bims-kimdis 2023-01-22 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–01–22
37 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Supplementation with medium-chain fatty acids increases body weight loss during very low-calorie ketogenic diet: a retrospective analysis in a real-life setting.
The Antioxidant Potential of the Mediterranean Diet as a Predictor of Weight Loss after a Very Low-Calorie Ketogenic Diet (VLCKD) in Women with Overweight and Obesity.
Potential Therapeutic Strategies for Skeletal Muscle Atrophy.
Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interaction.
HAT- and HDAC-Targeted Protein Acetylation in the Occurrence and Treatment of Epilepsy.
Early Stage Alzheimer's Disease: Are Skeletal Muscle and Exercise the Key?
Urine ketone bodies and adverse outcomes in patients with acute ischemic stroke or TIA.
The NLRP3 inflammasome activation in subcutaneous, epicardial and pericardial adipose tissue in patients with coronary heart disease undergoing coronary by-pass surgery.
NADPH Oxidase-Mediated Testicular Oxidative Imbalance Regulates the TXNIP/NLRP3 Inflammasome Axis Activation after Ischemia Reperfusion Injury.
NLRP3, the inflammasome and COVID-19 infection.
Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease.
Tackling Inflammation at its Source in Heart Failure: Are Mitochondria the Key?
Increase in hematocrit with SGLT-2 inhibitors - Hemoconcentration from diuresis or increased erythropoiesis after amelioration of hypoxia?
Targeting mitochondria to extend physically active lifespan.
Autophagy in Atherosclerotic Plaque Cells: Targeting NLRP3 Inflammasome for Self-Rescue.
Emerging concepts in heart failure management and treatment: focus on SGLT2 inhibitors in heart failure with preserved ejection fraction.
Neutral effect of SGLT2 inhibitors on lipoprotein metabolism: From clinical evidence to molecular mechanisms.
Fasting and fasting mimicking diets in cancer prevention and therapy.
Protein engineering reveals that gasdermin A preferentially targets mitochondrial membranes over the plasma membrane during pyroptosis.
Ketogenic diet: Possible mechanism, old and new applications.
The high dose of inulin exacerbated food allergy through the excess accumulation of short-chain fatty acids in a BABL/c mouse model.
Is aging a "Retro"spective event?
Anti-inflammatory effects of NaB and NaPc in Acinetobacter baumannii-stimulated THP-1 cells via TLR-2/NF-κB/ROS/NLRP3 pathway.
Impact of aging on mitochondrial respiration in various organs.
Butyrate Improves Neuroinflammation and Mitochondrial Impairment in Cerebral Cortex and Synaptic Fraction in an Animal Model of Diet-Induced Obesity.
The Circadian Biology of Heart Failure.
TAX1BP1 protects against myocardial infarction-associated cardiac anomalies through inhibition of inflammasomes in a RNF34/MAVS/NLRP3-dependent manner.
Loss of skeletal muscle estrogen related receptors leads to severe exercise intolerance.
Phenolic and quinone methide nor-triterpenes as selective NLRP3 inflammasome inhibitors.
Gasdermin D pore-forming activity is redox-sensitive.
Challenging Dogma about Myonuclei Behavior in Skeletal Muscle Cells.
Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways.
Discovery of alantolactone as a natural NLRP3 inhibitor to alleviate NLRP3-driven inflammatory diseases in mice.
Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies.
Low-carbohydrate diets in type 1 diabetes: balancing benefits and risks.
Intrinsic cardiorespiratory fitness modulates clinical and molecular response to caloric restriction.
FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis.

J Transl Med. 2023 Jan 16. 21(1): 29

Supplementation with medium-chain fatty acids increases body weight loss during very low-calorie ketogenic diet: a retrospective analysis in a real-life setting.

Claudia Vetrani, Ludovica Verde, Silvia Savastano, Annamaria Colao, Giovanna Muscogiuri, Luigi Barrea.

   BACKGROUND: Very low-calorie ketogenic diet (VLCKD) has shown to significantly reduce body weight and fat mass, as well as inflammation. These effects are supported by nutritional ketosis, which triggers the utilization of the ketone body as an energy source. Medium-chain fatty acids (MCTs) might serve as potential enhancers of ketone bodies production with a greater effect on weight loss. Nevertheless, no clinical studies have evaluated the effect of MCTs supplementation in addition to VLCKD. Therefore, the present study aimed to evaluate whether the supplementation with MCTs can induce a greater weight reduction during the ketogenic phase of VLCKD.
METHODS: In this retrospective study, 263 women with overweight/obesity (body mass index, BMI: 35.7 ± 5.3 kg/m2) aged 37.5 ± 14.2 years followed one of these dietary protocols for 45 days: (a) Control group, 83 participants (31.6%) (VLCKD without MCTs), (b) VLCKD + MCTs group, 86 participants (32.7%) (MCTs supplementation - 20 g/day- during VLCKD starting from the first day of the active phase), (c) VLCKD + earlyMCTs, 94 participants (35.7%) (MCTs supplementation - 20 g/day-starting from 5 days before the beginning of the VLCKD active phase. Anthropometric measures, body composition, and c-reactive protein (CRP) concentrations were collected at the beginning and at the end (45 days) of the VLCKD intervention.
RESULTS: MCTs supplementation significantly decreased body weight, BMI, and waist circumference as compared to the control group, with a greater effect in the VLCKD + earlyMCTs group. A two-fold decrease in fat mass and an increase in muscle mass were observed in the VLCKD + earlyMCTs group as compared to the control group. As for inflammation, hs-CRP concentrations (assessed as absolute percent change) were significantly lower in the VLCKD + MCTs group (p = 0.009) and the VLCKD + earlyMCTs group (p = 0.011) than in the control group. A logistic regression model showed that VLCKD + earlyMCTs increase the likelihood of improvement of BMI classes (OR: 1.85, 95% CI 1.02-3.36) also after adjusting for the potential confounding factors.
CONCLUSION: MCTs supplementation (20 g/day) may be a useful tool to enhance the beneficial effect of VLCKD on the reduction of body weight and fat mass. In particular, MCTs supplementation before the beginning of the VLCKD active phase might facilitate ketosis thus contributing to the effectiveness of the nutritional intervention.

Keywords:  Diet; Inflammation; Ketogenic diet; Ketone bodies; Medium-chain fatty acids (MCTs); Nutritional ketosis; Obesity; VLCKD

DOI:  https://doi.org/10.1186/s12967-023-03880-7
Antioxidants (Basel). 2022 Dec 22. pii: 18. [Epub ahead of print]12(1):

The Antioxidant Potential of the Mediterranean Diet as a Predictor of Weight Loss after a Very Low-Calorie Ketogenic Diet (VLCKD) in Women with Overweight and Obesity.

Ludovica Verde, Maria Dalamaga, Xavier Capó, Giuseppe Annunziata, Maria Hassapidou, Annamaria Docimo, Silvia Savastano, Annamaria Colao, Giovanna Muscogiuri, Luigi Barrea.

  Obesity involves a chronic state of low-grade inflammation, which is linked to the development of several comorbidities. Recently, the very low-calorie ketogenic diet (VLCKD) has gained great interest in the treatment of obesity, almost ousting the ancient and healthy Mediterranean diet (MD). However, because these dietary regimens exploit different pathophysiological mechanisms, we hypothesize that adherence to the MD may play a role in determining the efficacy of the VLCKD. We enrolled 318 women (age 38.84 ± 14.37 years; BMI 35.75 ± 5.18 kg/m²) and assessed their anthropometric parameters, body compositions, and adherence to the MD (with the PREvención con DIetaMEDiterránea (PREDIMED) questionnaire) at baseline. The anthropometric parameters and body composition were repeated at the end of the VLCKD. At the end of the VLCKD, the women with high adherence to the MD achieved the best results in terms of weight loss and improved body composition. Specifically, the women who were above the median of fat mass (FM)% reduction had the best MD pattern, characterized by a higher consumption of extra virgin olive oil (EVOO), fruits, vegetables, and red wine, as well as a higher adherence to the MD than the women who were below the same median. In a multiple regression analysis, the PREDIMED score was the main predictor of the FM% reduction score and came in first, followed by fruit, EVOO, and glasses of wine, in predicting the percentage reduction in FM. A PREDIMED score value of > 5 could serve as a threshold to identify patients who are more likely to lose FM at the end of the VLCKD. In conclusion, high adherence to the MD resulted in higher VLCKD efficacy. This could be due to the antioxidant and anti-inflammatory properties of the MD, which are capable of establishing a metabolic set-up that is favorable to the onset of more effective ketosis.

Keywords:  Mediterranean diet; antioxidant; obesity; very low-calorie ketogenic diet (VLCKD); weight loss

DOI:  https://doi.org/10.3390/antiox12010018
Antioxidants (Basel). 2022 Dec 26. pii: 44. [Epub ahead of print]12(1):

Potential Therapeutic Strategies for Skeletal Muscle Atrophy.

Li Huang, Ming Li, Chunyan Deng, Jiayi Qiu, Kexin Wang, Mengyuan Chang, Songlin Zhou, Yun Gu, Yuntian Shen, Wei Wang, Ziwei Huang, Hualin Sun.

  The maintenance of muscle homeostasis is vital for life and health. Skeletal muscle atrophy not only seriously reduces people's quality of life and increases morbidity and mortality, but also causes a huge socioeconomic burden. To date, no effective treatment has been developed for skeletal muscle atrophy owing to an incomplete understanding of its molecular mechanisms. Exercise therapy is the most effective treatment for skeletal muscle atrophy. Unfortunately, it is not suitable for all patients, such as fractured patients and bedridden patients with nerve damage. Therefore, understanding the molecular mechanism of skeletal muscle atrophy is crucial for developing new therapies for skeletal muscle atrophy. In this review, PubMed was systematically screened for articles that appeared in the past 5 years about potential therapeutic strategies for skeletal muscle atrophy. Herein, we summarize the roles of inflammation, oxidative stress, ubiquitin-proteasome system, autophagic-lysosomal pathway, caspases, and calpains in skeletal muscle atrophy and systematically expound the potential drug targets and therapeutic progress against skeletal muscle atrophy. This review focuses on current treatments and strategies for skeletal muscle atrophy, including drug treatment (active substances of traditional Chinese medicine, chemical drugs, antioxidants, enzyme and enzyme inhibitors, hormone drugs, etc.), gene therapy, stem cell and exosome therapy (muscle-derived stem cells, non-myogenic stem cells, and exosomes), cytokine therapy, physical therapy (electroacupuncture, electrical stimulation, optogenetic technology, heat therapy, and low-level laser therapy), nutrition support (protein, essential amino acids, creatine, β-hydroxy-β-methylbutyrate, and vitamin D), and other therapies (biomaterial adjuvant therapy, intestinal microbial regulation, and oxygen supplementation). Considering many treatments have been developed for skeletal muscle atrophy, we propose a combination of proper treatments for individual needs, which may yield better treatment outcomes.

Keywords:  cytokine therapy; drug treatment; gene therapy; skeletal muscle atrophy; stem cell therapy

DOI:  https://doi.org/10.3390/antiox12010044
Pharmacol Rev. 2023 Jan 20. pii: PHARMREV-AR-2022-000629. [Epub ahead of print]

Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interaction.

Qiang Ma.

  The nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multi-protein complex that combines sensing, regulation, and effector functions to regulate inflammation in health and disease. NLRP3 is activated by a diverse range of inflammation-instigating signals known as pathogen associated molecular patterns and danger associated molecular patterns. Upon activation, NLRP3 oligomerizes and recruits partner proteins to form a supramolecular platform to process the maturation and release of interleukin (IL)-1β, IL-18, and gasdermin D, major mediators of inflammation and inflammatory cell death termed pyroptosis. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide range of disease conditions, including chronic inflammatory disease that are associated with lifestyle and dietary changes, aging, and environmental exposures and have become the leading cause of death worldwide. Pharmacological targeting of NLRP3 and signaling demonstrated promising efficacy in ameliorating a list of disease conditions in animal models. These findings underscore the potential and importance of NLRP3 as a druggable target for treating a range of diseases. In this review, recent progress in understanding the structure and mechanism of action of the NLRP3 inflammasome is discussed with focus on pharmacological inhibition of NLRP3 by small molecule inhibitors. New structural and mechanistic insights into NLRP3 activation and inhibitor-NLRP3 interactions would aid in the rational design and pharmacological evaluation of NLRP3 inhibitors for treatment of human disease. Significance Statement The NLRP3 inflammasome plays central role in innate immune sensing and control of inflammation. Pharmacological inhibition of NLRP3 demonstrated promising efficacy in a range of diseases in animal models. Recent elucidation of the structure and inhibitor binding of NLRP3 generated new insights into its mode of action and inhibitor-NLRP3 interaction at molecular levels, providing new framework for developing small chemical inhibitors of NLRP3 with improved efficacy and specificity against chronic disease that has become major health concerns worldwide.

Keywords:  anti-inflammatory drugs; immunopharmacology; inflammation; protein structure

DOI:  https://doi.org/10.1124/pharmrev.122.000629
Biomedicines. 2022 Dec 29. pii: 88. [Epub ahead of print]11(1):

HAT- and HDAC-Targeted Protein Acetylation in the Occurrence and Treatment of Epilepsy.

Jie Wang, Feng Yun, Jiahui Sui, Wenpeng Liang, Dingding Shen, Qi Zhang.

  Epilepsy is a common and severe chronic neurological disorder. Recently, post-translational modification (PTM) mechanisms, especially protein acetylation modifications, have been widely studied in various epilepsy models or patients. Acetylation is regulated by two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs catalyze the transfer of the acetyl group to a lysine residue, while HDACs catalyze acetyl group removal. The expression of many genes related to epilepsy is regulated by histone acetylation and deacetylation. Moreover, the acetylation modification of some non-histone substrates is also associated with epilepsy. Various molecules have been developed as HDAC inhibitors (HDACi), which have become potential antiepileptic drugs for epilepsy treatment. In this review, we summarize the changes in acetylation modification in epileptogenesis and the applications of HDACi in the treatment of epilepsy as well as the mechanisms involved. As most of the published research has focused on the differential expression of proteins that are known to be acetylated and the knowledge of whole acetylome changes in epilepsy is still minimal, a further understanding of acetylation regulation will help us explore the pathological mechanism of epilepsy and provide novel ideas for treating epilepsy.

Keywords:  acetylation; deacetylation; epilepsy; histone acetyltransferases (HATs); histone deacetylase inhibitors (HDACi); histone deacetylases (HDACs)

DOI:  https://doi.org/10.3390/biomedicines11010088
J Appl Physiol (1985). 2023 Jan 19.

Early Stage Alzheimer's Disease: Are Skeletal Muscle and Exercise the Key?

Matthew H Brisendine, Joshua C Drake.

  Alzheimer's disease (AD) is the most common form of dementia affecting approximately 6.5 million people in the United States alone. The development of AD progresses over a span of years to possible decades before resulting in cognitive impairment and clinically diagnosed AD. The time leading up to a clinical diagnosis is known as the preclinical phase, a time in which recent literature has noted a more severe loss of body mass and more specifically lean muscle mass and strength prior to diagnosis. Mitochondria dysfunction in neurons is also closely associated with AD, and mitochondrial dysfunction has been seen to occur in skeletal muscle with mild cognitive impairment prior to AD manifestation. Evidence from animal models of AD suggest a close link between skeletal muscle mass, mitochondria function, and cognition. Exercise is a powerful stimulus for improving mitochondria function, muscle health, and offers benefits to cognition has been suggested as a possible therapeutic strategy for AD. However, evidence for beneficial effects of exercise in AD afflicted populations and animal models have produced conflicting results. In this mini-review, we discuss these findings and highlight potential avenues for further investigation that may lead to the implementation of exercise as a therapeutic intervention to delay or prevent the development of AD.

Keywords:  alzheimer's disease; exercise; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00659.2022
Atheroscler Plus. 2022 Apr;48 20-26

Urine ketone bodies and adverse outcomes in patients with acute ischemic stroke or TIA.

Anxin Wang, Xue Tian, Yingting Zuo, Qin Xu, Xia Meng, Pan Chen, Hao Li, Yongjun Wang.

   Background and aims: Urine ketone bodies have been considered as predictors of stroke in diabetic patients, however, the role of urine ketone bodies in the prognosis of stroke has not been investigated well. This study aimed to investigate the association between urine ketone bodies and adverse outcomes in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA).
Methods: This study enrolled 14 015 patients with AIS or TIA who screened for urine ketone bodies from the Third China National Stroke Registry. Status of urine ketone bodies were classified into negative, suspicious positive and positive. The outcomes were all-cause death and poor functional outcomes (modified Rankin Scale [mRS] 2-6/3-6) at 3 months and 1 year. Multivariable Cox proportional hazards regressions and logistic regressions were adopted to explore the associations.
Results: Participants with negative, suspicious positive and positive urine ketone bodies were 12979 (92.61%), 480 (3.42%) and 556 (3.97%). After multivariate adjustment, patients with positive urine ketone bodies had a higher risk of all-cause death (hazard ratio, 1.74; confidence interval [CI], 1.07-2.83), a higher proportion of mRS score 2-6 (Odds ratio [OR], 1.85; 95% CI, 1.51-2.27), mRS score 3-6 (OR, 2.00; 95% CI, 1.61-2.48) at 3 months, compared to those with negative urine ketone bodies. Significant associations persisted at 1 year. Furthermore, there was no significant interaction of diabetes status and alcohol use with urine ketone bodies.
Conclusions: Positive urine ketone bodies can independently predict all-cause death and poor functional outcomes in patients with AIS or TIA.

Keywords:  Acute ischemic stroke; All-cause death; Poor functional outcomes; Transient ischemic attack; Urine ketone bodies

DOI:  https://doi.org/10.1016/j.athplu.2022.03.001
Atheroscler Plus. 2022 Apr;48 47-54

The NLRP3 inflammasome activation in subcutaneous, epicardial and pericardial adipose tissue in patients with coronary heart disease undergoing coronary by-pass surgery.

Sissel Åkra, Ingebjørg Seljeflot, Bjørn Braathen, Vibeke Bratseth, Charlotte Holst Hansen, Harald Arnesen, Theis Tønnessen, Svein Solheim.

   Background and aims: Epicardial and pericardial adipose tissue (EAT and PAT) associate with atherosclerosis, however, discussed to have different inflammatory properties. We examined the NLRP3 inflammasome related pathway, playing a pivotal role in atherosclerosis, in EAT, PAT and subcutaneous AT (SAT), their relationship to cell types and anthropometric measures in patients undergoing coronary artery bypass grafting.
Methods: Biopsies from EAT, PAT and SAT were collected from 52 patients with coronary heart disease (CHD) (median body weight 85.0 kg) and 22 controls. RNA was extracted and expression of interleukin (IL)-1β, IL-18, NLRP3, Caspase-1, toll-like receptor 4 (TLR4), IL-6, IL-6 receptor and gp130 were analyzed by RT-PCR.
Results: Limited differences in any genes between CHD patients and controls. IL-18 and IL-6 were 4-fold higher expressed in EAT versus PAT (p < 0.01, both) and SAT (p < 0.001, both), whereas caspase-1, IL-6R and gp130 were higher expressed in SAT compared to the other compartments (all p = 0.06-<0.001). Significant correlations between SAT and PAT gene expressions (r = 0.358-0.579, all p ≤ 0.01). Especially NLRP3 and TLR4 associated with the expression of macrophages in all compartments (all p < 0.001). In EAT IL-18 correlated inversely with the expression of macrophages and T-cells. In SAT and PAT most of the mediators associated with body weight.
Conclusions: Higher expression of IL-18 and IL-6 was observed in EAT in our non-obese CHD patients, not related to inflammatory cells. The NLRP3 inflammasome activation in SAT that mirrored PAT, both related to anthropometrics, suggest that SAT samples, being easily available, to a certain degree, represent adipose tissue inflammation in general.

Keywords:  Coronary heart disease; Epicardial adipose tissue; Interleukin-18; Interleukin-6; NLRP3 inflammasome; Pericardial adipose tissue; Subcutaneous adipose tissue

DOI:  https://doi.org/10.1016/j.athplu.2022.03.005
Antioxidants (Basel). 2023 Jan 07. pii: 145. [Epub ahead of print]12(1):

NADPH Oxidase-Mediated Testicular Oxidative Imbalance Regulates the TXNIP/NLRP3 Inflammasome Axis Activation after Ischemia Reperfusion Injury.

Duaah Almarzouq, May Al-Maghrebi.

  Oxidative stress, inflammation and germ cell death are the main characteristics of testicular ischemia reperfusion injury (tIRI), which is considered as the underlying mechanism for testicular torsion and detorsion. The study aimed to examine the effect of tIRI-activated NADPH oxidase (NOX) on the expression of the NLRP3 inflammasome pathway components. Three groups of male Sprague-Dawley rats (n = 12 each) were studied: sham, unilateral tIRI only and tIRI treated with apocynin, a NOX-specific inhibitor. The tIRI rat model was subjected to 1 h of ischemia followed by 4 h of reperfusion. H&E staining, real time PCR, biochemical assays, and Western blot were utilized to evaluate spermatogenic damage, gene expression, oxidative stress markers, and NLRP3 pathway components, respectively. As a result of tIRI, decreased total antioxidant capacity and suppressed activities of superoxide dismutase and catalase were associated with spermatogenic arrest. The components of the NLRP3 inflammasome pathway (TXNIP, NLRP3, ASC, caspase-1, GSDMD, MMP-9) were upregulated transcriptionally and post-transcriptionally during tIRI. In parallel, tissue inflammation was demonstrated by a marked increase in the concentrations of myeloperoxidase, IL-1β, and IL-18. Apocynin treatment prevented testicular oxidative stress and inflammation. Thus, NOX inhibition by apocynin prevented ROS accumulation, proinflammatory cytokine overexpression and NLRP3 inflammasome activation during tIRI.

Keywords:  NADPH oxidase; NLRP3 inflammasome; ischemia reperfusion injury; oxidative stress; testis

DOI:  https://doi.org/10.3390/antiox12010145
QJM. 2023 Jan 20. pii: hcad011. [Epub ahead of print]

NLRP3, the inflammasome and COVID-19 infection.

Maureen Yin, Laura Marrone, Christian G Peace, Luke A J O'Neill.

Severe coronavirus disease 2019 (COVID-19) is characterized by respiratory failure, shock, or multiorgan dysfunction, often accompanied by systemic hyperinflammation and dysregulated cytokine release. These features are linked to the intense and rapid stimulation of the innate immune response. The NLRP3 inflammasome is a central player in inflammatory macrophage activation which via caspase-1 activation leads to the release of the mature forms of the pro-inflammatory cytokines IL-1β and IL-18, and via cleavage of Gasdermin D pyroptosis, an inflammatory form of cell death. Here we discuss the role of NLRP3 activation in COVID-19 and clinical trials currently underway to target NLRP3 to treat severe COVID-19.

DOI: https://doi.org/10.1093/qjmed/hcad011
J Cell Physiol. 2023 Jan 17.

Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease.

Abbas Shahi, Shima Afzali, Zahra Firoozi, Poopak Mohaghegh, Ali Moravej, Ali Hosseinipour, Maryam Bahmanyar, Yaser Mansoori.

  There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self-limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis-related proteins like caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), proinflammatory cytokines like IL-1 and IL-18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well-defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.

Keywords:  Kawasaki disease; NLRP3; inflammasomes; inflammation; interleukin-1β; pyroptosis

DOI:  https://doi.org/10.1002/jcp.30948
JACC Basic Transl Sci. 2022 Dec;7(12): 1197-1199

Tackling Inflammation at its Source in Heart Failure: Are Mitochondria the Key?

Michael N Sack.



Keywords:  heart failure with reduced ejection fraction; mitochondrial function; nicotinamide adenine dinucleotide; nicotinamide riboside; sterile inflammation

DOI:  https://doi.org/10.1016/j.jacbts.2022.07.008
Diabetes Metab Syndr. 2022 Dec 30. pii: S1871-4021(22)00319-8. [Epub ahead of print]17(2): 102702

Increase in hematocrit with SGLT-2 inhibitors - Hemoconcentration from diuresis or increased erythropoiesis after amelioration of hypoxia?

Preethika Ekanayake, Sunder Mudaliar.

BACKGROUND AND AIMS: The SGLT2-inhibitors significantly reduce heart failure hospitalization and progression to end-stage kidney disease. An increase in hemoglobin/hematocrit is seen with SGLT2i-inhibitor treatment. This increase has been attributed to hemoconcentration resulting from a diuretic effect. In this review, we present evidence suggesting that the hematocrit increase is not due to hemoconcentration, but to an increase in erythropoiesis due to amelioration of hypoxia and more efficient erythropoietin production with SGLT2-inhibitor treatment.
METHODS: We performed a detailed review of the literature in PubMed for articles describing various mechanisms linking hematocrit increase with SGLT2-inhibitor use to their cardio-renal benefits.
RESULTS: The best predictor of cardio-renal benefits with SGLT2-inhibitors is an increase in hematocrit and hemoglobin. If this hemoconcentration is a results of diuresis, this would be associated with volume contraction and a deterioration in renal function, as seen with long-term diuretic use. This is the opposite of what is seen with the use of SGLT2-inhibitors, which are associated with long-term preservation of renal function. There is now growing evidence that the increase in hematocrit can be attributed to an increase in erythropoiesis due to amelioration of renal hypoxia and more efficient erythropoietin production with SGLT2-inhibitor treatment. Increased erythropoiesis leads to an increase in RBC count which improves myocardial/renal tissue oxygenation and function.
CONCLUSION: The increase in hematocrit with SGLT2i treatment is not due to hemoconcentration, but to an increase in erythropoiesis due to amelioration of hypoxia and more efficient erythropoietin production with SGLT2i treatment.

DOI: https://doi.org/10.1016/j.dsx.2022.102702
Aging (Albany NY). 2023 Jan 16. undefined

Targeting mitochondria to extend physically active lifespan.

Bumsoo Ahn.



Keywords:  mitochondria; neurogenic atrophy; peroxiredoxin; retrograde effect; sarcopenia

DOI:  https://doi.org/10.18632/aging.204494
Biomolecules. 2022 Dec 21. pii: 15. [Epub ahead of print]13(1):

Autophagy in Atherosclerotic Plaque Cells: Targeting NLRP3 Inflammasome for Self-Rescue.

Xuelian Li, Xianjie Zhu, Yumiao Wei.

  Atherosclerosis (AS) is a lipid-driven disorder of the artery intima characterized by the equilibrium between inflammatory and regressive processes. A protein complex called NLRP3 inflammasome is involved in the release of mature interleukin-1β (IL-1β), which is connected to the initiation and progression of atherosclerosis. Autophagy, which includes macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy, is generally recognized as the process by which cells transfer their constituents to lysosomes for digestion. Recent studies have suggested a connection between vascular inflammation and autophagy. This review summarizes the most recent studies and the underlying mechanisms associated with different autophagic pathways and NLRP3 inflammasomes in vascular inflammation, aiming to provide additional evidence for atherosclerosis research.

Keywords:  NLRP3 inflammasome; atherosclerosis; autophagy; mitophagy

DOI:  https://doi.org/10.3390/biom13010015
Drugs Context. 2023 ;pii: 2022-7-1. [Epub ahead of print]12

Emerging concepts in heart failure management and treatment: focus on SGLT2 inhibitors in heart failure with preserved ejection fraction.

Andrea Beatriz De Lorenzi, Edgardo Kaplinsky, Marx Rivera Zambrano, Laia Tomás Chaume, Joan Monell Rosas.

  The role of sodium-glucose cotransporter 2 inhibitors (SLTG2i), developed initially as glucose-lowering agents, has represented a novelty in patients with heart failure (HF) and reduced ejection fraction (HFrEF) since dapagliflozin (DAPA-HF study) and empagliflozin (EMPEROR-Reduced study) were able to reduce morbidity and mortality in this setting regardless of the presence or absence of diabetes. In previous large clinical trials (EMPA-REG OUTCOME study, CANVAS, DECLARE-TIMI 58), SGLT2i have been shown to attenuate HF progression expressed by reducing the risk of HF hospitalizations in patients with type 2 diabetes mellitus mostly without HF at baseline. This benefit was then corroborated with positive results in HF outcomes (cardiovascular mortality and HF hospitalizations) in patients with HF with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) trials. Several biological mechanisms apart from the glycosuria are attributed to these agents in this last context, including anti-inflammatory effects, reduction of fibrosis and apoptosis, improvement of myocardial metabolism, mitochondrial function optimization, and oxidative stress protection. Moreover, SGLT2i can also improve ventricular loading conditions by forcing diuresis and natriuresis, and by enhancing vascular and renal function. In addition, SGLT2i can reduce myocardial passive stiffness (diastolic function) by enforcing the phosphorylation of myofilament modulatory proteins. This article provided an overview of the main pathophysiological characteristics of HFpEF and of the diverse mechanisms of action of SGLT2i in this setting. The supporting clinical evidence of SGLT2i in HFpEF (EMPEROR-Preserved and DELIVER trials) is also reviewed. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment.

Keywords:  DELIVER; EMPEROR-Preserved; SGLT2 inhibitors; dapagliflozin; empagliflozin; heart failure with preserved ejection fraction

DOI:  https://doi.org/10.7573/dic.2022-7-1
Pharmacol Res. 2023 Jan 16. pii: S1043-6618(23)00023-3. [Epub ahead of print]188 106667

Neutral effect of SGLT2 inhibitors on lipoprotein metabolism: From clinical evidence to molecular mechanisms.

Elena Osto, Fabrizia Bonacina, Angela Pirillo, Giuseppe Danilo Norata.

  Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk.

Keywords:  Atherosclerotic cardiovascular disease; Lipids; Low-density lipoprotein cholesterol; Sodium-glucose cotransporter 2

DOI:  https://doi.org/10.1016/j.phrs.2023.106667
Trends Cancer. 2023 Jan 14. pii: S2405-8033(22)00268-0. [Epub ahead of print]

Fasting and fasting mimicking diets in cancer prevention and therapy.

Olga Blaževitš, Maira Di Tano, Valter D Longo.

  Fasting mimicking diets (FMDs) are emerging as effective dietary interventions with the potential to improve healthspan and decrease the incidence of cancer and other age-related diseases. Unlike chronic dietary restrictions or water-only fasting, FMDs represent safer and less challenging options for cancer patients. FMD cycles increase protection in healthy cells while sensitizing cancer cells to various therapies, partly by generating complex environments that promote differential stress resistance (DSR) and differential stress sensitization (DSS), respectively. More recent data indicate that FMD cycles enhance the efficacy of a range of drugs targeting different cancers in mice by stimulating antitumor immunity. Here, we report on the effects of FMD cycles on cancer prevention and treatment and the mechanisms implicated in these effects.

Keywords:  cancer treatment; differential stress resistance (DSR); differential stress sensitization (DSS); fasting mimicking diet

DOI:  https://doi.org/10.1016/j.trecan.2022.12.006
J Biol Chem. 2023 Jan 12. pii: S0021-9258(23)00040-6. [Epub ahead of print] 102908

Protein engineering reveals that gasdermin A preferentially targets mitochondrial membranes over the plasma membrane during pyroptosis.

Hannah C Kondolf, Dana A D'Orlando, George R Dubyak, Derek W Abbott.

  When activated, gasdermin family members are thought to be pore-forming proteins that cause lytic cell death. Despite this, numerous studies have suggested that the threshold for lytic cell death is dependent on which gasdermin family member is activated. Determination of the propensity of various gasdermin family members to cause pyroptosis has been handicapped by the fact that for many of them, the mechanisms and timing of their activation are uncertain. In this manuscript, we exploit the recently discovered exosite-mediated recognition of gasdermin D (GSDMD) by the inflammatory caspases to develop a system that activates gasdermin family members in an efficient and equivalent manner. We leverage this system to show that upon activation, GSDMD and gasdermin A (GSDMA) exhibit differential subcellular localization, differential plasma membrane permeabilization, and differential lytic cell death. While GSDMD localizes rapidly to both the plasma membrane and organelle membranes, GSDMA preferentially localizes to the mitochondria with delayed and diminished accumulation at the plasma membrane. As a consequence of this differential kinetics of subcellular localization, N-terminal GSDMA results in early mitochondrial dysfunction relative to plasma membrane permeabilization. This study thus challenges the assumption that gasdermin family members effect cell death through identical mechanisms and establishes that their activation in their respective tissues of expression likely results in different immunological outcomes.

Keywords:  GSDMA; GSDMD; cell death; mitochondria; plasma membrane; protein engineering; protein-lipid interactions; pyroptosis

DOI:  https://doi.org/10.1016/j.jbc.2023.102908
Exp Physiol. 2023 Jan 17.

Ketogenic diet: Possible mechanism, old and new applications.

Roberto Cannataro.

DOI: https://doi.org/10.1113/EP090858
Int J Biol Macromol. 2023 Jan 13. pii: S0141-8130(23)00110-1. [Epub ahead of print]230 123234

The high dose of inulin exacerbated food allergy through the excess accumulation of short-chain fatty acids in a BABL/c mouse model.

Qiang Xie, Kaiyu Mu, Chen Chen, Shimin Gu, Dan Luo, Wenhui Fu, Wentong Xue.

  Inulin dietary supplement is conventionally beneficial to gut health and can potentially prevent food allergy (FA). This study aimed to determine how dietary inulin interventions at different doses affect the OVA-induced FA in a BALB/c mouse model. Although the middle dose of inulin (50 mg per mouse) showed the best therapeutic effect on FA, high-inulin supplementation (80 mg per mouse) provoked severe allergic and intestinal inflammatory responses, which were characterized by elevated serum allergic inflammation-related factor levels, dysfunctional gut barrier, unbalanced luminal pH value, decrease in intestinal antioxidant capacity, and disordered gut microecology. Moreover, profiling of SCFAs indicated that the high-inulin-induced excess accumulation of SCFAs in the colon was responsible for the gut immune disorders. Spearman correlation analysis unraveled that the featured bacterial taxa in the high-inulin-treated mice were Ruminococcaceae and Bifidobacterium, of which the relative abundance was negatively correlated with expression of tight junction proteins and improvement of T cell homeostasis, and positively correlated with levels of allergic inflammation-related indexes. Our work suggested that high-inulin dietary supplementation can be detrimental to allergic individuals and highlighted the importance for personalized use of inulin-type dietary supplements to safely improve human health.

Keywords:  Food allergy; Gut microbiota; Intestinal barrier function; Inulin; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.123234
Cell. 2023 Jan 19. pii: S0092-8674(22)01583-5. [Epub ahead of print]186(2): 233-235

Is aging a "Retro"spective event?

Nirmalya Dasgupta, Peter D Adams.

Reactivation of endogenous retroviruses (ERVs), the relics of ancient infections, has been implicated in a number of disease contexts. In this issue of Cell, Liu et al. show how reactivation of ERVs in old age can induce senescence. This awakening of ERVs is associated with their epigenetic derepression and contributes to age-associated chronic inflammation.

DOI: https://doi.org/10.1016/j.cell.2022.12.040
Acta Pharm. 2022 Dec 01. 72(4): 615-628

Anti-inflammatory effects of NaB and NaPc in Acinetobacter baumannii-stimulated THP-1 cells via TLR-2/NF-κB/ROS/NLRP3 pathway.

Chen Shu, Zhang Yan-Yan, Zhang Hai, Ding Long-Kun, Xi Yue, Yan Man, Sun Chang, Wu Liang, Hu Hao.

  This study evaluated the anti-inflammation effect of the three main short-chain fatty acids (SCFAs) on Acinetobacter baumannii-induced THP-1 cells. The three main SCFAs could inhibit A. baumannii-stimulated THP-1 cell NF-κB pathway activity and the expressions of NLRP3 inflamma-some and GSDMD, and increase autophagy. The three main SCFAs, especially the sodium butyrate (NaB), had the effect of down-regulation of ROS and TLR-2 expression in THP-1 cells. NaB and sodium propionate (NaPc), but not sodium acetate (NaAc), dramatically suppressed IL-1β and IFN-γ expression. The results indicated that NaB and NaPc could significantly inhibit the inflammation of THP-1 cells induced by A. baumannii, and the inhibitory effect was in the order of NaB > NaPc > NaAC. NaB and NaPc may inhibit inflammation through TLR-2/NF-κB/ROS/NLRP3 signaling pathway.

Keywords:  NLRP3; autophagy; inflammation; nuclear factor-κB (NF-κB); short-chain fatty acids (SCFAs)

DOI:  https://doi.org/10.2478/acph-2022-0036
Physiol Res. 2022 Dec 31. 71(S2): S227-S236

Impact of aging on mitochondrial respiration in various organs.

J Jedlička, Z Tůma, K Razak, R Kunc, A Kala, S Proskauer Pena, T Lerchner, K Ježek, J Kuncová.

Mitochondria are considered central regulator of the aging process; however, majority of studies dealing with the impact of age on mitochondrial oxygen consumption focused on skeletal muscle concluding (although not uniformly) a general declining trend with advancing age. In addition, gender related differences in mitochondrial respiration have not been satisfactorily described yet. The aim of the present study was to evaluate mitochondrial oxygen consumption in various organs of aging male and female Fischer 344 rats at the ages of 6, 12 and 24 months. Mitochondrial respiration of homogenized (skeletal muscle, left and right heart ventricle, hippocampus, cerebellum, kidney cortex), gently mechanically permeabilized (liver) tissue or intact cells (platelets) was determined using high-resolution respirometry (oxygraphs O2k, Oroboros, Austria). The pattern of age-related changes differed in each tissue: in the skeletal muscle and kidney cortex of both sexes and in female heart, parameters of mitochondrial respiration significantly declined with age. Resting respiration of intact platelets displayed an increasing trend and it did not correlate with skeletal muscle respiratory states. In the heart of male rats and brain tissues of both sexes, respiratory states remained relatively stable over analyzed age categories with few exceptions of lower mitochondrial oxygen consumption at the age of 24 months. In the liver, OXPHOS capacity was higher in females than in males with either no difference between the ages of 6 and 24 months or even significant increase at the age of 24 months in the male rats. In conclusion, the results of our study indicate that the concept of general pattern of age-dependent decline in mitochondrial oxygen consumption across different organs and tissues could be misleading. Also, the statement of higher mitochondrial respiration in females seems to be conflicting, since the gender-related differences may vary with the tissue studied, combination of substrates used and might be better detectable at younger ages than in old animals.
Antioxidants (Basel). 2022 Dec 20. pii: 4. [Epub ahead of print]12(1):

Butyrate Improves Neuroinflammation and Mitochondrial Impairment in Cerebral Cortex and Synaptic Fraction in an Animal Model of Diet-Induced Obesity.

Gina Cavaliere, Angela Catapano, Giovanna Trinchese, Fabiano Cimmino, Eduardo Penna, Amelia Pizzella, Claudia Cristiano, Adriano Lama, Marianna Crispino, Maria Pina Mollica.

  Neurodegenerative diseases (NDDs) are characterized by cognitive impairment and behavioural abnormalities. The incidence of NDDs in recent years has increased globally and the pathological mechanism is not fully understood. To date, plentiful evidence has showed that metabolic alterations associated with obesity and related issues such as neuroinflammation, oxidative stress and mitochondrial dysfunction may represent an important risk factor, linking obesity and NDDs. Numerous studies have indicated a correlation between diet and brain activities. In this context, a key role is played by mitochondria located in the synaptic fraction; indeed, it has been shown that high-fat diets cause their dysfunction, affecting synaptic plasticity. In this scenario, the use of natural molecules that improve brain mitochondrial function represents an important therapeutic approach to treat NDDs. Recently, it was demonstrated that butyrate, a short-chain fatty acid is capable of counteracting obesity in an animal model, modulating mitochondrial function. The aim of this study has been to evaluate the effects of butyrate on neuroinflammatory state, oxidative stress and mitochondrial dysfunction in the brain cortex and in the synaptic fraction of a mouse model of diet-induced obesity. Our data have shown that butyrate partially reverts neuroinflammation and oxidative stress in the brain cortex and synaptic area, improving mitochondrial function and efficiency.

Keywords:  butyrate; mitochondrial function; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.3390/antiox12010004
Circ Res. 2023 Jan 20. 132(2): 223-237

The Circadian Biology of Heart Failure.

Nadim El Jamal, Ronan Lordan, Sarah L Teegarden, Tilo Grosser, Garret FitzGerald.

  Driven by autonomous molecular clocks that are synchronized by a master pacemaker in the suprachiasmatic nucleus, cardiac physiology fluctuates in diurnal rhythms that can be partly or entirely circadian. Cardiac contractility, metabolism, and electrophysiology, all have diurnal rhythms, as does the neurohumoral control of cardiac and kidney function. In this review, we discuss the evidence that circadian biology regulates cardiac function, how molecular clocks may relate to the pathogenesis of heart failure, and how chronotherapeutics might be applied in heart failure. Disrupting molecular clocks can lead to heart failure in animal models, and the myocardial response to injury seems to be conditioned by the time of day. Human studies are consistent with these findings, and they implicate the clock and circadian rhythms in the pathogenesis of heart failure. Certain circadian rhythms are maintained in patients with heart failure, a factor that can guide optimal timing of therapy. Pharmacologic and nonpharmacologic manipulation of circadian rhythms and molecular clocks show promise in the prevention and treatment of heart failure.

Keywords:  biological clocks; chronotherapy; circadian clocks; circadian rhythm; heart failure

DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321369
Sci Bull (Beijing). 2021 Aug 30. pii: S2095-9273(21)00066-9. [Epub ahead of print]66(16): 1669-1683

TAX1BP1 protects against myocardial infarction-associated cardiac anomalies through inhibition of inflammasomes in a RNF34/MAVS/NLRP3-dependent manner.

Haixia Xu, Wenjun Yu, Shiqun Sun, Congye Li, Jun Ren, Yingmei Zhang.

  Acute myocardial infarction (MI), one of the most common cardiovascular emergencies, is a leading cause of morbidity and mortality. Ample evidence has revealed an essential role for inflammasome activation and autophagy in the pathogenesis of acute MI. Tax1-binding protein 1 (TAX1BP1), an adaptor molecule involved in termination of proinflammatory signaling, serves as an important selective autophagy adaptor, but its role in cardiac ischemia remains elusive. This study examined the role of TAX1BP1 in myocardial ischemic stress and the underlying mechanisms involved. Levels of TAX1BP1 were significantly downregulated in heart tissues of patients with ischemic heart disease and in a left anterior descending (LAD) ligation-induced model of acute MI. Adenovirus carrying TAX1BP1 was delivered into the myocardium. The acute MI induced procedure elicited an infarct and cardiac dysfunction, the effect of which was mitigated by TAX1BP1 overexpression with little effect from viral vector alone. TAX1BP1 nullified acute MI-induced activation of the NLRP3 inflammasome and associated mitochondrial dysfunction. TAX1BP1 overexpression suppressed NLRP3 mitochondrial localization by inhibiting the interaction of NLRP3 with mitochondrial antiviral signaling protein (MAVS). Further investigation revealed that ring finger protein 34 (RNF34) was recruited to interact with TAX1BP1 thereby facilitating autophagic degradation of MAVS through K27-linked polyubiquitination of MAVS. Knockdown of RNF34 using siRNA nullified TAX1BP1 yielded protection against hypoxia-induced MAVS mitochondrial accumulation, NLRP3 inflammasome activation and associated loss of mitochondrial membrane potential. Taken together, our results favor a cardioprotective role for TAX1BP1 in acute MI through repression of inflammasome activation in a RNF34/MAVS-dependent manner.

Keywords:  Acute myocardial infarction; Autophagic degradation; Mitochondrial antiviral signaling protein; NLRP3 inflammasome; RNF34; TAX1BP1

DOI:  https://doi.org/10.1016/j.scib.2021.01.030
Mol Metab. 2023 Jan 13. pii: S2212-8778(23)00004-2. [Epub ahead of print] 101670

Loss of skeletal muscle estrogen related receptors leads to severe exercise intolerance.

Jean-Sébastien Wattez, Elodie Eury, Bethany C Hazen, Alexa Wade, Sarah Chau, Shu-Ching Ou, Aaron P Russell, Yoshitake Cho, Anastasia Kralli.

   OBJECTIVE: Skeletal muscle oxidative capacity is central to physical activity, exercise capacity and whole-body metabolism. The three estrogen related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle remain unclear. The main aim of this study was to compare the relative contributions of ERRs to oxidative capacity in glycolytic and oxidative muscle, and to determine defects associated with loss of skeletal muscle ERR function.
METHODS: We assessed ERR expression, generated mice lacking one or two ERRs specifically in skeletal muscle and compared the effects of ERR loss on the transcriptomes of EDL (predominantly glycolytic) and soleus (oxidative) muscles. We also determined the consequences of the loss of ERRs for exercise capacity and energy metabolism in mice with the most severe loss of ERR activity.
RESULTS: ERRs are induced in skeletal muscle in response to an exercise bout. Mice lacking both ERRα and ERRγ (ERRα/γ dmKO) had the broadest and most dramatic disruption in skeletal muscle gene expression. The most affected pathway was "mitochondrial function", in particular Oxphos and TCA cycle genes, and transcriptional defects were more pronounced in the glycolytic EDL than the oxidative soleus. Mice lacking ERRβ and ERRγ, the two isoforms expressed highly in oxidative muscles, also exhibited defects in lipid and branch chain amino acid metabolism genes, specifically in the soleus. The pronounced disruption of oxidative metabolism in ERRα/γ dmKO mice led to pale muscles, decreased oxidative capacity, histochemical patterns reminiscent of minicore myopathies, and severe exercise intolerance, with the dmKO mice unable to switch to lipid utilization upon running. ERRα/γ dmKO mice showed no defects in whole-body glucose and energy homeostasis.
CONCLUSIONS: Our findings define gene expression programs in skeletal muscle that depend on different combinations of ERRs, and establish a central role for ERRs in skeletal muscle oxidative metabolism and exercise capacity. Our data reveal a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, and show that ERR isoform-specific phenotypes are driven in part, but not exclusively, by their relative levels in different muscles.

Keywords:  Estrogen related receptor (ERR); Exercise capacity; Exercise intolerance; Mitochondrial oxidative metabolism; Multi-minicore myopathy; Skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2023.101670
Bioorg Chem. 2023 Jan 14. pii: S0045-2068(23)00022-6. [Epub ahead of print]132 106362

Phenolic and quinone methide nor-triterpenes as selective NLRP3 inflammasome inhibitors.

Laura González-Cofrade, Jack P Green, Irene Cuadrado, Ángel Amesty, Sandra Oramas-Royo, David Brough, Ana Estévez-Braun, Sonsoles Hortelano, Beatriz de Las Heras.

  Dysregulated inflammasome activity, particularly of the NLRP3 inflammasome, is associated with the development of several inflammatory diseases. The study of molecules directly targeting NLRP3 is an emerging field in the discovery of new therapeutic compounds for the treatment of inflammatory disorders. Friedelane triterpenes are biologically active phytochemicals having a wide range of activities including anti-inflammatory effects. In this work, we evaluated the potential anti-inflammatory activity of phenolic and quinonemethide nor-triterpenes (1-11) isolated from Maytenus retusa and some semisynthetic derivatives (12-16) through inhibition of the NLRP3 inflammasome in macrophages. Among them, we found that triterpenes 6 and 14 were the most potent, showing markedly reduced caspase-1 activity, IL-1β secretion (IC50 = 1.15 µM and 0.19 µM, respectively), and pyroptosis (IC50 = 2.21 µM and 0.13 µM, respectively). Further characterization confirmed their selective inhibition of NLRP3 inflammasome in both canonical and non-canonical activation pathways with no effects on AIM2 or NLRC4 inflammasome activation.

Keywords:  ASC; IL-1β; Macrophages; Maytenus retusa; NLRP3 inflammasome; Nor-friedelane triterpenes; Pyroptosis

DOI:  https://doi.org/10.1016/j.bioorg.2023.106362
Cell Rep. 2023 Jan 19. pii: S2211-1247(23)00019-0. [Epub ahead of print]42(1): 112008

Gasdermin D pore-forming activity is redox-sensitive.

Pascal Devant, Elvira Boršić, Elsy M Ngwa, Haopeng Xiao, Edward T Chouchani, Jay R Thiagarajah, Iva Hafner-Bratkovič, Charles L Evavold, Jonathan C Kagan.

  Reactive oxygen species (ROS) regulate the activities of inflammasomes, which are innate immune signaling organelles that induce pyroptosis. The mechanisms by which ROS control inflammasome activities are unclear and may be multifaceted. Herein, we report that the protein gasdermin D (GSDMD), which forms membrane pores upon cleavage by inflammasome-associated caspases, is a direct target of ROS. Exogenous and endogenous sources of ROS, and ROS-inducing stimuli that prime cells for pyroptosis induction, promote oligomerization of cleaved GSDMD, leading to membrane rupture and cell death. We find that ROS enhance GSDMD activities through oxidative modification of cysteine 192 (C192). Within macrophages, GSDMD mutants lacking C192 show impaired ability to form membrane pores and induce pyroptosis. Reciprocal mutagenesis studies reveal that C192 is the only cysteine within GSDMD that mediates ROS responsiveness. Cellular redox state is therefore a key determinant of GSDMD activities.

Keywords:  CP: Immunology; Ragulator-Rag; cysteine oxidation; gasdermin D; pyroptosis; reactive oxygen species

DOI:  https://doi.org/10.1016/j.celrep.2023.112008
Function (Oxf). 2023 ;4(1): zqac068

Challenging Dogma about Myonuclei Behavior in Skeletal Muscle Cells.

Espen E Spangenburg.

DOI: https://doi.org/10.1093/function/zqac068
Immunol Rev. 2023 Jan 19.

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways.

George R Dubyak, Brandon A Miller, Eric Pearlman.

  Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.

Keywords:  NETosis; gasdermin; inflammasome; interleukin-1β; neutrophil; pyroptosis

DOI:  https://doi.org/10.1111/imr.13186
Br J Pharmacol. 2023 Jan 20.

Discovery of alantolactone as a natural NLRP3 inhibitor to alleviate NLRP3-driven inflammatory diseases in mice.

Weifeng Li, Haowen Xu, Jingjing Shao, Jiahao Chen, Yimin Lin, Zhiwei Zheng, Yi Wang, Wu Luo, Guang Liang.

   BACKGROUND AND PURPOSE: NLRP3 inflammasome activation is involved in many inflammatory diseases, however, no small-molecule inhibitors of NLRP3 have been clinically used so far. Discovery of natural NLRP3 inhibitors may be beneficial to the design and development of molecules targeting NLRP3. Alantolactone (ALA) is a natural compound isolated from a traditional Chinese medicinal plant with anti-inflammatory activity, but the precise target of ALA remains unclear.
EXPERIMENTAL APPROACH: The inhibitory activity of 150 natural compounds against NLRP3-driven IL-1β production was screened in macrophages. Mice models of gouty arthritis and acute lung injury were used to determine the efficacy of the potential compound.
KEY RESULTS: Among 150 compounds in an in-house natural products bank, ALA was found to possess the highest inhibitory activity against LPS + ATP-induced IL-1β production in macrophages. We demonstrated that ALA suppressed the IL-1β secretion, the caspase-1 activation, and pyroptosis in LPS + ATP-challenged macrophages. Further studies showed that ALA directly bound to the NACHT domain of NLRP3 to inhibit the activation and assembly of NLRP3 inflammasome. The molecular simulation showed that Arg335 in NLRP3 might be a critical residue for ALA binding, leading to suppression of NLRP3-NEK7 interaction. The in vivo studies validated that ALA significantly alleviated NLRP3-driven inflammatory diseases, including acute lung injury and gouty arthritis.
CONCLUSION AND IMPLICATIONS: In summary, we identified ALA as a natural inhibitor of NLRP3 inflammasome by directly targeting NLRP3 NACHT domain. ALA shows great potential in the treatment of NLRP3-driven diseases and the development of novel NLRP3 inhibitors.

Keywords:  NLRP3 inflammasome; acute lung injury; alantolactone; gouty arthritis; macrophage

DOI:  https://doi.org/10.1111/bph.16036
Cell Stress Chaperones. 2023 Jan 18.

Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies.

Xinxin Liu, Chenchen Guo, Qiming Zhang.

  Mitochondria are dynamic organelles that alter their morphology through fission (fragmentation) and fusion (elongation). These morphological changes correlate highly with mitochondrial functional adaptations to stressors, such as hypoxia, pressure overload, and inflammation, and are important in the setting of heart failure. Pathological mitochondrial remodeling, characterized by increased fission and reduced fusion, is associated with impaired mitochondrial respiration, increased mitochondrial oxidative stress, abnormal cytoplasmic calcium handling, and increased cardiomyocyte apoptosis. Considering the impact of the mitochondrial morphology on mitochondrial behavior and cardiomyocyte performance, altered mitochondrial dynamics could be expected to induce or exacerbate the pathogenesis and progression of heart failure. However, whether alterations in mitochondrial fission and fusion accelerate or retard the progression of heart failure has been the subject of intense debate. In this review, we first describe the physiological processes and regulatory mechanisms of mitochondrial fission and fusion. Then, we extensively discuss the pathological contributions of mitochondrial fission and fusion to heart failure. Lastly, we examine potential therapeutic approaches targeting mitochondrial fission/fusion to treat patients with heart failure.

Keywords:  DRP1; Heart failure; MFN1/2; Mitochondrial fission; Mitochondrial fusion; OPA1

DOI:  https://doi.org/10.1007/s12192-023-01321-4
Curr Opin Endocrinol Diabetes Obes. 2023 Jan 23.

Low-carbohydrate diets in type 1 diabetes: balancing benefits and risks.

Michael Hancock, Kharis Burns, Seng Khee Gan, Gerard T Chew.

PURPOSE OF REVIEW: Interest in the use of calorie restriction with low-carbohydrate diets for patients with type 1 diabetes appears to be increasing despite physicians' discomfort about its longer term outcomes. A divergence in opinion regarding the balance of benefits and safety may lead to patient disengagement from conventional medical supervision. This review describes the current evidence regarding the benefits and risks of these diets and suggests a way forward to addressing this potential misalignment between the aims of patients and their physicians.
RECENT FINDINGS: Benefits on glycaemia are observed in many studies, with improved HbA1c, time within target range and reduced glycaemic variability. A characteristic lipid profile with high LDL cholesterol is observed in many patients, but association with future cardiovascular events is undefined. A negative impact on growth has been identified in the paediatric population, and impact on mental health and disordered eating is of theoretical concern, without measurement in clinical studies.
SUMMARY: Patients will continue to trial and, with immediate glycaemic benefits, potentially remain on lower carbohydrate diets irrespective of concern by treating physicians about potential longer term risks. A supportive multidisciplinary approach with greater nutritional supervision and more research is required, to allow these patients to achieve their desired glycaemic outcomes without compromising longer term safety.

DOI: https://doi.org/10.1097/MED.0000000000000797
Mol Metab. 2023 Jan 12. pii: S2212-8778(23)00002-9. [Epub ahead of print] 101668

Intrinsic cardiorespiratory fitness modulates clinical and molecular response to caloric restriction.

Johanna Y Fleischman, Nathan R Qi, Mary K Treutelaar, Steven L Britton, Lauren G Koch, Jun Z Li, Charles F Burant.

   OBJECTIVE: Caloric restriction (CR) is one extrinsic intervention that can improve metabolic health, and it shares many phenotypical parallels with intrinsic high cardiorespiratory fitness (CRF), including reduced adiposity, increased cardiometabolic health, and increased longevity. CRF is a highly heritable trait in humans and has been established in a genetic rat model selectively bred for high (HCR) and low (LCR) CRF, in which the HCR live longer and have reduced body weight compared to LCR. This study addresses whether the inherited high CRF phenotype occurs through similar mechanisms by which CR promotes health and longevity.
METHODS: We compared HCR and LCR male rats fed ad libitum (AL) or calorically restricted (CR) for multiple physiological, metabolic, and molecular traits, including running capacity at 2, 8, and 12 months; per-hour metabolic cage activity over daily cycles at 6 and 12 months; and plasma lipidomics, liver and muscle transcriptomics, and body composition after 12 months of treatment.
RESULTS: LCR-CR developed a physiological profile that mirrors the high-CRF phenotype in HCR-AL, including reduced adiposity and increased insulin sensitivity. HCR show higher spontaneous activity than LCR. Temporal modeling of hourly energy expenditure (EE) dynamics during the day, adjusted for body weight and hourly activity levels, suggest that CR has an EE-suppressing effect, and high-CRF has an EE-enhancing effect. Pathway analysis of gene transcripts indicates that HCR and LCR both show a response to CR that is similar in the muscle and different in the liver.
CONCLUSIONS: CR provides LCR a health-associated positive effect on physiological parameters that strongly resemble HCR. Analysis of whole-body EE and transcriptomics suggests that HCR and LCR show line-dependent responses to CR that may be accreditable to difference in genetic makeup. The results do not preclude the possibility that CRF and CR pathways may converge.

Keywords:  Caloric restriction; Cardiorespiratory fitness; Metabolism; Mitochondria; Muscle

DOI:  https://doi.org/10.1016/j.molmet.2023.101668
Elife. 2023 Jan 17. pii: e83075. [Epub ahead of print]12

FGF21 protects against hepatic lipotoxicity and macrophage activation to attenuate fibrogenesis in nonalcoholic steatohepatitis.

Cong Liu, Milena Schönke, Borah Spoorenberg, Joost M Lambooij, Hendrik J P van der Zande, Enchen Zhou, Maarten E Tushuizen, Anne-Christine Andreasson, Andrew Park, Stephanie Oldham, Martin Uhrbom, Ingela Ahlstedt, Yasuhiro Ikeda, Kristina Wallenius, Xiao-Rong Peng, Bruno Guigas, Mariëtte R Boon, Yanan Wang, Patrick C N Rensen.

  Analogues of the hepatokine FGF21 are in clinical development for type 2 diabetes and nonalcoholic steatohepatitis (NASH) treatment. Although their glucose-lowering and insulin-sensitizing effects have been largely unraveled, the mechanisms by which they alleviate liver injury have only been scarcely addressed. Here, we aimed to unveil the mechanisms underlying the protective effects of FGF21 on NASH using APOE*3-Leiden.CETP mice, a well-established model for human-like metabolic diseases. Liver-specific FGF21 overexpression was achieved in mice, followed by administration of a high-fat high-cholesterol diet for 23 weeks. FGF21 prevented hepatic lipotoxicity, accompanied by activation of thermogenic tissues and attenuation of adipose tissue inflammation, improvement of hyperglycemia and hypertriglyceridemia, and upregulation of hepatic programs involved in fatty acid oxidation and cholesterol removal. Furthermore, FGF21 inhibited hepatic inflammation, as evidenced by reduced Kupffer cell (KC) activation, diminished monocyte infiltration and lowered accumulation of monocyte-derived macrophages. Moreover, FGF21 decreased lipid- and scar-associated macrophages, which correlated with less hepatic fibrosis as demonstrated by reduced collagen accumulation. Collectively, hepatic FGF21 overexpression limits hepatic lipotoxicity, inflammation and fibrogenesis. Mechanistically, FGF21 blocks hepatic lipid influx and accumulation through combined endocrine and autocrine signaling, respectively, which prevents KC activation and lowers the presence of lipid- and scar-associated macrophages to inhibit fibrogenesis.

Keywords:  immunology; inflammation; medicine; mouse

DOI:  https://doi.org/10.7554/eLife.83075