bims-kimdis 2024-03-24 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–03–24
28 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic Diet Alleviates Mechanical Allodynia in the Models of Inflammatory and Neuropathic Pain in Male Mice.
Endurance training increases mitochondrial myoglobin and enhances its interaction with complex IV in rat plantaris muscle.
Introduction and modification of the ketogenic diet in an adult patient with glucose transporter 1 deficiency syndrome.
Differential utilisation of subcellular skeletal muscle glycogen pools: a comparative analysis between 1 and 15 min of maximal exercise.
Monocarboxylate transporter 4 deficiency enhances high-intensity interval training-induced metabolic adaptations in skeletal muscle.
MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.
Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice.
Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.
Muscle-UCP3 in the regulation of energy metabolism.
A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
Skeletal muscle atrophy after sciatic nerve damage: Mechanistic insights.
ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury.
Muscle fibre typology affects whole-body metabolic rate during isolated muscle contractions and human locomotion.
Structural determinants of mitochondrial STAT3 targeting and function.
Targeting NAD+ Metabolism to Modulate Autoimmunity and Inflammation.
The NLRP3 inhibitor, OLT1177 attenuates brain injury in experimental intracerebral hemorrhage.
Treadmill training impacts the skeletal muscle molecular clock after ischemia stroke in rats.
Effects of aerobic exercise on the regulation of mitochondrial carrier homolog-2 and its influence on the catabolic and anabolic activity of lipids in the mesenteric adipose tissue of obese mice.
Exercise training improves diabetic renal injury by reducing fetuin-A, oxidative stress and inflammation in type 2 diabetic rats.
Novel chemotype NLRP3 inhibitors that target the CRID3-binding pocket with high potency.
Sodium butyrate activates the KATP channels to regulate the mechanism of Parkinson's disease microglia model inflammation.
Caloric Restriction Rejuvenates Skeletal Muscle Growth in Heart Failure With Preserved Ejection Fraction.
TGF-β signaling in health, disease, and therapeutics.
Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment.
Anti-inflammatory effect of echinacoside in collagen-induced arthritis via Nrf2/Drp1 pathway.
Plant-based and early time-restricted eating for the prevention and treatment of type 2 diabetes in adults: A narrative review.
A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.
INTERMITTENT FASTING AND LONGEVITY: FROM ANIMAL MODELS TO IMPLICATION FOR HUMANS.

Biol Pharm Bull. 2024 ;47(3): 629-634

Ketogenic Diet Alleviates Mechanical Allodynia in the Models of Inflammatory and Neuropathic Pain in Male Mice.

Kei Eto, Masanori Ogata, Yoshitaka Toyooka, Toru Hayashi, Hitoshi Ishibashi.

  Inflammation is involved in the induction of chronic inflammatory and neuropathic pain. Moreover, the ketogenic diet, a high-fat, low-carbohydrate, and adequate protein diet, has an anti-inflammatory effect. Thus, we hypothesized that a ketogenic diet has a therapeutic effect on both types of chronic pain. In the present study, we investigated the effect of a ketogenic diet on mechanical allodynia, a chronic pain symptom, in formalin-induced chronic inflammatory pain and nerve injury-induced neuropathic pain models using adult male mice. Formalin injection into the hind paw induced mechanical allodynia in both the injected and intact hind paws, and the ketogenic diet alleviated mechanical allodynia in both hind paws. In addition, the ketogenic diet prevented formalin-induced edema. Furthermore, the diet alleviated mechanical allodynia induced by peripheral nerve injury. Thus, these findings indicate that a ketogenic diet has a therapeutic effect on chronic pain induced by inflammation and nerve injury.

Keywords:  chronic pain; inflammation; ketogenic diet; nerve injury

DOI:  https://doi.org/10.1248/bpb.b23-00732
Acta Physiol (Oxf). 2024 Mar 21. e14139

Endurance training increases mitochondrial myoglobin and enhances its interaction with complex IV in rat plantaris muscle.

Rikuhide Koma, Tsubasa Shibaguchi, Tatsuya Yamada, Yudai Nonaka, Thomas Jue, Ayaka Yamazaki, Kazumi Masuda.

   AIM: Endurance exercise training is known to increase mitochondrial respiration in skeletal muscle. However, the molecular mechanisms behind this are not fully understood. Myoglobin (Mb) is a member of the globin family, which is highly expressed in skeletal and cardiac muscles. We recently found that Mb localizes inside mitochondria in skeletal muscle and interacts with cytochrome c oxidase subunit IV (COXIV), a subunit of mitochondrial complex IV, which regulates respiration by augmenting complex IV activity. In the present study, we investigated the effect of endurance training on Mb-COXIV interaction within mitochondria in rat skeletal muscle.
METHODS: Eight-week-old male Wistar rats were subjected to 6-week treadmill running training. Forty-eight hours after the last training session, the plantaris muscle was removed under anesthesia and used for biochemical analysis.
RESULTS: The endurance training increased mitochondrial content in the skeletal muscle. It also augmented complex IV-dependent oxygen consumption and complex IV activity in isolated mitochondria from skeletal muscle. Furthermore, endurance training increased Mb expression at the whole muscle level. Importantly, mitochondrial Mb content and Mb-COXIV binding were increased by endurance training.
CONCLUSION: These findings suggest that an increase in mitochondrial Mb and the concomitant enhancement of Mb interaction with COXIV may contribute to the endurance training-induced upregulation of mitochondrial respiration by augmenting complex IV activity.

Keywords:  mitochondrial localization; myoglobin; skeletal muscle

DOI:  https://doi.org/10.1111/apha.14139
Epileptic Disord. 2024 Mar 16.

Introduction and modification of the ketogenic diet in an adult patient with glucose transporter 1 deficiency syndrome.

Shin Nabatame, Kanako Kishimoto, Toshiyuki Mano.



Keywords:  adulthood; glucose transporter 1 deficiency syndrome; ketogenic diet; medium-chain triglyceride

DOI:  https://doi.org/10.1002/epd2.20218
J Physiol. 2024 Mar 19.

Differential utilisation of subcellular skeletal muscle glycogen pools: a comparative analysis between 1 and 15 min of maximal exercise.

Camilla Tvede Schytz, Niels Ørtenblad, Kasper Degn Gejl, Joachim Nielsen.

  In skeletal muscle, glycogen particles are distributed both within and between myofibrils, as well as just beneath the sarcolemma. Their precise localisation may influence their degradation rate. Here, we investigated how exercise at different intensities and durations (1- and 15-min maximal exercise) with known variations in glycogenolytic rate and contribution from anaerobic metabolism affects utilisation of the distinct pools. Furthermore, we investigated how decreased glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise affect the storage of glycogen particles (size, numerical density, localisation). Twenty participants were divided into two groups performing either a 1-min (n = 10) or a 15-min (n = 10) maximal cycling exercise test. In a randomised, counterbalanced, cross-over design, the exercise tests were performed following short-term consumption of two distinct diets with either high or moderate carbohydrate content (10 vs. 4 g kg-1 body mass (BM) day-1 ) mediating a difference in total energy consumption (240 vs. 138 g kg-1 BM day-1 ). Muscle biopsies from m. vastus lateralis were obtained before and after the exercise tests. Intermyofibrillar glycogen was preferentially utilised during the 1-min test, whereas intramyofibrillar glycogen was preferentially utilised during the 15-min test. Lowering carbohydrate and energy intake after glycogen-depleting exercise reduced glycogen availability by decreasing particle size across all pools and diminishing numerical density in the intramyofibrillar and subsarcolemmal pools. In conclusion, distinct subcellular glycogen pools were differentially utilised during 1-min and 15-min maximal cycling exercise. Additionally, lowered carbohydrate and energy consumption after glycogen-depleting exercise altered glycogen storage by reducing particle size and numerical density, depending on subcellular localisation. KEY POINTS: In human skeletal muscle, glycogen particles are localised in distinct subcellular compartments, referred to as intermyofibrillar, intramyofibrillar and subsarcolemmal pools. The intermyofibrillar and subsarcolemmal pools are close to mitochondria, while the intramyofibrillar pool is at a distance from mitochondria. We show that 1 min of maximal exercise is associated with a preferential utilisation of intermyofibrillar glycogen, and, on the other hand, that 15 min of maximal exercise is associated with a preferential utilisation of intramyofibrillar glycogen. Furthermore, we demonstrate that reduced glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise is characterised by a decreased glycogen particle size across all compartments, with the numerical density only diminished in the intramyofibrillar and subsarcolemmal compartments. These results suggest that exercise intensity influences the subcellular pools of glycogen differently and that the dietary content of carbohydrates and energy is linked to the size and subcellular distribution of glycogen particles.

Keywords:  carbohydrate; fatigue; high-intensity exercise; performance; skeletal muscle fibres; subcellular glycogen; transmission electron microscopy

DOI:  https://doi.org/10.1113/JP285762
J Physiol. 2024 Mar 21.

Monocarboxylate transporter 4 deficiency enhances high-intensity interval training-induced metabolic adaptations in skeletal muscle.

Yuki Tamura, Eunbin Jee, Karina Kouzaki, Takaya Kotani, Koichi Nakazato.

  High-intensity exercise stimulates glycolysis, subsequently leading to elevated lactate production within skeletal muscle. While lactate produced within the muscle is predominantly released into the circulation via the monocarboxylate transporter 4 (MCT4), recent research underscores lactate's function as an intercellular and intertissue signalling molecule. However, its specific intracellular roles within muscle cells remains less defined. In this study, our objective was to elucidate the effects of increased intramuscular lactate accumulation on skeletal muscle adaptation to training. To achieve this, we developed MCT4 knockout mice and confirmed that a lack of MCT4 indeed results in pronounced lactate accumulation in skeletal muscle during high-intensity exercise. A key finding was the significant enhancement in endurance exercise capacity at high intensities when MCT4 deficiency was paired with high-intensity interval training (HIIT). Furthermore, metabolic adaptations supportive of this enhanced exercise capacity were evident with the combination of MCT4 deficiency and HIIT. Specifically, we observed a substantial uptick in the activity of glycolytic enzymes, notably hexokinase, glycogen phosphorylase and pyruvate kinase. The mitochondria also exhibited heightened pyruvate oxidation capabilities, as evidenced by an increase in oxygen consumption when pyruvate served as the substrate. This mitochondrial adaptation was further substantiated by elevated pyruvate dehydrogenase activity, increased activity of isocitrate dehydrogenase - the rate-limiting enzyme in the TCA cycle - and enhanced function of cytochrome c oxidase, pivotal to the electron transport chain. Our findings provide new insights into the physiological consequences of lactate accumulation in skeletal muscle during high-intensity exercises, deepening our grasp of the molecular intricacies underpinning exercise adaptation. KEY POINTS: We pioneered a unique line of monocarboxylate transporter 4 (MCT4) knockout mice specifically tailored to the ICR strain, an optimal background for high-intensity exercise studies. A deficiency in MCT4 exacerbates the accumulation of lactate in skeletal muscle during high-intensity exercise. Pairing MCT4 deficiency with high-intensity interval training (HIIT) results in a synergistic boost in high-intensity exercise capacity, observable both at the organismal level (via a treadmill running test) and at the muscle tissue level (through an ex vivo muscle contractile function test). Coordinating MCT4 deficiency with HIIT enhances both the glycolytic enzyme activities and mitochondrial capacity to oxidize pyruvate.

Keywords:  exercise; glycolysis; high‐intensity interval training; lactate; metabolism; mitochondria; monocarboxylate transporter; skeletal muscle

DOI:  https://doi.org/10.1113/JP285719
Sci Rep. 2024 Mar 21. 14(1): 6751

MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.

Michael J Bround, Eaman Abay, Jiuzhou Huo, Julian R Havens, Allen J York, Donald M Bers, Jeffery D Molkentin.

Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo.

DOI: https://doi.org/10.1038/s41598-024-57340-3
Int J Biol Macromol. 2024 Mar 17. pii: S0141-8130(24)01767-7. [Epub ahead of print]265(Pt 1): 130962

Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice.

Makoto Harada, Siyu Han, Mengya Shi, Jianhong Ge, Shixiang Yu, Jonathan Adam, Jerzy Adamski, Markus F Scheerer, Susanne Neschen, Martin Hrabe de Angelis, Rui Wang-Sattler.

  Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.

Keywords:  Branched-chain amino acids; Diabetic ketoacidosis; Lactic acidosis; Metformin adds to SGLT2i; SGLT2i monotherapy

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.130962
Dev Cell. 2024 Mar 18. pii: S1534-5807(24)00110-2. [Epub ahead of print]

Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.

Daiana N Moretti-Horten, Carlotta Peselj, Asli Aras Taskin, Lisa Myketin, Uwe Schulte, Oliver Einsle, Friedel Drepper, Marcin Luzarowski, F-Nora Vögtle.

  Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio of the electron transport chain (ETC) and ATP synthase must be tightly controlled, and assembly requires coordinated integration of proteins encoded in the nuclear and mitochondrial genome. How correct OXPHOS stoichiometry is achieved is unknown. We identify the MitochondrialRegulatory hub for respiratoryAssembly (MiRA) platform, which synchronizes ETC and ATP synthase biogenesis in yeast. Molecularly, this is achieved by a stop-and-go mechanism: the uncharacterized protein Mra1 stalls complex IV assembly. Two "Go" signals are required for assembly progression: binding of the complex IV assembly factor Rcf2 and Mra1 interaction with an Atp9-translating mitoribosome induce Mra1 degradation, allowing synchronized maturation of complex IV and the ATP synthase. Failure of the stop-and-go mechanism results in cell death. MiRA controls OXPHOS assembly, ensuring correct stoichiometry of protein machineries encoded by two different genomes.

Keywords:  complex stoichiometry; mitochondria; mitoribosome; protein complex assembly; protein import; protein quality control; respiratory chain

DOI:  https://doi.org/10.1016/j.devcel.2024.02.011
Mitochondrion. 2024 Mar 16. pii: S1567-7249(24)00030-8. [Epub ahead of print] 101872

Muscle-UCP3 in the regulation of energy metabolism.

Lucio Della Guardia, Livio Luzi, Roberto Codella.

  Uncoupling protein-3 (UCP3) is a mitochondria-regulatory protein with potential energy- homeostatic functions. This study explores the role of UCP3 in the regulation of muscle- and energy metabolism. UCP3 is critical for tuning substrate utilization, favoring lipid oxidation, particularly in conditions of high-fat availability. While UCP3 is non-essential for lipid oxidation during energy excess, it proves vital during fasting, indicating an energy-homeostatic trait. Preliminary evidence indicates UCP3' promotion of glucose uptake and oxidation, at least in conditions of high glucose/low fat availability. However, the dynamics of how fats and glucose differentially influence UCP3 remain undefined. UCP3 exhibits inducible proton transport and uncoupling activity, operating in a dual manner: a resting state with no/low activity and an activated state in the presence of activators. Uncoupling may enhance thermogenesis in specific conditions and in the presence of activators such as fatty acids, thyroid hormones, and catecholamines. This energy-dissipative activity adapts to varying energy availability, balancing energy dissipation with fatty acid oxidation to optimize whole-body energy homeostasis: fasting triggers UCP3 upregulation, enhancing lipid utilization while suppressing uncoupling. Additionally, UCP3 upregulation induces glucose and lipid disposal from the bloodstream and decreases tri-/diglyceride storage in muscle. This process improves mitochondrial functionality and insulin signaling, leading to enhanced systemic gluco-metabolic balance and protection from metabolic conditions. Reviewed evidence suggests that UCP3 plays a crucial role in adapting the system to changing energy conditions. However, the precise role of UCP3 in regulating metabolism requires further elucidation.

Keywords:  Energy expenditure; Lipid oxidation; Metabolic diseases; Mitochondria; Thermogenesis; Uncoupling proteins

DOI:  https://doi.org/10.1016/j.mito.2024.101872
bioRxiv. 2024 Mar 07. pii: 2024.03.05.583623. [Epub ahead of print]

A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.

Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.

Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3×3×3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities 11 , thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.

DOI: https://doi.org/10.1101/2024.03.05.583623
Eur J Pharmacol. 2024 Mar 15. pii: S0014-2999(24)00194-8. [Epub ahead of print]970 176506

Skeletal muscle atrophy after sciatic nerve damage: Mechanistic insights.

Aarti Yadav, Rajesh Dabur.

  Sciatic nerve injury leads to molecular events that cause muscular dysfunction advancement in atrophic conditions. Nerve damage renders muscles permanently relaxed which elevates intracellular resting Ca2+ levels. Increased Ca2+ levels are associated with several cellular signaling pathways including AMPK, cGMP, PLC-β, CERB, and calcineurin. Also, multiple enzymes involved in the tricarboxylic acid cycle and oxidative phosphorylation are activated by Ca2+ influx into mitochondria during muscle contraction, to meet increased ATP demand. Nerve damage induces mitophagy and skeletal muscle atrophy through increased sensitivity to Ca2+-induced opening of the permeability transition pore (PTP) in mitochondria attributed to Ca2+, ROS, and AMPK overload in muscle. Activated AMPK interacts negatively with Akt/mTOR is a highly prevalent and well-described central pathway for anabolic processes. Over the decade several reports indicate abnormal behavior of signaling machinery involved in denervation-induced muscle loss but end up with some controversial outcomes. Therefore, understanding how the synthesis and inhibitory stimuli interact with cellular signaling to control muscle mass and morphology may lead to new pharmacological insights toward understanding the underlying mechanism of muscle loss after sciatic nerve damage. Hence, the present review summarizes the existing literature on denervation-induced muscle atrophy to evaluate the regulation and expression of differential regulators during sciatic damage.

Keywords:  Ca(2+) overload; Mitophagy; Muscle atrophy; Reactive oxygen species; Sciatic nerve injury

DOI:  https://doi.org/10.1016/j.ejphar.2024.176506
Hepatol Commun. 2024 Apr 01. pii: e0399. [Epub ahead of print]8(4):

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury.

Fei Li, Zhu Guan, Yiyun Gao, Yan Bai, Xinyu Zhan, Xingyue Ji, Jian Xu, Haoming Zhou, Zhuqing Rao.

BACKGROUND: Fatty livers are widely accepted as marginal donors for liver transplantation but are more susceptible to liver ischemia and reperfusion (IR) injury. Increased macrophage-related inflammation plays an important role in the aggravation of fatty liver IR injury. Here, we investigate the precise mechanism by which endoplasmic reticulum (ER) stress activates macrophage NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling by regulating mitochondrial calcium overload in fatty liver IR.
METHODS: Control- and high-fat diet-fed mice were subjected to a partial liver IR model. The ER stress, mitochondrial calcium levels, and NLRP3 signaling pathway in macrophages were analyzed.
RESULTS: Liver steatosis exacerbated liver inflammation and IR injury and enhanced NLRP3 activation in macrophages. Myeloid NLRP3 deficiency attenuated intrahepatic inflammation and fatty liver injury following IR. Mechanistically, increased ER stress and mitochondrial calcium overload were observed in macrophages obtained from mouse fatty livers after IR. Suppression of ER stress by tauroursodeoxycholic acid effectively downregulated mitochondrial calcium accumulation and suppressed NLRP3 activation in macrophages, leading to decreased inflammatory IR injury in fatty livers. Moreover, Xestospongin-C-mediated inhibition of mitochondrial calcium influx decreased reactive oxygen species (ROS) expression in macrophages after IR. Scavenging of mitochondrial ROS by mito-TEMPO suppressed macrophage NLRP3 activation and IR injury in fatty livers, indicating that excessive mitochondrial ROS production was responsible for macrophage NLRP3 activation induced by mitochondrial calcium overload. Patients with fatty liver also exhibited upregulated activation of NLRP3 and the ER stress signaling pathway after IR.
CONCLUSIONS: Our findings suggest that ER stress promotes mitochondrial calcium overload to activate ROS/NLRP3 signaling pathways within macrophages during IR-stimulated inflammatory responses associated with fatty livers.

DOI: https://doi.org/10.1097/HC9.0000000000000399
J Physiol. 2024 Mar 17.

Muscle fibre typology affects whole-body metabolic rate during isolated muscle contractions and human locomotion.

Wannes Swinnen, Eline Lievens, Wouter Hoogkamer, Friedl De Groote, Wim Derave, Benedicte Vanwanseele.

  The wide variation in muscle fibre type distribution across individuals, along with the very different energy consumption rates in slow versus fast muscle fibres, suggests that muscle fibre typology contributes to inter-individual differences in metabolic rate during exercise. However, this has been hard to demonstrate due to the gap between a single muscle fibre and full-body exercises. We investigated the isolated effect of triceps surae muscle contraction velocity on whole-body metabolic rate during cyclic contractions in individuals a priori selected for their predominantly slow (n = 11) or fast (n = 10) muscle fibre typology by means of proton magnetic resonance spectroscopy (1 H-MRS). Subsequently, we examined their whole-body metabolic rate during walking and running at 2 m/s, exercises with comparable metabolic rates but distinct triceps surae muscle force and velocity demands (walking: low force, high velocity; running: high force, low velocity). Increasing triceps surae contraction velocity during cyclic contractions elevated net whole-body metabolic rate for both typology groups. However, the slow group consumed substantially less net metabolic energy at the slowest contraction velocity, but the metabolic difference between groups diminished at faster velocities. Consistent with the more economic force production during slow contractions, the slow group exhibited lower metabolic rates than the fast group while running, whereas metabolic rates were similar during walking. These findings provide important insights into the influence of muscle fibre typology on whole-body metabolic rate and emphasize the importance of considering muscle mechanical demands to understand muscle fibre typology related differences in whole-body metabolic rates. KEY POINTS: Muscle fibre typology is often suggested to affect whole-body metabolic rate, yet convincing in vivo evidence is lacking. Using isolated plantar flexor muscle contractions in individuals a priori selected for their predominantly slow or fast muscle fibre typology, we demonstrated that having predominantly slow muscle fibres provides a metabolic advantage during slow muscle contractions, but this benefit disappeared at faster contractions. We extended these results to full-body exercises, where we demonstrated that higher proportions of slow fibres associated with better economy during running but not when walking. These findings provide important insights into the influence of muscle fibre typology on whole-body metabolic rate and emphasize the importance of considering muscle mechanical demands to understand muscle fibre typology related differences in whole-body metabolic rate.

Keywords:  contraction velocity; economy; locomotion; muscle fibre type; triceps surae

DOI:  https://doi.org/10.1113/JP285846
Mitochondrial Commun. 2024 ;2 1-13

Structural determinants of mitochondrial STAT3 targeting and function.

Isabelle J Marié, Tanaya Lahiri, Özlem Önder, Kojo S J Elenitoba-Johnson, David E Levy.

  Signal transducer and activator of transcription (STAT) 3 has been found within mitochondria in addition to its canonical role of shuttling between cytoplasm and nucleus during cytokine signaling. Mitochondrial STAT3 has been implicated in modulation of cellular metabolism, largely through effects on the respiratory electron transport chain. However, the structural requirements underlying mitochondrial targeting and function have remained unclear. Here, we show that mitochondrial STAT3 partitions between mitochondrial compartments defined by differential detergent solubility, suggesting that mitochondrial STAT3 is membrane associated. The majority of STAT3 was found in an SDS soluble fraction copurifying with respiratory chain proteins, including numerous components of the complex I NADH dehydrogenase, while a minor component was found with proteins of the mitochondrial translation machinery. Mitochondrial targeting of STAT3 required the amino-terminal domain, and an internal linker domain motif also directed mitochondrial translocation. However, neither the phosphorylation of serine 727 nor the presence of mitochondrial DNA was required for the mitochondrial localization of STAT3. Two cysteine residues in the STAT3 SH2 domain, which have been previously suggested to be targets for protein palmitoylation, were also not required for mitochondrial translocation, but were required for its function as an enhancer of complex I activity. These structural determinants of STAT3 mitochondrial targeting and function provide potential therapeutic targets for disrupting the activity of mitochondrial STAT3 in diseases such as cancer.

Keywords:  Electron transport chain; Mitochondrial import; Stat3

DOI:  https://doi.org/10.1016/j.mitoco.2024.01.001
J Immunol. 2024 Apr 01. 212(7): 1043-1050

Targeting NAD+ Metabolism to Modulate Autoimmunity and Inflammation.

Jing Wu, Kim Han, Michael N Sack.

NAD+ biology is involved in controlling redox balance, functioning as a coenzyme in numerous enzymatic reactions, and is a cofactor for Sirtuin enzymes and a substrate for multiple regulatory enzyme reactions within and outside the cell. At the same time, NAD+ levels are diminished with aging and are consumed during the development of inflammatory and autoimmune diseases linked to aberrant immune activation. Direct NAD+ augmentation via the NAD+ salvage and Priess-Handler pathways is being investigated as a putative therapeutic intervention to improve the healthspan in inflammation-linked diseases. In this review, we survey NAD+ biology and its pivotal roles in the regulation of immunity and inflammation. Furthermore, we discuss emerging studies evaluate NAD+ boosting in murine models and in human diseases, and we highlight areas of research that remain unresolved in understanding the mechanisms of action of these nutritional supplementation strategies.

DOI: https://doi.org/10.4049/jimmunol.2300693
Int Immunopharmacol. 2024 Mar 15. pii: S1567-5769(24)00387-4. [Epub ahead of print]131 111869

The NLRP3 inhibitor, OLT1177 attenuates brain injury in experimental intracerebral hemorrhage.

Mei Fang, Fan Xia, Jiayan Wang, Chengyang Wang, Bang Teng, Shenglan You, Manrui Li, Xiameng Chen, Xin Hu.

   BACKGROUND AND PURPOSE: It has been reported activation of NLRP3 inflammasome after intracerebral hemorrhage (ICH) ictus exacerbates neuroinflammation and brain injury. We hypothesized that inhibition of NLRP3 by OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could reduce brain edema and attenuate brain injury in experimental ICH.
METHODS: ICH was induced by injection of autologous blood into basal ganglia in mice models. Sixty-three C57Bl/6 male mice were randomly grouped into the sham, vehicle, OLT1177 (Dapansutrile, 200 mg/kg intraperitoneally) and treated for consecutive three days, starting from 1 h after ICH surgery. Behavioral test, brain edema, brain water content, blood-brain barrier integrity and vascular permeability, cell apoptosis, and NLRP3 and its downstream protein levels were measured.
RESULTS: OLT1177 significantly reduced cerebral edema after ICH and contributed to the attenuation of neurological deficits. OLT1177 could preserve blood-brain barrier integrity and lessen vascular leakage. In addition, OLT1177 preserved microglia morphological shift and significantly inhibited the activation of caspase-1 and release of IL-1β. We also found that OLT1177 can protect against neuronal loss in the affected hemisphere.
CONCLUSIONS: OLT1177 (dapansutrile) could significantly attenuate the brain edema after ICH and effectively alleviate the neurological deficit. This result suggests that the novel NLRP3 inhibitor, OLT1177, might serve as a promising candidate for the treatment of ICH.

Keywords:  Inflammation; Intracerebral Hemorrhage; NLRP3 inflammasome; OLT1177

DOI:  https://doi.org/10.1016/j.intimp.2024.111869
Heliyon. 2024 Mar 30. 10(6): e27430

Treadmill training impacts the skeletal muscle molecular clock after ischemia stroke in rats.

Mai Li, Yong Yin, Dongdong Qin.

   Objective: Stroke is frequently associated with muscle mass loss. Treadmill training is considered the most effective treatment for sarcopenia. Circadian rhythms are closely related to exercise and have been extensively studied. The skeletal muscle has its molecular clock genes. Exercise may regulate skeletal muscle clock genes. This study evaluated the effects of early treadmill training on the skeletal muscle molecular clock machinery in rats with stroke and determined the relationship of these changes with exercise-induced improvements in skeletal muscle health.
Materials and methods: Overall, 168 Sprague-Dawley rats were included in this study. We established an ischemic stroke rat model of sarcopenia. Finally, 144 rats were randomly allocated to four groups (36 per group): normal, sham, middle cerebral artery occlusion, and training. Neurological scores, rotating rod test, body weight, muscle circumference, wet weight, and hematoxylin-eosin staining were assessed. Twenty-four rats were used for transcriptome sequencing. Gene and protein expressions of skeletal muscles, such as brain muscle arnt-like 1, period 1, and period 2, were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays.
Results: Neurological function scores and rotating rod test results improved after treadmill training. Nine differentially expressed genes were identified by comparing the sham group with the hemiplegic side of the model group. Seventeen differentially expressed genes were identified between the hemiplegic and non-hemiplegic sides. BMAL1, PER1, and PER2 mRNA levels increased on both sides after treadmill training. BMAL1 expression increased, and PER1 expression decreased on both sides, whereas PER2 expression decreased on the hemiplegic side but increased on the non-hemiplegic side.
Conclusion: Treadmill training can mitigate muscle loss and regulate skeletal muscle clock gene expression following ischemic stroke. Exercise affects the hemiplegic side and has a positive regulatory effect on the non-hemiplegic side.

Keywords:  Circadian rhythm; Ischemia stroke; Sarcopenia; Skeletal muscle molecular clock; Treadmill training

DOI:  https://doi.org/10.1016/j.heliyon.2024.e27430
Life Sci. 2024 Mar 14. pii: S0024-3205(24)00156-5. [Epub ahead of print] 122567

Effects of aerobic exercise on the regulation of mitochondrial carrier homolog-2 and its influence on the catabolic and anabolic activity of lipids in the mesenteric adipose tissue of obese mice.

Diego Gomes de Melo, Vivian Cristina da Cruz Rodrigues, Gustavo José de Sá Pereira, Thais Dantis Pereira de Campos, Raphael Dos Santos Canciglieri, José Rodrigo Pauli, Adelino Sanchez Ramos da Silva, Célio Junior da Costa Fernandes, Leandro Pereira de Moura.

  The aim was to understand the direct impact of aerobic short-term exercise on lipid metabolism, specifically in regulating the mitochondrial carrier homolog 2 (MTCH2) and how it interferes with lipid metabolism in mesenteric adipose tissue. Swiss mice were divided into three groups: control, sedentary obese, and exercised obese. The obese groups were induced into obesity for fourteen weeks of a high-fat diet, and the trained submitted to seven aerobic exercise sessions. The exercise proved the significant increase of the pPerilipin-1, a hormone-sensitive lipase gene, and modulates lipid metabolism by increasing the expression of Mtch2 and acetyl Co-A carboxylase, perhaps occurring as feedback to regulate lipid metabolism in adipose tissue. In conclusion, we demonstrate, for the first time, how aerobic physical exercise increases Mtch2 transcription in mesenteric adipose tissue. This increase was due to changes in energy demand caused by exercise, confirmed by observing the significant reduction in mesenteric adipose tissue mass in the exercised group. Also, we showed that physical exercise increased the phosphorylative capacity of PLIN1, a protein responsible for the degradation of fatty acids in the lipid droplet, providing acyl and glycerol for cellular metabolism. Although our findings demonstrate evidence of MTCH2 as a protein that regulates lipid homeostasis, scant knowledge exists concerning the signaling of the MTCH2 pathway in regulatingfatty acid metabolism. Therefore, unveiling the means of molecular signaling of MTCH2 demonstrates excellent potential for treating obesity.

Keywords:  Aerobic training; Inflammation; Mesenteric adipose tissue; Mitochondria; Obesity

DOI:  https://doi.org/10.1016/j.lfs.2024.122567
Heliyon. 2024 Mar 30. 10(6): e27749

Exercise training improves diabetic renal injury by reducing fetuin-A, oxidative stress and inflammation in type 2 diabetic rats.

Shadan Saberi, Majid Askaripour, Mohammad Khaksari, Mohammad Amin Rajizadeh, Mohammad Abbas Bejeshk, Mohammad Akhbari, Elham Jafari, Kayvan Khoramipour.

   Background: Diabetic kidney disease (DKD) stands as a primary contributor to end-stage renal disease, associated with heightened mortality in cardiovascular diseases. This study aimed to explore the impact of an eight-week high-intensity interval training (HIIT) on renal injury in diabetic rats.
Methods: Twenty-eight male Wistar rats were randomly allocated into four groups: healthy control (CTL), diabetic control (DC), exercise (EX), and diabetes-exercise (D + EX). Induction of diabetes in the DC and D + EX groups occurred through a two-month high-fat diet followed by a single dose of 35 mg/kg streptozotocin (STZ). Rats in the EX and D + EX groups underwent 4-10 intervals of HIIT (80-100% Vmax) over 8 weeks. Subsequently, pathological and biochemical parameters were assessed in the serum and kidney tissue of the experimental groups.
Results: In the DC group, diabetes led to elevated kidney damage, glomerulosclerosis, fasting blood glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index, animal weight, kidney dysfunction, albuminuria, and glomerular filtration rate. Additionally, serum and kidney levels of fetuin-A increased, along with kidney levels of KIM-1. Mechanistically, diabetes induction resulted in kidney inflammation by elevating levels of tumor necrosis factor-alpha (TNF-α), transforming growth factor beta (TGF-β), and interleukin 6 (IL-6), while reducing IL-10 levels and increasing the IL-6/IL-10 ratio. Furthermore, diabetes triggered renal oxidative stress, evidenced by increased Malondialdehyde (MDA) levels and decreased levels of glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD). HIIT mitigated the adverse effects of diabetes in the D + EX group compared to the DC group.
Conclusion: Our findings suggest that HIIT ameliorates type 2 diabetes (T2D)-induced kidney damage by mitigating inflammation, lowering serum levels of fetuin-A, and bolstering antioxidant defenses. This study highlights the potential of HIIT as a time-efficient intervention for diabetic nephropathy.

Keywords:  Diabetic kidney disease; Fetuin-A; High-intensity interval training; Inflammation; Kim-1; Oxidative stress

DOI:  https://doi.org/10.1016/j.heliyon.2024.e27749
Life Sci Alliance. 2024 Jun;pii: e202402644. [Epub ahead of print]7(6):

Novel chemotype NLRP3 inhibitors that target the CRID3-binding pocket with high potency.

Lieselotte Vande Walle, Madhukar Said, Oonagh Paerewijck, Arinna Bertoni, Marco Gattorno, Bruno Linclau, Mohamed Lamkanfi.

The NLRP3 inflammasome plays a central role in various human diseases. Despite significant interest, most clinical-grade NLRP3 inhibitors are derived from sulfonylurea inhibitor CRID3 (also called MCC950). Here, we describe a novel chemical class of NLRP3-inhibiting compounds (NIC) that exhibit potent and selective NLRP3 inflammasome inhibition in human monocytes and mouse macrophages. BRET assays demonstrate that they physically interact with NLRP3. Structural modeling further reveals they occupy the same binding site of CRID3 but in a critically different conformation. Furthermore, we show that NIC-11 and NIC-12 lack the off-target activity of CRID3 against the enzymatic activity of carbonic anhydrases I and II. NIC-12 selectively reduces circulating IL-1ß levels in the LPS-endotoxemia model in mice and inhibits NLRP3 inflammasome activation in CAPS patient monocytes and mouse macrophages with about tenfold increased potency compared with CRID3. Altogether, this study unveils a new chemical class of highly potent and selective NLRP3-targeted inhibitors with a well-defined molecular mechanism to complement existing CRID3-based NLRP3 inhibitors in pharmacological studies and serve as novel chemical leads for the development of NLRP3-targeted therapies.

DOI: https://doi.org/10.26508/lsa.202402644
Immun Inflamm Dis. 2024 Mar;12(3): e1194

Sodium butyrate activates the KATP channels to regulate the mechanism of Parkinson's disease microglia model inflammation.

Ye Xu, Laofu Wen, Yunyi Tang, Zhenqiang Zhao, Miaojing Xu, Tan Wang, Zhibin Chen.

   BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder. Microglia-mediated neuroinflammation has emerged as an involving mechanism at the initiation and development of PD. Activation of adenosine triphosphate (ATP)-sensitive potassium (KATP ) channels can protect dopaminergic neurons from damage. Sodium butyrate (NaB) shows anti-inflammatory and neuroprotective effects in some animal models of brain injury and regulates the KATP channels in islet β cells. In this study, we aimed to verify the anti-inflammatory effect of NaB on PD and further explored potential molecular mechanisms.
METHODS: We established an in vitro PD model in BV2 cells using 1-methyl-4-phenylpyridinium (MPP+ ). The effects of MPP+ and NaB on BV2 cell viability were detected by cell counting kit-8 assays. The morphology of BV2 cells with or without MPP+ treatment was imaged via an optical microscope. The expression of Iba-1 was examined by the immunofluorescence staining. The intracellular ATP content was estimated through the colorimetric method, and Griess assay was conducted to measure the nitric oxide production. The expression levels of pro-inflammatory cytokines and KATP channel subunits were evaluated by reverse transcription-quantitative polymerase chain reaction and western blot analysis.
RESULTS: NaB (5 mM) activated the KATP channels through elevating Kir6.1 and Kir6.1 expression in MPP+ -challenged BV2 cells. Both NaB and pinacidil (a KATP opener) suppressed the MPP+ -induced activation of BV2 cells and reduced the production of nitrite and pro-inflammatory cytokines in MPP+ -challenged BV2 cells.
CONCLUSION: NaB treatment alleviates the MPP+ -induced inflammatory responses in microglia via activation of KATP channels.

Keywords:  ATP-sensitive potassium channels; Parkinson's disease; microglia; neuroinflammation; sodium butyrate

DOI:  https://doi.org/10.1002/iid3.1194
JACC Basic Transl Sci. 2024 Feb;9(2): 223-240

Caloric Restriction Rejuvenates Skeletal Muscle Growth in Heart Failure With Preserved Ejection Fraction.

Ever Espino-Gonzalez, Peter G Tickle, Raffaele Altara, Harrison Gallagher, Chew W Cheng, Viktor Engman, Nathanael Wood, Gustavo Jose Justo da Silva, Mattia Scalabrin, Xinyue Yu, Ziyi Zhong, Michael A Colman, Nadira Y Yuldasheva, George W Booz, Volker Adams, Marcelo G Pereira, Alessandro Cataliotti, Lee D Roberts, Stuart Egginton, T Scott Bowen.

  Heart failure with preserved ejection fraction (HFpEF) is a major clinical problem, with limited treatments. HFpEF is characterized by a distinct, but poorly understood, skeletal muscle pathology, which could offer an alternative therapeutic target. In a rat model, we identified impaired myonuclear accretion as a mechanism for low myofiber growth in HFpEF following resistance exercise. Acute caloric restriction rescued skeletal muscle pathology in HFpEF, whereas cardiac therapies had no effect. Mechanisms regulating myonuclear accretion were dysregulated in patients with HFpEF. Overall, these findings may have widespread implications in HFpEF, indicating combined dietary with exercise interventions as a beneficial approach to overcome skeletal muscle pathology.

Keywords:  HFpEF; diet; exercise training; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1016/j.jacbts.2023.09.014
Signal Transduct Target Ther. 2024 Mar 22. 9(1): 61

TGF-β signaling in health, disease, and therapeutics.

Ziqin Deng, Tao Fan, Chu Xiao, He Tian, Yujia Zheng, Chunxiang Li, Jie He.

Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.

DOI: https://doi.org/10.1038/s41392-024-01764-w
Cell Death Discov. 2024 Mar 20. 10(1): 148

Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment.

Yong Liu, Jin-Ling Huo, Kaidi Ren, Shaokang Pan, Hengdao Liu, Yifeng Zheng, Jingfang Chen, Yingjin Qiao, Yang Yang, Qi Feng.

Diabetic cardiomyopathy (DCM), an important complication of diabetes mellitus (DM), is one of the most serious chronic heart diseases and has become a major cause of heart failure worldwide. At present, the pathogenesis of DCM is unclear, and there is still a lack of effective therapeutics. Previous studies have shown that the homeostasis of mitochondria and the endoplasmic reticulum (ER) play a core role in maintaining cardiovascular function, and structural and functional abnormalities in these organelles seriously impact the occurrence and development of various cardiovascular diseases, including DCM. The interplay between mitochondria and the ER is mediated by the mitochondria-associated ER membrane (MAM), which participates in regulating energy metabolism, calcium homeostasis, mitochondrial dynamics, autophagy, ER stress, inflammation, and other cellular processes. Recent studies have proven that MAM is closely related to the initiation and progression of DCM. In this study, we aim to summarize the recent research progress on MAM, elaborate on the key role of MAM in DCM, and discuss the potential of MAM as an important therapeutic target for DCM, thereby providing a theoretical reference for basic and clinical studies of DCM treatment.

DOI: https://doi.org/10.1038/s41420-024-01918-3
Adv Clin Exp Med. 2024 Mar 20.

Anti-inflammatory effect of echinacoside in collagen-induced arthritis via Nrf2/Drp1 pathway.

Xiaoyan Wang, Lingxinyu Li, Mengyun Zhang, Ruike Ji, Na Li, Kun Wang, Zhufeng Chen.

   BACKGROUND: Oxidative damage plays an important role in the progression of rheumatoid arthritis (RA). Emerging research evidence suggests that natural antioxidants may effectively ameliorate this disease.
OBJECTIVES: To investigate the therapeutic effect of echinacoside (ECH) in a collagen-induced arthritis (CIA) mouse model and thus elucidate the underlying molecular mechanism in RA.
MATERIAL AND METHODS: Collagen-induced arthritis mice were intraperitoneally administered 1% dimethyl sulfoxide (DMSO) (control) or 0.6 mg of ECH every other day for 1 month. Arthritis scores and the number of affected paws were assessed. On day 60, mice were euthanized, synovial tissue specimens were obtained, and serum interleukin (IL)-6 and IL-1â expression levels were measured. Mitochondrial morphologies, reactive oxygen species (ROS) content, expression of dynamin-related protein 1 (Drp1), IL-6, nod-like receptor protein 3 (NLRP3), kelch-like ECH-associated protein 1 (Keap1), and nuclear factor-erythroid-2-related factor 2 (Nrf2) contents in synovium were analyzed and compared between DMSOand ECH-treated CIA mice.
RESULTS: Following ECH treatment, mitochondria of CIA-induced mice were found to be elongated, while their arthritis scores, inflammation and the number of affected paws, and the expression levels of Drp1, NLRP3, IL-6, ROS, and Keap1 were all found to be significantly reduced. Conversely, the level of antioxidant factor Nrf2 was found to be elevated. Further, mitochondrial fission was found to be inhibited in synovial tissues.
CONCLUSIONS: Our findings validate the therapeutic efficacy of ECH in the CIA mouse model. Echinacoside may suppress oxidative stress and inhibit inflammation by regulating the Nrf2/Drp1 pathway, thus supporting its utility in the treatment of RA.

Keywords:  Drp1 protein; antioxidant effect; echinacoside; mitochondrial fission; rheumatoid arthritis

DOI:  https://doi.org/10.17219/acem/184640
Can J Diabetes. 2024 Mar 19. pii: S1499-2671(24)00058-3. [Epub ahead of print]

Plant-based and early time-restricted eating for the prevention and treatment of type 2 diabetes in adults: A narrative review.

David M Goldman, Cassandra B Warbeck, Thomas J Waterfall, Adam Sud, Michael Quarshie, Joel C Craddock.

  Type 2 diabetes (T2D) is a significant public health challenge for which effective lifestyle interventions are needed. A growing body of evidence supports the use of both plant-based eating patterns and early time-restricted eating (eTRE) for the prevention and treatment of T2D, but research has not yet explored the potential of these dietary strategies in combination. This narrative review assessed the evidence by which plant-based diets, in conjunction with eTRE, could support T2D care. The electronic databases Medline and the Web of Science were searched for relevant articles published throughout the last decade. Observational research has found that healthy plant-based eating patterns and eTRE are associated with reductions in T2D risk. Interventional trials demonstrated that plant-based diets promote improvements in A1C, insulin resistance, glycemic control, and cardiometabolic risk factors. These changes may be mediated, in part, by reductions in oxidative stress, dietary acid load, and hepatocellular and intramyocellular lipids. Early TRE strategies were also shown to improve insulin resistance and glycemic control, and mechanisms of action included enhanced regulation of circadian rhythm and increased metabolic flexibility. Integrating these dietary strategies may produce additive benefits, mediated by reduced visceral adiposity and beneficial shifts in gut microbiota composition. However, potential barriers to concurrent implementation of these interventions may exist, including social challenges, scheduling constraints, and tolerance. Prospective trials are needed to examine their acceptability and clinical effects.

Keywords:  early time-restricted eating; intermittent fasting; plant-based diets; type 2 diabetes; vegan diets; vegetarian diets

DOI:  https://doi.org/10.1016/j.jcjd.2024.03.002
Mol Neurodegener. 2024 Mar 19. 19(1): 26

A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.

Rebecca Z Fan, Carolina Sportelli, Yanhao Lai, Said S Salehe, Jennifer R Pinnell, Harry J Brown, Jason R Richardson, Shouqing Luo, Kim Tieu.

   BACKGROUND: Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial dynamics. Partial inhibition of this protein is protective in experimental models of neurological disorders such as Parkinson's disease and Alzheimer's disease. The protective mechanism has been attributed primarily to improved mitochondrial function. However, the observations that Drp1 inhibition reduces protein aggregation in such neurological disorders suggest the involvement of autophagy. To investigate this potential novel protective mechanism of Drp1 inhibition, a model with impaired autophagy without mitochondrial involvement is needed.
METHODS: We characterized the effects of manganese (Mn), which causes parkinsonian-like symptoms in humans, on autophagy and mitochondria by performing dose-response studies in two cell culture models (stable autophagy HeLa reporter cells and N27 rat immortalized dopamine neuronal cells). Mitochondrial function was assessed using the Seahorse Flux Analyzer. Autophagy flux was monitored by quantifying the number of autophagosomes and autolysosomes, as well as the levels of other autophagy proteins. To strengthen the in vitro data, multiple mouse models (autophagy reporter mice and mutant Drp1+/- mice and their wild-type littermates) were orally treated with a low chronic Mn regimen that was previously reported to increase α-synuclein aggregation and transmission via exosomes. RNAseq, laser captured microdissection, immunofluorescence, immunoblotting, stereological cell counting, and behavioural studies were used. RESULTS IN VITRO: data demonstrate that at low non-toxic concentrations, Mn impaired autophagy flux but not mitochondrial function and morphology. In the mouse midbrain, RNAseq data further confirmed autophagy pathways were dysregulated but not mitochondrial related genes. Additionally, Mn selectively impaired autophagy in the nigral dopamine neurons but not the nearby nigral GABA neurons. In cells with a partial Drp1-knockdown and Drp1+/- mice, Mn induced autophagic impairment was significantly prevented. Consistent with these observations, Mn increased the levels of proteinase-K resistant α-synuclein and Drp1-knockdown protected against this pathology.
CONCLUSIONS: This study demonstrates that improved autophagy flux is a separate mechanism conferred by Drp1 inhibition independent of its role in mitochondrial fission. Given that impaired autophagy and mitochondrial dysfunction are two prominent features of neurodegenerative diseases, the combined protective mechanisms targeting these two pathways conferred by Drp1 inhibition make this protein an attractive therapeutic target.

Keywords:  Autophagy; Dynamin related protein 1; Manganese; Mitochondrial dynamics; Mitochondrial dysfunction; Parkinson’s disease; Protein aggregation; α-synuclein

DOI:  https://doi.org/10.1186/s13024-024-00708-w
Ageing Res Rev. 2024 Mar 16. pii: S1568-1637(24)00092-8. [Epub ahead of print] 102274

INTERMITTENT FASTING AND LONGEVITY: FROM ANIMAL MODELS TO IMPLICATION FOR HUMANS.

Olha Strilbytska, Svitlana Klishch, Kenneth B Storey, Alexander Koliada, Oleh Lushchak.

  In recent years, intermittent fasting (IF) and its numerous modifications have been increasingly suggested as a promising therapy for age-related problems and a non-pharmacological strategy to extend lifespan. Despite the great variability in feeding schedules that we describe in the current work, underlying physiological processes are the same and include a periodic switch from glucose metabolism (generated by glycogenolysis) to fatty acids and fatty acid-derived ketones. Many of the beneficial effects of IF appear to be mediated by optimization of energy utilization. Findings to date from both human and animal experiments indicate that fasting improves physiological function, enhances performance, and slows aging and disease processes. In this review, we discuss some of the remarkable discoveries about the beneficial effects of IF on metabolism, endocrine and cardiovascular systems, cancer prevention, brain health, neurodegeneration and aging. Experimental studies on rodent models and human investigations are summarized to compare the outcomes and underlying mechanisms of IF. Metabolic and cellular responses triggered by IF could help to achieve the aim of preventing disease, and maximizing healthspan and longevity with minimal side effects.

Keywords:  aging; health; intermittent fasting; nutrition

DOI:  https://doi.org/10.1016/j.arr.2024.102274