bims-kimdis 2025-05-18 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–05–18
seventeen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Acute ketone monoester ingestion lowers resting cerebral blood flow: a randomized cross-over trial.
The multifaceted roles of ketones in physiology.
To transfer mitochondria or not to transfer mitochondria: ADP does the trick.
β-hydroxybutyrate attenuates diabetic renal and muscular pathologies in a streptozotocin-induced diabetic model.
Exercise Attenuates Skeletal Muscle Atrophy in Senescent SAMP8 Mice: Metabolic Insights from NMR-Based Metabolomics.
NLRP3 inflammasome inhibits mitophagy during the progression of temporal lobe epilepsy.
Long-Term Moderate Increase in Medium-Chain Fatty Acids Intake Enhances Muscle Metabolism and Function in Mice.
Mitochondrial coupling efficiency and myofiber type related to blood pressure 22 h after high-intensity exercise in premenopausal women.
The Effect and Mechanism of Regular Exercise on Improving Insulin Impedance: Based on the Perspective of Cellular and Molecular Levels.
Butyrate Derivatives Exhibited Anti-Inflammatory Effects and Enhanced Intestinal Barrier Integrity in Porcine Cell Culture Models.
NLRP3 inflammasome: structure, mechanism, drug-induced organ toxicity, therapeutic strategies, and future perspectives.
Musclin Counteracts Skeletal Muscle Dysfunction and Exercise Intolerance in Heart Failure With Preserved Ejection Fraction.
Mitochondria-membranous organelle contacts at a glance.
NLRP3 inflammasome activation expands immunosuppressive myeloid stroma and antagonizes the therapeutic benefit of STING activation in glioblastoma.
Effects of high-intensity interval training on metabolic impairments in liver tissue of rats with type 2 diabetes: a metabolomics-based approach.
How are estimated cellular turnover rates influenced by the dynamics of a source population?
Unlocking the cellular mystery: how proton pump inhibitors may alter the dementia landscape.

J Physiol. 2025 May 11.

Acute ketone monoester ingestion lowers resting cerebral blood flow: a randomized cross-over trial.

Aedan J Rourke, Claudia M S Yong, Geoff B Coombs, Addriana R Odisho, Jenna A Nash, Jack Bone, Baraa K Al-Khazraji, Jeremy J Walsh.

  Exogenous ketone monoester (KME) supplements rapidly increase plasma beta-hydroxybutyrate (β-OHB) and may impact cerebral blood flow (CBF). However, it is currently unknown how acute KME ingestion impacts resting CBF and whether differences in KME dose have differential effects on CBF regulation. The purpose of this study was to investigate the effect of two separate KME doses on resting CBF in young adults. On separate days and in a double-blind, placebo-controlled, cross-over design, 20 participants (10 females; aged 23 ± 3 years) ingested either: (1) High-KME (0.6 g kg-1 β-OHB); (2) Low-KME (0.3 g kg-1 β-OHB); or (3) placebo drink, and quietly rested for 120 min. Global CBF (gCBF) was assessed using duplex ultrasound of the internal carotid and vertebral arteries, and transcranial Doppler ultrasound was used to assess middle cerebral artery blood velocity at baseline, 45 min and 120 min post-ingestion. End-tidal CO2 ( PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_2}}}$ ) was measured using a gas analyser. β-OHB was measured in venous blood. At 45 min post-ingestion, gCBF was significantly reduced by 10.6% in Low-KME and by 14.6% in High-KME compared to baseline. At 120 min, gCBF returned towards baseline in Low-KME, whereas gCBF was further reduced by 19.1% in High-KME compared to baseline. KME dose-dependent reductions in PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_2}}}$ may have contributed to these reductions in gCBF following KME ingestion. These novel findings provide a foundational characterization of the impact of KME on resting CBF, which prompts further investigation building on these results to isolate underlying mechanisms and develop dosing protocols to mitigate potential CO2 disruptions. KEY POINTS: Beta-hydroxybutyrate (β-OHB) is a signalling molecule and β-OHB infusion increases cerebral blood flow (CBF) in humans. Ingestion of higher doses of a ketone monoester (KME) supplement have been shown to lower blood pH and arterial CO2, which are important regulators of CBF. This double-blind and placebo-controlled cross-over study tested the effects of two separate KME doses (Low-KME and High-KME) on resting CBF, end-tidal CO2 and systemic haemodynamics over a 2 h period post-ingestion in young adults. Low-KME reduced CBF 45 min post-ingestion and High-KME reduced CBF at both 45 and 120 min post-ingestion, which corresponded with dose-dependent reductions in end-tidal CO2. The findings from this trial represent a foundational characterization of the effects of KME dose on resting CBF.

Keywords:  beta‐hydroxybutyrate; cardiorespiratory stress; cerebral blood flow; cerebrovascular; dose–response; double‐blind; end‐tidal CO2; exogenous ketone supplements; placebo‐controlled

DOI:  https://doi.org/10.1113/JP287320
Exp Physiol. 2025 May 11.

The multifaceted roles of ketones in physiology.

Seyed Amirhossein Tabatabaei Dakhili, Kunyan Yang, Magnus J Stenlund, John R Ussher.

  The production of ketones, referred to as ketogenesis, plays an essential role in maintaining energy homeostasis during prolonged fasting/starvation, which primarily stems from its ability to serve as a fuel source to support neuronal ATP production, thereby limiting muscle wasting. Over the years, the field has come to appreciate that ketones are much more than just a fuel source supporting neuronal metabolism, as many other oxidative organs, such as the heart and skeletal muscle, are capable of metabolizing ketones. Furthermore, ketones appear to be an important fuel source for exercising muscle. Beyond supporting ATP production, it is also becoming widely recognized that ketones are powerful signalling molecules, as they serve as ligands for G-protein coupled receptors and can even modify gene expression via regulating DNA post-translational modifications. As they play a key role in supporting whole-body physiology, it is not surprising that perturbations in ketone metabolism can contribute to various pathologies, particularly in relation to cardiometabolic diseases. Some of the strongest evidence supporting the aforementioned statement is seen for both heart failure and type 2 diabetes. Accordingly, we will review herein the multifaceted roles of ketones in supporting whole-body physiology, while interrogating the evidence to suggest whether modifying ketone metabolism may have a therapeutic role in the management of heart failure and type 2 diabetes.

Keywords:  heart failure; ketogenesis; ketone oxidation; ketones; type 2 diabetes

DOI:  https://doi.org/10.1113/EP092243
PLoS Biol. 2024 Aug;22(8): e3002754

To transfer mitochondria or not to transfer mitochondria: ADP does the trick.

Jaromir Novak, Jiri Neuzil.

Horizontal mitochondrial transfer (HMT) has emerged as a novel phenomenon in cell biology, but it is unclear how this process of intercellular movement of mitochondria is regulated. A new study in PLOS Biology reports that ADP released by stressed cells is a signal that triggers HMT.

DOI: https://doi.org/10.1371/journal.pbio.3002754
Nutrition. 2025 Apr 07. pii: S0899-9007(25)00110-8. [Epub ahead of print]137 112792

β-hydroxybutyrate attenuates diabetic renal and muscular pathologies in a streptozotocin-induced diabetic model.

Rahmawati Aisyah, Shohei Katsuya, Kenshu Miyata, Zhenhgyu Chen, Mayu Horii, Ayane Kudo, Thanutchaporn Kumrungsee, Jun Tsubota, Noriyuki Yanaka.

  Diabetes and its associated complications are the leading cause of mortality worldwide. Strategies have been rapidly developed to reduce diabetic complications and the overall quality of life of patients with diabetes. β-hydroxybutyrate (BHB), the most abundant ketone body generated from fatty acids in the liver, provides energy sources under nutrient deprivation and has various potential health benefits as a functional food. However, its role in diabetic pathologies is unclear. In this study, we examined the effect of BHB on the kidney and muscle functions in streptozotocin (STZ)-induced diabetic mice. BHB supplementation exerted anti-inflammatory effects on the kidneys and improved renal tubule injury and fibrosis in STZ-induced mice. Furthermore, BHB alleviated diabetes-induced muscle atrophy, indicated by the increased fiber area and normalized fiber area distribution in BHB-supplemented STZ-treated mice. Our study demonstrates the beneficial effects of BHB in improving diabetic complications, particularly diabetic nephropathy and myopathy, and highlights the potential of BHB as a functional food for the treatment of diabetes.

Keywords:  Diabetic myopathy; Diabetic nephropathy; Streptozotocin; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.nut.2025.112792
Molecules. 2025 Apr 30. pii: 2003. [Epub ahead of print]30(9):

Exercise Attenuates Skeletal Muscle Atrophy in Senescent SAMP8 Mice: Metabolic Insights from NMR-Based Metabolomics.

Wenfang Wu, Linglin Zhang, Yifen Chen, Caihua Huang, Longhe Yang, Donghai Lin.

  Age-related skeletal muscle atrophy is a major health concern in the elderly, contributing to reduced mobility, increased risk of falls, and metabolic dysfunction. The senescence-accelerated prone 8 (SAMP8) mouse model, known for its rapid aging and early cognitive decline, serves as an essential model for studying age-related muscle degeneration. While previous studies have shown that exercise attenuates muscle atrophy by promoting regeneration and improving strength, the underlying metabolic mechanisms remain poorly understood. This study used the SAMP8 model to evaluate the effects of exercise on muscle atrophy and associated metabolic changes. Our results show that exercise promoted muscle growth by reducing body weight, increasing skeletal muscle mass, and decreasing fat accumulation. Furthermore, exercise improved grip strength, muscle tone, and muscle fiber cross-sectional area, thereby preserving muscle functionality. NMR-based metabolomic analysis identified key metabolic pathways modulated by exercise, including glycine, serine, and threonine metabolism; alanine, aspartate, and glutamate metabolism; pyruvate metabolism; and taurine and hypotaurine metabolism. These findings underscore the therapeutic potential of exercise in combating age-related muscle wasting and elucidate the metabolic pathways underlying its benefits.

Keywords:  NMR-based metabolomics; SAMP8; aging; exercise; skeletal muscle

DOI:  https://doi.org/10.3390/molecules30092003
Sci Rep. 2025 May 10. 15(1): 16341

NLRP3 inflammasome inhibits mitophagy during the progression of temporal lobe epilepsy.

Mengqian Wu, Cong Yu, Fuli Wen, Yunfei Li, Xu Zhang, Yinzhou Wang, Xiaoqian Chen, Xingyong Chen.

  Epilepsy is a neurological disorder involving mitochondrial dysfunction and neuroinflammation. This study examines the relationship between NLRP3 inflammasome activation and mitophagy in the temporal lobe epilepsy, which has not been reported before. A pilocarpine-induced epileptic rat model was used to assess seizure activity and neuronal loss. Pyroptosis markers (NLRP3, cleaved Gasdermin D, IL-1β/IL-18), and autophagy/mitophagy activity (LC3B-II/I, BNIP3, TOMM20/LC3B colocalization) were analyzed via immunofluorescence, Western blot, and transmission electron microscopy. NLRP3 inhibitors and anti-IL-1β antibodies were administered to evaluate therapeutic effects. Epileptic rats exhibited progressive neuronal loss and seizure aggravation, correlating with NLRP3 inflammasome activation and pyroptosis. While general autophagy was upregulated, mitophagy was selectively impaired in the hippocampus. NLRP3 activation promoted IL-1β release, which suppressed mitophagy via PPTC7 upregulation. NLRP3 activation inhibitor (MCC950) and anti-IL-1β treatment restored mitophagy and reduced seizures. NLRP3 inflammasome-driven pyroptosis exacerbates epilepsy by impairing mitophagy activity via IL-1β/PPTC7. Targeted NLRP3 inhibition mitigates this cascade, offering a promising strategy for refractory epilepsy.

Keywords:  Autophagy; Mitophagy; NLRP3 inflammasome; Pyroptosis; Temporal lobe epilepsy

DOI:  https://doi.org/10.1038/s41598-025-01087-y
Int J Mol Sci. 2025 Apr 26. pii: 4126. [Epub ahead of print]26(9):

Long-Term Moderate Increase in Medium-Chain Fatty Acids Intake Enhances Muscle Metabolism and Function in Mice.

Ziwei Zhang, Cong Wu, Shuo Wang, Yishan Tong, Jiapeng Huang, Chuwen Xue, Tiehan Cao, Katsuhiko Suzuki.

  Medium-chain fatty acids (MCFAs) refer to a mixture of fatty acids typically composed of 6 to 12 carbon atoms. The unique transport and rapid metabolism of MCFAs provide more clinical benefits than other substrates, such as long-chain fatty acids. Although many studies have shown that MCFAs may improve exercise capacity and muscle strength, applications have mainly been limited to low doses. This study explores the effects of high-dose MCFA intake on muscle strength and exercise endurance. Mice were fed high-fat diets containing 30, 35, and 40% (w/w) MCFAs for 12 weeks, and measurements of grip strength and submaximal endurance exercise capacity were conducted to evaluate muscle function. Results showed that compared to the 30% MCFAs group, the absolute grip strength in the 35 and 40% MCFAs groups significantly increased; in terms of endurance performance, the 35% MCFAs group showed a significant increase compared to the 40% MCFAs group. These results were mainly achieved by promoting muscle regeneration and differentiation and inhibiting the expression of the ubiquitin-proteasome pathway. This study demonstrates that moderately increasing MCFA intake can improve the effects of obesity-induced muscle atrophy. However, excessive intake may reduce the impact of improvement.

Keywords:  exercise tolerance; grip strength; medium-chain fatty acids; muscle differentiation; muscle regeneration; protein catabolism

DOI:  https://doi.org/10.3390/ijms26094126
Eur J Appl Physiol. 2025 May 10.

Mitochondrial coupling efficiency and myofiber type related to blood pressure 22 h after high-intensity exercise in premenopausal women.

Gary R Hunter, Gordon Fisher, Stephen J Carter, Douglas R Moellering.

  Previously we have shown that systolic blood pressure (SBP) increases in African American (AA) women but decreases in European American (EA) women ≈22 h after a high-intensity exercise bout, suggesting delayed recovery in the AA women. We, therefore, sought to determine whether myofiber type, systemic vascular resistance (SVR), and mitochondrial coupling efficiency may contribute to elevated blood pressure in AA women following a bout of high-intensity exercise. Premenopausal EA (9) and AA (7) women were aerobically trained for 8-16 weeks and V˙O2peak was evaluated. After 2 days without exercise, participants were evaluated for myofiber type, mitochondrial respiration using high-resolution respirometry, and SVR 22 h following 1 h of high-intensity interval cycle ergometry. AAs had higher SBP and DBP and type IIx myofiber % but lower type IIa myofiber %. SBP was significantly related to SVR (0.71), RCR (0.44), type IIa myofiber type (- 0.48), and type IIx myofiber type (0.53). DBP was significantly related to SVR (0.58) and the respiratory acceptor control ratio (state 3/state 4, termed RCR, 0.69). SBP remained significantly higher in AAs even after adjusting for type IIx myofiber type, RCR, SVR, or V˙O2peak adjusted for FFM, and additionally, DBP remained significantly higher after adjusting for type IIx myofiber type, RCR, or V˙O2peak adjusted for FFM. These results support the premise that mitochondrial RCR, type IIx myofiber type, and SVR may contribute to increased blood pressure ≈22 h following a bout of high-intensity exercise. Still, racial differences were not explained by any of these variables.

Keywords:  Exercise training; Hypertension; Interval exercise; Respirometry; Skeletal muscle; Vascular health

DOI:  https://doi.org/10.1007/s00421-025-05805-2
Int J Mol Sci. 2025 Apr 28. pii: 4199. [Epub ahead of print]26(9):

The Effect and Mechanism of Regular Exercise on Improving Insulin Impedance: Based on the Perspective of Cellular and Molecular Levels.

Tingran Zhang, Yongsen Liu, Yi Yang, Jiong Luo, Chen Hao.

  Insulin resistance is more common in the elderly, and with the improvement in people's living standards and changes in lifestyle habits, the incidence of insulin resistance in other age groups is also increasing year by year. Overweight and obesity caused by abnormal fat metabolism or accumulation can significantly reduce glucose intake, which is the direct cause of insulin resistance and the trigger for the occurrence and development of type II diabetes. This article reviews and analyzes relevant literature on empirical research on the effect of regular exercise on improving insulin resistance. It was found that the most important step in carbohydrate metabolism is the translocation of glucose transporter 4 (GLUT4) to the cell membrane, carrying water-soluble glucose through the lipid soluble cell membrane to complete carbohydrate transport. The process of glucose transporter protein translocation to the cell membrane can be driven by two different signaling pathways: one is the insulin information transfer pathway (ITP), the second is to induce the ITP of monophosphate-activated protein kinase (AMPK) through hypoxia or muscle contraction. For type II diabetes patients, the insulin signal transmission pathway through insulin receptors (IRS1, IRS2) and phosphatidylinositol 3-kinase (PI3K) (PI3K) is damaged, which results in the decrease in glucose absorption stimulated by insulin in skeletal muscle, while the noninsulin signal transmission pathway of AMPK in these patients is normal. It can be seen that regular exercise can regulate glucose intake and the metabolism of skeletal muscle, improve insulin resistance, reduce fasting blood glucose and glycosylated hemoglobin in diabetes patients, and thus, effectively regulate blood glucose. However, many steps in the molecular mechanism of how exercise training improves systemic insulin resistance are still not fully understood, and further discussion is needed in the future.

Keywords:  hyperglycemia; information transfer pathway; insulin resistance; molecular biology; regular exercise

DOI:  https://doi.org/10.3390/ijms26094199
Animals (Basel). 2025 Apr 30. pii: 1289. [Epub ahead of print]15(9):

Butyrate Derivatives Exhibited Anti-Inflammatory Effects and Enhanced Intestinal Barrier Integrity in Porcine Cell Culture Models.

Lauren Kovanda, Monika Hejna, Tina Du, Yanhong Liu.

  Butyrate and its derivatives may influence inflammatory status and physiology in a variety of organisms and organ systems. Inflammatory conditions of the gastrointestinal tract, such as post-weaning diarrhea, negatively impact swine. Dietary intervention with butyrate-based compounds should be considered a strategy to improve disease resistance in pigs. We aimed to assess the properties of different forms of butyrate treatments using porcine cell culture experiments. This assessment may inform future in vivo feed experiments designed to determine its potential application of the dietary supplements for pigs. An intestinal porcine enterocyte cell line, IPEC-J2, was seeded at 5 × 103 cells/mL in 96-well plates to confirm cell viability by MTT assay for each dose range used in the current experiments (0, 0.5, 1, 2, 4 mM butyric acid or tributyrin; 0, 1, 2, 4, 8 mM sodium butyrate or monobutyrin). For transepithelial electrical resistance (TEER) analysis, IPEC-J2 was seeded at 5 × 105 cells/mL in 12-well transwell inserts and treated with 5 levels of each butyrate derivative after adherence (n = 5). TEER was measured at 24, 48, and 72 h post-treatment to quantify intestinal barrier integrity of IPEC-J2 monolayers. Butyric acid, sodium butyrate, and monobutyrin significantly increased (p < 0.05) TEER in IPEC-J2 at different time points compared with control. Further, porcine alveolar macrophages (PAMs) were harvested from donor weaned piglets (n = 6) via bronchoalveolar lavage and isolated for primary culture (6 × 105 cells/well, 6-well plates). PAMs were treated with five levels of each butyrate derivative with or without lipopolysaccharide (LPS, 1 μg/mL) challenge. The concentrations of TNF-α and IL-1β in cell culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Butyric acid and sodium butyrate treatments reduced the production of TNF-α in LPS-challenged PAMs (linear; p < 0.05). Different butyrate derivatives exerted anti-inflammatory properties and improved intestinal barrier integrity.

Keywords:  IPEC-J2; butyrate; butyrate derivatives; porcine-alveolar macrophages; pro-inflammatory cytokines; transepithelial electrical resistance

DOI:  https://doi.org/10.3390/ani15091289
RSC Med Chem. 2025 May 13.

NLRP3 inflammasome: structure, mechanism, drug-induced organ toxicity, therapeutic strategies, and future perspectives.

Desh Deepak Singh.

Drug-induced toxicity is an important issue in clinical medicine, which typically results in organ dysfunction and adverse health consequences. The family of NOD-like receptors (NLRs) includes intracellular proteins involved in recognizing pathogens and triggering innate immune responses, including the activation of the NLRP3 inflammasome. The NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3) inflammasome is a critical component for both innate and adaptive immune responses and has been implicated in various drug-induced toxicities, including hepatic, renal, and cardiovascular diseases. The unusual activation of the NLRP3 inflammasome causes the release of pro-inflammatory cytokines, such as IL-1β and IL-18, which can lead to more damage to tissues. Targeting NLRP3 inflammasome is a potential therapeutic endeavour for suppressing drug-induced toxicity. This review provides insights into the mechanism, drug-induced organ toxicity, therapeutic strategies, and prospective therapeutic approaches of the NLRP3 inflammasome and summarizes the developing therapies that target the inflammasome unit. This review has taken up one of the foremost endeavours in understanding and inhibiting the NLRP3 inflammasome as a means of generating safer pharmacological therapies.

DOI: https://doi.org/10.1039/d5md00167f
Circ Heart Fail. 2025 May 13. e012350

Musclin Counteracts Skeletal Muscle Dysfunction and Exercise Intolerance in Heart Failure With Preserved Ejection Fraction.

Eng Leng Saw, Louis Dominic Werner, Hannah L Cooper, David R Pimental, Payman Zamani, Julio A Chirinos, María Valero-Muñoz, Flora Sam.

   BACKGROUND: Exercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF) and is characterized by skeletal muscle (SkM) dysfunction with impaired oxidative capacity. To maintain oxidative capacity, the SkM secretes myokines such as musclin, which has been shown to potentiate NP (natriuretic peptide) signaling and induce PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1 alpha) signaling. We sought to investigate the role of musclin in SkM dysfunction in HFpEF. For this study, we selected the oxidative-predominant SkM soleus in HFpEF mice and vastus lateralis from patients with HFpEF.
METHODS: Using the SAUNA model, mice underwent HFpEF induction by uninephrectomy, d-aldosterone infusion, and 1% sodium chloride drinking water for 4 weeks. Exogenous musclin was given to HFpEF mice every 2 days during the last 2 weeks of HFpEF induction. Molecular analyses were conducted on blood samples and SkM from HFpEF mice and patients with HFpEF.
RESULTS: In HFpEF mice and patients with HFpEF, increased musclin expression was accompanied by decreased cyclic guanosine monophosphate levels and PGC-1α expression in SkM, suggesting impaired NP signaling. Exogenous administration of musclin in mice with HFpEF demonstrated augmented circulating musclin levels and potentiated NP signaling in SkM as shown by increased PKG1 (protein kinase G1) activity and PGC-1α expression. This was associated with a transition from type-2A to type-1 fiber (type-1 has more endurance) and increased succinate dehydrogenase activity, hindlimb blood flow, and capillary density in the soleus muscle. Exogenous musclin also mitigated cardiac hypertrophy without affecting blood pressure or diastolic function. Most importantly, HFpEF mice treated with musclin demonstrated improved functional and exercise capacity.
CONCLUSIONS: Musclin mediates beneficial effects in SkM and heart with improved exercise capacity likely by improving oxidative capacity in SkM. Future studies are warranted to address the therapeutic efficacy of exogenous musclin in humans with HFpEF.

Keywords:  exercise tolerance; heart failure; muscle, skeletal; myokines; natriuretic peptides

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.012350
J Cell Sci. 2025 May 01. pii: jcs263895. [Epub ahead of print]138(9):

Mitochondria-membranous organelle contacts at a glance.

Antigoni Diokmetzidou, Luca Scorrano.

  Mitochondrial contact sites are specialized interfaces where mitochondria physically interact with other organelles. Stabilized by molecular tethers and defined by unique proteomic and lipidomic profiles, these sites enable direct interorganellar communication and functional coordination, playing crucial roles in cellular physiology and homeostasis. Recent advances have expanded our knowledge of contact site-resident proteins, illuminated the dynamic and adaptive nature of these interfaces, and clarified their contribution to pathophysiology. In this Cell Science at a Glance article and the accompanying poster, we summarize the mitochondrial contacts that have been characterized in mammals, the molecular mechanisms underlying their formation, and their principal functions.

Keywords:  Contact sites; Mitochondria; Organelles

DOI:  https://doi.org/10.1242/jcs.263895
Cancer Res Commun. 2025 May 16.

NLRP3 inflammasome activation expands immunosuppressive myeloid stroma and antagonizes the therapeutic benefit of STING activation in glioblastoma.

Spencer T Lea, Chao-Hsien Chen, Jun Wei, Ivana William, Ines Lopez Del Castillo, Michael A Curran.

Glioblastoma is the most common and deadly primary brain malignancy and is clinically refractory to immunotherapy. Active NLRP3 inflammasome signaling and IL-1β secretion has been observed in glioblastoma (GBM), and NLRP3-driven myeloid derived suppressor cell (MDSC) recruitment can mediate cancer immune evasion. Agonists of the cytosolic dsDNA-sensing Stimulator of Interferon Genes (STING) pathway can mediate proinflammatory conversion of cancer MDSC; however, secretion of the NLRP3 products IL-1β and IL-18 has also been observed in certain myeloid populations following STING activation. Here we aimed to determine both the potential mechanistic synergy between STING and NLRP3 agonists, and the effects of this innate immune combination on the GBM tumor immune landscape. We find that STING activation does not prime pro-IL-1β expression for activated NLRP3 inflammasome secretion. In subcutaneous GL261 GBM, we show that NLRP3 activation expands the immunosuppressive myeloid stroma primarily via granulocytic MDSC recruitment and antagonizes the benefit of STING activation. In brain GL261, we find that NLRP3 activation expands granulocytic MDSC but does not antagonize the therapeutic benefit of STING activation. Finally, we report that mesenchymal subtype GBM tumors have elevated neutrophil, IL-1β , and NLRP3 gene expression, a setting where our data suggests NLRP3 activation could counteract STING agonists.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0189
J Physiol Biochem. 2025 May 16.

Effects of high-intensity interval training on metabolic impairments in liver tissue of rats with type 2 diabetes: a metabolomics-based approach.

Kayvan Khoramipour, Mohammad Amin Rajizadeh, Mohammad Khaksari, Mansour Aminzadeh, Paula Crespo-Escobar, Alejandro Santos-Lozano, Mohammad Arjmand.

  Our aim was to study the metabolic effects of eight weeks of high-intensity interval training (HIIT) on the liver of rats with type 2 diabetes (T2D) using untargeted metabolomics. Twenty male Wistar rats, were divided into four groups (n = 5 per group): control (CTL), type 2 diabetes (DB), HIIT (EX), and type 2 diabetes + HIIT (DTX). A two months of a high-fat diet followed by a single dose of streptozotocin (35 mg/kg body weight) was used to induce T2D. Animals in the EX and DTX groups were trained for eight weeks (5 times per week, 4-10 running intervals at 80-100% of their maximum velocity). Metabolomic data were collected using proton nuclear magnetic resonance (¹H-NMR) to assess metabolic changes in the liver after training. Data were then pre-processed using ProMetab (MATLAB) for baseline correction, normalisation and binning. Fasting blood glucose (FBG) levels were analysed using a repeated-measures mixed ANOVA [i.e., time as the within-subject factor (Baseline - Month 0, Post-induction - Month 2, and Post-intervention - Month 4) and gruop (CTL, DB, HIIT, DTX) as the between-subject factor]. A one-way ANOVA with Tukey's post hoc test (p < 0.05) was applied to assess differences in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Multivariate analysis - using sparse partial least squares discriminant analysis (sPLS-DA) - was performed to identify key metabolites, followed by pathway analysis (MetaboAnalyst) to determine significantly affected metabolic pathways. DB group showed higher HOMA-IR than CTL and DTX groups (p < 0.05). Furthermore, distinct clustering patterns was shown for metabolites by multivariate analysis. Key altered metabolic pathways included valine, leucine, and isoleucine biosynthesis; glutathione metabolism; pantothenate and coenzyme A biosynthesis; fructose and mannose metabolism; glycine, serine, and threonine metabolism; cysteine and methionine metabolism; arginine biosynthesis; tyrosine metabolism; histidine metabolism; beta-alanine metabolism; propanoate metabolism; glycolysis/gluconeogenesis; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine and proline metabolism; and thiamine metabolism. These results suggest that eight weeks of HIIT may reverse metabolic changes induced by T2D in the rat liver, potentially contributing to reduced FBG and HOMA-IR levels. Clinical trial number: Not applicable.

Keywords:  High-intensity interval training; Liver metabolism; Metabolomics; Type 2 diabetes

DOI:  https://doi.org/10.1007/s13105-025-01085-8
PLoS Comput Biol. 2025 May 12. 21(5): e1013052

How are estimated cellular turnover rates influenced by the dynamics of a source population?

Arpit C Swain, José A M Borghans, Rob J de Boer.

Estimating production and loss rates of cell populations is essential but difficult. The current state-of-the-art method to estimate these rates involves mathematical modelling of deuterium labelling experiments. Current models typically assume that the labelling in the precursors of the population of interest (POI) is proportional to the deuterium enrichment in body water/glucose. This assumption is not always true and it is known that this can have a significant effect on the rates estimated from labelling experiments. Here we quantify the effect that different turnover (replacement) rates of the precursors can have on the estimated proliferation and loss rates of a POI by explicitly modelling the dynamics of the precursors. We first confirm earlier results that the labelling curve of the POI only reflects its own turnover rate if either the turnover rate of the precursors is sufficiently fast, or the contribution from the precursors is sufficiently small. Next, we describe three realistic scenarios with a slowly turning over precursor population, and show how this changes the interpretation of the different parameter estimates. Our analyses underpin that uniquely identifying the turnover rate of a POI requires measurements (or knowledge) on the turnover of its immediate precursors.

DOI: https://doi.org/10.1371/journal.pcbi.1013052
Brain Res. 2025 May 12. pii: S0006-8993(25)00261-6. [Epub ahead of print] 149702

Unlocking the cellular mystery: how proton pump inhibitors may alter the dementia landscape.

Maneesh Mohan, Ashi Mannan, Shareen Singh, Thakur Gurjeet Singh.

  Proton pump inhibitors (PPIs) have become virtually the sole class of histamine-2 receptor antagonists due to their greater effectiveness and general availability. However, concern has been increasing about long-term use and some possible neurological adverse effects, including a link with dementia. Several studies indicate that long-term use of PPIs can raise the risk for both Alzheimer's disease (AD) and non-Alzheimer's dementia, though there is opposing evidence. Neurological side effects of PPIs are cognitive impairment, neuropathies, depression, anxiety, and hallucinations. The mechanisms are unknown but could be due to PPIs crossing the BBB and interfering with neuronal function or causing systemic deficiencies, e.g., vitamin B12 deficiency. Vitamin B12 is essential for cognitive function, and its deficiency has been linked to dementia. PPIs also cause B12 deficiency by inhibiting gastric acid secretion, which is required for B12 absorption. B12 deficiency causes hyperhomocysteinemia, which facilitates tau hyperphosphorylation and amyloid-β (Aβ) deposition, major pathological hallmarks of AD. PPIs have also been found to disrupt amyloid precursor protein processing, mitochondrial function, and neuroinflammation, further enhancing neurodegenerative processes. Experimental evidence indicates that PPIs affect brain homeostasis through inhibition of vacuolar ATPases, modulation of microglial Aβ phagocytosis, and induction of synaptic dysfunction. While the specific molecular mechanisms are unknown, findings suggest that long-term PPI exposure could contribute to neurodegeneration, especially in elderly patients. With increasing dementia prevalence, additional clinical research is needed to ascertain whether PPIs are a causative agent or a contributing factor to cognitive impairment.

Keywords:  Amyloid Beta (Aβ); Cognitive Decline; Dementia; Neurofibrillary Tangles (NFTs); Vitamin B12

DOI:  https://doi.org/10.1016/j.brainres.2025.149702