bims-kimdis 2025-03-09 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–03–09
twenty-one papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic diet and microRNAs: focus on cognitive function.
The Impact of Ketogenic Nutrition on Obesity and Metabolic Health: Mechanisms and Clinical Implications.
Therapeutic Ketosis for Heart Failure: A State-of-the-Art-Review.
Beta-Hydroxybutyrate Attenuates Bronchial Smooth Muscle Pro-Inflammatory Cytokine Production.
Multisystem impact of altering acid load of ingested exogenous ketone supplements at rest in young healthy adults.
Effects of Ketone Ester Supplementation on Cognition and Appetite in Individuals with and Without Metabolic syndrome: A Randomized Trial.
D-BHB supplementation before moderate-intensity exercise suppresses lipolysis and selectively blunts exercise-induced long-chain acylcarnitine increase in pilot study of patients with long-chain fatty acid oxidation disorders.
Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.
Modulation of M1 and M2 macrophage polarization by metformin: Implications for inflammatory diseases and malignant tumors.
Loteprednol etabonate alleviates NLRP3 inflammasome-associated inflammatory diseases in mice by suppressing the transcription of IL-1β.
Successful application of dietary ketogenic metabolic therapy in patients with glioblastoma: a clinical study.
Vitamin D and its receptor in skeletal muscle are associated with muscle disease manifestation, lipid metabolism and physical fitness of patients with myositis.
Long-term leucine supplementation increases body weight in goats by controlling appetite and muscle protein synthesis under protein-restricted conditions.
Body Weight Changes During Ramadan Intermittent Fasting: A Cross-Sectional Study of Healthy Adults in Turkey.
Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts.
Exploring NLRP3-related phenotypic fingerprints in human macrophages using Cell Painting assay.
Alternate-day fasting differentially affects body composition, metabolic and immune response to fasting in male rats exposed to early-life adversity: Modulatory role of cafeteria diet.
High-intensity interval training alleviates ethanol-induced renal damage: A study on inflammation, oxidative stress, and histopathological changes in rats.
Impact of Short-Chain Fatty Acids on Glucose, Fatty Acid and Leucine Metabolism in Primary Human Myotubes.
Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.
Dodging mitochondrial mislocalization.

Front Nutr. 2025 ;12 1545832

Ketogenic diet and microRNAs: focus on cognitive function.

Diana Marisol Abrego-Guandique, Erika Cione, Maria Cristina Caroleo, Diego A Bonilla, Roberto Cannataro.

  Cognition is a mental process of understanding and learning driven by memory. Recent advances in molecular biology and neuroscience have revealed a fascinating interplay between cognitive function and microRNAs (miRNAs). The ketogenic diet (KD) is a low-carbohydrate, high-fat, and adequate-protein diet that triggers the synthesis of ketone bodies, establishing ketosis. Recent and accumulating studies on human and animal models have shown that the KD benefits neurodegenerative diseases, where cognition is affected. The KD can also modulate miRNAs, molecules that are dysregulated in the brains of individuals with Alzheimer's disease, where cognition is lost. In this mini-review, we provide an overview of the function of miRNAs in neurodevelopment and cognition. We also explore how the KD in human studies can enhance cognitive function and highlight the protective role of microRNAs in neurological conditions.

Keywords:  biomarker; cognitive function; ketogenic diet; ketone bodies; microRNAs

DOI:  https://doi.org/10.3389/fnut.2025.1545832
Nutr Rev. 2025 Feb 26. pii: nuaf010. [Epub ahead of print]

The Impact of Ketogenic Nutrition on Obesity and Metabolic Health: Mechanisms and Clinical Implications.

Marta Biesiekierska, Maura Strigini, Agnieszka Śliwińska, Luciano Pirola, Aneta Balcerczyk.

  The ketogenic diet (KD) has recently gained increasing popularity. This high-fat, adequate-protein, and carbohydrate-poor eating pattern leads to nutritional ketosis. The KD has long been known for its antidiabetic and antiepileptic effects and has been used therapeutically in these contexts. Recently, the KD, due to its effectiveness in inducing weight loss, has also been proposed as a possible approach to treat obesity. Likewise, a KD is currently explored as a supporting element in the treatment of obesity-associated metabolic disorders and certain forms of cancer. Here, we discuss the metabolic and biochemical mechanisms at play during the shift of metabolism to fatty acids and fatty acid-derived ketone bodies as main fuel molecules, in the substitution of carbohydrates, in ketogenic nutrition. Different sources of ketone bodies and KDs as alternatives to glucose and carbohydrates as main energy substrates are discussed, together with an attempt to weigh the benefits and risks posed by the chronic use of a KD in the context of weight loss, and also considering the molecular effects that ketone bodies exert on metabolism and on the endocrine system.

Keywords:  beta-hydroxybutyrate; inflammatory response; ketogenic diet; ketone bodies; lipid metabolism; obesity

DOI:  https://doi.org/10.1093/nutrit/nuaf010
J Card Fail. 2025 Mar 03. pii: S1071-9164(25)00101-0. [Epub ahead of print]

Therapeutic Ketosis for Heart Failure: A State-of-the-Art-Review.

Nandan Kodur, Christopher Nguyen, W H Wilson Tang.

  Heart failure is characterized by an energy-deprived heart, and in recent years it has been found that the failing heart increases ketone body oxidation to meet its energy demands. Accumulating evidence suggests that this metabolic adaptation is cardioprotective, suggesting that interventions that boost blood ketone levels could aid the failing heart. Indeed, multiple small clinical trials with short-term follow up have demonstrated that supplying the failing heart with exogenous ketone bodies may improve myocardial function across various manifestations of heart failure. As such, therapeutic ketosis, which is a metabolic state in which blood ketone levels are mildly elevated, could have great potential to ameliorate heart failure. Therapeutic ketosis can be achieved endogenously via exercise or dietary practices, exogenously via supplementation with ketone bodies, or pharmacologically via treatment with a sodium-glucose cotransporter-2 inhibitor. Although ketosis-inducing practices cannot be routinely recommended to patients with heart failure at this time due to a lack of robust data regarding the long-term benefits and risks, anecdotal evidence suggests that some patients have begun to adopt ketosis-inducing practices, so it is important for clinicians to be aware of how to optimally manage patients who are in therapeutic ketosis. In this review, we discuss myocardial ketone metabolism in heart failure, the current evidence for therapeutic ketosis in patients with heart failure, a framework to distinguish between therapeutic ketosis and the pathologic state of ketoacidosis, and practical considerations for managing patients adhering to ketosis-inducing practices.

Keywords:  heart failure; ketone bodies; ketosis; therapeutic ketosis

DOI:  https://doi.org/10.1016/j.cardfail.2025.01.028
bioRxiv. 2025 Feb 20. pii: 2025.02.19.639048. [Epub ahead of print]

Beta-Hydroxybutyrate Attenuates Bronchial Smooth Muscle Pro-Inflammatory Cytokine Production.

V Amanda Fastiggi, Madeleine M Mank, Matthew E Poynter.

Asthma is a common airway condition causing breathing difficulties due to reversible airflow obstruction. It often affects obese individuals, with symptoms triggered by environmental factors that induce immune responses, leading to inflammation and bronchoconstriction. Bronchial smooth muscle (BSM) plays a central role in airway narrowing, driven by type 2 immune responses involving cytokines like IL-4, IL-5, and IL-13, along with leukocytes including eosinophils and type 2 T-helper cells. These responses cause structural changes such as fibrosis and airway thickening, while BSM cells worsen asthma by releasing pro-inflammatory cytokines in response to allergens, microbial signals, or inflammatory cytokines from other cells. While current treatments manage asthma in most patients, alternative therapies are needed for difficult-to-treat cases, particularly prevalent in obese, allergic individuals. Emerging research suggests that therapeutic ketosis, induced by dietary changes or ketone supplementation, may reduce airway hyperresponsiveness and inflammation. The primary ketone body, β-hydroxybutyrate (BHB), produced during carbohydrate scarcity, acts via cell-surface receptors and transporters, potentially mitigating asthma symptoms. Weight loss and caloric restriction increase ketone levels, correlating with reduced inflammation and improved asthma outcomes. We hypothesized that β-hydroxybutyrate (BHB) reduces bronchoconstriction and inflammation in asthma by targeting bronchial smooth muscle. Using human bronchial smooth muscle cells (HBSMC) in vitro, we demonstrate herein that BHB suppresses IL-1β-induced pro-inflammatory cytokine production through Free Fatty Acid Receptor 3 (FFAR3) activation. These findings suggest that bronchial smooth muscle is a key target of therapeutic ketosis, supporting BHB's potential benefits in preclinical asthma models.

DOI: https://doi.org/10.1101/2025.02.19.639048
Am J Physiol Regul Integr Comp Physiol. 2025 Mar 01. 328(3): R386-R395

Multisystem impact of altering acid load of ingested exogenous ketone supplements at rest in young healthy adults.

Tyler S McClure, Jeffrey D Buxton, Brendan Egan, Emma Plank, Makenna Isles, Dana L Ault, Philip J Prins, Andrew P Koutnik.

  Disruptions to acid-base are observed in extreme environments as well as respiratory and metabolic diseases. Exogenous ketone supplements (EKSs) have been proposed to mitigate these processes and provide therapeutic benefits by altering acid-base balance and metabolism, but direct comparison of various forms of EKS is lacking. Twenty healthy participants (M/F: 10/10; age: 20.6 ± 2.0 yr, height: 1.72 ± 0.08 m, body mass: 67.9 ± 10.2 kg) participated in a single-blind, randomized crossover design comparing ingestion of the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-βHB) ketone monoester (KME), KME + sodium bicarbonate (KME + BIC), an R-βHB ketone salt (KS), and a flavor-matched placebo. Acid-base balance, blood R-βHB, glucose and lactate concentrations, blood gases, respiratory gas exchange, autonomic function, and cognitive performance were assessed at baseline and various timepoints for up to 120 min after ingestion. Compared with placebo (PLA), blood R-βHB concentrations were elevated in each EKS condition (∼2-4 mM; P < 0.01), and blood glucose concentrations were lower. Blood pH was lower in KME (-0.07 units), and higher in KS and KME + BIC (+0.05 units), compared with PLA (all P < 0.05). Heart rate was elevated, and autonomic function was altered in KME + BIC. There were no differences between conditions for blood gases, respiratory gas exchange, blood pressure, or cognitive performance. Exploratory analyses of between-sex differences demonstrated males and females responded similarly across all outcome measures. Altering the acid load of EKS modulated the response of blood R-βHB and glucose concentrations but had only modest effects on other outcome measures at rest in young healthy adults, with no differences observed between sexes.NEW & NOTEWORTHY Altering the acid load of ingested exogenous ketone supplements altered post-ingestion responses of circulating glucose and R-βHB concentrations, heart rate, and autonomic function, but did not alter blood gases, respiratory gas exchange, blood pressure, or cognitive performance at rest in young healthy adults.

Keywords:  acid load; bicarbonate; blood gases; exogenous ketosis; metabolism

DOI:  https://doi.org/10.1152/ajpregu.00057.2024
J Diet Suppl. 2025 Mar 04. 1-19

Effects of Ketone Ester Supplementation on Cognition and Appetite in Individuals with and Without Metabolic syndrome: A Randomized Trial.

Austin J Graybeal, Ryan S Aultman, Caleb F Brandner, Anabelle Vallecillo-Bustos, Abby T Compton, Sydney H Swafford, Ta'Quoris A Newsome, Jon Stavres.

  There are currently no non-pharmacological solutions to combat the appetite and cognitive dysfunctions associated with metabolic syndrome (MetS). Ketosis may be a potential solution, though the restrictive nature of dietary ketosis limits its long-term utility. Oral administration of exogenous ketone esters (KE) independently induces ketosis, eliciting hyperketonemia without the need for prolonged dietary restrictions. However, the acute effects of oral KEs on appetite and cognition have not been evaluated in individuals with MetS. For this randomized, single-blind, placebo-controlled, matched-pairs crossover study, 10 individuals with MetS and 10 without (non-MetS) matched for age, sex, and race/ethnicity completed a cardiometabolic screening/familiarization visit and two experimental trials. During the experimental trials, cognitive function, subjective appetite, and respiratory gases were measured at baseline and for 2h following the ingestion of a randomly assigned KE or placebo drink. Post-trial food intake was also collected. Independent of MetS group, indices of working memory significantly improved (p ≤ .035), and blood glucose significantly decreased (p < .001), following KE ingestion. However, after the KE condition, markers of subjective appetite (p ≤ .048) only decreased in the non-MetS group. Post-trial relative fat intake was higher in the MetS group than the non-MetS group following the KE (p = .002), and lower after the KE than the placebo for the non-MetS group (p = .028). Our findings indicate that while cognitive function may increase following KE ingestion independent of MetS, appetite may only decrease in those without MetS; providing further insight to our understanding of the behavioral and metabolic responses to exogenous ketosis.

Keywords:  Appetite; NCT05651243; cognition; ketones; ketosis; metabolic syndrome

DOI:  https://doi.org/10.1080/19390211.2025.2473371
Mol Genet Metab. 2025 Feb 25. pii: S1096-7192(25)00061-7. [Epub ahead of print]144(4): 109070

D-BHB supplementation before moderate-intensity exercise suppresses lipolysis and selectively blunts exercise-induced long-chain acylcarnitine increase in pilot study of patients with long-chain fatty acid oxidation disorders.

Ashley N Gregor, Philippe Delerive, Bernard Cuenoud, Irina Monnard, Karine Redeuil, Cary O Harding, Melanie B Gillingham.

  Patients with long-chain fatty acid oxidation disorders (LC-FAOD) have impaired endogenous ketone production due to defects in the beta-oxidation pathway. We explored supplementation of exogenous D-beta-hydroxybutyrate (D-BHB) as an alternative source of energy in a randomized, double-blinded crossover pilot study. Participants ≥18 years of age with a diagnosis of LC-FAOD completed two moderate-intensity treadmill exercises following an oral supplementation of D-BHB salts or an isocaloric maltodextrin beverage. Five subjects (1 VLCADD, 2 CPT2D, 2 LCHADD), 60 % male, mean age = 33 years were enrolled. Mild to moderate GI symptoms were related to ingestion of D-BHB. Plasma D-BHB was increased after oral D-BHB compared to maltodextrin (p < .001) with an average concentration of 0.43 mM in the post-exercise period. During exercise, free fatty acids (p = .01), fold change in long-chain acylcarnitine species (LC-AC) (p ≤ .03) and systolic BP (p = .02) were lower after D-BHB compared to the maltodextrin beverage. D-BHB suppresses lipolysis and selectively blunts exercise-induced long-chain acylcarnitines. There were no differences between beverages in acetylcarnitine, blood glucose, creatine kinase, VO2, HR, RPE or respiratory exchange ratio. Consumption of the D-BHB beverage was safe and well-tolerated. Plasma D-BHB levels achieved mild ketosis and suppressed lipolysis and the associated rise in LC-AC, but fell short of stimulating the energetic effects that might have resulted in altered exercise parameters such as RER, or HR. In conclusion, our results provide a strong rationale for future studies aimed toward defining the optimal multiple-dose regimen of D-BHB per day that might improve exercise tolerance and understanding the long-term impact of treatment in LC-FAOD subjects.

Keywords:  D-Beta-hydroxybutyrate; Long-chain acylcarnitines; Long-chain fatty acid oxidation disorders

DOI:  https://doi.org/10.1016/j.ymgme.2025.109070
Mech Ageing Dev. 2025 Feb 27. pii: S0047-6374(25)00020-X. [Epub ahead of print] 112044

Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.

Claudie Gabillard-Lefort, Théophile Thibault, Guy Lenaers, Rudolf J Wiesner, Jeanne Mialet-Perez, Olivier R Baris.

  Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.

Keywords:  Aging; Cardiovascular diseases; Inflammation; Mitochondria; Mitochondrial dynamics; Senescence; mtDNA

DOI:  https://doi.org/10.1016/j.mad.2025.112044
Int Immunopharmacol. 2025 Mar 01. pii: S1567-5769(25)00335-2. [Epub ahead of print]151 114345

Modulation of M1 and M2 macrophage polarization by metformin: Implications for inflammatory diseases and malignant tumors.

Sara Jafarzadeh, Maryam Nemati, Raziyeh Zandvakili, Abdollah Jafarzadeh.

  Macrophages perform an essential role in the body's defense mechanisms and tissue homeostasis. These cells exhibit plasticity and are categorized into two phenotypes, including classically activated/M1 pro-inflammatory and alternatively activated/M2 anti-inflammatory phenotypes. Functional deviation in macrophage polarization occurs in different pathological conditions that need correction. In addition to antidiabetic impacts, metformin also possesses multiple biological activities, including immunomodulatory, anti-inflammatory, anti-tumorigenic, anti-aging, cardioprotective, hepatoprotective, and tissue-regenerative properties. Metformin can influence the polarization of macrophages toward M1 and M2 phenotypes. The ability of metformin to support M2 polarization and suppress M1 polarization could enhance its anti-inflammatory properties and potentiate its protective effects in conditions such as chronic inflammatory diseases, atherosclerosis, and obesity. However, in metformin-treated tumors, the proportion of M2 macrophages is decreased, while the frequency ratio of M1 macrophages is increased, indicating that metformin can modulate macrophage polarization from a pro-tumoral M2 state to an anti-tumoral M1 phenotype in malignancies. Metformin affects macrophage polarization through AMPK-dependent and independent pathways involving factors, such as NF-κB, mTOR, ATF, AKT/AS160, SIRT1, STAT3, HO-1, PGC-1α/PPAR-γ, and NLRP3 inflammasome. By modulating cellular metabolism and apoptosis, metformin can also influence macrophage polarization. This review provides comprehensive evidence regarding metformin's effects on macrophage polarization and the underlying mechanisms. The polarization-inducing capabilities of metformin may provide significant therapeutic applications in various inflammatory diseases and malignant tumors.

Keywords:  Atherosclerosis; Inflammation; M1/M2 macrophages; Macrophages; Malignant tumors; Metformin

DOI:  https://doi.org/10.1016/j.intimp.2025.114345
Int J Biol Macromol. 2025 Mar 01. pii: S0141-8130(25)02195-6. [Epub ahead of print]306(Pt 3): 141644

Loteprednol etabonate alleviates NLRP3 inflammasome-associated inflammatory diseases in mice by suppressing the transcription of IL-1β.

Lirui Ye, Weichen Huang, Weiling Li, Yulin Yao, Qian Peng, Zhengqi Fu, Shoufeng Xie, Qi He, Yuchen Liu, Pin Wan, Binlian Sun.

  Excessive activation of the NLRP3 inflammasome leads to cellular inflammation and tissue damage. Finding an inhibitor of its activation is urgent need for NLRP3 inflammasome-associated inflammatory diseases. In this study, we identified Loteprednol etabonate (LE), a well-known anti-inflammatory drug for ocular conditions, as a potent inhibitor of NLRP3 inflammasome activation through screening an FDA-approved drug library. In cellular models, LE significantly reduced IL-1β transcription, suppressed NLRP3 inflammasome activation, and finally inhibited the maturation and secretion of IL-1β and GSDMD-mediated pyroptosis. Mechanistic investigations showed that LE might inhibit IL-1β transcription by blocking both NF-κB and AP-1 signaling pathways. Furthermore, in mouse models of NLRP3 inflammasome-associated inflammatory diseases, including LPS-induced sepsis and DSS-induced colitis, intraperitoneal injection of LE significantly suppressed inflammatory response and improved mice survival rate. Collectively, these findings identify LE as a novel inhibitor of NLRP3 inflammasome activation, offering a promising therapeutic strategy for the treatment of NLRP3 inflammasome-associated inflammatory diseases.

Keywords:  Colitis; IL-1β; Loteprednol etabonate; NLRP3 inflammasome; Pyroptosis; Sepsis

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.141644
Front Nutr. 2024 ;11 1489812

Successful application of dietary ketogenic metabolic therapy in patients with glioblastoma: a clinical study.

Andreas Kiryttopoulos, Athanasios E Evangeliou, Irene Katsanika, Ioannis Boukovinas, Nikolaos Foroglou, Basilios Zountsas, Angeliki Cheva, Vaios Nikolopoulos, Thomas Zaramboukas, Tomas Duraj, Thomas N Seyfried, Martha Spilioti.

   Introduction: Glioblastoma multiforme (GBM) ranks as one of the most aggressive primary malignant tumor affecting the brain. The persistent challenge of treatment failure and high relapse rates in GBM highlights the need for new treatment approaches. Recent research has pivoted toward exploring alternative therapeutic methods, such as the ketogenic diet, for GBM.
Methods: A total of 18 patients with GBM, 8 women and 10 men, aged between 34 and 75 years participated in a prospective study, examining the impact of ketogenic diet on tumor progression. The pool of patients originated from our hospital during the period from January 2016 until July 2021 and were followed until January 2024. As an assessment criterion, we set an optimistic target for adherence to the ketogenic diet beyond 6 months. We considered the therapeutic combination successful if the survival reached at least 3 years.
Results: Among the 18 patients participating in the study, 6 adhered to the ketogenic diet for more than 6 months. Of these patients, one patient passed away 43 months after diagnosis, achieving a survival of 3 years; another passed away at 36 months, narrowly missing the 3-year survival mark; and one is still alive at 33 months post-diagnosis but has yet to reach the 3-year milestone and is, therefore, not included in the final survival rate calculation. The remaining 3 are also still alive, completing 84,43 and 44 months of life, respectively. Consequently, the survival rate among these patients is 4 out of 6, or 66.7%. Of the 12 patients who did not adhere to the diet, only one reached 36 months of survival, while the rest have died in an average time of 15.7 ± 6.7 months, with a 3-year survival rate of 8.3%. Comparing the survival rates of the two groups, we see that the difference is 58.3% (66.7% versus 8.3%) and is statistically significant with p < 0.05 (0.0114) and X2 = 6.409.
Discussion: The outcomes observed in these patients offer promising insights into the potential benefits of the ketogenic diet on the progression of glioblastoma multiforme when compared to those who did not follow the diet consistently.

Keywords:  brain; diet; glioblastoma; ketogenic; metabolic; multiforme; tumor

DOI:  https://doi.org/10.3389/fnut.2024.1489812
Arthritis Res Ther. 2025 Mar 04. 27(1): 48

Vitamin D and its receptor in skeletal muscle are associated with muscle disease manifestation, lipid metabolism and physical fitness of patients with myositis.

Lucia Vernerová, Martina Vokurková, Nikoleta Alchus Laiferová, Michal Nemec, Maja Špiritović, Oksana Mytiai, Sabína Oreská, Martin Klein, Kateřina Kubínová, Veronika Horváthová, Tereza Kropáčková, László Wenchich, Michal Tomčík, Jozef Ukropec, Barbara Ukropcová, Jiří Vencovský.

   BACKGROUND: Low levels of vitamin D have been associated with several autoimmune diseases. A growing body of evidence supports the association of vitamin D with skeletal muscle damage, regeneration, and energy and lipid metabolism. The aim was to analyse vitamin D and its receptor (VDR) in the muscle tissue of patients with idiopathic inflammatory myopathies (IIM) and to relate them to clinical parameters and muscle lipid and energy metabolism.
METHODS: Forty-six patients with IIM and 67 healthy controls (HC) were included in the study. 27 IIM patients participated in a 24-week exercise intervention. Muscle biopsies were obtained from 7 IIM patients before/after training, 13 non-exercising IIM controls, and 21 HC. Circulating concentrations of 25(OH)D and 1,25(OH)D were measured. Gene expression of VDR and CYP27B1, the enzyme converting 25(OH)D to hormonally active 1,25(OH)D, was determined by qPCR in muscle tissue and primary muscle cells. Lipid oxidative metabolism was assessed in muscle tissue (mRNA, qPCR) and primary muscle cells (radioactive assays).
RESULTS: Lower levels of active 1,25(OH)D were observed in IIM patients compared with HC (mean ± SD: 125.0 ± 45.4 vs. 164.7 ± 49.2 pmol/L; p < 0.0001). 25(OH)D was associated with CRP (r = -0.316, p = 0.037), MITAX (r = -0.311, p = 0.040) and HAQ (r = -0.390, p = 0.009) in IIM. After 24 weeks of training, active 1,25(OH)D was associated with MMT8 (r = 0.866, p < 0.0001), FI-2 (r = 0.608, p = 0.013) and HAQ (r = -0.537, p = 0.032). Gene expression of both VDR and CYP27B1 in primary muscle cells decreased after training (p = 0.031 and p = 0.078, respectively). Associations of VDR mRNA in muscle tissue with MMT-8 (IIM: r = -0.559, p = 0.013), serum CK (HC: r = 0.484, p = 0.031), myoglobin (IIM: r = 0.510, p = 0.026) and myostatin (IIM: r = -0.519, p = 0.023) were observed. The expression of VDR in differentiated muscle cells correlated negatively with the complete oxidation of palmitic acid (r = -0.532, p = 0.028). Muscle mRNA of carnitine palmitoyl transferase 1 (CPT1) (downregulated in IIM, p = 0.001) correlated positively with serum 1,25(OH) vitamin D (r = 0.410, p = 0.042).
CONCLUSION: Reduced biologically active vitamin D in circulation suggests its impaired metabolism in IIM. Serum vitamin D levels and gene expression of its receptor and activating enzyme in muscle tissue were modified by regular exercise and associated with disease manifestations, physical fitness, and muscle lipid metabolism of IIM patients.

Keywords:  Lipid metabolism; Mitochondria; Muscle; Myositis; Physical activity; Vitamin D

DOI:  https://doi.org/10.1186/s13075-025-03516-9
Anim Nutr. 2025 Mar;20 404-418

Long-term leucine supplementation increases body weight in goats by controlling appetite and muscle protein synthesis under protein-restricted conditions.

Xiaokang Lv, Aoyu Jiang, Jinling Hua, Zixin Liu, Qiongxian Yan, Shaoxun Tang, Jinhe Kang, Zhiliang Tan, Jian Wu, Chuanshe Zhou.

  An inadequate amino acid (AA) supply in animals under protein-restricted conditions can slow skeletal muscle growth. Protein translation can be activated by short-term leucine (Leu) stimulation; however, whether muscle mass increases under long-term Leu supplementation and how the gut and muscle respond to Leu supplementation are largely unknown. In this study, we investigated if muscle mass increases with long-term Leu supplementation under protein-restricted conditions. We identified changes in the link between the gut and muscles under different amino acid supply conditions, using goats as the study object. A total of 27 Xiangdong black male goats with average initial body weight (BW) of 10.88 ± 1.22 kg were randomly divided into three dietary treatments: a normal protein diet (NP, 14.24% crude protein [CP]); a low protein diet (LP, 8.27% CP with supplemental 1.66% rumen-protected lysine [RPLys] and 0.09% rumen-protected methionine [RPMet]); and LP diet with rumen-protected Leu (RPLeu) (LP + RPLeu, 8.75% CP with supplemental 1.66% RPLys, 0.09% RPMet and 1.46% RPLeu). The animal trial lasted for 110 d, consisting of 20 d of adaptation and a 90 d of experimental period. The results showed that long-term protein restriction increased gut tryptophan hydroxylase 1 (TPH1) activity (P < 0.001), tryptophan (Trp) catabolism (P < 0.001), and 5-hydroxytryptamine (5-HT) synthesis (P < 0.001), which all subsequently reduced goat appetite. Long-term Leu supplementation inhibited 5-HT synthesis (P < 0.001), decreased Trp catabolism in the gut, and increased appetite in goats. Long-term protein restriction enhanced jejunal and ileal branched-chain amino acid transferase (BCAT) (P < 0.001) and branched-chain α-Keto acid dehydrogenase (BCKD) (P = 0.048) activities, which increased branched-chain amino acid (BCAA) catabolism. Immunofluorescence results showed that protein restriction decreased the intestinal mucosal expression of solute carrier family 1 member 5 (SLC1A5) (P = 0.032) and solute carrier family 7 member 5 (SLC7A5) (P < 0.001), reduced BCAA transport from the mucosa to the blood, lowered BCAA levels in the blood (P < 0.001). Western blot results showed that protein restriction inhibited mammalian target of rapamycin (mTOR) pathway activation in goat muscles. Leu supplementation increased BCAA translocation from the intestine to the blood and promoted activation of the muscle mTOR pathway and protein synthesis. In conclusion, our results suggest that Leu supplementation in low-protein diets improves appetite and alleviates the inhibition of muscle protein synthesis in goats.

Keywords:  5-Hydroxytryptamine; Amino acid transport; Goat; Leucine; Protein synthesis; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.aninu.2024.09.005
J Nutr Metab. 2025 ;2025 8851660

Body Weight Changes During Ramadan Intermittent Fasting: A Cross-Sectional Study of Healthy Adults in Turkey.

ISRI Research Group

  Introduction: This study explores the impact of observing Ramadan intermittent fasting (RIF) on body weight in Turkish residents, marking it as the first study conducted in Turkey to investigate the interplay of religious fasting with dietary changes amid the COVID-19 pandemic. We hypothesized that observing Ramadan fasting would result in weight loss attributable to dietary changes, while decreased physical activity would correlate with weight gain during this period. Methods: A cross-sectional survey was conducted among Muslims aged 18+ in Turkey who fasted at least two days during Ramadan 2021. Data were collected via Google Forms, with 1669 participants recruited through social media. Descriptive statistics summarized participant characteristics, and Pearson's Chi-square tests assessed weight change differences. Binary logistic regression identified predictors of weight gain, adjusting for factors such as sex, age, physical activity, water consumption, and diet. Results: Of the 1669 respondents (53.6% female), 49.4% perceived their weight as normal, while 47.0% classified themselves as overweight or obese. Logistic regression indicated that decreased physical activity (AOR = 1.618, p=0.001) and increased fat intake (AOR = 1.9, 95% CI 1.2-2.9) were significant predictors of weight gain. Conclusion: Our findings emphasize the importance of promoting healthy eating and regular physical activity during Ramadan.

Keywords:  Turkey; calorie restriction; intermittent fasting; lifestyle; time-restricted eating; weight changes

DOI:  https://doi.org/10.1155/jnme/8851660
Cell Rep. 2025 Mar 05. pii: S2211-1247(25)00148-2. [Epub ahead of print]44(3): 115377

Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts.

Brian M Spurlock, Yifang Xie, Yiran Song, Shea N Ricketts, James Rock Hua, Haley R Chi, Meenakshi Nishtala, Rustem Salmenov, Jiandong Liu, Li Qian.

  Cardiomyocytes (CMs) rely on mitochondrial energy produced in highly interconnected mitochondrial networks. Direct reprogramming of cardiac fibroblasts (CFs) into induced CMs (iCMs) shows promise for treating cardiac injury, but little work has investigated mitochondrial energetics and morphology during the conversion of CFs to iCMs. We characterized mitochondria during direct cardiac reprogramming of murine neonatal CFs (mnCFs). Reprogramming increased mitochondrial respiration and interconnectivity but not to the levels of native CMs. We therefore investigated whether perturbations to mitochondrial dynamics impacted reprogramming. Mitochondrial fusion (joining) was essential for iCM generation, while various fission (dividing) genes were reprogramming barriers. In particular, the loss of mitochondrial fission regulator 1 like (Mtfr1l) significantly increased the yield of functionally mature iCMs and induced mitochondrial fusion and respiration. These changes were countered by the concomitant loss of fusion effector optical atrophy protein 1 (Opa1). The present study advances our understanding of mitochondrial barriers to and mechanisms of direct cardiac reprogramming.

Keywords:  CP: Metabolism; CP: Stem cell research; Mtfr1l; cell fate conversion; direct cardiac reprogramming; machine learning; mitochondria; mitochondrial dynamics; mitochondrial energetics; mitochondrial fission; mitochondrial fusion; regenerative medicine

DOI:  https://doi.org/10.1016/j.celrep.2025.115377
iScience. 2025 Mar 21. 28(3): 111961

Exploring NLRP3-related phenotypic fingerprints in human macrophages using Cell Painting assay.

Matthew Herring, Eva Särndahl, Oleksandr Kotlyar, Nikolai Scherbak, Magnus Engwall, Roger Karlsson, Mikael Ejdebäck, Alexander Persson, Andi Alijagic.

  Existing research has proven difficult to understand the interplay between upstream signaling events during NLRP3 inflammasome activation. Additionally, events downstream of inflammasome complex formation such as cytokine release and pyroptosis can exhibit variation, further complicating matters. Cell Painting has emerged as a prominent tool for unbiased evaluation of the effect of perturbations on cell morphological phenotypes. Using this technique, phenotypic fingerprints can be generated that reveal connections between phenotypes and possible modes of action. To the best of our knowledge, this was the first study that utilized Cell Painting on human THP-1 macrophages to generate phenotypic fingerprints in response to different endogenous and exogenous NLRP3 inflammasome triggers and to identify phenotypic features specific to NLRP3 inflammasome complex formation. Our results demonstrated that not only can Cell Painting generate morphological fingerprints that are NLRP3 trigger-specific but it can also identify cellular fingerprints associated with NLRP3 inflammasome activation.

Keywords:  Biological sciences research methodologies; Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.111961
PLoS One. 2025 ;20(3): e0313103

Alternate-day fasting differentially affects body composition, metabolic and immune response to fasting in male rats exposed to early-life adversity: Modulatory role of cafeteria diet.

Sara C Sagae, Edson D R Paz, Bárbara Zanardini, Ana Claudia Amaral, Gabriela A Bronczek, Patrícia Koehler-Santos, Jarbas R de Oliveira, Celso R Franci, Márcio V F Donadio, Parker J Holman, Charlis Raineki.

The increased risk for obesity and metabolic disorders following early-life adversity is aggravated by poor diet (e.g., cafeteria diet). Alternate-day fasting (ADF) is a dietary regimen shown to improve immune and metabolic dysfunction related to obesity. Here, we evaluate if ADF can ameliorate the negative effects of early-life adversity and/or cafeteria diet on biological, immune and metabolic parameters. At weaning, animals reared under normal or adverse conditions (i.e., low bedding) were fed either standard chow or cafeteria diets ad libitum or subjected to an ADF regimen. In adulthood, we measured 24-hour fasted cholesterol, triglycerides, cytokines, oxidative stress markers, and body composition parameters including perigonadal, retroperitoneal, and brown fat pad weight. Animals exposed to early-life adversity respond differently to cafeteria diet and ADF. Adverse reared animals fed chow diet in the ADF regimen showed the largest reduction in body weight and perigonadal and retroperitoneal fat pad weight, the smallest increase in corticosterone levels, and the largest increase in TNF-α levels. However, the differential effects of the ADF regimen on body, perigonadal and retroperitoneal fat weight observed in adversely reared animals fed chow diet compared to controls were not present if the adversely reared animals were fed cafeteria diet in the ADF regimen. Furthermore, adversely reared animals fed cafeteria diet in the ADF regimen showed high IL-1β and IL-6 levels. Together, the data suggest that the altered vulnerability to metabolic and immune dysfunction following early-life adversity is not just due to the type of diet but also how the diet is consumed.

DOI: https://doi.org/10.1371/journal.pone.0313103
Drug Alcohol Depend Rep. 2025 Mar;14 100320

High-intensity interval training alleviates ethanol-induced renal damage: A study on inflammation, oxidative stress, and histopathological changes in rats.

Najmeh Sadat Hosseini, Sara Shirazpour, Gholamreza Sepehri, Shahriar Dabiri, Manzumeh Shamsi Meymandi.

   Background: This study examines if high-intensity interval training (HIIT) can reduce ethanol-induced kidney damage by modulating cytokines and reducing oxidative stress.
Method: Thirty male Wistar rats were randomly assigned to five groups (n = 6): CON (saline control), ET (ethanol; 3 mg/kg of 20 % ethanol gavage), HIIT (8 weeks of HIIT), HIIT-SL (saline + HIIT), and HIIT-ET (ethanol + HIIT). Kidney tissues were collected for biochemical analysis of cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10); oxidative stress markers, including malondialdehyde (MDA); and antioxidants, including total antioxidant capacity (TAC), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Histopathology and serum levels of albumin, urea, and creatinine were evaluated. Statistical significance was assessed using GraphPad Prism (p < 0.05).
Results: Chronic ethanol consumption increased pro-inflammatory cytokines TNF-α and IL-6 (p < 0.0001) and decreased anti-inflammatory IL-10 (p < 0.0001). Histopathology revealed tubular necrosis, and hyaline casts. HIIT reduced TNF-α and IL-6 while increasing IL-10 (p < 0.0001), showing an anti-inflammatory effect. The HIIT-ET group had fewer hyaline casts and less tubular necrosis compared to the ET group, although hyperemia persisted. HIIT improved antioxidant levels (TAC, GPx, SOD) and reduced oxidative stress (MDA) (p < 0.05). Serum urea and creatinine were higher in the ET group but lower in the HIIT-ET group; albumin levels were increased with HIIT.
Conclusion: The study shows HIIT effectively reduces ET-induced kidney damage by decreasing oxidative stress and inflammation, suggesting it as a promising non-drug approach to manage ET-related renal issues.

Keywords:  Ethanol; HIIT; Inflammation; Kidney Damage; Oxidative Stress

DOI:  https://doi.org/10.1016/j.dadr.2025.100320
Endocrinol Diabetes Metab. 2025 Mar;8(2): e70042

Impact of Short-Chain Fatty Acids on Glucose, Fatty Acid and Leucine Metabolism in Primary Human Myotubes.

Ragna Husby Tingstad, Oliwia Witczak, Siver Beajani, Seung Hee Seo, Nils Gunnar Løvsletten, Christine Skagen, Mari Charlotte Wik Myhrstad, Vibeke Helen Telle-Hansen, Lars Eide, Arild Christian Rustan, Vigdis Aas.

   INTRODUCTION: Short-chain fatty acids (SCFAs) are small molecule metabolites mainly produced during microbial fermentation of dietary fibre in the gut and have been shown to have a beneficial impact on human health. The aim of this study was to evaluate the effect of SCFAs on human skeletal muscle energy metabolism.
METHODS: Primary human myotubes were analysed for glucose and fatty acid (oleic acid) metabolism, as well as insulin sensitivity and protein synthesis in the presence or absence of SCFAs.
RESULTS: The most pronounced effects of SCFAs were observed on 14C-oleic acid uptake and oxidation, as well as 14C-leucine uptake and protein synthesis, following butyrate treatment. Butyrate increased 14C-leucine accumulation twofold, potentially due to protein incorporation. On the other hand, the conversion of 14C-leucine into free fatty acids was reduced by more than 50% by butyrate. Both 14C-acetate and 14C-butyrate were shown to be taken up and utilised by primary human myotubes. None of the SCFAs were found to influence glucose metabolism or insulin effects.
CONCLUSION: The results from the current study thus suggest that among the SCFAs, butyrate emerges as the most powerful SCFA in regulating primary human myotube metabolism.

Keywords:  acetate; butyrate; energy metabolism; leucine; myotubes; propionate; protein synthesis; short‐chain fatty acids

DOI:  https://doi.org/10.1002/edm2.70042
Neurobiol Dis. 2025 Mar 04. pii: S0969-9961(25)00078-6. [Epub ahead of print] 106862

Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.

Yifei Zheng, Jiahui Yang, Xuanyao Li, Linjie Qi, Zhuo Zheng, Jiming Kong, Guohui Zhang, Ying Guo.

  Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.

Keywords:  Mitochondrial quality control; Neurodegenerative diseases; Neuron; Senescence; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.nbd.2025.106862
Nat Rev Mol Cell Biol. 2025 Mar 06.

Dodging mitochondrial mislocalization.

Lisa Heinke.

DOI: https://doi.org/10.1038/s41580-025-00840-5