressive cytokine Tgfb1 and increased that of the neutrophil chemoattractant Cxcl2. Preconditioning decreased Tlr2 and tended to decrease Il10 transcript abundance. In opposition to the preconditioning experiment, continuous treatment of BHB during the S. uberis challenge linearly increased abundance of Tlr2 and Il10 transcripts. Continuous BHB treatment also increased expression of Il1b. In conclusion, BHB treatment altered macrophage inflammatory responses during an S. uberis challenge; however, the direction of this response was dependent on whether BHB was added to the medium during the S. uberis challenge. Future studies should be conducted using bovine macrophages and in vivo approaches to examine BHB effects during an S. uberis challenge.

DOI: https://doi.org/10.3168/jdsc.2020-0038
Biology (Basel). 2022 Oct 24. pii: 1556. [Epub ahead of print]11(11):

Diet-Related Changes of Short-Chain Fatty Acids in Blood and Feces in Obesity and Metabolic Syndrome.

Tamás Ilyés, Ciprian N Silaghi, Alexandra M Crăciun.

  Obesity-related illnesses are one of the leading causes of death worldwide. Metabolic syndrome has been associated with numerous health issues. Short-chain fatty acids (SCFAs) have been shown to have multiple effects throughout the body, both directly as well as through specific G protein-coupled receptors. The main SCFAs produced by the gut microbiota are acetate, propionate, and butyrate, which are absorbed in varying degrees from the large intestine, with some acting mainly locally and others systemically. Diet has the potential to influence the gut microbial composition, as well as the type and amount of SCFAs produced. High fiber-containing foods and supplements increase the production of SCFAs and SCFA-producing bacteria in the gut and have been shown to have bodyweight-lowering effects. Dietary supplements, which increase SCFA production, could open the way for novel approaches to weight loss interventions. The aim of this review is to analyze the variations of fecal and blood SCFAs in obesity and metabolic syndrome through a systematic search and analysis of existing literature.

Keywords:  diet; metabolic syndrome; obesity; short-chain fatty acids

DOI:  https://doi.org/10.3390/biology11111556
J Clin Lipidol. 2022 Nov 02. pii: S1933-2874(22)00295-1. [Epub ahead of print]

Elevated LDL-cholesterol levels among lean mass hyper-responders on low-carbohydrate ketogenic diets deserve urgent clinical attention and further research.

Nicholas G Norwitz, Michael R Mindrum, Philippe Giral, Anatol Kontush, Adrian Soto-Mota, Thomas R Wood, Dominic P D'Agostino, Venkat S Manubolu, Matthew Budoff, Ronald M Krauss.



Keywords:  Atherosclerotic cardiovascular disease; Carbohydrate restriction; HDL cholesterol; Ketogenic diet; LDL cholesterol; Lean mass hyper-responder; Triglycerides

DOI:  https://doi.org/10.1016/j.jacl.2022.10.010
JACC Asia. 2022 Jun;2(3): 287-293

Clinical Benefits of Sodium-Glucose Cotransporter 2 Inhibitors and the Mechanisms Underlying Their Cardiovascular Effects.

Yoshiaki Kubota, Wataru Shimizu.

  In addition to showing antidiabetic effects, sodium-glucose cotransporter 2 (SGLT2) inhibitors also reduce cardiovascular events in patients with type 2 diabetes mellitus. In major trials of cardiovascular outcomes, SGLT2 inhibitors have been shown to improve cardiovascular and renal outcomes, including reduced rehospitalization in patients with heart failure, regardless of the presence of diabetes. A recent report showed that the benefits of SGLT2 inhibitors in terms of cardiovascular deaths/admissions caused by heart failure and reduced ejection fraction were greater in Asians than in Whites. In this review, the first part demonstrates the results of recent clinical trials and their clinical implications and outlines current trials and upcoming research areas. The second part provides a general overview of the current understanding of the mechanisms of the cardiovascular benefits of SGLT2 inhibitors.

Keywords:  ATP, adenosine triphosphate; DPP-4, dipeptidyl peptidase-4; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; SGLT2, sodium–glucose cotransporter 2; T2DM, type 2 diabetes mellitus; diabetes; heart failure; sodium–glucose cotransporter 2 inhibitor

DOI:  https://doi.org/10.1016/j.jacasi.2022.03.009
Int J Mol Sci. 2022 Nov 07. pii: 13653. [Epub ahead of print]23(21):

Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed.

Alina M Bețiu, Lavinia Noveanu, Iasmina M Hâncu, Ana Lascu, Lucian Petrescu, Christoph Maack, Eskil Elmér, Danina M Muntean.

  Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.

Keywords:  adverse effects; cardiovascular drugs; drug interaction; drug intoxication; drug toxicity; lactic acidosis; mitochondria function and morphology

DOI:  https://doi.org/10.3390/ijms232113653
Trends Biochem Sci. 2022 Nov 03. pii: S0968-0004(22)00273-0. [Epub ahead of print]

The NLRP3 inflammasome: activation and regulation.

Jie Xu, Gabriel Núñez.

  The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a cytoplasmic supramolecular complex that is activated in response to cellular perturbations triggered by infection and sterile injury. Assembly of the NLRP3 inflammasome leads to activation of caspase-1, which induces the maturation and release of interleukin-1β (IL-1β) and IL-18, as well as cleavage of gasdermin D (GSDMD), which promotes a lytic form of cell death. Production of IL-1β via NLRP3 can contribute to the pathogenesis of inflammatory disease, whereas aberrant IL-1β secretion through inherited NLRP3 mutations causes autoinflammatory disorders. In this review, we discuss recent developments in the structure of the NLRP3 inflammasome, and the cellular processes and signaling events controlling its assembly and activation.

Keywords:  Golgi; metabolism; mitochondria; phosphorylation; potassium efflux; ubiquitination

DOI:  https://doi.org/10.1016/j.tibs.2022.10.002
Genetics. 2022 Nov 02. pii: iyac160. [Epub ahead of print]

Mitochondrial dysfunction, aging, and the mitochondrial unfolded protein response in Caenorhabditis elegans.

Cole M Haynes, Siegfried Hekimi.

  We review the findings that establish that perturbations of various aspects of mitochondrial function, including oxidative phosphorylation, can promote lifespan extension, with different types of perturbations acting sometimes independently and additively on extending lifespan. We also review the great variety of processes and mechanisms that together form the mitochondrial unfolded protein response. We then explore the relationships between different types of mitochondrial dysfunction-dependent lifespan extension and the mitochondrial unfolded protein response. We conclude that, although several ways that induce extended lifespan through mitochondrial dysfunction require a functional mitochondrial unfolded protein response, there is no clear indication that activation of the mitochondrial unfolded protein response is sufficient to extend lifespan, despite the fact that the mitochondrial unfolded protein response impacts almost every aspect of mitochondrial function. In fact, in some contexts, mitochondrial unfolded protein response activation is deleterious. To explain this pattern, we hypothesize that, although triggered by mitochondrial dysfunction, the lifespan extension observed might not be the result of a change in mitochondrial function.

Keywords:  UPRmt; WormBook; aging; mitochondria

DOI:  https://doi.org/10.1093/genetics/iyac160
JDS Commun. 2022 Sep;3(5): 362-367

Effects of dietary butyrate supplementation and oral nonsteroidal antiinflammatory drug administration on uterine inflammation and interval to first ovulation in postpartum dairy cows.

L E Engelking, M Gobikrushanth, M Oba, D J Ambrose.

This study evaluated the effects of dietary butyrate supplementation and oral nonsteroidal antiinflammatory drug (NSAID) administration on uterine inflammation and the interval from calving to first ovulation (ICFO; in days). We hypothesized that a combination of dietary butyrate and oral NSAID would reduce uterine inflammation and decrease ICFO. Sixty-five cows were enrolled in a 2 × 2 factorial design and assigned to receive an iso-energetic diet containing a supplement of either butyrate (fatty acid-coated calcium butyrate) or control (commercial fat and calcium carbonate mixture) at 1.42% of diet dry matter, during the calving transition period from -28 (±3) to +24 (±3) days in milk (DIM; calving = d 0). At 12 to 24 h postcalving, cows received an oral NSAID (1 mg of meloxicam/kg of BW) or a placebo (food dye). Ovarian ultrasonography was performed weekly from 14 DIM until first ovulation or up to 56 DIM. Endometrial cytology was performed at 28 DIM to assess uterine inflammation based on polymorphonuclear leukocytes (PMN). No interactions were detected between treatments. The proportions of cows with high (>18%) endometrial PMN did not differ between butyrate and control diets or between NSAID and placebo. Mean (± standard error of mean) ICFO did not differ between butyrate (28 ± 2 d) and control (25 ± 2 d) or between NSAID (29 ± 2 d) and placebo (24 ± 2 d). However, the ovulation rate up to 56 DIM (hazard ratio: 0.61; 95% confidence interval: 0.35 to 1.04) established by survival analysis tended to be lower in NSAID than in placebo. In conclusion, dietary butyrate supplementation and oral NSAID administration did not reduce endometrial inflammation or the mean ICFO, but NSAID-treated cows tended to have a lower rate of ovulation up to 56 DIM.

DOI: https://doi.org/10.3168/jdsc.2022-0207
Front Nutr. 2022 ;9 1011732

Butyrate: Connecting the gut-lung axis to the management of pulmonary disorders.

Renan Oliveira Corrêa, Pollyana Ribeiro Castro, René Moser, Caroline Marcantonio Ferreira, Valerie F J Quesniaux, Marco Aurélio Ramirez Vinolo, Bernhard Ryffel.

  Short-chain fatty acids (SCFAs) are metabolites released by bacterial components of the microbiota. These molecules have a wide range of effects in the microbiota itself, but also in host cells in which they are known for contributing to the regulation of cell metabolism, barrier function, and immunological responses. Recent studies indicate that these molecules are important players in the gut-lung axis and highlight the possibility of using strategies that alter their intestinal production to prevent or treat distinct lung inflammatory diseases. Here, we review the effects of the SCFA butyrate and its derivatives in vitro and in vivo on murine models of respiratory disorders, besides discussing the potential therapeutic use of butyrate and the other SCFAs in lung diseases.

Keywords:  butyrate; inflammation; lung-gut axis; pulmonary disorders; short-chain fatty acids (SCFA)

DOI:  https://doi.org/10.3389/fnut.2022.1011732
Life (Basel). 2022 Nov 09. pii: 1829. [Epub ahead of print]12(11):

The Anti-Inflammatory Effect of Novel Antidiabetic Agents.

Panagiotis Theofilis, Marios Sagris, Evangelos Oikonomou, Alexios S Antonopoulos, Gerasimos Siasos, Kostas Tsioufis, Dimitris Tousoulis.

  The incidence of type 2 diabetes (T2DM) has been increasing worldwide and remains one of the leading causes of atherosclerotic disease. Several antidiabetic agents have been introduced in trying to regulate glucose control levels with different mechanisms of action. These agents, and sodium-glucose cotransporter-2 inhibitors in particular, have been endorsed by contemporary guidelines in patients with or without T2DM. Their widespread usage during the last three decades has raised awareness in the scientific community concerning their pleiotropic mechanisms of action, including their putative anti-inflammatory effect. In this review, we delve into the anti-inflammatory role and mechanism of the existing antidiabetic agents in the cardiovascular system and their potential use in other chronic sterile inflammatory conditions.

Keywords:  DPP4 inhibitors; GLP-1 receptor agonist; SGLT-2 inhibitor; diabetes mellitus; inflammation

DOI:  https://doi.org/10.3390/life12111829
Cells. 2022 Oct 25. pii: 3361. [Epub ahead of print]11(21):

The Role of Crosstalk between Adipose Cells and Myocytes in the Pathogenesis of Sarcopenic Obesity in the Elderly.

Mauro Zamboni, Gloria Mazzali, Anna Brunelli, Tanaz Saatchi, Silvia Urbani, Anna Giani, Andrea P Rossi, Elena Zoico, Francesco Fantin.

  As a result of aging, body composition changes, with a decline in muscle mass and an increase in adipose tissue (AT), which reallocates from subcutaneous to visceral depots and stores ectopically in the liver, heart and muscles. Furthermore, with aging, muscle and AT, both of which have recognized endocrine activity, become dysfunctional and contribute, in the case of positive energy balance, to the development of sarcopenic obesity (SO). SO is defined as the co-existence of excess adiposity and low muscle mass and function, and its prevalence increases with age. SO is strongly associated with greater morbidity and mortality. The pathogenesis of SO is complex and multifactorial. This review focuses mainly on the role of crosstalk between age-related dysfunctional adipose and muscle cells as one of the mechanisms leading to SO. A better understanding of this mechanisms may be useful for development of prevention strategies and treatments aimed at reducing the occurrence of SO.

Keywords:  adipokines; adipose tissue; myokines; sarcopenic obesity; skeletal muscle

DOI:  https://doi.org/10.3390/cells11213361
Chem Commun (Camb). 2022 Nov 10.

Ketone-derived 2,3-dihydroquinazolinones in N-heteroarene C-H alkylation via C-C bond scission under oxidative metal catalysis.

Pinku Prasad Mondal, Amit Pal, Athira K Prakash, Basudev Sahoo.

A silver-catalysed oxidative sp2 C-H alkylation of N-heteroarenes with ketone-derived 2,3-dihydroquinazolinones at room temperature is developed. The combination of a metal catalyst and perdisulfate oxidant promotes the rarely explored thermal activation of pre-aromatic 2,3-dihydroquinazolinone to generate an alkyl radical, supported by mechanistic studies. In addition to the broad scope, good functionality tolerance, late stage functionalization of APIs, and synthesis of a novel Papaverine analogue, the utilization of an N-heteroarene C-H bond and ketone as a non-trivial alkyl radical source represents the salient feature of this method.

DOI: https://doi.org/10.1039/d2cc04947c
Ageing Res Rev. 2022 Nov 04. pii: S1568-1637(22)00222-7. [Epub ahead of print]82 101780

Energy metabolism and frailty: The potential role of exercise-induced myokines - A narrative review.

Duarte Barros, Elisa A Marques, José Magalhães, Joana Carvalho.

  Frailty is a complex condition that emerges from dysregulation in multiple physiological systems. Increasing evidence suggests the potential role of age-related energy dysregulation as a key driver of frailty. Exercise is considered the most efficacious intervention to prevent and even ameliorate frailty as it up-tunes and improves the function of several related systems. However, the mechanisms and molecules responsible for these intersystem benefits are not fully understood. The skeletal muscle is considered a secretory organ with endocrine functions that can produce and secrete exercise-related molecules such as myokines. These molecules are cytokines and other peptides released by muscle fibers in response to acute and/or chronic exercise. The available evidence supports that several myokines can elicit autocrine, paracrine, or endocrine effects, partly mediating inter-organ crosstalk and also having a critical role in improving cardiovascular, metabolic, immune, and neurological health. This review describes the current evidence about the potential link between energy metabolism dysregulation and frailty and provides a theoretical framework for the potential role of myokines (via exercise) in counteracting frailty. It also summarizes the physiological role of selected myokines and their response to different acute and chronic exercise protocols in older adults.

Keywords:  Exercise; Exerkines; Frailty; Glucose metabolism; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.arr.2022.101780
World J Cardiol. 2022 Oct 26. 14(10): 561-564

Euglycemic diabetic ketoacidosis: A rare but serious side effect of sodium-glucose co-transporter 2 inhibitors.

Nenad Lakušić, Ivana Sopek Merkaš, Ana Marija Slišković, Dora Cerovec.

  Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients. A rare, but potentially life-threatening complication of SGLT2 inhibitor use is euglycemic diabetic ketoacidosis. We described a case of a middle-aged male patient with type 2 diabetes who developed metabolic ketoacidosis after a few days of empagliflozin administration. SGLT2 inhibitor related ketoacidosis presents with euglycemia or only modestly elevated glucose blood concentrations, which causes delayed detection and treatment of ketoacidosis. There are multiple possible risk factors and mechanism that might contribute to the pathogenesis of ketoacidosis. It is implied that SGLT2 inhibitor use and prescription by non-diabetologists (cardiologists, nephrologists, family physicians, etc.) will continue to grow in the future. It is important to inform the general cardiac public about this rare but serious side effect of SGLT2 inhibitors.

Keywords:  Chronic heart failure; Euglycemic diabetic ketoacidosis; Sodium-glucose co-transporter 2 inhibitors

DOI:  https://doi.org/10.4330/wjc.v14.i10.561
Clin Biomech (Bristol, Avon). 2022 Oct 25. pii: S0268-0033(22)00238-8. [Epub ahead of print]100 105808

Short-time recovery skeletal muscle from dexamethasone-induced atrophy and weakness in old female rats.

Karin Alev, Maire Aru, Arved Vain, Ando Pehme, Priit Kaasik, Teet Seene.

  BACKGROUND: Several pathological conditions (atrophy, dystrophy, spasticity, inflammation) can change muscle biomechanical parameters. Our previous works have shown that dexamethasone treatment changes skeletal muscle tone, stiffness, elasticity. Exercise training may oppose the side effects observed during dexamethasone treatment. The purpose of this study was to examine the changes in biomechanical parameters (tone, stiffness, elasticity) of skeletal muscle occurring during dexamethasone treatment and subsequent short-time recovery from glucocorticoid-induced muscle atrophy and weakness, as well as the effect of mild therapeutic exercise.METHODS: 17 old female rats, aged 22 months were used in this study. The hand-held and non-invasive device (MyotonPRO, Myoton Ltd., Tallinn, Estonia) was used to study changes in biomechanical properties of muscle. Additionally, body and muscle mass, hind limb grip strength were assessed.
FINDINGS: Results showed that dexamethasone treatment alters muscle tone, stiffness and elasticity. During 20-day recovery period all measured parameters gradually improved towards the average baseline, however, remaining significantly lower than these values. The body and muscle mass, hind limb grip strength of the rats decreased considerably in the groups that received glucocorticoids. After 20 days of recovery, hind limb grip strength of the animals was slightly lower than the baseline value and mild therapeutic exercise had a slight but not significant effect on hind limb grip strength. Biomechanical parameters improved during the recovery period, but only dynamic stiffness and decrement retuned to baseline value.
INTERPRETATION: The study results show that monitoring muscle biomechanical parameters allows to assess the recovery of atrophied muscle from steroid myopathy.

Keywords:  Glucocorticoids myopathy; Muscle elasticity; Muscle stiffness; Muscle tone; Therapeutic exercise

DOI:  https://doi.org/10.1016/j.clinbiomech.2022.105808
Nutr Rev. 2022 Nov 04. pii: nuac092. [Epub ahead of print]

The effects of fasting diets on nonalcoholic fatty liver disease.

Zeinab Mokhtari, Elham Hosseini, Azita Hekmatdoost, Natasha Haskey, Deanna L Gibson, Gholamreza Askari.

  Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. There is no confirmed treatment for NAFLD as yet. Recently, fasting regimens and their relationship to NAFLD have drawn a great deal of attention in the literature. We review the current evidence that supports fasting diets as an adjunctive therapeutic strategy for patients with NAFLD and address potential action mechanisms. We reason that the fasting diets might be a promising approach for modulating hepatic steatosis, fibroblast growth factors 19 and 21 signaling, lipophagy, and the metabolic profile.

Keywords:  Diet; Fasting; NAFLD; NASH; Nonalcoholic fatty liver disease; Time-restricted feeding

DOI:  https://doi.org/10.1093/nutrit/nuac092
Trends Endocrinol Metab. 2022 Oct 29. pii: S1043-2760(22)00180-1. [Epub ahead of print]

Can sodium-glucose cotransporter 2 inhibitors 'spin the thread of life'?

Giuseppe Maltese, Theocharis Koufakis, Kalliopi Kotsa, Janaka Karalliedde.

  Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were first used as antidiabetic agents that lower the blood glucose levels by promoting glycosuria. In recent years, randomised clinical trials have demonstrated that SGLT2i reduce cardiovascular-renal events and all-cause mortality in people with and without diabetes. The cardio-renal benefits observed are independent of glucose lowering effect and multiple mechanisms have been proposed for these results. SGLT2i can exert anti-ageing effects on the vasculature and other body organs through several signalling pathways including the activation of the nuclear factor erythroid-2-related factor 2 and the induction of antioxidant enzymes. We speculate that the pro-longevity effects of the SGLT2i are mediated by soluble Klotho, an anti-ageing kidney-derived hormone and an emerging therapeutic target for cardio-renal diseases.

Keywords:  Klotho; SGLT2i; ageing; longevity; type 2 diabetes

DOI:  https://doi.org/10.1016/j.tem.2022.10.002
Front Cardiovasc Med. 2022 ;9 1011429

Benefits of SGLT2 inhibitors in arrhythmias.

Jinghan Gao, Genlong Xue, Ge Zhan, Xinying Wang, Jiatian Li, Xiaolei Yang, Yunlong Xia.

  Some studies have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors can definitively attenuate the occurrence of cardiovascular diseases such as heart failure (HF), dilated cardiomyopathy (DCM), and myocardial infarction. With the development of research, SGLT2 inhibitors can also reduce the risk of arrhythmias. So in this review, how SGLT2 inhibitors play a role in reducing the risk of arrhythmia from the perspective of electrical remodeling and structural remodeling are explored and then the possible mechanisms are discussed. Specifically, we focus on the role of SGLT2 inhibitors in Na+ and Ca2 + homeostasis and the transients of Na+ and Ca2 +, which could affect electrical remodeling and then lead to arrythmia. We also discuss the protective role of SGLT2 inhibitors in structural remodeling from the perspective of fibrosis, inflammation, oxidative stress, and apoptosis. Ultimately, it is clear that SGLT2 inhibitors have significant benefits on cardiovascular diseases such as HF, myocardial hypertrophy and myocardial infarction. It can be expected that SGLT2 inhibitors can reduce the risk of arrhythmia.

Keywords:  SGLT2 inhibitors; arrhythmia; electrical remodeling; mechanisms; structural remodeling

DOI:  https://doi.org/10.3389/fcvm.2022.1011429
Front Immunol. 2022 ;13 967989

Hunting down NLRP3 inflammasome: An executioner of radiation-induced injury.

Han Cheng, Lingling Chen, Minchun Huang, Jin Hou, Zhifeng Chen, Xiaojun Yang.

  Radiotherapy is one of the mainstream treatment modalities for several malignancies. However, radiation-induced injury to surrounding normal tissues limits its efficacy. The NLRP3 inflammasome is an essential mechanism of innate immunity that reacts to challenges from endogenous danger signals and pathological microbes. A growing body of evidence has demonstrated a key role of NLRP3 inflammasome in the pathogenesis of radiation-induced tissue injury. Despite accumulating evidence, the potential value of the NLRP3 inflammasome in the management of radiation-induced tissue injury is not adequately recognized. We conducted a literature review to characterize the relationship between NLRP3 inflammasome and radiation injury. By analyzing recent evidence, we identify NLRP3 inflammasome as one of the executioners of radiation-induced injury, since it responds to the challenges of radiation, induces cell pyroptosis and tissue dysfunction, and initiates non-resolving inflammation and fibrosis. Based on these concepts, we propose early intervention/prevention strategies targeting NLRP3 inflammasome in a radiation context, which may help resolve imperative clinical problems.

Keywords:  NLRP3 inflammasome; ROS; inflammasome activation; pyroptosis; radiation injury; therapeutic target

DOI:  https://doi.org/10.3389/fimmu.2022.967989