bims-kimdis 2025-02-16 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–02–16
fourteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic diet induces an inflammatory reactive astrocytes phenotype reducing glioma growth.
Mitigating muscle loss during weight loss: can nutritional ketosis make a difference? A call for more research.
Association between circulating ketone bodies and subclinical atherosclerosis: Multi-Ethnic Study of Atherosclerosis (MESA).
The Alleviative Effect of Sodium Butyrate on Dexamethasone-Induced Skeletal Muscle Atrophy.
Vitamin C protects against doxorubicin induced skeletal muscle atrophy: Role of oxidative stress.
The Role of Myokines in Liver Diseases.
NLRP3 inflammasome in health and disease (Review).
Exercise alters molecular profiles of inflammation and substrate metabolism in human white adipose tissue.
Exogenous hydrogen sulfide improves non-alcoholic fatty liver disease by inhibiting endoplasmic reticulum stress/NLRP3 inflammasome pathway.
Effects of time-restricted eating and resistance training on skeletal muscle tissue quantity, quality and function in postmenopausal women with overweight or obesity: A study protocol.
Potential Role of High-Intensity Interval Training-Induced Increase in Humanin Levels for the Management of Type 2 Diabetes.
The effects of acute bouts of exercise in fasted vs. fed states on glucose and lipid metabolism in healthy adults: A systematic review and meta-analysis of randomized clinical trials.
Mitochondrial respiratory analysis of cryopreserved PBMCs isolated from human blood.
Group-mediated exercise for chronic conditions: an urgent need for implementation and scale-up.

Cell Mol Life Sci. 2025 Feb 08. 82(1): 73

Ketogenic diet induces an inflammatory reactive astrocytes phenotype reducing glioma growth.

Maria Rosito, Javeria Maqbool, Alice Reccagni, Micol Mangano, Tiziano D'Andrea, Arianna Rinaldi, Giovanna Peruzzi, Beatrice Silvestri, Alessandro Rosa, Flavia Trettel, Giuseppina D'Alessandro, Myriam Catalano, Sergio Fucile, Cristina Limatola.

  The use of a ketogenic diet (KD) in glioma is currently tested as an adjuvant treatment in standard chemotherapy regimens. The metabolic shift induced by the KD leads to the generation of ketone bodies that can influence glioma cells and the surrounding microenvironment, but the mechanisms have not yet been fully elucidated. Here, we investigated the potential involvement of glial cells as mediators of the KD-induced effects on tumor growth and survival rate in glioma-bearing mice. Specifically, we describe that exposing glioma-bearing mice to a KD or to β-hydroxybutyrate (β-HB), one of the main KD metabolic products, reduced glioma growth in vivo, induced a pro-inflammatory phenotype in astrocytes and increased functional glutamate transporters. Moreover, we described increased intracellular basal Ca2+ levels in GL261 glioma cells treated with β-HB or co-cultured with astrocytes. These data suggest that pro-inflammatory astrocytes triggered by β-HB can be beneficial in counteracting glioma proliferation and neuronal excitotoxicity, thus protecting brain parenchyma.

Keywords:  Astrocytes; Astrogliosis; Glioma; Ketogenic diet; Microglia; Pro-inflammatory astrocytes; β-HB

DOI:  https://doi.org/10.1007/s00018-025-05600-4
Obesity (Silver Spring). 2025 Feb 13.

Mitigating muscle loss during weight loss: can nutritional ketosis make a difference? A call for more research.

Shaminie J Athinarayanan, Jeff S Volek.

Weight loss (WL) has an important role in managing obesity and type 2 diabetes, but preserving lean body mass (LBM) during WL is essential for maintaining muscle function and metabolic health. Significant WL with incretin mimetic-based therapies, similar to bariatric surgery, raises concerns regarding disproportionate LBM loss, which may lead to physical frailty. Recent analyses have suggested that high adherence to a ketogenic diet may mitigate LBM loss while improving physical function, even with substantial WL. However, more research is needed to understand the mechanisms behind LBM preservation in nutritional ketosis and the role of other lifestyle interventions. Future studies of pharmacological, surgical, and lifestyle-driven WL interventions should also assess LBM, physical function, and frailty. Research in this area is essential for developing strategies that optimize patient outcomes, especially for those who are considering their options for the treatment of obesity.

DOI: https://doi.org/10.1002/oby.24235
J Cardiovasc Comput Tomogr. 2025 Feb 08. pii: S1934-5925(25)00041-3. [Epub ahead of print]

Association between circulating ketone bodies and subclinical atherosclerosis: Multi-Ethnic Study of Atherosclerosis (MESA).

Parag Anilkumar Chevli, Alexander C Razavi, Joni K Evans, Richard Kazibwe, Margery A Connelly, Sadiya S Khan, Ambarish Pandey, Matthew C Tattersall, James H Stein, Michael D Shapiro.

DOI: https://doi.org/10.1016/j.jcct.2025.02.001
Cell Biol Int. 2025 Feb 12.

The Alleviative Effect of Sodium Butyrate on Dexamethasone-Induced Skeletal Muscle Atrophy.

Xingchen Zhao, Mingqiang Zhu, Zifan Wang, Ming Gao, Yifei Long, Shuo Zhou, Wei Wang.

  Skeletal muscle mass is significantly negatively regulated by glucocorticoids. Following glucocorticoid administration, the balance between protein synthesis and breakdown in skeletal muscle is disrupted, shifting towards a predominance of catabolic metabolism. Short-chain fatty acids like sodium butyrate have been found to regulate inflammatory reactions and successively activate signaling pathways. The preventive benefits of sodium butyrate against dexamethasone-induced skeletal muscle atrophy and myotube atrophy models were examined in this work, and the underlying mechanism was clarified. A total of 32 6-week-old C57BL/6 inbred male mice were randomly assigned to one of four groups and treated with dexamethasone to induce muscle atrophy and sodium butyrate. We found that sodium succinate alleviated dexamethasone-induced myotube atrophy in the myotube atrophy model by lowering the gene expression of two E3 ubiquitin ligases, Atrogin-1 and MURF1, and activating the AKT/mTOR signaling pathway. Pertussis toxin reversed this effect, indicating that G protein-coupled receptors were involved in sodium butyrate's action as a mediator. Additionally, pre-treatment with sodium butyrate lowered weight and muscle mass loss in a mouse model of skeletal muscle atrophy, dramatically decreased the MURF1 gene expression and decreased the nuclear translocation of the glucocorticoid receptor. In conclusion, this study shows that sodium butyrate inhibits the expression of atrophy genes, thus preventing the breakdown of proteins and the loss of muscle mass, while also inhibiting weight loss, in animal models.

Keywords:  dexamethasone; skeletal muscle atrophy; sodium butyrate

DOI:  https://doi.org/10.1002/cbin.70003
Can J Physiol Pharmacol. 2025 Feb 12.

Vitamin C protects against doxorubicin induced skeletal muscle atrophy: Role of oxidative stress.

Antonio Viana do Nascimento Filho, Filipe Fernandes Stoyell-Conti, Akolkar Gauri, Lara Susan Silva Lima, Nathalia Bernardes, Maria Claudia Irigoyen, Pawan Singal, Kátia De Angelis, Danielle da Silva Dias.

Doxorubicin is known for its significant cardiotoxicity, driven in part by elevated oxidative stress (OS). Furthermore, preclinical models have demonstrated that doxorubicin induces skeletal muscle atrophy. While vitamin C has been recognized as a valuable pharmacological intervention for mitigating cardiac toxicity, its impact on doxorubicin-induced skeletal muscle atrophy is still to be determined. Therefore, this study aimed to investigate the effects of vitamin C on the skeletal muscle of rats subjected to doxorubicin exposure. Indeed, doxorubicin led to a reduction in body weight and gastrocnemius muscle weight. It also increased H2O2, protein oxidation and lipid peroxidation in the gastrocnemius. On the other hand, vitamin C was able to prevent the loss in skeletal muscle mass, as well as, the increase in markers of oxidative stress. In addition, negative correlations between gastrocnemius muscle mass and markers of cell damage were found. In conclusion, vitamin C emerges as a protective agent against doxorubicin-induced skeletal muscle atrophy and oxidative stress. This suggests its potential application as a prophylactic measure for patients undergoing doxorubicin treatment. Keywords: Doxorubicin, Vitamin C, Oxidative Stress, Skeletal Muscle.

DOI: https://doi.org/10.1139/cjpp-2024-0154
Int J Mol Sci. 2025 Jan 25. pii: 1043. [Epub ahead of print]26(3):

The Role of Myokines in Liver Diseases.

Hiroki Nishikawa, Soo Ki Kim, Akira Asai.

  Myokine is a general term for hormones, peptides, and other substances secreted by skeletal muscle. Myokine has attracted much attention in recent years as a key substance for understanding the mechanism of "exercise and health". Skeletal muscle accounts for about 40% of the total human weight and is now recognized as an endocrine organ that produces myokines, which have physiological activity. Representative myokines include IL-6, myostatin, irisin, brain-derived neurotropic factor, fibroblast growth factor-21, and decorin. On the other hand, sarcopenia, defined by quantitative and qualitative loss of skeletal muscle, is a condition that has received much attention in recent years because of its close correlation with prognosis. In patients with chronic liver disease (CLD), sarcopenia is a common complication. Mechanisms underlying sarcopenia in CLD patients have been reported to involve protein-energy malnutrition, which is characteristic of patients with cirrhosis, signaling involved in protein synthesis and degradation, myokines such as myostatin and decorin, the ubiquitin-proteasome pathway, sex hormones such as testosterone, dysbiosis, and insulin resistance, etc., in addition to aging. Each of these pathological conditions is thought to be intricately related to each other, leading to sarcopenia. This review will summarize the relationship between CLD and myokines.

Keywords:  IL-6; liver; muscle–gut–liver axis; myokine; myostatin; sarcopenia

DOI:  https://doi.org/10.3390/ijms26031043
Int J Mol Med. 2025 03;pii: 48. [Epub ahead of print]55(3):

NLRP3 inflammasome in health and disease (Review).

Haoran Wang, Li Ma, Weiran Su, Yangruoyu Liu, Ning Xie, Jun Liu.

  Activation of inflammasomes is the activation of inflammation‑related caspase mediated by the assembly signal of multi‑protein complex and the maturity of inflammatory factors, such as IL‑1β and IL‑18. Among them, the Nod‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied type of inflammatory corpuscle at present, which is involved in the occurrence and development of numerous human diseases. Therefore, targeting the NLRP3 inflammasome has become the focus of drug development for related diseases. In this paper, the research progress of the NLRP3 inflammasome in recent years is summarized, including the activation and regulation of NLRP3 and its association with diseases. A deep understanding of the regulatory mechanism of NLRP3 will be helpful to the discovery of new drug targets and the development of therapeutic drugs.

Keywords:  NLRP3 inflammasome; cell organ; disease; gene therapy; inhibitor; ion flow; metabolic regulation

DOI:  https://doi.org/10.3892/ijmm.2025.5489
Am J Physiol Endocrinol Metab. 2025 Feb 11.

Exercise alters molecular profiles of inflammation and substrate metabolism in human white adipose tissue.

Maria F Pino, Pieter Dijkstra, Katie L Whytock, Cheehoon Ahn, Gongxin Yu, James A Sanford, Josh Hansen, Chelsea Hutchinson, Marina A Gritsenko, Paul D Piehowski, Joshua N Adkins, Elvis A Carnero, Stuart C Sealfon, Elena Zaslavsky, Venugopalan Nair, Steven R Smith, Lauren M Sparks.

  White adipose tissue (WAT) plays a significant role in whole-body energy homeostasis, and its excess typifies obesity. In addition to WAT quantity, perturbations in the basic cellular processes of WAT (i.e. quality) are also associated with obesity and metabolic disease. Exercise training alleviates metabolic perturbations associated with obesity; however, the underlying molecular mechanisms that drive these metabolic adaptations in WAT are not well described. Abdominal subcutaneous WAT biopsies were collected after an acute bout of exercise (1 day after) at baseline and following three weeks of supervised aerobic training in sedentary overweight women (n = 6) without alterations in body weight and fat mass. RNA-seq, global proteomics, and phosphoproteomics in WAT revealed training-induced changes in 1527 transcripts, 154 proteins, and 144 phosphosites, respectively. Training decreased abundance of transcripts and proteins involved in inflammation and components of the extracellular matrix (ECM) and increased abundance of transcripts and proteins related with fatty acid esterification and lipolysis. In summary, short-term aerobic training significantly reduces local inflammation and increases lipid metabolism in WAT of sedentary overweight women - independent of alterations in body and fat mass. As such, some of the health benefits of aerobic training may occur through molecular alterations in WAT (i.e. enhanced quality) rather than a sheer reduction in WAT quantity.

Keywords:  ECM; adipose tissue; inflammation; metabolism; training

DOI:  https://doi.org/10.1152/ajpendo.00339.2024
Mol Cell Biochem. 2025 Feb 08.

Exogenous hydrogen sulfide improves non-alcoholic fatty liver disease by inhibiting endoplasmic reticulum stress/NLRP3 inflammasome pathway.

Xiaodi Fu, Qi Zhang, Yuhang Chen, Ying Li, Honggang Wang.

  Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, and its exact pathogenesis has not been fully studied. Hydrogen sulfide (H2S) is the third gas signaling molecule discovered in mammals, following nitric oxide and carbon monoxide. It has the effects of anti-inflammation, anti-apoptosis, and so on, thereby playing an important role in many diseases. However, the role and mechanism of exogenous H2S in NAFLD are not fully understood. In this study, we constructed in vitro and in vivo NAFLD models by feeding mice a high-fat diet and stimulating hepatocytes with palmitic acid, respectively, to investigate the improvement effect and mechanism of exogenous H2S on NAFLD. The results showed that NaHS (a donor of H2S) treatment alleviated lipid accumulation, inflammation, apoptosis and pyroptosis, and downregulated endoplasmic reticulum (ER) stress and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NRRP3) inflammasome in NAFLD. The activation of NLRP3 inflammasome weakened NaHS improvement of NAFLD, indicating that exogenous H2S ameliorated NAFLD by inhibiting NLRP3 inflammasome-mediated lipid synthesis, inflammation, apoptosis and pyroptosis. Similarly, the activation of ER stress weakened NaHS improvement of NAFLD and NaHS inhibition of NLRP3 inflammasome, indicating that exogenous H2S suppressed NLRP3 inflammasome by downregulating ER stress, thus improving NAFLD. Additionally, the protein expressions of NLRP3 and cleaved caspase-1 were downregulated after inhibiting the reactive oxygen species (ROS)/extracellular signal-regulated kinases (ERK) and ROS/thioredoxin-interacting protein (TXNIP) pathways, indicating that ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways. In conclusion, our results indicated that exogenous H2S inhibited NLRP3 inflammasome-mediated hepatocytes inflammation, lipid synthesis, apoptosis and pyroptosis by downregulating ER stress, thereby improving NAFLD; Furthermore, ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways in NAFLD. ER stress/NLRP3 inflammasome is expected to become a new target of H2S for treating NAFLD.

Keywords:  Endoplasmic reticulum stress; Hydrogen sulfide; NLRP3 inflammasome; Non-alcoholic fatty liver disease; Pyroptosis

DOI:  https://doi.org/10.1007/s11010-025-05220-3
Nutr Metab Cardiovasc Dis. 2024 Dec 30. pii: S0939-4753(24)00478-2. [Epub ahead of print] 103844

Effects of time-restricted eating and resistance training on skeletal muscle tissue quantity, quality and function in postmenopausal women with overweight or obesity: A study protocol.

V M Alfaro-Magallanes, M Medrano, J Echarte, M Osés, C Izquierdo, M De Caridad-Concepción, A Galbete, F Idoate, A Zugasti, M E Petrina, E Goñi, M J Ribelles, M Amasene, L Arenaza, C Tejada, E Elejalde, U Azcarate, O Ruiz-Sarrias, O Sayar-Beristain, A García-Ramos, C Martínez-Labari, C Armendariz-Brugos, A Villanueva, J R Ruiz, R Cabeza, I Labayen.

   BACKGROUND & AIMS: Time-restricted eating (TRE) shows promise for weight loss and improving menopause-related body composition and cardiometabolic health, but its effects on skeletal muscle tissue (SMT) in postmenopausal women are unknown. This study investigates the effects of three weight loss interventions over 12 weeks on SMT quantity, quality, function, and cardiometabolic health in postmenopausal women with overweight/obesity, with effects persistence evaluated at a 12-month follow-up.
METHODS AND RESULTS: In this randomized controlled trial, 78 postmenopausal women (50-65 years; BMI 25-40 kg/m2; sedentary lifestyle; eating window ≥12 h/day; no severe metabolic impairments) will be recruited. Participants will be randomly assigned to one of three groups for 12 weeks: TRE, TRE + resistance training, or CR + resistance training. The TRE groups will reduce their eating window to 8 h and receive nutritional advice to adhere to a Mediterranean diet. The CR group will follow a personalized hypocaloric diet (-500 kcal/day). Resistance training groups will perform supervised resistance training 3 times/week.
PRIMARY OUTCOME: Change in SMT quantity measured by MRI at baseline and after 12 weeks.
SECONDARY OUTCOMES: intermuscular adipose tissue (IMAT), strength, power, body weight and composition, and cardiometabolic risk factors.
CONCLUSION: This study will illustrate the effects of TRE and TRE combined with resistance exercise compared with the currently recommended obesity-lifestyle treatment on SMT quantity, quality, function, and cardiometabolic markers. The results will offer insights into dietary strategies to combat obesity and metabolic diseases without increasing sarcopenia risk in postmenopausal women, a sparsely studied and particularly affected population.

Keywords:  Diet; Intermittent fasting; Intermuscular adipose tissue; Menopause; Obesity; Sarcopenia

DOI:  https://doi.org/10.1016/j.numecd.2024.103844
J Cell Mol Med. 2025 Feb;29(3): e70396

Potential Role of High-Intensity Interval Training-Induced Increase in Humanin Levels for the Management of Type 2 Diabetes.

Afsaneh Soltany, Farhad Daryanoosh, Firouzeh Gholampour, Najmeh Sadat Hossini, Kayvan Khoramipour.

  This study investigated the effect of 8 weeks of high-intensity interval training (HIIT) on oxidative stress, inflammation, and apoptosis in rats with type 2 diabetes (T2D), focusing on the role of the Humanin (HN). In this study, 28 male Wistar rats were assigned to one of four groups: healthy control (CO), diabetes control (T2D), exercise (EX), and diabetes + exercise (T2D + EX). After diabetes induction (2-month high-fat diet and injection of 35 mg/kg streptozotocin), the animals in the EX and T2D + EX groups underwent an 8-week HIIT protocol (4-10, interval of 80%-100% of maximum speed). HOMA-IR, fasting blood glucose, and HN levels were measured in the serum. The expression of HN, Bax, Bcl-2, CAT, GPx, MDA, TNFα, and IL-10 was measured in the soleus muscle. Our results showed that the serum level of HN and the muscle levels of IL-10, SOD, CAT, and Bax were higher in the T2D + EX group than in the T2D group. However, the HOMA-IR index and the muscle levels of MDA, TNFα, and Bcl-2 were lower in the T2D + EX group than in the T2D group. Muscle levels of HN and GPx showed no significant difference between the T2D + EX and T2D groups. The result of Pearson analysis showed a significant correlation between HN and MDA, SOD, Bax and Bcl-2. This study provides evidence that there is a correlation between serum Humanin levels and HIIT. HIIT benefits T2D rats by reducing inflammation and oxidative stress. Given Humanin's established involvement in inflammation and oxidative stress, it is possible that the benefits of HIIT on T2D rats are mediated by humanin.

Keywords:  HIIT; apoptosis; humanin; inflammation; oxidative stress

DOI:  https://doi.org/10.1111/jcmm.70396
Clin Nutr ESPEN. 2025 Feb 05. pii: S2405-4577(25)00062-2. [Epub ahead of print]66 320-331

The effects of acute bouts of exercise in fasted vs. fed states on glucose and lipid metabolism in healthy adults: A systematic review and meta-analysis of randomized clinical trials.

Fatemeh Kazeminasab, Pegah Rafiee, Maryam Miraghajani, Heitor O Santos, Michael E Symonds, Sara K Rosenkranz.

   AIMS: Exercise while fasted is often promoted as beneficial for lipid metabolism, as it may confer superior metabolic adaptations compared with exercise performed in the fed state. The aim of this systematic review and meta-analysis was to determine the effects of acute exercise in fasted versus fed states on glucose and lipid metabolism in healthy adults.
DATA EXTRACTION: A systematic review and meta-analysis was performed by searching PubMed, Scopus, and Web of Science databases up to July 2023, for randomized clinical trials that determined the effects of exercise in fasted vs. fed states on glucose and lipid metabolism (serum glucose, insulin, triacylglycerol, free fatty acid (FFA) concentrations, and respiratory exchange ratio (RER)) in healthy adults. Meta-analyses were conducted to determine weighted mean differences (WMD) and 95 % confidence intervals.
ANALYSIS: The current meta-analysis included 28 studies with a total sample of 302 healthy adults, with exercise durations ranging from 36 to 150 min. Acute exercise performed while fasted was associated with significant increases from pre- to post-exercise in fasted serum glucose [WMD = 0.263 mmol/L, p = 0.009] and insulin [WMD = 8.84 mU/mL, p = 0.001], and significantly decreases in FFA [WMD = -0.121 mmol/L, p = 0.019] when compared with exercise in the fed state. However, no significant differences were reported for changes in triacylglycerol or RER from pre- to post-exercise when comparing fasted vs. fed states.
CONCLUSION: When compared with exercise in the fed state, exercise performed while fasted was associated with larger increases in glucose and insulin levels, along with larger decreases in FFA levels. Thus, our results do not suggest that acute fasted exercise is necessarily better for glucose or lipid metabolism when compared with exercise performed in the fed state. It is possible, albeit unlikely, that acute bouts of exercise performed while fasted may result in some degree of metabolic impairment.

Keywords:  Carbohydrate; Energy metabolism; Exercise training; Glucose; Lipid

DOI:  https://doi.org/10.1016/j.clnesp.2025.02.002
Cryobiology. 2025 Feb 13. pii: S0011-2240(25)00018-5. [Epub ahead of print]118 105212

Mitochondrial respiratory analysis of cryopreserved PBMCs isolated from human blood.

C Payne, E Louw, N Baines, B Botha, C Lombard, B Allwood, G Maarman.

  Mitochondrial bioenergetics of PBMCs have been linked with several factors that contribute to a better understanding of several human diseases. Due to the complex logistics of clinical studies, samples are often cryopreserved for later analysis. Current data on whether cryopreservation negatively affects the mitochondrial function of PBMCs is discrepant. We isolated and cryopreserved peripheral blood mononuclear cells (PBMCs) from human whole blood and tested mitochondrial function using a substrate-uncoupler-inhibitor-titration protocol on the Oroboros instrument. After three months of storage in a cryopreservation medium (at -80 °C), several aspects of mitochondrial bioenergetics were measured. We demonstrate that cryopreservation did not adversely affect mitochondrial parameters (routine, leak, complex-I linked OXPHOS, cytochrome-c response, ETS capacity, the contributions of the N and S-pathways to ETS, ROX, complex-IV activity and mitochondrial coupling). Therefore, after three months of cryopreservation at -80 °C, human PBMC-mitochondria were fully coupled and functional. Therefore, clinical studies may cryopreserve PBMCs for later mitochondrial analyses.

Keywords:  Cryopreserved PBMCs; Mitochondrial respiration; Oroboros

DOI:  https://doi.org/10.1016/j.cryobiol.2025.105212
Br J Sports Med. 2025 Feb 11. pii: bjsports-2024-109318. [Epub ahead of print]

Group-mediated exercise for chronic conditions: an urgent need for implementation and scale-up.

Tim Rees, Mark R Beauchamp, Mark Stevens, Matthew Low, Thomas W Wainwright.



Keywords:  Exercise; Health; Sports medicine

DOI:  https://doi.org/10.1136/bjsports-2024-109318