bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023–10–01
forty-six papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins
  1. Editorial for "The Role of Ketogenic Diet in Human Health and Diseases": The Multifaceted Impact of Ketogenic Diets on Health and Disease.
  2. The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.
  3. Can a modified ketogenic diet be a nutritional strategy for patients with McArdle disease? Results from a randomized, single-blind, placebo-controlled, cross-over study.
  4. Regulation of adult stem cell function by ketone bodies.
  5. Preimplantation embryo exposure to ketone bodies exerts sex-specific effects on mouse fetal and placental transcriptomes.
  6. Ketone Bodies Induce Unique Inhibition of Tumor Cell Proliferation and Enhance the Efficacy of Anti-Cancer Agents.
  7. Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia.
  8. Calponin 2 regulates ketogenesis to mitigate acute kidney injury.
  9. Short-term fasting of mice elevates circulating fibroblast growth factor 23 (FGF23).
  10. Age-related changes of skeletal muscle metabolic response to contraction are also sex-dependent.
  11. Effect of Eccentric Exercise on Metabolic Health in Diabetes and Obesity.
  12. Effects of the order of endurance and high intensity interval exercise in combined training on mice skeletal muscle metabolism.
  13. Effects of Ketone Monoester and Bicarbonate Co-Ingestion on Cycling Performance in WorldTour Cyclists.
  14. Protein-protein interactions and related inhibitors involved in the NLRP3 inflammasome pathway.
  15. A new turn-on fluorescent probe for fast detection of diabetic biomarker beta-hydroxybutyrate in vitro.
  16. Phosphate burden induces vascular calcification through a NLRP3-caspase-1-mediated pyroptotic pathway.
  17. Transcriptomic and metabolomic insights into the roles of exogenous β-hydroxybutyrate acid for the development of rumen epithelium in young goats.
  18. Redox Regulation of Microglial Inflammatory Response: Fine Control of NLRP3 Inflammasome through Nrf2 and NOX4.
  19. The Role of Ketone Bodies in Treatment Individualization of Glioblastoma Patients.
  20. Overview and prospect of NAFLD: Significant roles of nutrients and dietary patterns in its progression or prevention.
  21. The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases.
  22. The gasdermins: a pore-forming protein family expressed in the epidermis.
  23. [Succinyl CoA:3 oxoacid CoA transferase deficiency: A case report].
  24. Inflammasomes in Atherosclerosis-From Pathophysiology to Treatment.
  25. Mitochondrion-NLRP3 inflammasome activation in macrophages: A novel mechanism of the anti-inflammatory effect of Notopterygium in rheumatoid arthritis treatment.
  26. The effect of insulin resistance on extracellular BCAA accumulation and SLC25A44 expression in a myotube model of skeletal muscle insulin resistance.
  27. Anabolic Resistance in the Pathogenesis of Sarcopenia in the Elderly: Role of Nutrition and Exercise in Young and Old People.
  28. Molecular effects of dietary interventions-A clinical perspective.
  29. Insights into the regulation of mitochondrial functions by PKA-mediated phosphorylation.
  30. Editorial: Mitochondrial dysfunction as a target in neurodegenerative diseases.
  31. Metformin Protects Rat Skeletal Muscle from Physical Exercise-Induced Injury.
  32. Role of Mitochondria in the Regulation of Effector Functions of Granulocytes.
  33. Role of Oxidative Stress in Mitochondrial Function: Relevance for Liver Function.
  34. A single 36-h water-only fast vastly remodels the plasma lipidome.
  35. The Effect of SERCA Activation on Functional Characteristics and Signaling of Rat Soleus Muscle upon 7 Days of Unloading.
  36. Metabolic adaptations in pressure overload hypertrophic heart.
  37. Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.
  38. The fountain of youth of mitochondrial research: Research is targeting mitochondrial dysfunction to tackle aging and much more, but hype is an increasing concern.
  39. NLRP3 inflammasome involves in the pathophysiology of sepsis-induced myocardial dysfunction by multiple mechanisms.
  40. SGLT2 inhibitors among patients with heart failure with preserved ejection fraction: A meta-analysis of randomised controlled trials.
  41. The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases.
  42. Pitfalls of Mitochondrial Redox Signaling Research.
  43. SGLT-2 inhibitors improve cardiovascular and renal outcomes in patients with CKD: a systematic review and meta-analysis.
  44. Mitochondrial Dynamics and Insulin Secretion.
  45. Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
  46. Butyrate protects against MRSA pneumonia via regulating gut-lung microbiota and alveolar macrophage M2 polarization.
  1. Nutrients. 2023 Sep 17. pii: 4027. [Epub ahead of print]15(18):
    Editorial for "The Role of Ketogenic Diet in Human Health and Diseases": The Multifaceted Impact of Ketogenic Diets on Health and Disease.
    Mikiko Watanabe, Silvia Savastano, Carla Lubrano, Giovanni Spera.
      The ketogenic diet (KD), characterized by a very low carbohydrate intake and variable protein, fat and calorie intake, has long been in the spotlight for its potential therapeutic applications [...].
    DOI:  https://doi.org/10.3390/nu15184027
  2. J Atheroscler Thromb. 2023 Sep 28.
    The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.
    Yuichiro Arima.
      Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.
    Keywords:  Aging; Cardiovascular diseases; Ketone body metabolism; Mitochondria
    DOI:  https://doi.org/10.5551/jat.RV22011
  3. Clin Nutr. 2023 Sep 20. pii: S0261-5614(23)00293-5. [Epub ahead of print]42(11): 2124-2137
    Can a modified ketogenic diet be a nutritional strategy for patients with McArdle disease? Results from a randomized, single-blind, placebo-controlled, cross-over study.
    Nicoline Løkken, Maja Risager Nielsen, Mads Godtfeldt Stemmerik, Charlotte Ellerton, Karoline Lolk Revsbech, Margaret Macrae, Anna Slipsager, Bjørg Krett, Gry Hatting Beha, Frida Emanuelsson, Gerrit van Hall, Rosaline Quinlivan, John Vissing.
       BACKGROUND: McArdle disease is caused by myophosphorylase deficiency leading to blocked glycogenolysis in skeletal muscle. Consequently, individuals with McArdle disease have intolerance to physical activity, muscle fatigue, and pain. These symptoms vary according to the availability of alternative fuels for muscle contraction. In theory, a modified ketogenic diet (mKD) can provide alternative fuels in the form of ketone bodies and potentially boost fat oxidation.
    METHODS: This randomized, single-blind, placebo-controlled, cross-over study aimed to investigate if a mKD improves exercise capacity in individuals with McArdle disease. Participants were randomized to follow a mKD (75-80% fat, 15% protein, 5-10% carbohydrates) or placebo diet (PD) first for three weeks, followed by a wash-out period, and then the opposite diet. The primary outcome was change in heart rate during constant-load cycling. Secondary outcomes included change in plasma metabolites, perceived exertion, indirect calorimetry measures, maximal exercise capacity, and patient-reported outcomes.
    RESULTS: Fifteen out of 20 patients with genetically verified McArdle disease completed all study visits, and 14 were included in the data analyses. We found that the mKD induced a metabolic shift towards increased fat oxidation (∼60% increase), and a 19-fold increase in plasma β-hydroxybutyrate (p < 0.05). The mKD did not improve heart rate responses during constant-load cycling but did improve patient-reported outcomes and maximal exercise capacity (∼20% increase) compared to the PD.
    CONCLUSION: The mKD did not alleviate all McArdle disease-related symptoms but did induce some positive changes. To date, no satisfactory treatment options exist other than exercise training. To that end, a mKD can be a possible nutritional strategy for some individuals with McArdle disease who are motivated to undertake a restrictive diet.
    CLINICAL TRIAL REGISTRATION: clinical trials.gov: NCT04044508.
    Keywords:  Glycogen storage disease type V; McArdle disease; Modified ketogenic diet; Randomized clinical trial
    DOI:  https://doi.org/10.1016/j.clnu.2023.09.006
  4. Front Cell Dev Biol. 2023 ;11 1246998
    Regulation of adult stem cell function by ketone bodies.
    Ole Emil Andersen, Jens Vase Poulsen, Jean Farup, Antoine de Morree.
      Adult stem cells play key roles in tissue homeostasis and regeneration. Recent evidence suggests that dietary interventions can significantly impact adult stem cell function. Some of these effects depend on ketone bodies. Adult stem cells could therefore potentially be manipulated through dietary regimens or exogenous ketone body supplementation, a possibility with significant implications for regenerative medicine. In this review we discuss recent findings of the mechanisms by which ketone bodies could influence adult stem cells, including ketogenesis in adult stem cells, uptake and transport of circulating ketone bodies, receptor-mediated signaling, and changes to cellular metabolism. We also discuss the potential effects of ketone bodies on intracellular processes such as protein acetylation and post-transcriptional control of gene expression. The exploration of mechanisms underlying the effects of ketone bodies on stem cell function reveals potential therapeutic targets for tissue regeneration and age-related diseases and suggests future research directions in the field of ketone bodies and stem cells.
    Keywords:  adult stem cells; beta-hydroxybutyrylation; cellular metabolism; ketone bodies; regenerative medicine; stem cell function; tissue homeostasis
    DOI:  https://doi.org/10.3389/fcell.2023.1246998
  5. Reprod Biomed Online. 2023 Jul 28. pii: S1472-6483(23)00420-0. [Epub ahead of print]47(5): 103320
    Preimplantation embryo exposure to ketone bodies exerts sex-specific effects on mouse fetal and placental transcriptomes.
    Emma G Whatley, Thi T Truong, Alexandra J Harvey, David K Gardner.
       RESEARCH QUESTION: Does in vitro exposure of preimplantation mouse embryos to the ketone bodies β-hydroxybutyrate (βOHB) and acetoacetate (AcAc) impact post-transfer fetal and placental gene expression?
    DESIGN: Blastocysts cultured in vitro with or without 2 mmol/l βOHB alone ('βOHB') or combined with 0.8 mmol/l AcAc ('Keto') underwent embryo transfer. Transcriptional profiles of sexed placenta, liver and brain at gestational day 14.5 were examined via RNA sequencing and DAVID functional analysis.
    RESULTS: A sexually dimorphic response to in vitro ketone exposure was observed. Both βOHB and Keto exposure down-regulated genes related to oxidative phosphorylation specifically in female liver. βOHB down-regulated female placental steroid biosynthetic processes, while Keto treatment up-regulated genes relevant to blood vessel formation and cell migration in male placenta. Brain transcriptomes were minimally affected. X-linked genes and chromatin modifiers were identified as differentially expressed in both liver and placenta, alluding to a sex-specific regulatory mechanism.
    CONCLUSIONS: Transient preimplantation ketone exposure perturbs sex-specific fetal liver and placental gene expression, demonstrating a developmental programming effect that warrants future investigation of the postnatal metabolic health of male and female offspring.
    Keywords:  Acetoacetate; Developmental origins of health and disease; Ketogenic diet; Nutrients; Periconception; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.rbmo.2023.103320
  6. Biomedicines. 2023 Sep 12. pii: 2515. [Epub ahead of print]11(9):
    Ketone Bodies Induce Unique Inhibition of Tumor Cell Proliferation and Enhance the Efficacy of Anti-Cancer Agents.
    Anna I Miller, David Diaz, Bo Lin, Patryk K Krzesaj, Sarah Ustoyev, Alfred Shim, Eugene J Fine, Ehsan Sarafraz-Yazdi, Matthew R Pincus, Richard D Feinman.
      The ketone bodies, sodium and lithium salts of acetoacetate (AcAc) and sodium 3-hydroxybutyrate (3-HB; commonly called beta-hydroxybutyrate) have been found to inhibit the proliferation of cancer cells. Previous studies have suggested that lithium itself may be an inhibiting agent but may be additive or synergistic with the effect of AcAc. We previously found that sodium acetoacetate (NaAcAc) inhibits the growth of human colon cancer cell line SW480. We report here similar results for several other cancer cell lines including ovarian, cervical and breast cancers. We found that NaAcAc does not kill cancer cells but rather blocks their proliferation. Similar inhibition of growth was seen in the effect of lithium ion alone (as LiCl). The effect of LiAcAc appears to be due to the combined effects of acetoacetate and the lithium ion. The ketone bodies, when given together with chemotherapeutic agents, rapamycin, methotrexate and the new peptide anti-cancer agent, PNC-27, substantially lowers their IC50 values for cancer cell, killing suggesting that ketone bodies and ketogenic diets may be powerful adjunct agents in treating human cancers.
    Keywords:  IC50 values; cancer cell viability; chemotherapeutic agents; ketone bodies
    DOI:  https://doi.org/10.3390/biomedicines11092515
  7. Biomolecules. 2023 Aug 30. pii: 1330. [Epub ahead of print]13(9):
    Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia.
    Yu Zhou, Ruohan Lu, Fusheng Lin, Shu Chen, Qi-Qing He, Guoyang Wu, Caihua Huang, Donghai Lin.
      Cachexia (CAC) is a debilitating metabolic syndrome. Although dietary interventions are attractive, long-term adherence to specific diets is difficult to maintain and can lead to systemic side effects. Ethyl 3-hydroxybutyrate (EHB) is a commonly used food additive found in wine and Tribolium castaneum. In this study, we investigated the effects of EHB administration in cachectic mice. After a single intraperitoneal injection of EHB into mice, 3-hydroxybutyrate (3-HB) levels were significantly increased in the serum and gastrocnemius of mice. The administration of EHB alleviated cachexia-related symptoms, ameliorated skeletal muscle atrophy, and improved survival in cachectic mice. In addition, the supplementation of cachectic mice with 3-HB by EHB administration significantly reduced tumor weights, indicating the anti-tumor effects of 3-HB. Remarkably, the addition of 3-HB to the culture medium significantly attenuated the C2C12 myotube atrophy induced by the culture supernatant of CT26 cell lines, highlighting its potential to counteract the destructive effects of tumor-derived elements on muscle tissue. NMR-based metabolomics analysis provided insights into the underlying mechanisms and revealed that the anti-cachexia effects of 3-HB treatment can be attributed to three key mechanisms: the promotion of the TCA cycle and the attenuation of proteolysis, the promotion of protein synthesis and the improvement of metabolic homeostasis, and a reduction in inflammation and an enhancement of the antioxidant capacity. This study provided compelling evidence for the protective effects of 3-HB treatment on the cachectic gastrocnemius and highlighted the efficacy of EHB administration as a ketone supplementation approach to achieve nutritional ketosis without the need for dietary restriction.
    Keywords:  3-hydroxybutyrate; Ethyl 3-hydroxybutyrate; cancer cachexia; ketogenic diet; metabonomics
    DOI:  https://doi.org/10.3390/biom13091330
  8. JCI Insight. 2023 Sep 26. pii: e170521. [Epub ahead of print]
    Calponin 2 regulates ketogenesis to mitigate acute kidney injury.
    Yuan Gui, Zachary Palanza, Priya R Gupta, Hanwen Li, Yuchen Pan, Yuanyuan Wang, Geneva R Hargis, Donald L Kreutzer, Yanlin Wang, Sheldon I Bastacky, Yansheng Liu, Silvia Liu, Dong Zhou.
      Calponin 2 (CNN2) is a prominent actin stabilizer. It regulates fatty acid oxidation (FAO) by interacting with estrogen receptor 2 (ESR2) to determine kidney fibrosis. However, whether CNN2 is actively involved in acute kidney injury (AKI) remains unclear. Here, we report that CNN2 was induced in human and animal kidneys after AKI. Knockdown of CNN2 preserved kidney function, mitigated tubular cell death and inflammation, and promoted cell proliferation. Distinct from kidney fibrosis, proteomics showed that the key elements in the FAO pathway have few changes during AKI, but we identified that 3-hydroxymethylglutaryl-CoA synthase 2 (Hmgcs2), a rate-limiting enzyme of endogenous ketogenesis that promotes cell self-renewal, was markedly increased in CNN2 knockdown kidneys. The ketone bodies β-hydroxybutyrate and ATP production were increased in CNN2 knockdown mice. Mechanistically, CNN2 interacts with ESR2 to negatively regulate activities of mitochondrial sirtuin 5. Activated sirtuin 5 subsequently desuccinylates Hmgcs2 to produce energy for mitigating AKI. Understanding CNN2-mediated discrete fine-tuning of protein posttranslational modification is critical to optimize organ performance after AKI.
    Keywords:  Apoptosis; Mouse models; Nephrology; Pericytes
    DOI:  https://doi.org/10.1172/jci.insight.170521
  9. Acta Physiol (Oxf). 2023 Sep 25. e14049
    Short-term fasting of mice elevates circulating fibroblast growth factor 23 (FGF23).
    Martina Feger, Jana Alber, Jörg Strotmann, Andrea Grund, Maren Leifheit-Nestler, Dieter Haffner, Michael Föller.
       AIMS: Phosphate and vitamin D homeostasis are controlled by fibroblast growth factor 23 (FGF23) from bone suppressing renal phosphate transport and enhancing 24-hydroxylase (Cyp24a1), thereby inactivating 1,25(OH)2 D3 . Serum FGF23 is correlated with outcomes in several diseases. Fasting stimulates the production of ketone bodies. We hypothesized that fasting can induce FGF23 synthesis through the production of ketone bodies.
    METHODS: UMR106 cells and isolated neonatal rat ventricular myocytes (NRVM) were treated with ketone body β-hydroxybutyrate. Mice were fasted overnight, fed ad libitum, or treated with β-hydroxybutyrate. Proteins and further blood parameters were determined by enzyme-linked immunoassay (ELISA), western blotting, immunohistochemistry, fluorometric or colorimetric methods, and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR).
    RESULTS: β-Hydroxybutyrate stimulated FGF23 production in UMR106 cells in a nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB)-dependent manner, and in NRVMs. Compared to fed animals, fasted mice exhibited higher β-hydroxybutyrate and FGF23 serum levels (based on assays either detecting C-terminal or intact, biologically active FGF23 only), cardiac, pancreatic, and thymic Fgf23 and renal Cyp24a1 expression, and lower 1,25(OH)2 D3 serum concentration as well as renal Slc34a1 and αKlotho (Kl) expression. In contrast, Fgf23 expression in bone and serum phosphate, calcium, plasma parathyroid hormone (PTH) concentration, and renal Cyp27b1 expression were not significantly affected by fasting.
    CONCLUSION: Short-term fasting increased FGF23 production, as did administration of β-hydroxybutyrate, effects possibly of clinical relevance in view of the increasing use of FGF23 as a surrogate parameter in clinical monitoring of diseases. The fasting state of patients might therefore affect FGF23 tests.
    Keywords:  FGF23; NFκB; phosphate; vitamin D; αKlotho
    DOI:  https://doi.org/10.1111/apha.14049
  10. J Physiol. 2023 Sep 23.
    Age-related changes of skeletal muscle metabolic response to contraction are also sex-dependent.
    Matthew D Campbell, Danijel Djukovic, Daniel Raftery, David J Marcinek.
      Mitochondria adapt to increased energy demands during muscle contraction by acutely altering metabolite fluxes and substrate oxidation. With age, an impaired mitochondrial metabolic response may contribute to reduced exercise tolerance and decreased skeletal muscle mass, specific force, increased overall fatty depositions in the skeletal muscle, frailty and depressed energy maintenance. We hypothesized that elevated energy stress in mitochondria with age alters the capacity of mitochondria to utilize different substrates following muscle contraction. To test this hypothesis, we used in vivo electrical stimulation to simulate high-intensity intervals (HII) or low intensity steady-state (LISS) exercise in young (5-7 months) and aged (27-29 months) male and female mice to characterize effects of age and sex on mitochondrial substrate utilization in skeletal muscle following contraction. Mitochondrial respiration using glutamate decreased in aged males following HII and glutamate oxidation was inhibited following HII in both the contracted and non-stimulated muscle of aged female muscle. Analyses of the muscle metabolome of female mice indicated that changes in metabolic pathways induced by HII and LISS contractions in young muscle are absent in aged muscle. To test improved mitochondrial function on substrate utilization following HII, we treated aged females with elamipretide (ELAM), a mitochondrially-targeted peptide shown to improve mitochondrial bioenergetics and restore redox status in aged muscle. ELAM removed inhibition of glutamate oxidation and showed increased metabolic pathway changes following HII, suggesting rescuing redox status and improving bioenergetic function in mitochondria from aged muscle increases glutamate utilization and enhances the metabolic response to muscle contraction in aged muscle. KEY POINTS: Acute local contraction of gastrocnemius can systemically alter mitochondrial respiration in non-stimulated muscle. Age-related changes in mitochondrial respiration using glutamate or palmitoyl carnitine following contraction are sex-dependent. Respiration using glutamate after high-intensity contraction is inhibited in aged female muscle. Metabolite level and pathway changes following muscle contraction decrease with age in female mice. Treatment with the mitochondrially-targeted peptide elamipretide can partially rescue metabolite response to muscle contraction.
    Keywords:  age; high-intensity intervals; low-intensity steady-state; metabolism; mitochondrial adaptation; sarcopenia; sex specific effects
    DOI:  https://doi.org/10.1113/JP285124
  11. Sports Med Open. 2023 Sep 29. 9(1): 91
    Effect of Eccentric Exercise on Metabolic Health in Diabetes and Obesity.
    Gergő Szűcs, Márton Pipicz, Márton Richárd Szabó, Tamás Csont, László Török, Csaba Csonka.
      There is a growing body of evidence showing the importance of physical activity against civilization-induced metabolic diseases, including type 2 diabetes (T2DM) and obesity. Eccentric contraction, when skeletal muscles generate force by lengthening, is a unique type of skeletal muscle activity. Eccentric contraction may lead to better power production characteristics of the muscle because eccentric contraction requires less energy and can result in higher tension. Therefore, it is an ideal tool in the rehabilitation program of patients. However, the complex metabolic effect (i.e., fat mass reduction, increased lipid oxidation, improvement in blood lipid profile, and increased insulin sensitivity) of the eccentric contraction alone has scarcely been investigated. This paper aims to review the current literature to provide information on whether eccentric contraction can influence metabolic health and body composition in T2DM or obesity. We also discussed the potential role of myokines in mediating the effects of eccentric exercise. A better understanding of the mechanism of eccentric training and particularly their participation in the regulation of metabolic diseases may widen their possible therapeutic use and, thereby, may support the fight against the leading global risks for mortality in the world.
    Keywords:  Diabetic; Downhill; Eccentric training; Exercise; Impaired glucose tolerance; Insulin resistance; Lengthening contraction; Metabolism; Obesity; Overweight; Prediabetes
    DOI:  https://doi.org/10.1186/s40798-023-00596-2
  12. Am J Physiol Regul Integr Comp Physiol. 2023 Sep 25.
    Effects of the order of endurance and high intensity interval exercise in combined training on mice skeletal muscle metabolism.
    Takanaga Shirai, Kazuki Uemichi, Tohru Takemasa.
      Endurance exercise (EE) mainly improves oxidative capacity, whereas, high intensity interval exercise (HIIE) improves also glycolytic capacity. There is a growing body of evidence that suggests that combining endurance exercise (EE) with high-intensity interval exercise (HIIE) can lead to improved athletic performance and fitness outcomes compared to either form of exercise alone. This study aimed to elucidate whether the order in which EE and HIIE are performed in combined training affected oxidative metabolism and glycolysis in mice skeletal muscle. 7 weeks of age male ICR mice were divided into 3 groups: CON (Control), EE-HIIE, HIIE-EE. The total training period was 3 weeks (3 times / week). Mice performed running on a treadmill as endurance exercise and swimming with a weight load of 10% of body weight as swimming. EE prior to HIIE (EE-HIIE) improved running performance in the maximal EE capacity test (all-out test) and partly enhanced the expression levels of molecular signals involved in glycolysis when compared with HIIE prior to EE (HIIE-EE). The order of exercise did not, however, impact the expression of proteins related to mitochondrial dynamics, including those involved in the morphological changes of mitochondria through repeated fusion and fission, as well as oxidative energy metabolism. The findings suggest that the order of exercise has no significant impact on the expression of proteins associated with glycolytic and oxidative energy metabolism. Nevertheless, our results indicate that the order of EE-HIIE may enhance running performance.
    Keywords:  Combined training; Endurance exercise; High intensity interval exercise; Oxidative and glycolytic metabolism; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpregu.00077.2023
  13. Int J Sport Nutr Exerc Metab. 2023 Sep 26. 1-10
    Effects of Ketone Monoester and Bicarbonate Co-Ingestion on Cycling Performance in WorldTour Cyclists.
    Domingo Jesús Ramos-Campo, Francisco Javier López-Román, Silvia Pérez-Piñero, Raquel Ortolano, María Salud Abellán-Ruiz, Enrique Molina Pérez de Los Cobos, Antonio Jesús Luque-Rubia, Dag Van Elslande, Vicente Ávila-Gandía.
      The present randomized study investigated the effect of acute supplementation of 800 mg/kg of ketone monoester ingestion (KE) or placebo (PL) and 210 mg/kg of NaHCO3 co-ingestion on cycling performance of WorldTour cyclists during a road cycling stage simulation. Twenty-eight cyclists participated in the study (27.46 ± 4.32 years; 1.80 ± 0.06 m; 69.74 ± 6.36 kg). Performance, physiological, biochemical, and metabolism outcomes, gut discomfort, and effort perceived were assessed during a road cycling simulation composed of an 8-min time-trial (TT) performance + 30-s TT + 4.5 hr of outdoor cycling + a second 8-min TT + a second 30-s TT. Greater absolute and relative mean power during the first 8-min TT (F = 5.067, p = .033, ηp2=.163, F = 5.339, p = .029, ηp2=.170, respectively) was observed after KE than after PL (KE: 389 ± 34, PL: 378 ± 44 W, p = .002, d = 0.294 and KE: 5.60 ± 0.42, PL: 5.41 ± 0.44 W/kg, p = .001, d = 0.442). Additionally, greater concentration of β-hydroxybutyrate blood concentration (F = 42.195, p < .001, ηp2=.619) was observed after KE than after PL during the first steps of the stage (e.g., after warm-up KE: 1.223 ± 0.642, PL: 0.044 ± 0.058 mM, p < .001, d = 2.589), although the concentrations returned to near baseline after 4.5 hr of outdoor cycling. Moreover, higher values of anion gap were observed (F = 2.333, p = .026, ηp2=.080) after KE than after PL ingestion, after the warm-up and after the first 8-min and 30-s TT. Additionally, lower concentrations of HCO3- were reported in the KE condition after warm-up and after the first 8-min and 30-s TT. During the initial phase of the stage simulation, acute supplementation with KE + NaHCO3 co-ingestion enhanced 8-min TT cycling performance (3.1%) in WorldTour cyclists with a concomitant hyperketonaemia.
    Keywords:  acid–base status; ketosis; supplementation; time trial
    DOI:  https://doi.org/10.1123/ijsnem.2023-0078
  14. Cytokine Growth Factor Rev. 2023 Sep 16. pii: S1359-6101(23)00067-9. [Epub ahead of print]
    Protein-protein interactions and related inhibitors involved in the NLRP3 inflammasome pathway.
    Zhen-Yu Ma, Cheng Jiang, Li-Li Xu.
      NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) receptor serves as the central node of immune sensing in the innate immune system, and plays an important role in the initiation and progression of chronic diseases. Cryo-electron microscopy (cryo-EM) has provided insights into the conformation of various oligomers within the NLRP3 activation pathway, significantly advancing our understanding of the mechanisms underlying NLRP3 inflammasome activation. Despite the extensive network of protein-protein interactions (PPIs) involved in the assembly and activation of NLRP3 inflammasome, the utilization of protein-protein interactions has been relatively overlooked in the development of NLRP3 inhibitors. This review focuses on summarizing PPIs within the NLRP3 inflammasome activation pathway and small molecule inhibitors capable of interfering with PPIs to counteract the NLRP3 overactivation. Small molecule NLRP3 inhibitors have been gained significant attention owing to their remarkable efficacy, excellent safety profiles, and unique mechanisms of action.
    Keywords:  Anti-inflammasome; Inhibitors; Mechanism; NLRP3 inflammasome; PPIs
    DOI:  https://doi.org/10.1016/j.cytogfr.2023.09.003
  15. Spectrochim Acta A Mol Biomol Spectrosc. 2023 Sep 20. pii: S1386-1425(23)01122-8. [Epub ahead of print]304 123437
    A new turn-on fluorescent probe for fast detection of diabetic biomarker beta-hydroxybutyrate in vitro.
    Jin Wang, Xiaoqin Yang, Leilei Shen, Ruiyao Ni, Yijie Huang, Zhaosong Sui, Xiaohan Wang.
      Beta-hydroxybutyrate (β-HB) serve as a valuable diagnostic biomarker for Diabetic Ketoacidosis (DKA). Here, a new Schiff base fluorescent probe T was designed and synthesized to detect β-HB level in aqueous solution in vitro. The probe T can detect β-HB sensitively and selectively in DMF solution (5.0 × 10-5 M) among other interfering species (cations, anions, amino acids, biomarkers). The detection limit of probe T for β-HB was calculated to be 0.154 μM. These results demonstrate that the probe T may provide a convenient method for rapid detection of β-HB to diagnose diabetic ketoacidosis.
    Keywords:  Beta-hydroxybutyrate (β-HB); Diabetes; Diabetic ketoacidosis; Fluorescent probe
    DOI:  https://doi.org/10.1016/j.saa.2023.123437
  16. Life Sci. 2023 Sep 22. pii: S0024-3205(23)00758-0. [Epub ahead of print]332 122123
    Phosphate burden induces vascular calcification through a NLRP3-caspase-1-mediated pyroptotic pathway.
    Li-Chun Ho, Yu-Hsin Chen, Ting-Yun Wu, Ling-Zhen Kao, Shih-Yuan Hung, Hung-Hsiang Liou, Pei-Chun Chen, Pei-Jane Tsai, Hui-Kuan Lin, Yi-Che Lee, Hsi-Hao Wang, Yau-Sheng Tsai.
       AIMS: The aim of this study is to clarify the role of NLRP3 inflammasome in phosphate burden-induced vascular smooth muscle cell (VSMC) calcification.
    MAIN METHODS: VSMC calcification was induced using a high concentration of inorganic phosphate. After pharmacological inhibition or genetic silencing of the NLRP3 inflammasome, pyroptosis, or potassium efflux, the cells were examined by RT-qPCR, immunofluorescence, and western blotting to identify the NLRP3-mediated pathway for VSMC calcification.
    KEY FINDINGS: Calcified VSMCs with α-smooth muscle actin (α-SMA) disarray presented features of pyroptosis, including caspase-1 maturation, cleaved gasdermin D (GSDMD), and a high supernatant level of lactate dehydrogenase A. Pharmacological inhibitions of caspase-1 and pyroptosis attenuated VSMC calcification, whereas interleukin-1β receptor antagonism did not. Unlike canonical NLRP3 activation, osteogenic VSMCs did not upregulate NLRP3 expression. However, NLRP3 genetic silencing or inhibitions, which targets different domains of the NLRP3 protein, could ameliorate VSMC calcification by aborting caspase-1 and GSDMD activation. Furthermore, potassium efflux through the inward-rectifier potassium channel, and not through the P2X7 receptor, triggered NLRP3 inflammasome activation and VSMC calcification.
    SIGNIFICANCE: In the present study, we identified a potassium efflux-triggered NLRP3-caspase-1-mediated pyroptotic pathway for VSMC calcification that is unique and different from the canonical NLRP3 inflammasome activation. Therefore, targeting this pathway may serve as a novel therapeutic strategy for vascular calcification.
    Keywords:  NLRP3 inflammasome; Pyroptosis; Vascular calcification
    DOI:  https://doi.org/10.1016/j.lfs.2023.122123
  17. Anim Nutr. 2023 Dec;15 10-21
    Transcriptomic and metabolomic insights into the roles of exogenous β-hydroxybutyrate acid for the development of rumen epithelium in young goats.
    Yimin Zhuang, Jianmin Chai, Mahmoud M Abdelsattar, Yuze Fu, Naifeng Zhang.
      Beta-hydroxybutyric acid (BHBA), as one of the main metabolic ketones in the rumen epithelium, plays critical roles in cellular growth and metabolism. The ketogenic capacity is associated with the maturation of rumen in young ruminants, and the exogenous BHBA in diet may promote the rumen development. However, the effects of exogenous BHBA on rumen remain unknown. This is the first study to investigate the mechanisms of BHBA on gene expression and metabolism of rumen epithelium using young goats as a model through multi-omics techniques. Thirty-two young goats were divided into control, low dose, middle dose, and high dose groups by supplementation of BHBA in starter (0, 3, 6, and 9 g/day, respectively). Results demonstrated the dietary of BHBA promoted the growth performance of young goats and increased width and length of the rumen papilla (P < 0.05). Hub genes in host transcriptome that were positively related to rumen characteristics and BHBA concentration were identified. Several upregulated hub genes including NDUFC1, NDUFB4, NDUFB10, NDUFA11 and NDUFA1 were enriched in the gene ontology (GO) pathway of nicotinamide adenine dinucleotide (NADH) dehydrogenase (ubiquinone) activity, while ATP5ME, ATP5PO and ATP5PF were associated with ATP synthesis. RT-PCR revealed the expression of genes (HMGCS2, BDH1, SLC16A3, etc.) associated with lipolysis increased significantly by BHBA supplementation (P < 0.05). Metabolomics indicated that some metabolites such as glucose, palmitic acid, cortisol and capric acid were also increased (P < 0.05). This study revealed that BHBA promoted rumen development through altering NADH balance and accelerating lipid metabolism, which provides a theoretical guidance for the strategies of gastrointestinal health and development of young ruminants.
    Keywords:  Beta-hydroxybutyrate acid; Goat; Lipid metabolism; Metabolomics; Rumen; Transcriptome
    DOI:  https://doi.org/10.1016/j.aninu.2023.02.012
  18. Antioxidants (Basel). 2023 Sep 07. pii: 1729. [Epub ahead of print]12(9):
    Redox Regulation of Microglial Inflammatory Response: Fine Control of NLRP3 Inflammasome through Nrf2 and NOX4.
    Alejandra Palomino-Antolín, Céline Decouty-Pérez, Víctor Farré-Alins, Paloma Narros-Fernández, Ana Belen Lopez-Rodriguez, María Álvarez-Rubal, Inés Valencia, Francisco López-Muñoz, Eva Ramos, Antonio Cuadrado, Ana I Casas, Alejandro Romero, Javier Egea.
      The role of inflammation and immunity in the pathomechanism of neurodegenerative diseases has become increasingly relevant within the past few years. In this context, the NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in the activation of inflammatory responses by promoting the maturation and secretion of pro-inflammatory cytokines such as interleukin-1β and interleukin-18. We hypothesized that the interplay between nuclear factor erythroid 2-related factor 2 (Nrf2) and NADPH oxidase 4 (NOX4) may play a critical role in the activation of the NLRP3 inflammasome and subsequent inflammatory responses. After priming mixed glial cultures with lipopolysaccharide (LPS), cells were stimulated with ATP, showing a significant reduction of IL1-β release in NOX4 and Nrf2 KO mice. Importantly, NOX4 inhibition using GKT136901 also reduced IL-1β release, as in NOX4 KO mixed glial cultures. Moreover, we measured NOX4 and NLRP3 expression in wild-type mixed glial cultures following LPS treatment, observing that both increased after TLR4 activation, while 24 h treatment with tert-butylhydroquinone, a potent Nrf2 inducer, significantly reduced NLRP3 expression. LPS administration resulted in significant cognitive impairment compared to the control group. Indeed, LPS also modified the expression of NLRP3 and NOX4 in mouse hippocampus. However, mice treated with GKT136901 after LPS impairment showed a significantly improved discrimination index and recovered the expression of inflammatory genes to normal levels compared with wild-type animals. Hence, we here validate NOX4 as a key player in NLRP3 inflammasome activation, suggesting NOX4 pharmacological inhibition as a potent therapeutic approach in neurodegenerative diseases.
    Keywords:  KO mice; NLRP3 inflammasome; NOX4; Nrf2; glial cultures; inflammation and immunity; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/antiox12091729
  19. Brain Sci. 2023 Sep 11. pii: 1307. [Epub ahead of print]13(9):
    The Role of Ketone Bodies in Treatment Individualization of Glioblastoma Patients.
    Corina Tamas, Flaviu Tamas, Attila Kovecsi, Georgiana Serban, Cristian Boeriu, Adrian Balasa.
      Glioblastoma is the most common and aggressive primary brain tumor in adults. According to the 2021 WHO CNS, glioblastoma is assigned to the IDH wild-type classification, fulfilling the specific characteristic histopathology. We have conducted a prospective observational study to identify the glucose levels, ketone bodies, and the glucose-ketone index in three groups of subjects: two tumoral groups of patients with histopathological confirmation of glioblastoma (9 male patients, 7 female patients, mean age 55.6 years old) or grade 4 astrocytoma (4 male patients, 2 female patients, mean age 48.1 years old) and a control group (13 male patients, 9 female patients, mean age 53.9 years old) consisting of subjects with no personal pathological history. There were statistically significant differences between the mean values of glycemia (p value = 0.0003), ketones (p value = 0.0061), and glucose-ketone index (p value = 0.008) between the groups of patients. Mortality at 3 months in glioblastoma patients was 0% if the ketone levels were below 0.2 mM and 100% if ketones were over 0.5 mM. Patients with grade 4 astrocytoma and the control subjects all presented with ketone values of less than 0.2 mM and 0.0% mortality. In conclusion, highlighting new biomarkers which are more feasible to determine such as ketones or glucose-ketone index represents an essential step toward personalized medicine and survival prolongation in patients suffering from glioblastoma and grade 4 astrocytoma.
    Keywords:  astrocytoma; diet; glioblastoma; glucose; ketones; metabolism
    DOI:  https://doi.org/10.3390/brainsci13091307
  20. Hepatol Commun. 2023 Oct 01. pii: e0234. [Epub ahead of print]7(10):
    Overview and prospect of NAFLD: Significant roles of nutrients and dietary patterns in its progression or prevention.
    Tianyu Mao, Yiwen Sun, Xinyi Xu, Kang He.
      NAFLD is the most common chronic liver disease worldwide, characterized by lipid accumulation in the liver, and usually evolves from steatohepatitis to fibrosis, cirrhosis, or even HCC. Its incidence is rapidly rising in parallel with the increasing prevalence of obesity and metabolic syndrome. Current therapies are limited to lifestyle changes including dietary intervention and exercise, in which dietary modification exerts an important part in losing weight and preventing NAFLD. In this review, we briefly discuss the roles and mechanisms of dietary components including fructose, non-nutritive sweeteners, fat, proteins, and vitamins in the progression or prevention of NAFLD. We also summarize several popular dietary patterns such as calorie-restricted diets, intermittent fasting, ketogenic diets, Mediterranean diets, and dietary approach to stop hypertension diets and compare the effects of low-fat and low-carbohydrate diets in preventing the development of NAFLD. Moreover, we summarize the potential drugs targeting metabolic-related targets in NAFLD.
    DOI:  https://doi.org/10.1097/HC9.0000000000000234
  21. Biomolecules. 2023 Aug 25. pii: 1304. [Epub ahead of print]13(9):
    The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases.
    Donato D'Angelo, Rosario Rizzuto.
      Calcium (Ca2+) ions act as a second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. A lot of evidence demonstrates that the dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been shown.
    Keywords:  MCU; cancer; cardiovascular diseases; metabolic diseases; mitochondrial Ca2+ signaling; neurodegenerative disorders; skeletal muscle diseases
    DOI:  https://doi.org/10.3390/biom13091304
  22. Front Immunol. 2023 ;14 1254150
    The gasdermins: a pore-forming protein family expressed in the epidermis.
    Marta Slaufova, Tugay Karakaya, Michela Di Filippo, Paulina Hennig, Hans-Dietmar Beer.
      Gasdermins comprise a family of pore-forming proteins, which play critical roles in (auto)inflammatory diseases and cancer. They are expressed as self-inhibited precursor proteins consisting of an aminoterminal cytotoxic effector domain (NT-GSDM) and a carboxyterminal inhibitor domain (GSDM-CT) separated by an unstructured linker region. Proteolytic processing in the linker region liberates NT-GSDM, which translocates to membranes, forms oligomers, and induces membrane permeabilization, which can disturb the cellular equilibrium that can lead to cell death. Gasdermin activation and pore formation are associated with inflammation, particularly when induced by the inflammatory protease caspase-1 upon inflammasome activation. These gasdermin pores allow the release of the pro-inflammatory cytokines interleukin(IL)-1β and IL-18 and induce a lytic type of cell death, termed pyroptosis that supports inflammation, immunity, and tissue repair. However, even at the cellular level, the consequences of gasdermin activation are diverse and range from induction of programmed cell death - pyroptosis or apoptosis - to poorly characterized protective mechanisms. The specific effects of gasdermin activation can vary between species, cell types, the membrane that is being permeabilized (plasma membrane, mitochondrial membrane, etc.), and the overall biological state of the local tissue/cells. In epithelia, gasdermins seem to play crucial roles. Keratinocytes represent the main cell type of the epidermis, which is the outermost skin layer with an essential barrier function. Compared to other tissues, keratinocytes express all members of the gasdermin family, in part in a differentiation-specific manner. That raises questions regarding the specific roles of individual GSDM family members in the skin, the mechanisms and consequences of their activation, and the potential crosstalk between them. In this review, we summarize the current knowledge about gasdermins with a focus on keratinocytes and the skin and discuss the possible roles of the different family members in immunity and disease.
    Keywords:  gasdermin (GSDM); inflammasome; interleukin - 1; pyroptosis; skin
    DOI:  https://doi.org/10.3389/fimmu.2023.1254150
  23. Rev Med Inst Mex Seguro Soc. 2023 Sep 04. 61(5): 691-694
    [Succinyl CoA:3 oxoacid CoA transferase deficiency: A case report].
    Miguel Angel Jurado-Aguirre, Ana Elena Pérez-Verdín.
       Background: Succinyl-CoA:3 oxoacid CoA transferase deficiency (SCOTD) is a rare autosomal recessive disease, characterized by altered utilization of ketone bodies, with acute episodes of ketoacidosis.
    Clinical case: It is presented the case of a patient with SCOTD, with a first atypical episode accompanied by hyperglycemia, with 4 subsequent episodes with classic manifestations of the disease, presenting with a biochemical pattern of permanent ketonuria with marked elevation of ketone bodies (acetoacetate, 3 beta-hydroxybutyrate) in the study of urinary organic acids by gas chromatography and mass spectrometry, together with the clinical picture granting the diagnosis. It was started a maintenance therapy with a characteristic feeding plan; it was shown an adequate response to treatment, and the absence of permanent ketosis was surmised.
    Conclusion: Being a rare disease, the categorization of these patients as diabetic ketoacidosis is frequent. The clinical and biochemical characteristics with ketosis or persistent ketonuria should be analyzed very carefully, especially in patients presenting with hyperglycemia, which is an atypical manifestation of the disease, in order to make an early diagnosis and treatment, positively impacting the prognosis of patients.
    Keywords:  Acidosis; Diabetic Ketoacidosis; Ketone Bodies; Succinate-CoA Ligases
    DOI:  https://doi.org/10.5281/zenodo.8316483
  24. Pharmaceuticals (Basel). 2023 Aug 28. pii: 1211. [Epub ahead of print]16(9):
    Inflammasomes in Atherosclerosis-From Pathophysiology to Treatment.
    Panagiotis Theofilis, Evangelos Oikonomou, Christos Chasikidis, Konstantinos Tsioufis, Dimitris Tousoulis.
      Atherosclerosis, a chronic inflammatory disease characterized by arterial plaque accumulation, remains a significant global health challenge. In recent years, inflammasomes, the intracellular multiprotein complexes crucial for initiating innate immune responses, have emerged as key players in atherosclerosis pathophysiology. This review article aims to provide a comprehensive overview of the current understanding of inflammasome activation and its impact on atherosclerosis development and progression. We explore the intricate interplay between traditional cardiovascular risk factors and inflammasome activation, leading to the perpetuation of inflammatory cascades that drive plaque formation and instability. The review focuses on the molecular mechanisms underlying inflammasome activation, including the role of pattern recognition receptors and cytokines in this process. Moreover, we discuss the contribution of inflammasomes to endothelial dysfunction, foam cell formation, and vascular inflammation. Additionally, recent advances in therapeutic strategies targeting inflammasomes are examined, including pharmacological agents and potential immunomodulatory approaches. By collating and analyzing the current evidence, this review provides valuable insights into the potential of inflammasome-targeted therapies for atherosclerosis management and treatment. Understanding the pivotal role of inflammasomes in atherosclerosis pathophysiology offers promising prospects for developing effective and personalized therapeutic interventions that can mitigate the burden of this prevalent cardiovascular disorder and improve patient outcomes.
    Keywords:  NLRP3 inflammasome; atherosclerosis; inflammation
    DOI:  https://doi.org/10.3390/ph16091211
  25. Biomed Pharmacother. 2023 Sep 26. pii: S0753-3322(23)01358-6. [Epub ahead of print]167 115560
    Mitochondrion-NLRP3 inflammasome activation in macrophages: A novel mechanism of the anti-inflammatory effect of Notopterygium in rheumatoid arthritis treatment.
    Xiangxiang Liu, Xiaomei Chen, Cheng Zhang, Meixia Huang, Hongmin Yu, Yingzheng Wang, Yinghao Wang.
       OBJECTIVE: The mechanism by which Notopterygium (NE) regulates the nucleotide-binding, oligomerization domain (NOD)-like receptor family and pyrin domain-containing 3 (NLRP3) inflammasome to treat rheumatoid arthritis (RA) was investigated to reveal the scientific implications of NE in RA treatment.
    METHODS: Adjuvant arthritis (AA) rats were replicated. After NE intervention, the anti-inflammatory efficacy of NE in vivo was determined. The mechanism of NE in RA treatment was predicted by network pharmacology, and the key target for further experiments was found through the analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG). The effect of NE on the NLRP3 inflammasome in AA rats was verified. Furthermore, with the induction of inflammation in RAW264.7 cells by lipopolysaccharide (LPS), several techniques, such as Griess assay, enzyme linked immunosorbent assays, electron microscopy, and fluorescence probe technology, were used to investigate the anti-inflammatory and related mechanisms of NE in RA treatment.
    RESULTS: NE could inhibit inflammation in AA rats. KEGG results showed that NLRP3 participated in the top three pathways of NE in RA treatment. Through Western blotting and immunofluorescence assays, this study demonstrated that NE can regulate NLRP3, pro-Caspase-1, Caspase-1, and CD11b in the ankle joint of AA rats. NE may significantly reduce the LPS-induced inflammatory response of RAW264.7 cells by alleviating mitochondrial damage, reducing the number of mitochondrial deoxyribonucleic Acid and mitochondrial reactive oxygen species, inhibiting NLRP3 inflammasome activation.
    CONCLUSION: The anti-inflammatory and antirheumatic effect of NE may involve regulating NLRP3 inflammasome activation through mitochondria. NLRP3 is probably the key target molecule of NE in the treatment of RA.
    Keywords:  Mitochondria; NLRP3 inflammasome; Notopterygium; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.biopha.2023.115560
  26. Amino Acids. 2023 Sep 23.
    The effect of insulin resistance on extracellular BCAA accumulation and SLC25A44 expression in a myotube model of skeletal muscle insulin resistance.
    Caroline N Rivera, Rachel M Watne, Andrew J Wommack, Roger A Vaughan.
      Insulin resistance is often accompanied by elevated circulating branched-chain amino acids (BCAA). We investigated the effects of insulin resistance on the mitochondrial BCAA transporter, SLC25A44, using a myotube model of insulin resistance. Insulin sensitivity and SLC25A44 expression were assessed via Western blot. Liquid chromatography-mass spectrometry was used to evaluate extracellular BCAA media content. Insulin resistance reduced pAkt activation following insulin stimulation but did not alter SLC25A44 expression. Under select conditions, insulin resistance led to the accumulation of extracellular BCAA.
    Keywords:  Akt; Diabetes; Insulin resistance; Isoleucine; Leucine; Valine; pAkt
    DOI:  https://doi.org/10.1007/s00726-023-03336-8
  27. Nutrients. 2023 Sep 20. pii: 4073. [Epub ahead of print]15(18):
    Anabolic Resistance in the Pathogenesis of Sarcopenia in the Elderly: Role of Nutrition and Exercise in Young and Old People.
    Caterina Tezze, Marco Sandri, Paolo Tessari.
      The development of sarcopenia in the elderly is associated with many potential factors and/or processes that impair the renovation and maintenance of skeletal muscle mass and strength as ageing progresses. Among them, a defect by skeletal muscle to respond to anabolic stimuli is to be considered. Common anabolic stimuli/signals in skeletal muscle are hormones (insulin, growth hormones, IGF-1, androgens, and β-agonists such epinephrine), substrates (amino acids such as protein precursors on top, but also glucose and fat, as source of energy), metabolites (such as β-agonists and HMB), various biochemical/intracellular mediators), physical exercise, neurogenic and immune-modulating factors, etc. Each of them may exhibit a reduced effect upon skeletal muscle in ageing. In this article, we overview the role of anabolic signals on muscle metabolism, as well as currently available evidence of resistance, at the skeletal muscle level, to anabolic factors, from both in vitro and in vivo studies. Some indications on how to augment the effects of anabolic signals on skeletal muscle are provided.
    Keywords:  exercise; intracellular signals; nutrition; protein foods; protein synthesis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/nu15184073
  28. Acta Physiol (Oxf). 2023 Sep 27. e14050
    Molecular effects of dietary interventions-A clinical perspective.
    Kai-Dietrich Nüsken, Eva Nüsken.
      
    Keywords:  cell metabolism monitoring; diet intervention; molecular signature
    DOI:  https://doi.org/10.1111/apha.14050
  29. J Biochem. 2023 Sep 29. pii: mvad075. [Epub ahead of print]
    Insights into the regulation of mitochondrial functions by PKA-mediated phosphorylation.
    Shiori Akabane, Toshihiko Oka.
      Cyclic AMP (cAMP) - protein kinase A (PKA) signaling is a highly conserved pathway in eukaryotes and plays a central role in cell signaling cascades in response to environmental changes. Elevated cAMP levels promote the activation of PKA, which phosphorylates various downstream proteins. Many cytosolic and nuclear proteins, such as metabolic enzymes and transcriptional factors, have been identified as substrates for PKA, suggesting that PKA-mediated regulation occurs predominantly in the cytosol. Mitochondrial proteins are also phosphorylated by PKA, and PKA-mediated phosphorylation of mitochondrial proteins is considered to control a variety of mitochondrial functions, including oxidative phosphorylation, protein import, morphology, and quality control. In this review, we outline PKA mitochondrial substrates and summarize the regulation of mitochondrial functions through PKA-mediated phosphorylation.
    Keywords:  PKA; cAMP; mitochondria; phosphorylation
    DOI:  https://doi.org/10.1093/jb/mvad075
  30. Front Mol Neurosci. 2023 ;16 1271175
    Editorial: Mitochondrial dysfunction as a target in neurodegenerative diseases.
    Lorena Perrone.
      
    Keywords:  DRP1; cell-specific; microglia; mitochondria; mitophagy; neurodegeneration; proteomics; sex-specific
    DOI:  https://doi.org/10.3389/fnmol.2023.1271175
  31. Biomedicines. 2023 Aug 22. pii: 2334. [Epub ahead of print]11(9):
    Metformin Protects Rat Skeletal Muscle from Physical Exercise-Induced Injury.
    Giuliana Abbadessa, Eleonora Maniscalco, Loredana Grasso, Jasmin Popara, Federica Di Scipio, Francesco Franco, Daniele Mancardi, Fabio Pigozzi, Paolo Borrione, Giovanni Nicolao Berta, Silvia Racca.
      Metformin (Met) is a drug commonly prescribed in type 2 diabetes mellitus. Its efficacy is due to the suppression of hepatic gluconeogenesis, enhancement of peripheral glucose uptake and lower glucose absorption by the intestine. Recent studies have reported Met efficacy in other clinical applications, such as age-related diseases. Despite the wide clinical use of Met, its mechanism of action on muscle and its effect on muscle performance are unclear. We investigated the effects of Met combined with training on physical performance (PP) in healthy rats receiving Met for 8 weeks while undergoing daily moderate exercise. We evaluated the following: PP through graded endurance exercise test performed before the beginning of the training protocol and 48 h before the end of the training period; blood ALT, AST, LDH and CK-MB levels in order to address muscle damage; and several blood and muscle myokines and the expression of factors believed to be involved in muscle adaptation to exercise. Our data demonstrate that Met does not improve the positive effects of exercise on performance, although it protects myocytes from exercise-induced damage. Moreover, given that Met positively affects exercise-induced muscle adaptation, our data support the idea of the therapeutic application of Met when muscle function and structure are compromised.
    Keywords:  metformin; muscle adaptation; physical performance; skeletal muscle; training
    DOI:  https://doi.org/10.3390/biomedicines11092334
  32. Cells. 2023 Sep 05. pii: 2210. [Epub ahead of print]12(18):
    Role of Mitochondria in the Regulation of Effector Functions of Granulocytes.
    Nina V Vorobjeva, Maria A Chelombitko, Galina F Sud'ina, Roman A Zinovkin, Boris V Chernyak.
      Granulocytes (neutrophils, eosinophils, and basophils) are the most abundant circulating cells in the innate immune system. Circulating granulocytes, primarily neutrophils, can cross the endothelial barrier and activate various effector mechanisms to combat invasive pathogens. Eosinophils and basophils also play an important role in allergic reactions and antiparasitic defense. Granulocytes also regulate the immune response, wound healing, and tissue repair by releasing of various cytokines and lipid mediators. The effector mechanisms of granulocytes include the production of reactive oxygen species (ROS), degranulation, phagocytosis, and the formation of DNA-containing extracellular traps. Although all granulocytes are primarily glycolytic and have only a small number of mitochondria, a growing body of evidence suggests that mitochondria are involved in all effector functions as well as in the production of cytokines and lipid mediators and in apoptosis. It has been shown that the production of mitochondrial ROS controls signaling pathways that mediate the activation of granulocytes by various stimuli. In this review, we will briefly discuss the data on the role of mitochondria in the regulation of effector and other functions of granulocytes.
    Keywords:  apoptosis; degranulation; extracellular traps; granulocytes; inflammation; leukotrienes; mitochondria; mitochondria-targeted antioxidants; mitochondrial ROS production; oxidative burst
    DOI:  https://doi.org/10.3390/cells12182210
  33. Antioxidants (Basel). 2023 Sep 20. pii: 1784. [Epub ahead of print]12(9):
    Role of Oxidative Stress in Mitochondrial Function: Relevance for Liver Function.
    Jie Xu, Zhihui Feng.
      The traditional recognition of mitochondria as powerhouses that generate ATP and reactive oxygen species (ROS) via oxidative phosphorylation and the tricarboxylic acid cycle has ceased [...].
    DOI:  https://doi.org/10.3390/antiox12091784
  34. Front Cardiovasc Med. 2023 ;10 1251122
    A single 36-h water-only fast vastly remodels the plasma lipidome.
    Brian V Hong, Christopher H Rhodes, Joanne K Agus, Xinyu Tang, Chenghao Zhu, Jack Jingyuan Zheng, Angela M Zivkovic.
       Background: Prolonged fasting, characterized by restricting caloric intake for 24 h or more, has garnered attention as a nutritional approach to improve lifespan and support healthy aging. Previous research from our group showed that a single bout of 36-h water-only fasting in humans resulted in a distinct metabolomic signature in plasma and increased levels of bioactive metabolites, which improved macrophage function and lifespan in C. elegans.
    Objective: This secondary outcome analysis aimed to investigate changes in the plasma lipidome associated with prolonged fasting and explore any potential links with markers of cardiometabolic health and aging.
    Method: We conducted a controlled pilot study with 20 male and female participants (mean age, 27.5 ± 4.4 years; mean BMI, 24.3 ± 3.1 kg/m2) in four metabolic states: (1) overnight fasted (baseline), (2) 2-h postprandial fed state (fed), (3) 36-h fasted state (fasted), and (4) 2-h postprandial refed state 12 h after the 36-h fast (refed). Plasma lipidomic profiles were analyzed using liquid chromatography and electrospray ionization mass spectrometry.
    Results: Several lipid classes, including lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylethanolamine, and triacylglycerol were significantly reduced in the 36-h fasted state, while free fatty acids, ceramides, and sphingomyelin were significantly increased compared to overnight fast and fed states (P < 0.05). After correction for multiple testing, 245 out of 832 lipid species were significantly altered in the fasted state compared to baseline (P < 0.05). Random forest models revealed that several lipid species, such as LPE(18:1), LPC(18:2), and FFA(20:1) were important features in discriminating the fasted state from both the overnight fasted and postprandial state.
    Conclusion: Our findings indicate that prolonged fasting vastly remodels the plasma lipidome and markedly alters the concentrations of several lipid species, which may be sensitive biomarkers of prolonged fasting. These changes in lipid metabolism during prolonged fasting have important implications for the management of cardiometabolic health and healthy aging, and warrant further exploration and validation in larger cohorts and different population groups.
    Keywords:  cardiometabolic health; fasting; free fatty acids; lipidomic; lipids
    DOI:  https://doi.org/10.3389/fcvm.2023.1251122
  35. Biomolecules. 2023 09 06. pii: 1354. [Epub ahead of print]13(9):
    The Effect of SERCA Activation on Functional Characteristics and Signaling of Rat Soleus Muscle upon 7 Days of Unloading.
    Kristina A Sharlo, Irina D Lvova, Sergey A Tyganov, Ksenia A Zaripova, Svetlana P Belova, Tatiana Y Kostrominova, Boris S Shenkman, Tatiana L Nemirovskaya.
      Skeletal muscle abnormalities and atrophy during unloading are accompanied by the accumulation of excess calcium in the sarcoplasm. We hypothesized that calcium accumulation may occur, among other mechanisms, due to the inhibition of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity. Consequently, the use of the SERCA activator will reduce the level of calcium in the sarcoplasm and prevent the negative consequences of muscle unloading. Wistar rats were randomly assigned into one of three groups (eight rats per group): control rats with placebo (C), 7 days of unloading/hindlimb suspension with placebo (7HS), and 7 days of unloading treated with SERCA activator CDN1163 (7HSC). After seven days of unloading the soleus muscle, the 7HS group displayed increased fatigue in the ex vivo test, a significant increase in the level of calcium-dependent CaMK II phosphorylation and the level of tropomyosin oxidation, as well as a decrease in the content of mitochondrial DNA and protein, slow-type myosin mRNA, and the percentage of slow-type muscle fibers. All of these changes were prevented in the 7HSC group. Moreover, treatment with CDN1163 blocked a decrease in the phosphorylation of p70S6k, an increase in eEF2 phosphorylation, and an increase in MuRF-1 mRNA expression. Nevertheless, there were no differences in the degree of fast and slow muscle fiber atrophy between the 7HS and 7HSC groups. Conclusion: SERCA activation during 7 days of unloading prevented an increase in soleus fatigue, the decrease of slow-type myosin, mitochondrial markers, and markers of calcium homeostasis but had no effect on muscle atrophy.
    Keywords:  AMPK; ATP; MAFbx; MuRF1; muscle atrophy; soleus muscle unloading
    DOI:  https://doi.org/10.3390/biom13091354
  36. Heart Fail Rev. 2023 Sep 28.
    Metabolic adaptations in pressure overload hypertrophic heart.
    Jinfeng Wei, Xuefei Duan, Jiaying Chen, Dengwen Zhang, Jindong Xu, Jian Zhuang, Sheng Wang.
      This review article offers a detailed examination of metabolic adaptations in pressure overload hypertrophic hearts, a condition that plays a pivotal role in the progression of heart failure with preserved ejection fraction (HFpEF) to heart failure with reduced ejection fraction (HFrEF). The paper delves into the complex interplay between various metabolic pathways, including glucose metabolism, fatty acid metabolism, branched-chain amino acid metabolism, and ketone body metabolism. In-depth insights into the shifts in substrate utilization, the role of different transporter proteins, and the potential impact of hypoxia-induced injuries are discussed. Furthermore, potential therapeutic targets and strategies that could minimize myocardial injury and promote cardiac recovery in the context of pressure overload hypertrophy (POH) are examined. This work aims to contribute to a better understanding of metabolic adaptations in POH, highlighting the need for further research on potential therapeutic applications.
    Keywords:  Cardiac hypertrophy; Energy metabolism; Heart failure
    DOI:  https://doi.org/10.1007/s10741-023-10353-y
  37. Biomolecules. 2023 Sep 19. pii: 1409. [Epub ahead of print]13(9):
    Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.
    Haikel Dridi, Gaetano Santulli, Laith Bahlouli, Marco C Miotto, Gunnar Weninger, Andrew R Marks.
      Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca2+) handling, mitochondrial Ca2+ overload, and oxidative stress. In cardiomyocytes, Ca2+ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca2+ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca2+ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca2+ handling in heart failure and the potential therapeutic strategies.
    Keywords:  calcium; heart failure; mitochondria
    DOI:  https://doi.org/10.3390/biom13091409
  38. EMBO Rep. 2023 Sep 28. e58118
    The fountain of youth of mitochondrial research: Research is targeting mitochondrial dysfunction to tackle aging and much more, but hype is an increasing concern.
    Andrea Rinaldi.
      A new wave of studies is untangling the connection between primary genetic mitochondrial diseases and the role of mitochondria in aging: what are the implications for longevity?
    DOI:  https://doi.org/10.15252/embr.202358118
  39. Biomed Pharmacother. 2023 Sep 21. pii: S0753-3322(23)01295-7. [Epub ahead of print]167 115497
    NLRP3 inflammasome involves in the pathophysiology of sepsis-induced myocardial dysfunction by multiple mechanisms.
    Hongwei Zhang, Jian Liao, Litong Jin, Yan Lin.
      Sepsis-induced myocardial dysfunction (SIMD) is one of the serious health-affecting problems worldwide. At present, the mechanisms of SIMD are still not clearly elucidated. The NOD-like receptor protein 3 (NLRP3) inflammasome has been assumed to be involved in the pathophysiology of SIMD by regulating multiple biological processes. NLRP3 inflammasome and its related signaling pathways might affect the regulation of inflammation, autophagy, apoptosis, and pyroptosis in SIMD. A few molecular specific inhibitors of NLRP3 inflammasome (e.g., Melatonin, Ulinastatin, Irisin, Nifuroxazide, and Ginsenoside Rg1, etc.) have been developed, which showed a promising anti-inflammatory effect in a cellular or animal model of SIMD. These experimental findings indicated that NLRP3 inflammasome could be a promising therapeutic target for SIMD treatment. However, the clinical translation of NLRP3 inhibitors for treating SIMD still requires robust in vivo and preclinical trials.
    Keywords:  Inflammasome; Mechanism; NLRP3 Inhibitor; NOD-like receptor protein 3; Sepsis-induced myocardial dysfunction
    DOI:  https://doi.org/10.1016/j.biopha.2023.115497
  40. Medicine (Baltimore). 2023 Sep 29. 102(39): e34693
    SGLT2 inhibitors among patients with heart failure with preserved ejection fraction: A meta-analysis of randomised controlled trials.
    Akash Jaiswal, Vikash Jaiswal, Song Peng Ang, Muhammad Hanif, Ananya Vadhera, Vibhor Agrawal, Tushar Kumar, Anagha M Nair, VamsikalyanReddy Borra, Vamsi Garimella, Angela Ishak, Zarghoona Wajid, David Song, Abdelrahman M Attia, Helen Huang, Victor Hugo Aguilera Alvarez, Abhigan Babu Shrestha, Monodeep Biswas.
       BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been recommended in the practice guidelines for the treatment of patients with heart failure with reduced ejection fraction; however, their effects among patients with preserved ejection fraction have been debatable.
    OBJECTIVE: We aim to evaluate the SGLT2 inhibitor effect among patients with heart failure with reduced ejection fraction, including DELIVER and EMPEROR-Preserved trials.
    METHODS: We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until August 30th, 2022. Statistical analysis was performed by calculating hazard ratio (HR) using the random effect model with a 95% confidence interval (CI) and probability value (P). Statistical significance was met if 95% CI does not cross numeric "1" and P < .05.
    RESULTS: Six studies with a total of 15,989 total patients were included in the final analysis. The mean age of patients enrolled in SGLT2 inhibitors and placebo was 69.13 and 69.37 years, respectively. The median follow-up duration was 2.24 years. SGLT2 inhibitors reduced composite cardiovascular mortality or first hospitalization for heart failure (HR, 0.80 [95% CI: 0.74-0.87], P < .001, I2 = 0%), heart failure hospitalization (HR, 0.74 [95% CI: 0.67-0.82], P < .001, I2 = 0%) compared with placebo. However, all-cause mortality (HR, 0.97 [95% CI: 0.89-1.06], P = .54, I2 = 0%) and cardiovascular mortality (HR, 0.96 [95% CI: 0.82-1.13), P = .66, I2 = 35.09%] were comparable between both groups.
    CONCLUSION: Our study finding shows that SGLT2 inhibitors significantly reduced the risk of first HF hospitalization or cardiovascular death and HF hospitalization; however, all-cause mortality was comparable between the groups.
    DOI:  https://doi.org/10.1097/MD.0000000000034693
  41. Int J Mol Sci. 2023 Sep 12. pii: 13977. [Epub ahead of print]24(18):
    The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases.
    Sylwia Szrok-Jurga, Jacek Turyn, Areta Hebanowska, Julian Swierczynski, Aleksandra Czumaj, Tomasz Sledzinski, Ewa Stelmanska.
      This review highlights the complex role of fatty acid β-oxidation in brain metabolism. It demonstrates the fundamental importance of fatty acid degradation as a fuel in energy balance and as an essential component in lipid homeostasis, brain aging, and neurodegenerative disorders.
    Keywords:  aging; beta-oxidation; brain; fatty acid metabolism; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms241813977
  42. Antioxidants (Basel). 2023 Aug 31. pii: 1696. [Epub ahead of print]12(9):
    Pitfalls of Mitochondrial Redox Signaling Research.
    Petr Ježek.
      Redox signaling from mitochondria (mt) to the cytosol and plasma membrane (PM) has been scarcely reported, such as in the case of hypoxic cell adaptation or (2-oxo-) 2-keto-isocaproate (KIC) β-like-oxidation stimulating insulin secretion in pancreatic β-cells. Mutual redox state influence between mitochondrial major compartments, the matrix and the intracristal space, and the cytosol is therefore derived theoretically in this article to predict possible conditions, when mt-to-cytosol and mt-to-PM signals may occur, as well as conditions in which the cytosolic redox signaling is not overwhelmed by the mitochondrial antioxidant capacity. Possible peroxiredoxin 3 participation in mt-to-cytosol redox signaling is discussed, as well as another specific case, whereby mitochondrial superoxide release is diminished, whereas the matrix MnSOD is activated. As a result, the enhanced conversion to H2O2 allows H2O2 diffusion into the cytosol, where it could be a predominant component of the H2O2 release. In both of these ways, mt-to-cytosol and mt-to-PM signals may be realized. Finally, the use of redox-sensitive probes is discussed, which disturb redox equilibria, and hence add a surplus redox-buffering to the compartment, where they are localized. Specifically, when attempts to quantify net H2O2 fluxes are to be made, this should be taken into account.
    Keywords:  H2O2 release into intracristal space; MnSOD; cytosolic H2O2 release; matrix H2O2 release; peroxiredoxins; redox buffers; redox signaling from mitochondria; redox-sensitive probes
    DOI:  https://doi.org/10.3390/antiox12091696
  43. Sci Rep. 2023 09 23. 13(1): 15922
    SGLT-2 inhibitors improve cardiovascular and renal outcomes in patients with CKD: a systematic review and meta-analysis.
    Thomas A Mavrakanas, Michael A Tsoukas, James M Brophy, Abhinav Sharma, Karim Gariani.
      The effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on cardiovascular and renal outcomes has not been systematically reviewed across baseline kidney function groups. We conducted a systematic review and meta-analysis of randomized control trials (RCTs) with SGLT-2 inhibitors in patients with and without CKD. We performed a PubMed/Medline search of randomized, placebo-controlled, event-driven outcome trials of SGLT-2 inhibitors versus active or placebo control in patients with and without diabetes from inception to November 2022. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 (PROSPERO registration CRD4202016054). The primary outcome was cardiovascular death. Secondary outcomes included hospitalization for heart failure, major adverse cardiovascular events, CKD progression, all-cause mortality, treatment discontinuation, and acute kidney injury (AKI). The relative risk (RR) was estimated using a random-effects model. Twelve RCTs were included in this meta-analysis (89,191 patients, including 38,949 with eGFR < 60 ml/min/1.73m2). Use of an SGLT-2 inhibitor in patients with CKD was associated with a lower incidence of cardiovascular death (RR 0.87; 95% CI 0.79-0.95) and of heart failure (RR 0.67; 95% CI 0.61-0.75), compared with placebo. Heart failure risk reduction with SGLT-2 inhibitors was larger among patients with CKD compared with patients without CKD (RR for the interaction 0.87, 95% CI 0.75-1.02, and p-value for interaction 0.08). SGLT-2 inhibitors were associated with a lower incidence of CKD progression among patients with pre-existing CKD: RR 0.77 (95% CI 0.68-0.88), compared with placebo. Among patients with CKD, a lower risk of AKI (RR 0.82; 95% CI 0.72-0.93) and treatment discontinuation was seen with SGLT-2 inhibitors compared with placebo. SGLT-2 inhibitors offer substantial protection against cardiovascular and renal outcomes in patients with CKD. These results strongly advocate in favor of using them in patients with CKD and keeping them as kidney function declines.
    DOI:  https://doi.org/10.1038/s41598-023-42989-z
  44. Int J Mol Sci. 2023 Sep 07. pii: 13782. [Epub ahead of print]24(18):
    Mitochondrial Dynamics and Insulin Secretion.
    Uma D Kabra, Martin Jastroch.
      Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria, which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence has been put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked to defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of molecular mechanisms controlling mitochondrial dynamics, their dysfunction in pancreatic β cells, and pharmaceutical agents targeting mitochondrial dynamic proteins, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110, and 15-oxospiramilactone (S3).
    Keywords:  diabetes; fission; fusion; glucose-stimulated insulin secretion; mitochondrial dynamics; pancreatic beta cell
    DOI:  https://doi.org/10.3390/ijms241813782
  45. Int J Mol Sci. 2023 Sep 08. pii: 13835. [Epub ahead of print]24(18):
    Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
    Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Cecilia Bucci, Emanuele Marzetti.
      Mitophagy is crucial for maintaining mitochondrial quality. However, its assessment in vivo is challenging. The endosomal-lysosomal system is a more accessible pathway through which subtypes of extracellular vesicles (EVs), which also contain mitochondrial constituents, are released for disposal. The inclusion of mitochondrial components into EVs occurs in the setting of mild mitochondrial damage and during impairment of lysosomal function. By releasing mitochondrial-derived vesicles (MDVs), cells limit the unload of mitochondrial damage-associated molecular patterns with proinflammatory activity. Both positive and negative effects of EVs on recipient cells have been described. Whether this is due to the production of EVs other than those containing mitochondria, such as MDVs, holding specific biological functions is currently unknown. Evidence on the existence of different MDV subtypes has been produced. However, their characterization is not always pursued, which would be relevant to exploring the dynamics of mitochondrial quality control in health and disease. Furthermore, MDV classification may be instrumental in understanding their biological roles and promoting their implementation as biomarkers in clinical studies.
    Keywords:  damage-associated molecular patterns (DAMPs); endosomal–lysosomal system; exosomes; extracellular vesicles; inflammation; mitochondrial DNA; mitochondrial quality control; mitophagy; mitovesicles; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241813835
  46. mBio. 2023 Sep 27. e0198723
    Butyrate protects against MRSA pneumonia via regulating gut-lung microbiota and alveolar macrophage M2 polarization.
    Yan Zhao, Haoming Sun, Yiwei Chen, Qiang Niu, Yiting Dong, Mei Li, Ye Yuan, Xiaojun Yang, Qingzhu Sun.
      Methicillin-resistant Staphylococcus aureus (MRSA) is a well-recognized cause of bacterial pneumonia in general. The gut microbiota and their metabolic byproducts act as important modulators of the gut-lung axis. Our investigation indicates a significant reduction in the abundance of butyrate producer unclassified_f__Lachnospiraceae within the lung and gut microbiota of MRSA-infected mice, as well as a significant decrease in the levels of butyrate in gut and serum. Additionally, supplementary sodium butyrate (NaB) significantly reduces bacteria colonization in the lung, suppresses pro-inflammatory cytokines expression, and enhances lung tissue morphology in MRSA-treated mice. The results of high-throughput 16S rDNA sequencing demonstrate that NaB reshapes the gut and lung microbiota by drastically reducing the abundance of potential pathogenic bacteria in the gut and cell motility-related bacteria in the lung, which are induced by MRSA. Moreover, NaB treatment augments the gut and circulating butyrate levels. Mechanistically, NaB promotes signal transducer and activator of transcription 1 (STAT1) acetylation and inhibits dimer STAT1 phosphorylation by reducing the binding of histone deacetylase 3 to STAT1, thereby altering alveolar macrophage polarization toward the M2 phenotype. Collectively, our findings suggest that NaB exerts a preventative effect against MRSA-induced pneumonia by enhancing the gut-lung microbiota and promoting macrophage polarization toward an anti-inflammatory M2 phenotype. The prophylactic administration of NaB emerges as a promising strategy for combating MRSA pneumonia. IMPORTANCE Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) continues to carry a high burden in terms of mortality. With the roles of gut microbiota in mediating lung diseases being gradually uncovered, the details of the molecular mechanism of the "gut-lung axis" mediated by beneficial microorganisms and small-molecule metabolites have gradually attracted the attention of researchers. However, further studies are still necessary to determine the efficacy of microbial-based interventions. Our findings indicate that sodium butyrate (NaB) alleviates MRSA-induced pulmonary inflammation by improving gut-lung microbiota and promoting M2 polarization of alveolar macrophages. Therefore, the preventive administration of NaB might be explored as an effective strategy to control MRSA pneumonia.
    Keywords:  M2 polarization; MRSA pneumonia; alveolar macrophage; gut microbiota; lung microbiota; sodium butyrate
    DOI:  https://doi.org/10.1128/mbio.01987-23
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