bims-kimdis 2024-02-18 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒02‒18
twenty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Inflammation and oxidative stress in epileptic children: from molecular mechanisms to clinical application of ketogenic diet.
Role of ketogenic diet in neurodegenerative diseases focusing on Alzheimer diseases: The guardian angle.
Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.
Role of ketogenic diet and its effect on the periodontium. A scoping review.
Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes.
Very low-calorie ketogenic diet (VLCKD) in the management of hidradenitis suppurativa (Acne Inversa): an effective and safe tool for improvement of the clinical severity of disease. Results of a pilot study.
Ketogenic diet ameliorates high-fat diet-induced insulin resistance in mouse skeletal muscle by alleviating endoplasmic reticulum stress.
Associations of Skeletal Muscle Mass, Muscle Fat Infiltration, Mitochondrial Energetics, and Cardiorespiratory Fitness with Liver Fat Among Older Adults.
Exercise-induced β-hydroxybutyrate promotes Treg cell differentiation to ameliorate colitis in mice.
Fueling the Failing Heart: The Key May Be Ketones.
Chronic exercise improves hepatic acylcarnitine handling.
The role of mitophagy in metabolic diseases and its exercise intervention.
Exercise reduces pro-inflammatory lipids and preserves r`esolution mediators that calibrate macrophage-centric immune metabolism in spleen and heart following obesogenic diet in aging mice.
Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations.
Targeting the NLRP3 inflammasome in psoriasis.
Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension.
The effect of carbohydrate intake on glycaemic control in individuals with type 1 diabetes: a randomised, open-label, crossover trial.
Ceramides and mitochondrial homeostasis.
Time-restricted eating improves health because of energy deficit and circadian rhythm: A systematic review and meta-analysis.
Size or Strength? how components of muscle relate to behavioral and neuroelectric measures of executive function independent of aerobic fitness.
Sodium-glucose cotransporter-2 inhibitors in heart failure patients across the range of body mass index: a systematic review and meta-analysis of randomized controlled trials.
Endurance exercise preconditioning alleviates ferroptosis induced by doxorubicin-induced cardiotoxicity through mitochondrial superoxide-dependent AMPKα2 activation.

Rev Neurosci. 2024 Feb 14.

Inflammation and oxidative stress in epileptic children: from molecular mechanisms to clinical application of ketogenic diet.

Azam Ildarabadi, Seyedeh Nooshan Mir Mohammad Ali, Fatemeh Rahmani, Narjes Mosavari, Elham Pourbakhtyaran, Nima Rezaei.

  Childhood epilepsy affects up to 1 % of children. It has been shown that 30 % of patients are resistant to drug treatments, making further investigation of other potential treatment strategies necessary. One such approach is the ketogenic diet (KD) showing promising results and potential benefits beyond the use of current antiepileptic drugs. This study aims to investigate the effects of KD on inflammation and oxidative stress, as one of the main suggested mechanisms of neuroprotection, in children with epilepsy. This narrative review was conducted using the Medline and Google Scholar databases, and by searching epilepsy, drug-resistant epilepsy, child, children, ketogenic, ketogenic diet, diet, ketogenic, keto, ketone bodies (BHB), PUFA, gut microbiota, inflammation, inflammation mediators, neurogenic inflammation, neuroinflammation, inflammatory marker, adenosine modulation, mitochondrial function, MTOR pathway, Nrf2 pathway, mitochondrial dysfunction, PPARɣ, oxidative stress, ROS/RNS, and stress oxidative as keywords. Compelling evidence underscores inflammation and oxidative stress as pivotal factors in epilepsy, even in cases with genetic origins. The ketogenic diet effectively addresses these factors by reducing ROS and RNS, enhancing antioxidant defenses, improving mitochondrial function, and regulating inflammatory genes. Additionally, KD curbs pro-inflammatory cytokine and chemokine production by dampening NF-κB activation, inhibiting the NLRP3 inflammasome, increasing brain adenosine levels, mTOR pathway inhibition, upregulating PPARɣ expression, and promoting a healthy gut microbiota while emphasizing the consumption of healthy fats. KD could be considered a promising therapeutic intervention in patients with epilepsy particularly in drug-resistant epilepsy cases, due to its targeted approach addressing oxidative stress and inflammatory mechanisms.

Keywords:  diet; epilepsy; inflammation; ketogenic; oxidative stress

DOI:  https://doi.org/10.1515/revneuro-2023-0128
Ageing Res Rev. 2024 Feb 13. pii: S1568-1637(24)00051-5. [Epub ahead of print] 102233

Role of ketogenic diet in neurodegenerative diseases focusing on Alzheimer diseases: The guardian angle.

Hayder M Al-Kuraishy, Majid S Jabir, Ali K Albuhadily, Ali I Al-Gareeb, Sabrean F Jawad, Ayman A Swelum, Najah R Hadi.

  The ketogenic diet (KD) is a low-carbohydrate, adequate protein and high-fat diet. KD is primarily used to treat refractory epilepsy. KD was shown to be effective in treating different neurodegenerative diseases. Alzheimer disease (AD) is the first common neurodegenerative disease in the world characterized by memory and cognitive impairment. However, the underlying mechanism of KD in controlling of AD and other neurodegenerative diseases are not discussed widely. Therefore, this review aims to revise the fundamental mechanism of KD in different neurodegenerative diseases focusing on the AD. KD induces a fasting-like which modulates the central and peripheral metabolism by regulating mitochondrial dysfunction, oxidative stress, inflammation, gut-flora, and autophagy in different neurodegenerative diseases. Different studies highlighted that KD improves AD neuropathology by regulating synaptic neurotransmission and inhibiting of neuroinflammation and oxidative stress. In conclusion, KD improves cognitive function and attenuates the progression of AD neuropathology by reducing oxidative stress, mitochondrial dysfunction, and enhancing neuronal autophagy and brain BDNF.

Keywords:  Alzheimer disease; ketogenic diet; neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.arr.2024.102233
Cell Discov. 2024 Feb 13. 10(1): 17

Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.

Ya-Nan Qiao, Lei Li, Song-Hua Hu, Yuan-Xin Yang, Zhen-Zhen Ma, Lin Huang, Yan-Peng An, Yi-Yuan Yuan, Yan Lin, Wei Xu, Yao Li, Peng-Cheng Lin, Jing Cao, Jian-Yuan Zhao, Shi-Min Zhao.

Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

DOI: https://doi.org/10.1038/s41421-023-00636-x
Front Oral Health. 2024 ;5 1364578

Role of ketogenic diet and its effect on the periodontium. A scoping review.

Hala Al Taher, Aya Salah, Caroline Rammal, Sudhir Rama Varma.

  The purpose of this study is to investigate the relationship between the ketogenic diet and periodontitis, as well as the nature of such relationship. Furthermore, emphasis was given to know whether ketogenic diet causes changes in oral health parameters and more specifically on periodontal health. Studies from 2010 to 2023 were reviewed and analyzed. Databases used to search included PubMed, Mednet, Scopus, Cochrane, and Embase. The literature reviewed was limited to randomized clinical trials, observational studies, and case-control studies. Of the eight studies included, three studies found that diets with similarities to the ketone-based diet could have a significant positive impact on periodontal health. One study pointed to the potential positive effect of a diet such as keto, but no definitive conclusion could be made. The current body of evidence concluded that there may be a relationship between keto and periodontitis, although the evidence is not consistent. It can be implied, however, that it is a positive relationship as ketogenic diet has been shown to have an anti-inflammatory effect, reducing inflammatory markers found in many diseases, including periodontitis.

Keywords:  ketogenic diet; ketone diet; oral health; periodontal health; periodontitis

DOI:  https://doi.org/10.3389/froh.2024.1364578
Commun Biol. 2024 Feb 16. 7(1): 195

Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes.

Jacopo Di Lucente, Giuseppe Persico, Zeyu Zhou, Lee-Way Jin, Jon J Ramsey, Jennifer M Rutkowsky, Claire M Montgomery, Alexey Tomilov, Kyoungmi Kim, Marco Giorgio, Izumi Maezawa, Gino A Cortopassi.

The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer's Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-β (Aβ) levels. KD's 'main actor' is thought to be Beta-Hydroxy-butyrate (BHB) whose levels rose significantly in KD vs. CD mice, and BHB itself significantly rescued LTP in APP/PS1 hippocampi. KD's 6 most significant pathways induced in brains by RNAseq all related to Synaptic Plasticity. KD induced significant increases in synaptic plasticity enzymes p-ERK and p-CREB in both sexes, and of brain-derived neurotrophic factor (BDNF) in APP/PS1 females. We suggest KD rescues LTP through BHB's enhancement of synaptic plasticity. LTP falls in Mild-Cognitive Impairment (MCI) of human AD. KD and BHB, because they are an approved diet and supplement respectively, may be most therapeutically and translationally relevant to the MCI phase of Alzheimer's Disease.

DOI: https://doi.org/10.1038/s42003-024-05860-z
J Transl Med. 2024 Feb 13. 22(1): 149

Very low-calorie ketogenic diet (VLCKD) in the management of hidradenitis suppurativa (Acne Inversa): an effective and safe tool for improvement of the clinical severity of disease. Results of a pilot study.

Ludovica Verde, Sara Cacciapuoti, Giuseppina Caiazzo, Matteo Megna, Fabrizio Martora, Annarita Cavaliere, Maria Mattera, Maria Maisto, Gian Carlo Tenore, Annamaria Colao, Silvia Savastano, Giovanna Muscogiuri, Luigi Barrea.

  BACKGROUND: Hidradenitis suppurativa (HS), an inflammatory-based dermatological condition often associated with obesity, poses significant challenges in management. The very low-calorie ketogenic diet (VLCKD) has shown efficacy in addressing obesity, related metabolic disorders, and reducing chronic inflammation. However, its effects on HS remain underexplored. In this prospective pilot study, we aimed to investigate the impact of a 28-day active phase of VLCKD on HS in a sample of treatment-naive women with HS and excess weight.METHODS: Twelve women with HS and overweight or obesity (BMI 27.03 to 50.14 kg/m2), aged 21 to 54 years, meeting inclusion/exclusion criteria and agreeing to adhere to VLCKD, were included. Baseline lifestyle habits were assessed. The Sartorius score was used to evaluate the clinical severity of HS. Anthropometric parameters (waist circumference, weight, height, and body mass index), body composition via bioelectrical impedance analysis, levels of trimethylamine N-oxide (TMAO), oxidized low-density lipoprotein (oxLDL), and derivatives of reactive oxygen metabolites (dROMs) were assessed at baseline and after 28 days of the active phase of VLCKD.
RESULTS: VLCKD led to general improvements in anthropometric parameters and body composition. Notably, a significant reduction in the Sartorius score was observed after the intervention (Δ%: - 24.37 ± 16.64, p < 0.001). This reduction coincided with significant decreases in TMAO (p < 0.001), dROMs (p = 0.001), and oxLDL (p < 0.001) levels. Changes in the Sartorius score exhibited positive correlations with changes in TMAO (p < 0.001), dROMs (p < 0.001), and oxLDL (p = 0.002).
CONCLUSION: The 28-day active phase of VLCKD demonstrated notable improvements in HS severity and associated metabolic markers, highlighting the potential utility of VLCKD in managing HS and its association with metabolic derangements in women with overweight or obesity.

Keywords:  Acne inversa; Diet; Hidradenitis suppurativa; Inflammation; Ketogenic diet; Nutrition; Obesity; Phase angle; Skin; TMAO; VLCKD; Very Low-Calorie Ketogenic Diet

DOI:  https://doi.org/10.1186/s12967-024-04853-0
Biochem Biophys Res Commun. 2024 Feb 05. pii: S0006-291X(24)00094-9. [Epub ahead of print]702 149559

Ketogenic diet ameliorates high-fat diet-induced insulin resistance in mouse skeletal muscle by alleviating endoplasmic reticulum stress.

Qin Ma, Lincheng Jiang, Yuehua You, Hongbing Ni, Li Ma, Xiaojing Lin, Zhuyun Wang, Weiyan Yan, Xiaoqiu Xiao, Xinyu Li, Jibin Li.

  OBJECTIVE: Ketogenic diets (KD) have been shown to alleviate insulin resistance (IR) by exerting anti-lipogenic and insulin sensitizing effects in the liver through a variety of pathways. The present study sought to investigate whether a ketogenic diet also improves insulin sensitization in skeletal muscle cells through alleviating endoplasmic reticulum stress.METHODS: High-fat diet-induced IR mice were allowed to a 2-week ketogenic diet. Insulin resistance and glucose tolerance were evaluated through GTT, ITT, and HOMA-IR. The C2C12 myoblasts exposed to palmitic acid were used to evaluate the insulin sensitization effects of β-hydroxybutyric acid (β-OHB). Molecular mechanisms concerning ER stress signaling activation and glucose uptake were assessed.
RESULTS: The AKT/GSK3β pathway was inhibited, ER stress signaling associated with IRE1, PERK, and BIP was activated, and the number of Glut4 proteins translocated to membrane decreased in the muscle of HFD mice. However, all these changes were reversed after 2 weeks of feeding on a ketogenic diet. Consistently in C2C12 myoblasts, the AKT/GSK3β pathway was inhibited by palmitic acid (PA) treatment. The endoplasmic reticulum stress-related proteins, IRE1, and BIP were increased, and the number of Glut4 proteins on the cell membrane decreased. However, β-OHB treatment alleviated ER stress and improved the glucose uptake of C2C12 cells.
CONCLUSION: Our data reveal that KD ameliorated HFD-induced insulin resistance in skeletal muscle, which was partially mediated by inhibiting endoplasmic reticulum stress. The insulin sensitization effect of β-OHB is associated with up regulation of AKT/GSK3β pathway and the increase in the number of Glut4 proteins on the cell membrane.

Keywords:  Endoplasmic reticulum stress; Glucose transporter type 4; Insulin resistance; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.bbrc.2024.149559
J Gerontol A Biol Sci Med Sci. 2024 Feb 15. pii: glae047. [Epub ahead of print]

Associations of Skeletal Muscle Mass, Muscle Fat Infiltration, Mitochondrial Energetics, and Cardiorespiratory Fitness with Liver Fat Among Older Adults.

Daria Igudesman, Justine Mucinski, Stephanie Harrison, Peggy M Cawthon, Jennifer Linge, Bret H Goodpaster, Steven R Cummings, Russell T Hepple, Michael J Jurczak, Stephen B Kritchevsky, David Marcinek, Paul M Coen, Karen D Corbin.

  BACKGROUND: Muscle mass loss may be associated with liver fat accumulation, yet scientific consensus is lacking and evidence in older adults is scant. It is unclear which muscle characteristics might contribute to this association in older adults.METHODS: We associated comprehensive muscle-related phenotypes including muscle mass normalized to body weight (D3-creatine dilution), muscle fat infiltration (MRI), carbohydrate-supported muscle mitochondrial maximal oxidative phosphorylation (respirometry), and cardiorespiratory fitness (VO2 peak) with liver fat among older adults. Linear regression models adjusted for age, gender, technician (respirometry only), daily minutes of moderate to vigorous physical activity, and prediabetes/diabetes status tested main effects and interactions of each independent variable with waist circumference (high: women-≥88 cm, men-≥102 cm) and gender.
RESULTS: Among older adults aged 75 (IQR 73, 79 years; 59.8% women), muscle mass and liver fat were not associated overall (N=362) but were positively associated among participants with a high waist circumference (β: 25.2; 95%CI 11.7, 40.4; p=.0002; N=160). Muscle fat infiltration and liver fat were positively associated (β: 15.2; 95%CI 6.8, 24.3; p=.0003; N=378). Carbohydrate-supported maximum oxidative phosphorylation (before adjustment) and VO2 peak (after adjustment; β: -12.9; 95%CI -20.3, -4.8; p=0.003; N=361) were inversely associated with liver fat; adjustment attenuated the estimate for maximum oxidative phosphorylation although the point estimate remained negative (β: -4.0; 95%CI -11.6, 4.2; p=0.32; N=321).
CONCLUSIONS: Skeletal muscle-related characteristics are metabolically relevant factors linked to liver fat in older adults. Future research should confirm our results to determine whether trials targeting mechanisms common to liver and muscle fat accumulation are warranted.

Keywords:  hepatic issues; metabolism; muscle; physical function

DOI:  https://doi.org/10.1093/gerona/glae047
FASEB J. 2024 Feb 29. 38(4): e23487

Exercise-induced β-hydroxybutyrate promotes Treg cell differentiation to ameliorate colitis in mice.

Fengqi Hao, Miaomiao Tian, Huiyue Wang, Shuo Li, Xinyu Wang, Xin Jin, Yang Wang, Yang Jiao, Meihong Tian.

  Increasing attention is being paid to the mechanistic investigation of exercise-associated chronic inflammatory disease improvement. Ulcerative colitis (UC) is one type of chronic inflammatory bowel disease with increasing incidence and prevalence worldwide. It is known that regular moderate aerobic exercise (RMAE) reduces the incidence or risk of UC, and attenuates disease progression in UC patients. However, the mechanisms of this RMAE's benefit are still under investigation. Here, we revealed that β-hydroxybutyrate (β-HB), a metabolite upon prolonged aerobic exercise, could contribute to RMAE preconditioning in retarding dextran sulfate sodium (DSS)-induced mouse colitis. When blocking β-HB production, RMAE preconditioning-induced colitis amelioration was compromised, whereas supplementation of β-HB significantly rescued impaired β-HB production-associated defects. Meanwhile, we found that RMAE preconditioning significantly caused decreased colonic Th17/Treg ratio, which is considered to be important for colitis mitigation; and the downregulated Th17/Treg ratio was associated with β-HB. We further demonstrated that β-HB can directly promote the differentiation of Treg cell rather than inhibit Th17 cell generation. Furthermore, β-HB increased forkhead box protein P3 (Foxp3) expression, the core transcriptional factor for Treg cell, by enhancing histone H3 acetylation in the promoter and conserved noncoding sequences of the Foxp3 locus. In addition, fatty acid oxidation, the key metabolic pathway required for Treg cell differentiation, was enhanced by β-HB treatment. Lastly, administration of β-HB without exercise significantly boosted colonic Treg cell and alleviated colitis in mice. Together, we unveiled a previously unappreciated role for exercise metabolite β-HB in the promotion of Treg cell generation and RMAE preconditioning-associated colitis attenuation.

Keywords:  chronic inflammatory disease; moderate aerobic exercise; regulatory T cell; ulcerative colitis; β-Hydroxybutyrate

DOI:  https://doi.org/10.1096/fj.202301686RR
JACC Basic Transl Sci. 2024 Jan;9(1): 16-17

Fueling the Failing Heart: The Key May Be Ketones.

Adam J Chicco.



Keywords:  beta-hydroxybutyrate; branch chain amino acids; citrate synthase activity; failing heart; free fatty acids; glucose/lactate/pyruvate; heart failure; nonfailing heart; sarcomere length

DOI:  https://doi.org/10.1016/j.jacbts.2023.09.012
iScience. 2024 Mar 15. 27(3): 109083

Chronic exercise improves hepatic acylcarnitine handling.

Diego Hernández-Saavedra, J Matthew Hinkley, Lisa A Baer, Kelsey M Pinckard, Pablo Vidal, Shinsuke Nirengi, Andrea M Brennan, Emily Y Chen, Niven R Narain, Valerie Bussberg, Vladimir V Tolstikov, Michael A Kiebish, Christina Markunas, Olga Ilkayeva, Bret H Goodpaster, Christopher B Newgard, Laurie J Goodyear, Paul M Coen, Kristin I Stanford.

  Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial β-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Keywords:  Cell biology; Health sciences; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109083
Front Physiol. 2024 ;15 1339128

The role of mitophagy in metabolic diseases and its exercise intervention.

Shaokai Tang, Yuanwen Geng, Qinqin Lin.

  Mitochondria are energy factories that sustain life activities in the body, and their dysfunction can cause various metabolic diseases that threaten human health. Mitophagy, an essential intracellular mitochondrial quality control mechanism, can maintain cellular and metabolic homeostasis by removing damaged mitochondria and participating in developing metabolic diseases. Research has confirmed that exercise can regulate mitophagy levels, thereby exerting protective metabolic effects in metabolic diseases. This article reviews the role of mitophagy in metabolic diseases, the effects of exercise on mitophagy, and the potential mechanisms of exercise-regulated mitophagy intervention in metabolic diseases, providing new insights for future basic and clinical research on exercise interventions to prevent and treat metabolic diseases.

Keywords:  exercise; exerkine; metabolic disease; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.3389/fphys.2024.1339128
J Mol Cell Cardiol. 2024 Feb 14. pii: S0022-2828(24)00021-X. [Epub ahead of print]188 79-89

Exercise reduces pro-inflammatory lipids and preserves r`esolution mediators that calibrate macrophage-centric immune metabolism in spleen and heart following obesogenic diet in aging mice.

Ganesh V Halade, Gunjan Upadhyay, MathanKumar Marimuthu, Xuan Wanling, Vasundhara Kain.

  The study investigated the role of volunteer exercise and an obesogenic diet (OBD) in mice, focusing on the splenocardiac axis and inflammation-resolution signaling. Male C57BL/6J mice (2 months old) were assigned to control (CON) or OBD groups for ten months, then randomized into sedentary (Sed) or exercise (Exe) groups for two weeks. Leukocytes, heart function, structure, and spleen tissue examined for inflammation-resolution mediators and macrophage-centric gene transcripts. After two weeks of volunteer exercise, cardiac function shows limited changes, but structural changes were notable in the heart and spleen. Exercise induced cardiac nuclear hyperplasia observed in both CON and OBD groups. OBD-Sed mice showed splenic changes and increased neutrophils, whereas increased neutrophils were noted in the CON post exercise. OBD-Sed increased pro-inflammatory lipid mediators in the heart, reduced by exercise in OBD-Exe, while CON-Exe preserved resolution mediators. Chronic OBD-Sed depletes long chain fatty acids (DHA/EPA) in the heart and spleen, while exercise independently regulates lipid metabolism genes in both organs, affecting macrophage-centric lipid and lipoprotein pathways. Chronic obesity amplified cardiac inflammation, countered by exercise that lowered pro-inflammatory bioactive lipid mediators in the heart. OBD sustained inflammation in the heart and spleen, while exercise conserved resolution mediators in CON mice. In summary, these findings emphasize the interplay of diet with exercise and highlight the intricate connection of diet, exercise, inflammation-resolution signaling in splenocardiac axis and immune health.

Keywords:  Exercise/physical activity; Inflammation-resolution signaling; Lipid metabolism; Macrophages; Spleen and cardiac health

DOI:  https://doi.org/10.1016/j.yjmcc.2024.02.004
CNS Neurosci Ther. 2024 Feb;30(2): e14583

Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations.

Jiahui Sui, Longwu Zhan, Shengtao Ji, Wenwen Wu, Yuhan Chen, Feng Yun, Wenpeng Liang, Jie Wang, Maohong Cao, Dingding Shen, Qi Zhang.

  OBJECTIVE: To explore the mechanism involved in variable phenotypes of epilepsy models induced by γ-aminobutyric acid type A γ2 subunit (GABRG2) mutations.METHODS: The zebrafish carrying wild-type (WT) GABRG2, mutant GABRG2(P282S), GABRG2(F343L) and GABRG2(I107T) were established by Tol2kit transgenesis system and Gateway method. Behavioral analysis of different transgenic zebrafish was performed with the DanioVision Video-Track framework and the brain activity was analyzed by field potential recording with MD3000 Bio-signal Acquisition and Processing System. The transcriptome analysis was applied to detect the underlying mechanisms of variable phenotypes caused by different GABRG2 mutations.
RESULTS: The established Tg(hGABRG2P282S ) zebrafish showed hyperactivity and spontaneous seizures, which were more sensitive to chemical and physical epileptic stimulations. Traditional antiepileptic drugs, such as Clonazepam (CBZ) and valproic acid (VPA), could ameliorate the hyperactivity in Tg(hGABRG2P282S ) zebrafish. The metabolic pathway was significantly changed in the brain transcriptome of Tg(hGABRG2P282S ) zebrafish. In addition, the behavioral activity, production of pro-inflammatory factors, and activation of the IL-2 receptor signal pathway varied among the three mutant zebrafish lines.
CONCLUSION: We successfully established transgenic zebrafish epileptic models expressing human mutant GABRG2(P282S), in which CBZ and VPA showed antiepileptic effects. Differential inflammatory responses, especially the SOCS/JAK/STAT signaling pathway, might be related to the phenotypes of genetic epilepsy induced by GABRG2 mutations. Further study will expand the pathological mechanisms of genetic epilepsies and provide a theoretical basis for searching for effective drug treatment.

Keywords:  GABRG2; epilepsy; inflammatory response; mutation

DOI:  https://doi.org/10.1111/cns.14583
Int J Dermatol. 2024 Feb 12.

Targeting the NLRP3 inflammasome in psoriasis.

Xiuhui Chen, Guoliang Deng, Kaifeng Chen, Yanhong Chen, Weijun Ye, Ping Sun.

The NLRP3 inflammasome, a complex consisting of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3, has emerged as a critical mediator of pathological inflammation and a significant therapeutic target for various inflammatory diseases. Psoriasis, a chronic inflammatory skin condition without a definitive cure, has shown promising results in animal models through the inhibition of the NLRP3 inflammasome. This review aims to explore the development of the NLRP3 inflammasome in psoriasis and the molecular mechanisms responsible for its inhibition by natural products and small molecules currently being developed for psoriasis treatment. Furthermore, we are examining clinical trials using agents that block the NLRP3 pathway for the treatment of psoriasis. This study is timely to provide a new perspective on managing psoriasis.

DOI: https://doi.org/10.1111/ijd.17073
Mol Metab. 2024 Feb 13. pii: S2212-8778(24)00033-4. [Epub ahead of print] 101902

Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension.

Maarouf Baghdadi, Tobias Nespital, Carolina Monzó, Joris Deelen, Sebastian Grönke, Linda Partridge.

  Rapamycin, a powerful geroprotective drug, can have detrimental effects when administered chronically. We determined whether intermittent treatment of mice can reduce negative effects while maintaining benefits of chronic treatment. Chronic treatment induced glucose intolerance, which was partially ameliorated by intermittent treatment. Chronic and intermittent treatments increased lifespan equally in males, while in females chronic treatment resulted in slightly higher survival. The two treatments had equivalent effects on testicular degeneration, heart fibrosis and liver lipidosis. In males, the two treatment regimes led to a similar increase in motor coordination, heart rate and Q-T interval, and reduction in spleen weight, while in females, they equally reduced BAT inflammation and spleen weight and maintained heart rate and Q-T interval. However, other health parameters, including age related pathologies, were better prevented by continuous treatment. Hence, intermittent rapamycin treatment is effective in prolonging lifespan and reduces some side-effects of chronic treatment, but chronic treatment is more beneficial to healthspan.

Keywords:  Rapamycin; ageing; cancer; inflammation; metabolism; sex difference

DOI:  https://doi.org/10.1016/j.molmet.2024.101902
Lancet Reg Health Eur. 2024 Feb;37 100799

The effect of carbohydrate intake on glycaemic control in individuals with type 1 diabetes: a randomised, open-label, crossover trial.

Sofia Sterner Isaksson, Arndís F Ólafsdóttir, Simon Ivarsson, Henrik Imberg, Eva Toft, Sara Hallström, Ulf Rosenqvist, Marie Ekström, Marcus Lind.

  Background: Few studies have examined the effects of lower carbohydrate diets on glucose control in persons with type 1 diabetes (T1D). The objective of the study was to investigate whether a moderate carbohydrate diet improves glucose control in persons with T1D.Methods: A randomised, multicentre, open-label, crossover trial over 12 weeks. There were 69 individuals assessed for eligibility, 54 adults with T1D and HbA1c ≥ 58 mmol/mol (7.5%) were randomised. Interventions were moderate carbohydrate diet versus traditional diet (30 vs 50% of total energy from carbohydrates) over four weeks, with a four-week wash-out period between treatments. Masked continuous glucose monitoring was used to evaluate effects on glucose control. The primary endpoint was the difference in mean glucose levels between the last 14 days of each diet phase.
Findings: 50 individuals were included in the full analysis set with a mean baseline HbA1c of 69 mmol/mol (8.4%), BMI 29 kg/m2, age of 48 years, and 50% were female. The difference in mean glucose levels between moderate carbohydrate and traditional diet was -0.6 mmol/L, 95% CI -0.9 to -0.3, p < 0.001. Time in range increased during moderate carbohydrate diet by 4.7% (68 min/24 h) (95% CI 1.3 to 8.0), p = 0.008. Time above range (>10 mmol/L) decreased by 5.9% (85 min/24 h), 95% CI -9.6 to -2.2, p = 0.003. There were no significant differences in the standard deviation of glucose levels (95% CI -0.3 to 0.0 mmol/L, p = 0.15) or hypoglycaemia in the range <3.9 mmol/L (95% CI -0.4 to 2.9%, p = 0.13) and <3.0 mmol/L (95% CI -0.4 to 1.6%, p = 0.26). Four participants withdrew, none because of adverse events. There were no serious adverse events including severe hypoglycaemia and ketoacidosis. Mean ketone levels were 0.17 (SD 0.14) mmol/L during traditional and 0.18 (SD 0.13) mmol/L during moderate carbohydrate diet (p = 0.02).
Interpretation: A moderate carbohydrate diet is associated with decreases in mean glucose levels and time above range and increases in time in range without increased risk of hypoglycaemia or ketoacidosis compared with a traditional diet in individuals with T1D.
Funding: The Healthcare Board, Region Västra Götaland, The Dr P Håkansson Foundation and the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement [ALFGBG-966173].

Keywords:  Carbohydrates; Continuous glucose monitoring; Glycaemic control; Medical nutrition therapy; Type 1 diabetes mellitus

DOI:  https://doi.org/10.1016/j.lanepe.2023.100799
Cell Signal. 2024 Feb 13. pii: S0898-6568(24)00067-6. [Epub ahead of print] 111099

Ceramides and mitochondrial homeostasis.

Song Ding, Guorui Li, Tinglv Fu, Tianyu Zhang, Xiao Lu, Ning Li, Qing Geng.

  Lipotoxicity arises from the accumulation of lipid intermediates in non-adipose tissue, precipitating cellular dysfunction and death. Ceramide, a toxic byproduct of excessive free fatty acids, has been widely recognized as a primary contributor to lipotoxicity, mediating various cellular processes such as apoptosis, differentiation, senescence, migration, and adhesion. As the hub of lipid metabolism, the excessive accumulation of ceramides inevitably imposes stress on the mitochondria, leading to the disruption of mitochondrial homeostasis, which is typified by adequate ATP production, regulated oxidative stress, an optimal quantity of mitochondria, and controlled mitochondrial quality. Consequently, this review aims to collate current knowledge and facts regarding the involvement of ceramides in mitochondrial energy metabolism and quality control, thereby providing insights for future research.

Keywords:  Ceramide; ETC; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1016/j.cellsig.2024.111099
iScience. 2024 Feb 16. 27(2): 109000

Time-restricted eating improves health because of energy deficit and circadian rhythm: A systematic review and meta-analysis.

Yuwen Chang, Tingting Du, Xiangling Zhuang, Guojie Ma.

  Time-restricted eating (TRE) is an effective way to lose weight and improve metabolic health in animals. Yet whether and how these benefits apply to humans is unclear. This systematic review and meta-analysis examined the effect of TRE in people with overweight and obesity statuses. The results showed that TRE led to modest weight loss, lower waist circumference and energy deficits. TRE also improved body mass index, fat mass, lean body mass, systolic blood pressure, fasting glucose levels, fasting insulin levels, and HbA1c%. Subgroup analysis demonstrated more health improvements in the TRE group than the control group under the ad libitum intake condition than in the energy-prescribed condition. Eating time-of-day advantages were only seen when there was considerable energy reduction in the TRE group than the control group (ad libitum condition), implying that the benefits of TRE were primarily due to energy deficit, followed by alignment with eating time of day.

Keywords:  Health sciences; Human metabolism; Nutrition

DOI:  https://doi.org/10.1016/j.isci.2024.109000
Brain Cogn. 2024 Feb 14. pii: S0278-2626(24)00016-2. [Epub ahead of print]175 106139

Size or Strength? how components of muscle relate to behavioral and neuroelectric measures of executive function independent of aerobic fitness.

Nicholas W Baumgartner, Shih-Chun Kao.

  While previous research has linked cognitive function with resistance exercise, the nuanced links between muscle strength, mass, and neuroelectric function are less understood. Therefore, this study investigated the association of muscle strength and mass with inhibitory control (IC), working memory (WM), and related neuroelectric activity. A total of 123 18-50-year-old adults completed maximal aerobic capacity and strength tests, a body composition scan, and IC and WM tasks while the N2 and P3 components of event-related potentials were recorded. Bivariate correlations revealed aerobic fitness, strength, and mass were associated with behavioral and neuroelectric outcomes. After accounting for age, sex, and aerobic fitness, strength was associated with intra-individual response time variability, accuracy, and P3 latency during WM. Muscle mass was associated with N2 latency during IC. While relationships with behavioral outcomes did not persist after controlling for the opposite muscle outcome, greater strength and mass were related to shorter P3 latency during WM and shorter N2 latency during IC, respectively. These results provide initial evidence that muscle outcomes are associated with executive function and neuroelectric processing speed, suggesting distinct contributions of strength and mass to cognition. This work highlights the significance of maintaining muscle strength and mass alongside aerobic fitness for optimal cognitive health.

Keywords:  Event-Related Potentials (ERPs); Inhibitory Control; Muscle Mass; Muscle Strength; Processing Speed; Working Memory

DOI:  https://doi.org/10.1016/j.bandc.2024.106139
Intern Emerg Med. 2024 Feb 14.

Sodium-glucose cotransporter-2 inhibitors in heart failure patients across the range of body mass index: a systematic review and meta-analysis of randomized controlled trials.

Anastasia Adamou, David Dimitris Chlorogiannis, Ioannis G Kyriakoulis, Iliana Stamatiou, Despoina Koukousaki, Ioannis Kardoutsos, Dimitrios Sagris, Wolfram Doehner, George Ntaios.

  Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in patients with heart failure, with or without diabetes. We sought to assess whether there is an interaction of these effects with body mass index (BMI). A systematic review of the MEDLINE and Scopus databases (last search: November 15th, 2022) was performed according to the PRISMA statement. Studies eligible for this review were randomized control trials (RCTs) with patients with chronic heart failure with either preserved or reduced ejection fraction randomly assigned to SGLT2 inhibitors or placebo. Data were extracted independently by two reviewers. BMI was classified according to the WHO classification into under/normal weight (BMI: < 25 kg/m2), overweight (BMI: 25-29.9 kg/m2), obesity class I (BMI: 30-34.9 kg/m2), and obesity classes II/III (BMI: ≥ 35 kg/m2). All analyses were performed using RevMan 5.4. Among 1461 studies identified in the literature search, 3 were eligible and included in the meta-analysis. Among 14,737 patients (32.2% were women), 7,367 were randomized to an SGLT2 inhibitor (dapagliflozin or empagliflozin) and 7,370 to placebo. There were significantly fewer hospitalizations for HF (OR: 0.70, 95%CI: 0.64-0.76), cardiovascular deaths (OR:0.86, 95%CI: 0.77-0.97) and all-cause deaths (OR:0.90, 95%CI: 0.82-0.98) in the SGLT2 inhibitors group compared to the placebo group, without any interaction with BMI group (test for subgroup differences: x2 = 1.79, p = 0.62; x2 = 0.27, p = 0.97; x2 = 0.39, p = 0.94, respectively). There is no interaction between the efficacy of SGLT2 inhibitors and BMI in patients with HF with either preserved or reduced ejection fraction. SGLT2 inhibitors are associated with improved outcomes regardless of the BMI.Trial registration: PROSPERO ID: CRD42022383643.

Keywords:  BMI; Ejection fraction; HF; SGLT2

DOI:  https://doi.org/10.1007/s11739-024-03532-8
Redox Biol. 2024 Feb 08. pii: S2213-2317(24)00055-7. [Epub ahead of print]70 103079

Endurance exercise preconditioning alleviates ferroptosis induced by doxorubicin-induced cardiotoxicity through mitochondrial superoxide-dependent AMPKα2 activation.

Liang Wang, Yang Qiao, Jingzhi Yu, Qihao Wang, Xinyu Wu, Qiqi Cao, Zeyu Zhang, Zhen Feng, Huan He.

  Doxorubicin-induced cardiotoxicity (DIC) adversely impacts patients' long-term health and quality of life. Its underlying mechanism is complex, involving regulatory cell death mechanisms, such as ferroptosis and autophagy. Moreover, it is a challenge faced by patients undergoing cardiac rehabilitation. Endurance exercise (E-Exe) preconditioning effectively counters DIC injury, potentially through the adenosine monophosphate-activated protein kinase (AMPK) pathway. However, detailed studies on this process's mechanisms are scarce. Here, E-Exe preconditioning and DIC models were established using mice and primary cultured adult mouse cardiomyocytes (PAMCs). Akin to ferrostatin-1 (ferroptosis inhibitor), rapamycin (autophagic inducer), and MitoTEMPO (mitochondrial free-radical scavenger), E-Exe preconditioning effectively alleviated Fe2+ accumulation and oxidative stress and improved energy metabolism and mitochondrial dysfunction in DIC injury, as demonstrated by multifunctional, enzymatic, and morphological indices. However, erastin (ferroptosis inducer), 3-methyladenine (autophagic inhibitor), adenovirus-mediated AMPKα2 downregulation, and AMPKα2 inhibition by compound C significantly diminished these effects, both in vivo and in vitro. The results suggest a non-traditional mechanism where E-Exe preconditioning, under mild mitochondrial reactive oxygen species generation, upregulates and phosphorylates AMPKα2, thereby enhancing mitochondrial complex I activity, activating adaptive autophagy, and improving myocardial tolerance to DIC injury. Overall, this study highlighted the pivotal role of mitochondria in myocardial DIC-induced ferroptosis and shows how E-Exe preconditioning activated AMPKα2 against myocardial DIC injury. This suggests that E-Exe preconditioning could be a viable strategy for patients undergoing cardiac rehabilitation.

Keywords:  AMP-Activated protein kinaseα2; Doxorubicin-induced cardiotoxicity; Endurance exercise; Ferroptosis; Mitochondria

DOI:  https://doi.org/10.1016/j.redox.2024.103079