bims-kimdis 2024-03-03 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

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

Assessment of a one-week ketogenic diet on brain glycolytic metabolism and on the status epilepticus stage of a lithium-pilocarpine rat model.
Metabolic flexibility in postmenopausal women: Hormone replacement therapy is associated with higher mitochondrial content, respiratory capacity, and lower total fat mass.
A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults.
Effectiveness of high-fat and high-carbohydrate diets on body composition and maximal strength after 15 weeks of resistance training.
Suppression of NLRP3 inflammasome activation by astragaloside IV via promotion of mitophagy to ameliorate radiation-induced renal injury in mice.
The efficacy of low glycemic index diet on seizure frequency in pediatric patients with epilepsy: A systematic review and meta-analysis.
Monocyte NLRP3 inflammasome and interleukin-1β activation modulated by alpha-1 antitrypsin therapy in deficient individuals.
High-Resolution Respirometry for Mitochondrial Function in Rodent Brain.
Mitochondria in disease: changes in shapes and dynamics.
Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model.
MtDNA deletions and aging.
Dietary sodium acetate and sodium butyrate attenuate intestinal damage and improve lipid metabolism in juvenile largemouth bass (Micropterus salmoides) fed a high carbohydrate diet by reducing endoplasmic reticulum stress.
Alternate Day Fasting Leads to Improved Post-Stroke Motor Recovery in Mice.
New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation.
Role of mitochondrial potassium channels in ageing.
Mitochondrial derived vesicles- Quo Vadis?
Time-restricted feeding restores metabolic flexibility in adult mice with excess adiposity.
SERCA-1 conformational change exerted by the Ca2+-channel blocker diltiazem affects mammalian skeletal muscle function.

Sci Rep. 2024 Mar 01. 14(1): 5063

Assessment of a one-week ketogenic diet on brain glycolytic metabolism and on the status epilepticus stage of a lithium-pilocarpine rat model.

Matthieu Doyen, Clémentine Lambert, Emilie Roeder, Henri Boutley, Bailiang Chen, Julien Pierson, Antoine Verger, Emmanuel Raffo, Gilles Karcher, Pierre-Yves Marie, Fatiha Maskali.

The ketogenic diet (KD) has been shown to be effective in refractory epilepsy after long-term administration. However, its interference with short-term brain metabolism and its involvement in the early process leading to epilepsy remain poorly understood. This study aimed to assess the effect of a short-term ketogenic diet on cerebral glucose metabolic changes, before and after status epilepticus (SE) in rats, by using [18F]-FDG PET. Thirty-nine rats were subjected to a one-week KD (KD-rats, n = 24) or to a standard diet (SD-rats, n = 15) before the induction of a status epilepticus (SE) by lithium-pilocarpine administrations. Brain [18F]-FDG PET scans were performed before and 4 h after this induction. Morphological MRIs were acquired and used to spatially normalize the PET images which were then analyzed voxel-wisely using a statistical parametric-based method. Twenty-six rats were analyzed (KD-rats, n = 15; SD-rats, n = 11). The 7 days of the KD were associated with significant increases in the plasma β-hydroxybutyrate level, but with an unchanged glycemia. The PET images, recorded after the KD and before SE induction, showed an increased metabolism within sites involved in the appetitive behaviors: hypothalamic areas and periaqueductal gray, whereas no area of decreased metabolism was observed. At the 4th hour following the SE induction, large metabolism increases were observed in the KD- and SD-rats in areas known to be involved in the epileptogenesis process late-i.e., the hippocampus, parahippocampic, thalamic and hypothalamic areas, the periaqueductal gray, and the limbic structures (and in the motor cortex for the KD-rats only). However, no statistically significant difference was observed when comparing SD and KD groups at the 4th hour following the SE induction. A one-week ketogenic diet does not prevent the status epilepticus (SE) and associated metabolic brain abnormalities in the lithium-pilocarpine rat model. Further explorations are needed to determine whether a significant prevention could be achieved by more prolonged ketogenic diets and by testing this diet in less severe experimental models, and moreover, to analyze the diet effects on the later and chronic stages leading to epileptogenesis.

DOI: https://doi.org/10.1038/s41598-024-53824-4
Acta Physiol (Oxf). 2024 Feb 25. e14117

Metabolic flexibility in postmenopausal women: Hormone replacement therapy is associated with higher mitochondrial content, respiratory capacity, and lower total fat mass.

A S Kleis-Olsen, J E Farlov, E A Petersen, M Schmücker, M Flensted-Jensen, I Blom, A Ingersen, M Hansen, J W Helge, F Dela, S Larsen.

   AIM: To investigate effects of hormone replacement therapy in postmenopausal women on factors associated with metabolic flexibility related to whole-body parameters including fat oxidation, resting energy expenditure, body composition and plasma concentrations of fatty acids, glucose, insulin, cortisol, and lipids, and for the mitochondrial level, including mitochondrial content, respiratory capacity, efficiency, and hydrogen peroxide emission.
METHODS: 22 postmenopausal women were included. 11 were undergoing estradiol and progestin treatment (HT), and 11 were matched non-treated controls (CONT). Peak oxygen consumption, maximal fat oxidation, glycated hemoglobin, body composition, and resting energy expenditure were measured. Blood samples were collected at rest and during 45 min of ergometer exercise (65% VO2 peak). Muscle biopsies were obtained at rest and immediately post-exercise. Mitochondrial respiratory capacity, efficiency, and hydrogen peroxide emission in permeabilized fibers and isolated mitochondria were measured, and citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activity were assessed.
RESULTS: HT showed higher absolute mitochondrial respiratory capacity and post-exercise hydrogen peroxide emission in permeabilized fibers and higher CS and HAD activities. All respiration normalized to CS activity showed no significant group differences in permeabilized fibers or isolated mitochondria. There were no differences in resting energy expenditure, maximal, and resting fat oxidation or plasma markers. HT had significantly lower visceral and total fat mass compared to CONT.
CONCLUSION: Use of hormone therapy is associated with higher mitochondrial content and respiratory capacity and a lower visceral and total fat mass. Resting energy expenditure and fat oxidation did not differ between HT and CONT.

Keywords:  hormone replacement therapy; metabolic flexibility; mitochondrial function

DOI:  https://doi.org/10.1111/apha.14117
BMJ Open. 2024 Feb 27. 14(2): e076518

A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults.

Claire McDonald, Craig Alderson, Matthew G Birkbeck, Laura Brown, Silvia Del Din, Grainne G Gorman, Kieren Hollingsworth, Clare Massarella, Rana Rehman, Lynn Rochester, Avan Ap Sayer, Huizhong Su, Helen Tuppen, Charlotte Warren, Miles D Witham.

   INTRODUCTION: Sarcopenia is the age-associated loss of muscle mass and strength. Nicotinamide adenine dinucleotide (NAD) plays a central role in both mitochondrial function and cellular ageing processes implicated in sarcopenia. NAD concentrations are low in older people with sarcopenia, and increasing skeletal muscle NAD concentrations may offer a novel therapy for this condition. Acipimox is a licensed lipid-lowering agent known to act as an NAD precursor. This open-label, uncontrolled, before-and-after proof-of-concept experimental medicine study will test whether daily supplementation with acipimox improves skeletal muscle NAD concentrations.
METHODS AND ANALYSIS: Sixteen participants aged 65 and over with probable sarcopenia will receive acipimox 250 mg and aspirin 75 mg orally daily for 4 weeks, with the frequency of acipimox administration being dependent on renal function. Muscle biopsy of the vastus lateralis and MRI scanning of the lower leg will be performed at baseline before starting acipimox and after 3 weeks of treatment. Adverse events will be recorded for the duration of the trial. The primary outcome, analysed in a per-protocol population, is the change in skeletal muscle NAD concentration between baseline and follow-up. Secondary outcomes include changes in phosphocreatine recovery rate by 31P magnetic resonance spectroscopy, changes in physical performance and daily activity (handgrip strength, 4 m walk and 7-day accelerometry), changes in skeletal muscle mitochondrial respiratory function, changes in skeletal muscle mitochondrial DNA copy number and changes in NAD concentrations in whole blood as a putative biomarker for future participant selection.
ETHICS AND DISSEMINATION: The trial is approved by the UK Medicines and Healthcare Products Regulatory Agency (EuDRACT 2021-000993-28) and UK Health Research Authority and Northeast - Tyne and Wear South Research Ethics Committee (IRAS 293565). Results will be made available to participants, their families, patients with sarcopenia, the public, regional and national clinical teams, and the international scientific community.
PROTOCOL: Acipimox feasibility study Clinical Trial Protocol V.2 2/11/21.
TRIAL REGISTRATION NUMBER: The ISRCTN trial database (ISRCTN87404878).

Keywords:  Aging; Clinical Trial; Neuromuscular disease

DOI:  https://doi.org/10.1136/bmjopen-2023-076518
Adv Med Sci. 2024 Feb 28. pii: S1896-1126(24)00012-9. [Epub ahead of print]

Effectiveness of high-fat and high-carbohydrate diets on body composition and maximal strength after 15 weeks of resistance training.

Marek Kruszewski, Artur Kruszewski, Rafał Tabęcki, Stanisław Kuźmicki, Krzysztof Stec, Tadeusz Ambroży, Maksim Olegovich Aksenov, Maciej Merchelski, Tomasz Danielik.

   PURPOSE: The aim of this study was to compare High Carbohydrates Low Fat (HCLF) and Low Carbohydrate High Fat (LCHF) diets in terms of changes in body composition and maximal strength.
PATIENTS/METHODS: The study involved 48 men aged 25 ± 2.5, divided into two groups, one of which (n = 23) was following the LCHF diet and the other (n = 25) the HCLF diet. Both groups performed the same resistance training protocol for 15 weeks. Maximal strength in squat, bench press and deadlift was assessed pre- and post-intervention. Measurements of selected body circumferences and tissue parameters were made using the multifunctional, multi-frequency, direct bioelectric impedance InBody 770 analyzer from InBody Co., Ltd (Cerritos, California, USA). The team with the necessary qualifications and experience in research performed all the measurements and maintained participants' oversight throughout the entire length of the study.
RESULTS: Both nutritional approaches were effective in terms of reducing body fat mass. The HCLF group achieved greater skeletal muscle hypertrophy. Significant decreases in body circumferences, especially in the abdominal area, were observed for both dietary approaches. Maximal strength significantly increased in the HCLF group and decreased in the LCHF group.
CONCLUSION: Holistic analysis of the results led to the conclusion that both dietary approaches may elicit positive adaptations in body composition. The two approaches constitute useful alternatives for both recreational exercisers and physique athletes with body composition goals.

Keywords:  Body composition; High carbohydrate diet; Ketogenic diet; Maximal strength; Resistance training

DOI:  https://doi.org/10.1016/j.advms.2024.02.008
Transl Androl Urol. 2024 Jan 31. 13(1): 25-41

Suppression of NLRP3 inflammasome activation by astragaloside IV via promotion of mitophagy to ameliorate radiation-induced renal injury in mice.

Yanping Ding, Shuning Liu, Mengqing Zhang, Meile Su, Baoping Shao.

   Background: Irradiation (IR) promotes inflammation and apoptosis by inducing oxidative stress and/or mitochondrial dysfunction (MD). The kidneys are rich in mitochondria, and mitophagy maintains normal renal function by eliminating damaged mitochondria and minimizing oxidative stress. However, whether astragaloside IV (AS-IV) can play a protective role through the mitophagy pathway is not known.
Methods: We constructed a radiation injury model using hematoxylin and eosin (HE) staining, blood biochemical analysis, immunohistochemistry, TdT-mediated dUTP nick end labeling (TUNEL) staining, ultrastructural observation, and Western blot analysis to elucidate the AS-IV resistance mechanism for IR-induced renal injury.
Results: IR induced mitochondrial damage; the increase of creatinine (SCr), blood urea nitrogen (BUN) and uric acid (UA); and the activation of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome and apoptosis in renal tissue. AS-IV administration attenuated the IR-induced MD and reactive oxygen species (ROS) levels in the kidney; enhanced the levels of mitophagy-associated protein [PTEN-induced putative kinase 1 (PINK1)], parkin proteins, and microtubule-associated protein 1 light 3 (LC3) II/I ratio in renal tissues; diminished NLRP3 inflammasome activation-mediated proteins [cleaved cysteinyl aspartate-specific proteinase-1 (caspase-1), interleukin-1β (IL-1β)] and apoptosis-related proteins [cleaved caspase-9, cleaved caspase-3, BCL2-associated X (Bax)]; reduced SCr, BUN, and UA levels; and attenuated the histopathological alterations in renal tissue. Conversely, mitophagy inhibitor cyclosporin A (CsA) suppressed the AS-IV-mediated protection of renal tissue.
Conclusions: AS-IV can strongly diminish the activation and apoptosis of NLRP3 inflammasome, thus attenuating the renal injury induced by radiation by promoting the PINK1/parkin-mediated mitophagy. These findings suggest that AS-IV is a promising drug for treating IR-induced kidney injury.

Keywords:  PINK1/parkin; Renal injury; astragaloside IV (AS-IV); mitophagy; radiation

DOI:  https://doi.org/10.21037/tau-23-323
Seizure. 2024 Feb 21. pii: S1059-1311(24)00050-5. [Epub ahead of print]117 150-158

The efficacy of low glycemic index diet on seizure frequency in pediatric patients with epilepsy: A systematic review and meta-analysis.

Pejman Rohani, Reza Shervin Badv, Mohammad Hassan Sohouli, Nathalia Sernizon Guimarães.

   BACKGROUND: Despite extensive research examining the effect of a low glycemic index (LGI) diet on the frequency of seizures in patients with epilepsy, the findings are inconclusive. Hence, we performed a systematic review and meta-analysis in order to clarify the potential effect of a low glycemic index (LGI) diet on the frequency of seizures in children.
METHODS: A systematic review and meta-analysis written in accordance with the PRISMA checklist was realized using a comprehensive systematic search in four electronic databases until October 2023 without time or language restrictions. A random effects model was employed to combine the data. The main outcomes were analyzed using weight mean difference (WMD) and 95 % confidence interval (95 % CI). In total, 13 studies met the eligible criteria and were included.
RESULTS: The publications included in this study were published between 2005 and 2021. The duration of the interventions in the studies included in this analysis ranged from 6 to 58 weeks. Our findings indicated that the pooled efficacy rate for < 50 %, ≥ 50 %, > 90 % seizure reduction in patients with epilepsy receiving a low glycemic index diet was 39 % (95 % CI: 26, 52), 34 % (95 % CI: 23, 45), and 19 % (95 % CI: 13, 25), respectively. It seems that the efficacy of this ketogenic diet in reducing seizures is greater during a shorter intervention period than 12 weeks.
CONCLUSION: This systematic review and meta-analysis suggests that the low glycemia index diet can be beneficial as a treatment for epilepsy in pediatric patients.

Keywords:  Epilepsy; Ketogenic diet; Low glycemic index; Meta-analysis; Pediatrics; Seizure

DOI:  https://doi.org/10.1016/j.seizure.2024.02.013
Thorax. 2024 Feb 28. pii: thorax-2023-221071. [Epub ahead of print]

Monocyte NLRP3 inflammasome and interleukin-1β activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

Debananda Gogoi, Howard Yu, Michelle Casey, Rory Baird, Azeez Yusuf, Luke Forde, Michael E O' Brien, Jesse R West, Tammy Flagg, Noel G McElvaney, Edward Eden, Christian Mueller, Mark L Brantly, Patrick Geraghty, Emer P Reeves.

   INTRODUCTION: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1β secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers.
METHODS: Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1β secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors.
RESULTS: C3d acting via CR3 induces NLRP3 and pro-IL-1β production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1β secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1β (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation.
DISCUSSION: These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.

Keywords:  alpha1 antitrypsin deficiency; innate immunity; rare lung diseases

DOI:  https://doi.org/10.1136/thorax-2023-221071
Methods Mol Biol. 2024 ;2761 49-55

High-Resolution Respirometry for Mitochondrial Function in Rodent Brain.

Aishika Datta, Deepaneeta Sarmah, Bijoyani Ghosh, Nikita Rana, Anupom Borah, Pallab Bhattacharya.

  High-resolution mitochondrial respirometry is a modern technique that enables to measure mitochondrial respiration in various cell types. It contains chambers with oxygen sensors that measure oxygen concentration via polarography and calculate its consumption. The chamber contains plastic stoppers with injection ports that allow the injection of samples and different substrates, inhibitors, and uncoupler substances to measure mitochondrial respiration with high efficiency. These substances act on the mitochondrial electron transport chain (ETC) and help to assess the mitochondrial ATP production capacity and oxidative phosphorylation. The respirograph obtained with the help of software represents the oxygen consumption in each stage after adding different reagents.

Keywords:  ATP; High-resolution respirometry; Mitochondria; OXPHOS; Respiratory control ratio; SUIT protocol

DOI:  https://doi.org/10.1007/978-1-0716-3662-6_4
Trends Biochem Sci. 2024 Feb 23. pii: S0968-0004(24)00031-8. [Epub ahead of print]

Mitochondria in disease: changes in shapes and dynamics.

Brenita C Jenkins, Kit Neikirk, Prasanna Katti, Steven M Claypool, Annet Kirabo, Melanie R McReynolds, Antentor Hinton.

  Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular health. The dynamic nature of mitochondria is apparent in descriptions of different mitochondrial shapes [e.g., donuts, megamitochondria (MGs), and nanotunnels] and crista dynamics. This review explores the significance of dynamic alterations in mitochondrial morphology and regulators of mitochondrial and cristae shape. We focus on studies across tissue types and also describe new microscopy techniques for detecting mitochondrial morphologies both in vivo and in vitro that can improve understanding of mitochondrial structure. We highlight the potential therapeutic benefits of regulating mitochondrial morphology and discuss prospective avenues to restore mitochondrial bioenergetics to manage diseases related to mitochondrial dysfunction.

Keywords:  clinical diagnostics; contact sites; cristae dynamics; microscopy; mitochondrial morphology; mitochondrial shapes

DOI:  https://doi.org/10.1016/j.tibs.2024.01.011
EMBO Rep. 2024 Mar 01.

Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model.

Callum Dark, Nashia Ali, Sofya Golenkina, Vaibhav Dhyani, Ronnie Blazev, Benjamin L Parker, Kate T Murphy, Gordon S Lynch, Tarosi Senapati, S Sean Millard, Sarah M Judge, Andrew R Judge, Lopamudra Giri, Sarah M Russell, Louise Y Cheng.

  Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homologue ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.

Keywords:   Drosophila ; Cachexia; Lipid Metabolism; Muscle

DOI:  https://doi.org/10.1038/s44319-024-00102-z
Front Aging. 2024 ;5 1359638

MtDNA deletions and aging.

Charlotte Sprason, Trudy Tucker, David Clancy.

  Aging is the major risk factor in most of the leading causes of mortality worldwide, yet its fundamental causes mostly remain unclear. One of the clear hallmarks of aging is mitochondrial dysfunction. Mitochondria are best known for their roles in cellular energy generation, but they are also critical biosynthetic and signaling organelles. They also undergo multiple changes with organismal age, including increased genetic errors in their independent, circular genome. A key group of studies looking at mice with increased mtDNA mutations showed that premature aging phenotypes correlated with increased deletions but not point mutations. This generated an interest in mitochondrial deletions as a potential fundamental cause of aging. However, subsequent studies in different models have yielded diverse results. This review summarizes the research on mitochondrial deletions in various organisms to understand their possible roles in causing aging while identifying the key complications in quantifying deletions across all models.

Keywords:  aging; mitochondria; mitochondrial DNA; mitochondrial DNA deletions; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fragi.2024.1359638
Anim Nutr. 2024 Mar;16 443-456

Dietary sodium acetate and sodium butyrate attenuate intestinal damage and improve lipid metabolism in juvenile largemouth bass (Micropterus salmoides) fed a high carbohydrate diet by reducing endoplasmic reticulum stress.

Liulan Zhao, Liangshun Cheng, Yifang Hu, Xiaohui Li, Yihui Yang, Jin Mu, Lianfeng Shen, Guojun Hu, Kuo He, Haoxiao Yan, Qiao Liu, Song Yang.

  High-carbohydrate (HC) diets decrease the intestinal levels of sodium acetate (SA) and sodium butyrate (SB) and impair the gut health of largemouth bass; however, SA and SB have been shown to enhance immunity and improve intestinal health in farmed animals. Thus, the present study was to investigate the effects of dietary SA and SB on HC diet-induced intestinal injury and the potential mechanisms in juvenile largemouth bass. The experiment set five isonitrogenous and isolipidic diets, including a low-carbohydrate diet (9% starch) (LC), a high carbohydrate diet (18% starch) (HC), and the HC diet supplemented with 2 g/kg SA (HCSA), 2 g/kg SB (HCSB) or a combination of 1 g/kg SA and 1 g/kg SB (HCSASB). The feeding experiment was conducted for 8 weeks. A total of 525 juvenile largemouth bass with an initial body weight of 7.00 ± 0.20 g were used. The results showed that dietary SA and SB improved the weight gain rate and specific growth rate (P < 0.05) and ameliorated serum parameters (alkaline phosphatase, acid phosphatase, glutamate transaminase, and glutamic oxaloacetic transaminase) (P < 0.05). And, importantly, dietary SA and SB repaired the intestinal barrier by increasing the expression levels of zonula occludens-1, occludin, and claudin-7 (P < 0.05), reduced HC-induced intestinal damage, and alleviated intestinal inflammation and cell apoptosis by attenuating HC-induced intestinal endoplasmic reticulum stress (P < 0.05). Further results revealed that dietary SA and SB reduced HC-induced intestinal fat deposition by inhibiting adipogenesis and promoting lipolysis (P < 0.05). In summary, this study demonstrated that dietary SA and SB attenuated HC-induced intestinal damage and reduced excessive intestinal fat deposition in largemouth bass.

Keywords:  Endoplasmic reticulum stress; High carbohydrate diet; Intestine health; Lipid metabolism; Sodium acetate; Sodium butyrate

DOI:  https://doi.org/10.1016/j.aninu.2023.12.002
Neurorehabil Neural Repair. 2024 Feb 29. 15459683241232680

Alternate Day Fasting Leads to Improved Post-Stroke Motor Recovery in Mice.

Mahlet D Mersha, Robert Hubbard, Steven R Zeiler.

   BACKGROUND: Caloric restriction promotes neuroplasticity and recovery after neurological injury. In mice, we tested the hypothesis that caloric restriction can act post-stroke to enhance training-associated motor recovery.
METHODS: Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task following an 8-day delay. Mice underwent either ad libitum feeding or alternate day fasting beginning 1-day after stroke and persisting for either 7 days or the entire post-stroke training period until sacrifice.
RESULTS: Prior studies have shown that post-stroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice underwent alternate day fasting beginning 1-day post-stroke and persisting for either 7 days or the entire post-stroke training period until sacrifice. Recovery was independent of weight loss. Stroke volumes were similar across groups.
CONCLUSIONS: Post-stroke caloric restriction led to recovery of motor function independent of a protective effect on stroke volume. Prehension recovery improved even after ad libitum feeding was reinstituted suggesting that the observed motor recovery was not merely a motivational response. These data add to the growing evidence that post-stroke caloric restriction can enhance recovery.

Keywords:  caloric restriction; fasting; neuroplasticity; recovery; stroke

DOI:  https://doi.org/10.1177/15459683241232680
J Neuroimmune Pharmacol. 2024 Feb 29. 19(1): 7

New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation.

Triveni Kodi, Runali Sankhe, Adarsh Gopinathan, Krishnadas Nandakumar, Anoop Kishore.

  Inflammasomes are important modulators of inflammation. Dysregulation of inflammasomes can enhance vulnerability to conditions such as neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Among various inflammasomes, Nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) is the best-characterized inflammasome related to inflammatory and neurodegenerative diseases. NLRP3 is an intracellular sensor that recognizes pathogen-associated molecular patterns and damage-associated patterns resulting in the assembly and activation of NLRP3 inflammasome. The NLRP3 inflammasome includes sensor NLRP3, adaptor apoptosis-associated speck-like protein (ASC), and effector cysteine protease procaspase-1 that plays an imperative role in caspase-1 stimulation which further initiates a secondary inflammatory response. Regulation of NLRP3 inflammasome ameliorates NLRP3-mediated diseases. Much effort has been invested in studying the activation, and exploration of specific inhibitors and epigenetic mechanisms controlling NLRP3 inflammasome. This review gives an overview of the established NLRP3 inflammasome assembly, its brief molecular mechanistic activations as well as a current update on specific and non-specific NLRP3 inhibitors that could be used in NLRP3-mediated diseases. We also focused on the recently discovered epigenetic mechanisms mediated by DNA methylation, histone alterations, and microRNAs in regulating the activation and expression of NLRP3 inflammasome, which has resulted in a novel method of gaining insight into the mechanisms that modulate NLRP3 inflammasome activity and introducing potential therapeutic strategies for CNS disorders.

Keywords:  CNS disorders; DNA methylation; Epigenetic; Histone modifications; MicroRNAs; NLRP3 inflammasome

DOI:  https://doi.org/10.1007/s11481-024-10101-5
Mitochondrion. 2024 Feb 24. pii: S1567-7249(24)00015-1. [Epub ahead of print]76 101857

Role of mitochondrial potassium channels in ageing.

Lorenzo Flori, Jacopo Spezzini, Vincenzo Calderone, Lara Testai.

  Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life expectancy is also viewed as a condition in which many elderly will develop age-related diseases and disabilities, such as cardiovascular, metabolic, neurological and oncological ones. Currently, several recognized cellular hallmarks of senescence are taken in consideration to evaluate the level of biological ageing and are the topic to plan preventive/curative anti-ageing interventions, including genomic instability, epigenetic alterations, and mitochondrial dysfunction. In this scenario, alterations in the function/expression of mitochondrial ion channels have been found in ageing and associated to an impairment of calcium cycling and a reduced mitochondrial membrane potential. Although several ion channels have been described at mitochondrial level, undoubtedly the mitochondrial potassium (mitoK) channels are the most investigated. Therefore, this review summarized the evidence that sheds to light a correlation between age-related diseases and alteration of mitoK channels, focusing the attention of the main age-related diseases, i.e. cardiovascular, neurological and oncological ones.

Keywords:  Age-related disease; Ageing; Dysfunction; Mitochondria; mitoK channels

DOI:  https://doi.org/10.1016/j.mito.2024.101857
FEBS J. 2024 Feb 27.

Mitochondrial derived vesicles- Quo Vadis?

Reut Hazan Ben-Menachem, Ophry Pines, Ann Saada.

  Mitochondria are dynamic, intracellular organelles with a separate genome originating from prokaryotes. They perform numerous functions essential for cellular metabolism and energy production. Mitochondrial-derived vesicles (MDVs) are single or double membrane-enclosed vesicles, formed and released from the mitochondrial sub-compartments into the cytosol, in response to various triggers. MDVs interact with other organelles such as lysosomes and peroxisomes or may be incorporated and excreted via extracellular vesicles (EVs). MDVs selectively incorporate diverse protein and lipid cargoes and are involved in various functions such as mitochondrial quality control, immunomodulation, energy complementation, and compartmentalization and transport. This review aims to provide a summary of the current knowledge of MDVs biogenesis, release, cargoes, and roles.

Keywords:  membrane; mitochondria; mitochondrial-derived vesicles

DOI:  https://doi.org/10.1111/febs.17103
Front Nutr. 2024 ;11 1340735

Time-restricted feeding restores metabolic flexibility in adult mice with excess adiposity.

Lin Yan, Bret M Rust, Daniel G Palmer.

   Introduction: Obesity is prevalent with the adult population in the United States. Energy-dense diets and erratic eating behavior contribute to obesity. Time-restricted eating is a dietary strategy in humans that has been advanced to reduce the propensity for obesity. We hypothesized that time-restricted feeding (TRF) would improve metabolic flexibility and normalize metabolic function in adult mice with established excess adiposity.
Methods: Male C57BL/6NHsd mice were initially fed a high-fat diet (HFD) for 12 weeks to establish excess body adiposity, while control mice were fed a normal diet. Then, the HFD-fed mice were assigned to two groups, either ad libitum HFD or TRF of the HFD in the dark phase (12 h) for another 12 weeks.
Results and discussion: Energy intake and body fat mass were similar in TRF and HFD-fed mice. TRF restored rhythmic oscillations of respiratory exchange ratio (RER), which had been flattened by the HFD, with greater RER amplitude in the dark phase. Insulin sensitivity was improved and plasma cholesterol and hepatic triacylglycerol were decreased by TRF. When compared to HFD, TRF decreased transcription of circadian genes Per1 and Per2 and genes encoding lipid metabolism (Acaca, Fads1, Fads2, Fasn, Scd1, and Srebf1) in liver. Metabolomic analysis showed that TRF created a profile that was distinct from those of mice fed the control diet or HFD, particularly in altered amino acid profiles. These included aminoacyl-tRNA-biosynthesis, glutathione metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis pathways. In conclusion, TRF improved metabolic function in adult mice with excess adiposity. This improvement was not through a reduction in body fat mass but through the restoration of metabolic flexibility.

Keywords:  diet; excess adiposity; metabolomics; mice; time-restricted feeding

DOI:  https://doi.org/10.3389/fnut.2024.1340735
Cell Calcium. 2024 Feb 08. pii: S0143-4160(24)00010-1. [Epub ahead of print]119 102852

SERCA-1 conformational change exerted by the Ca2+-channel blocker diltiazem affects mammalian skeletal muscle function.

Aura Jiménez-Garduño, Ibrahim Ramirez-Soto, Ileana Miranda-Rodríguez, Sofía Gitler, Alicia Ortega.

  In skeletal muscle (SM), inward Ca2+-currents have no apparent role in excitation-contraction coupling (e-c coupling), however the Ca2+-channel blocker can affect twitch and tetanic muscle in mammalian SM. Experiments were conducted to study how diltiazem (DLZ) facilitates e-c coupling and inhibits contraction. 1) In complete Extensor Digitorum Longus (EDL) muscle and single intact fibres, 0.03 mM DLZ causes twitch potentiation and decreases force during tetanic activity, with increased fatigue. 2) In split open fibres isolated from EDL fibres, DLZ inhibits sarcoplasmic reticulum (SR) Ca2+-loading in a dose-dependent manner and has a potentiating effect on caffeine-induced SR Ca2+-release. 3) In isolated light SR (LSR) vesicles, SERCA1 hydrolytic activity is not affected by DLZ up to 0.2 mM. However, ATP-dependent Ca2+-uptake was inhibited in a dose-dependent manner at a concentration where e-c coupling is changed. 4) The passive Ca2+-efflux from LSR was reduced by half with 0.03 mM diltiazem, indicating that SR leaking does not account for the decreased Ca2+-uptake. 5) The denaturation profile of the SERCA Ca2+-binding domain has lower thermal stability in the presence of DLZ in a concentration-dependent manner, having no effect on the nucleotide-binding domain. We conclude that the effect of DLZ on SM is exerted by crossing the sarcolemma and interacting directly with the SERCA Ca2+-binding domain, affecting SR Ca2+-loading during relaxation, which has a consequence on SM contractility. Diltiazem effect on SM could be utilized as a tool to understand SM e-c coupling and muscle fatigue.

Keywords:  Calcium-channel blocker; Diltiazem; Excitation-contraction coupling; SERCA; Sarcoplasmic reticulum; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ceca.2024.102852