bims-kimdis 2023-09-17 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒09‒17
24 papers selected by
Matías Javier Monsalves Álvarez

Effects of ketone bodies on energy expenditure, substrate utilization, and energy intake in humans.
Exploring the impact of ketogenic diet on multiple sclerosis: obesity, anxiety, depression, and the glutamate system.
Quantitative Determination of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate (Ketone Ester) and Its Metabolites Beta-hydroxybutyrate, 1-3-Butanediol, and Acetoacetate in Human Plasma Using LC-MS.
Feasibility, Tolerability and efficacy of the ketogenic diet in children with drug-resistant epilepsy in Vietnam.
Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility.
Adherence to ketogenic diet in lifestyle interventions in adults with overweight or obesity and type 2 diabetes: a scoping review.
Long-term effectiveness and seizure recurrence risk factors of ketogenic diet for pediatric refractory epilepsy: Experience from a tertiary care center in China.
Skeletal muscle mitochondria in strength athletes: meeting energy needs with mitochondrial morphological changes.
Ketogenic diet changes microglial morphology and the hippocampal lipidomic profile differently in stress susceptible versus resistant male mice upon repeated social defeat.
Fantastic voyage: The journey of NLRP3 inflammasome activation.
Effects of Ketogenic Diet on Reproductive Hormones in Women With Polycystic Ovary Syndrome.
Infusions of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produce antidepressant-like effects on learned helplessness rats through BDNF-TrkB signaling and AMPA receptor activation, and strengthen learning ability.
β-hydroxybutyrate ameliorates sepsis-induced acute kidney injury.
Alleviative effect of poly-β-hydroxybutyrate on lipopolysaccharide-induced oxidative stress, inflammation and cell apoptosis in Cyprinus carpio.
Mitochondrial degradation: Mitophagy and beyond.
Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high-intensity interval training.
Divergent functions of NLRP3 inflammasomes in cancer: a review.
Long-term effects of a fat-directed FGF21 gene therapy in aged female mice.
Aging, adaptation and maladaptation.
Sodium-glucose cotransporter-2 inhibition in a CKD patient with severe heart failure treated by high-dose diuretics and peritoneal ultrafiltration: lesson for the clinical nephrologist.
Targeting the NLRP3 inflammasome for the treatment of hypertensive target organ damage: Role of natural products and formulations.
Low-carbohydrate diet and risk of cardiovascular disease, cardiovascular and all-cause mortality: a systematic review and meta-analysis of cohort studies.
Partial Skeletal Muscle-Specific Drp1 Knockout Enhances Insulin Sensitivity in Diet-Induced Obese Mice, But Not in Lean Mice.
Fasting and non-fasting plasma levels of monomethyl branched chain fatty acids: Implications for maple syrup urine disease.

J Lipid Res. 2023 Sep 11. pii: S0022-2275(23)00115-3. [Epub ahead of print] 100442

Effects of ketone bodies on energy expenditure, substrate utilization, and energy intake in humans.

Rodrigo Fernández-Verdejo, Jacob T Mey, Eric Ravussin.

  The potential of ketogenic approaches to regulate energy balance has recently gained attention since ketones may influence both energy expenditure and energy intake. In this narrative review, we summarized the most relevant evidence about the role of ketosis on energy expenditure, substrate utilization, and energy intake in humans. We considered different strategies to induce ketosis, such as fasting, dietary manipulation, and exogenous ketone sources. In general, ketosis does not have a major influence on energy expenditure but promotes a shift in substrate utilization towards ketone body oxidation. The strategies to induce ketosis by reduction of dietary carbohydrate availability (e.g., ketogenic diets) do not independently influence energy intake, being thus equally effective for weight loss as diets with higher carbohydrate content. In contrast, the intake of medium-chain triglycerides and ketone esters induces ketosis and appears to increase energy expenditure and reduce energy intake in the context of high carbohydrate availability. These latter strategies lead to slightly enhanced weight loss. Unfortunately, distinguishing the effects of the various ketogenic strategies per se from the effects of other physiological responses is not possible with the available human data. Highly controlled, inpatient studies using targeted strategies to isolate the independent effects of ketones are required to adequately address this knowledge gap.

Keywords:  Appetite; Beta-hydroxybutyrate; Dietary fat; Energy balance; Insulin; Ketosis; Lipids/Oxidation; Nutrition; Obesity

DOI:  https://doi.org/10.1016/j.jlr.2023.100442
Front Nutr. 2023 ;10 1227431

Exploring the impact of ketogenic diet on multiple sclerosis: obesity, anxiety, depression, and the glutamate system.

Jose Enrique de la Rubia Ortí, María Cuerda-Ballester, Claudia Emmanuela Sanchis-Sanchis, Jose María Lajara Romance, Esther Navarro-Illana, María Pilar García Pardo.

  Background: Multiple sclerosis (MS) is a neurodegenerative disorder. Individuals with MS frequently present symptoms such as functional disability, obesity, and anxiety and depression. Axonal demyelination can be observed and implies alterations in mitochondrial activity and increased inflammation associated with disruptions in glutamate neurotransmitter activity. In this context, the ketogenic diet (KD), which promotes the production of ketone bodies in the blood [mainly β-hydroxybutyrate (βHB)], is a non-pharmacological therapeutic alternative that has shown promising results in peripheral obesity reduction and central inflammation reduction. However, the association of this type of diet with emotional symptoms through the modulation of glutamate activity in MS individuals remains unknown.Aim: To provide an update on the topic and discuss the potential impact of KD on anxiety and depression through the modulation of glutamate activity in subjects with MS.
Discussion: The main findings suggest that the KD, as a source of ketone bodies in the blood, improves glutamate activity by reducing obesity, which is associated with insulin resistance and dyslipidemia, promoting central inflammation (particularly through an increase in interleukins IL-1β, IL-6, and IL-17). This improvement would imply a decrease in extrasynaptic glutamate activity, which has been linked to functional disability and the presence of emotional disorders such as anxiety and depression.

Keywords:  anxiety; depression; glutamate; ketogenic diets; multiple sclerosis; obesity

DOI:  https://doi.org/10.3389/fnut.2023.1227431
AAPS PharmSciTech. 2023 Sep 12. 24(7): 184

Quantitative Determination of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate (Ketone Ester) and Its Metabolites Beta-hydroxybutyrate, 1-3-Butanediol, and Acetoacetate in Human Plasma Using LC-MS.

Nimishraj Panse, Matthew Halquist, Phillip M Gerk.

  Ketone ester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) has gained popularity as an exogenous means to achieve ketosis. Regarding its potential as a therapeutic prodrug, it will be necessary to study its pharmacokinetic profile and its proximal metabolites (beta-hydroxybutyrate, 1,3-butanediol, and acetoacetate) in humans. Here we develop and validate two LC-MS methods for quantifying KE and its metabolites in human plasma. The first assay uses a C18 column to quantitate ketone ester, beta-hydroxybutyrate, and 1,3-butanediol, and the second assay uses a hydrophilic interaction liquid chromatography (HILIC) column for the quantitation of acetoacetate. The method was partially validated for intra- and inter-day accuracy and precision based on the ICH M10 guidelines. For both the assays, the intra- and inter-run accuracy was ±15% of the nominal concentration, and the precision (%CV) was <15% for all 4 molecules being quantified. The matrix effect for all molecules was evaluated and ranged from -62.1 to 44.4% (combined for all molecules), while the extraction recovery ranged from 65.1 to 119% (combined for all molecules). Furthermore, the metabolism of ketone ester in human plasma and human serum albumin was studied using the method. Non-saturable metabolism of ketone ester was seen in human plasma at concentrations as high as 5 mM, and human serum albumin contributed to the metabolism of ketone ester. Together, these assays can be used to track the entire kinetics of ketone ester and its proximal metabolites. The reverse-phase method was used to study the metabolic profile of KE in human plasma and the plasma protein binding of 1,3-BD.

Keywords:  LC-MS; bioanalysis; human plasma; ketone bodies; ketone ester

DOI:  https://doi.org/10.1208/s12249-023-02633-5
Epilepsia Open. 2023 Sep 15.

Feasibility, Tolerability and efficacy of the ketogenic diet in children with drug-resistant epilepsy in Vietnam.

Thuy-Minh-Thu Nguyen, Pierre Jallon, Christian Korff, Le-Trung-Hieu Nguyen, Sylvie Nguyen The Tich.

OBJECTIVES: According to the WHO, more than 50 million people have epilepsy. Among them, nearly 80% of patients with epilepsy live in developing countries and 75% of them do not have access to treatment. The ketogenic diet (KD) has been shown as an effective alternative for patients with drug-resistant epilepsy. Although it has been studied in Asia, no such studies have been conducted in Vietnam. The purpose of this study was to verify the feasibility and tolerability of KD in children with refractory epilepsies in Vietnam.METHODS: Children with drug-resistant epilepsy followed at Children's Hospital, Viet Nam treated by KD were included in a prospective study from June 2019 to October 2021. Side-effects, retention rate, number, and duration of seizures were recorded after 1, 3, 6, 9 and 12 months of KD. Patients were considered as respondents when a 50% seizure frequency was reached. Tolerance and acceptability of the KD were closely monitored.
RESULTS: Forty-six children were included but KD was contraindicated for one patient. Due to the COVID pandemic, we had to rely on internet exchanges to stay in touch with families. Meals had to be adapted to Vietnamese culinary habits. The retention rate decreased from 82.2% at 1 month to 40% at 12 months of follow-up. The incidence of side effects was 44.4% and occurred mainly during the first month. Fifteen patients out of 45 were considered as responders after 12 months.
SIGNIFICANCE: Our study was the first attempt to introduce KD in Vietnam. It demonstrated that this diet was feasible and well tolerated. The KD diet resulted in significant improvement for 30% of our patients with drug-resistant epilepsy. This percentage is lower than in some studies but warrants the use of KD as a valuable alternative in a country where many patients lack access to recent treatments.

DOI: https://doi.org/10.1002/epi4.12825
Basic Res Cardiol. 2023 Sep 09. 118(1): 37

Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility.

Casper Homilius, Jacob Marthinsen Seefeldt, Julie Sørensen Axelsen, Tina Myhre Pedersen, Trine Monberg Sørensen, Roni Nielsen, Henrik Wiggers, Jakob Hansen, Vladimir V Matchkov, Hans Erik Bøtker, Ebbe Boedtkjer.

  The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output and myocardial perfusion without affecting blood pressure in humans, but the cardiovascular sites of action remain obscure. Here, we test the hypothesis in rats that 3-OHB acts directly on the heart to increase cardiac contractility and directly on blood vessels to lower systemic vascular resistance. We investigate effects of 3-OHB on (a) in vivo hemodynamics using echocardiography and invasive blood pressure measurements, (b) isolated perfused hearts in Langendorff systems, and (c) isolated arteries and veins in isometric myographs. We compare Na-3-OHB to equimolar NaCl added to physiological buffers or injection solutions. At plasma concentrations of 2-4 mM in vivo, 3-OHB increases cardiac output (by 28.3±7.8%), stroke volume (by 22.4±6.0%), left ventricular ejection fraction (by 13.3±4.6%), and arterial dP/dtmax (by 31.9±11.2%) and lowers systemic vascular resistance (by 30.6±11.2%) without substantially affecting heart rate or blood pressure. Applied to isolated perfused hearts at 3-10 mM, 3-OHB increases left ventricular developed pressure by up to 26.3±7.4 mmHg and coronary perfusion by up to 20.2±9.5%. Beginning at 1-3 mM, 3-OHB relaxes isolated coronary (EC50=12.4 mM), cerebral, femoral, mesenteric, and renal arteries as well as brachial, femoral, and mesenteric veins by up to 60% of pre-contraction within the pathophysiological concentration range. Of the two enantiomers that constitute racemic 3-OHB, D-3-OHB dominates endogenously; but tested separately, the enantiomers induce similar vasorelaxation. We conclude that increased cardiac contractility and generalized systemic vasorelaxation can explain the elevated cardiac output during 3-OHB administration. These actions strengthen the therapeutic rationale for 3-OHB in heart failure management.

Keywords:  3-hydroxybutyrate; Contractile function; Enantiomers; Ketone bodies; Metabolism; Vasorelaxation

DOI:  https://doi.org/10.1007/s00395-023-01008-y
Nutr Diabetes. 2023 Sep 14. 13(1): 16

Adherence to ketogenic diet in lifestyle interventions in adults with overweight or obesity and type 2 diabetes: a scoping review.

Shiyu Li, Yan Du, Christiane Meireles, Kumar Sharma, Lu Qi, Alondra Castillo, Jing Wang.

BACKGROUND/OBJECTIVES: Despite the evidence supporting the efficacy of the ketogenic diet (KD) on weight and type 2 diabetes (T2D) management, adherence to the KD is challenging. Additionally, no studies have reported changes in PA among individuals with overweight/obesity and T2D who have followed KD. We mapped out the methods used to assess adherence to the KD and level of physical activity (PA) in lifestyle interventions for weight and T2D management in individuals with overweight/obesity and T2D and compared levels of KD adherence and PA in these interventions.METHODS: Articles published between January 2005 and March 2022 were searched in MEDLINE, CINAHL, and Scopus. Studies that included KD in lifestyle interventions for adults with T2D and overweight/obesity and measured ketone levels were included.
RESULTS: The eleven included studies comprised eight randomized controlled trials. They mainly used self-reported measures to evaluate adherence to the KD and level of PA. We found studies reported higher carbohydrate intake and lower fat intake than the KD regimen. Great inconsistencies were found among studies on the measurement and reporting of ketone and PA levels.
CONCLUSION: Our results demonstrated the need to develop intervention strategies to improve adherence to the KD, as well as the necessity of developing standardized diet and PA assessment tools to establish a stronger evidence base for including KD in lifestyle interventions for weight and T2D management among adults with overweight/obesity and T2D.

DOI: https://doi.org/10.1038/s41387-023-00246-2
Epileptic Disord. 2023 Sep 15.

Long-term effectiveness and seizure recurrence risk factors of ketogenic diet for pediatric refractory epilepsy: Experience from a tertiary care center in China.

Yunjian Zhang, Yijie Li, Yan Ni, Xiaoyan Gong, Zhongying Lu, Yuanfeng Zhou, Yi Wang, Lifei Yu, Shuizhen Zhou.

  OBJECTIVE: This study aimed to assess the long-term effectiveness and seizure recurrence risk in children with drug-resistant epilepsy who achieved seizure freedom on a ketogenic diet (KD). Predictors associated with seizure recurrence were also evaluated.METHODS: Patients with drug-resistant epilepsy who received KD therapy for at least three months between May 2011 and April 2020 were included. The clinical efficacy of the KD was evaluated. Patients who achieved seizure freedom for at least three months on the KD were focused. Multivariate Cox regression models were used to explore the risk factors of seizure relapse in patients who achieved seizure freedom.
RESULTS: This study included 288 patients (163 males, 125 females). The seizure-free rates of the KD at 3, 6, 12, and 24 months were 9.7%, 16.7%, 14.2%, and 9.0%, respectively. Additionally, the seizure reduction rates between 50% and 99% were 46.5%, 39.9%, 30.2%, and 20.5%, respectively. Patients with Angelman syndrome (AS) showed the highest efficacy rate, followed by those with Dravet syndrome (DS). Fifty-one patients achieved at least three months of seizure freedom on the KD. Seizures recurred in 24 (47.1%) patients. None of the patients with AS relapsed, while those with DS had the highest recurrence rate. The etiology of epilepsy, KD maintenance treatment period, and electroencephalography (EEG) abnormalities during follow-up differed significantly between patients with and without recurrence. However, multivariate Cox regression analysis indicated that a KD maintenance treatment period of less than 12 months and the presence of EEG abnormalities during follow-up were significantly correlated with a higher risk of relapse. Epilepsy control was restored in 3 of the 24 (12.5%) patients who experienced relapse.
SIGNIFICANCE: KD appears to be effective in children with various types of drug-resistant epilepsy. A short KD maintenance treatment period and EEG abnormalities during follow-up were associated with an increased risk of seizure recurrence.

Keywords:  Children; Intractable epilepsy; Ketogenic diet; Recurrence; Seizure freedom

DOI:  https://doi.org/10.1002/epd2.20160
J Physiol. 2023 Sep 12.

Skeletal muscle mitochondria in strength athletes: meeting energy needs with mitochondrial morphological changes.

Alyse L Lodigiani, Joseph C Morrison.



Keywords:  Olympic weightlifting; mitochondria; mitochondrial morphology; powerlifting; strength training; transmission electron microscopy

DOI:  https://doi.org/10.1113/JP285345
Brain Behav Immun. 2023 Sep 07. pii: S0889-1591(23)00270-2. [Epub ahead of print]

Ketogenic diet changes microglial morphology and the hippocampal lipidomic profile differently in stress susceptible versus resistant male mice upon repeated social defeat.

Fernando González Ibáñez, Torin Halvorson, Kaushik Sharma, Chloe Grace McKee, Micaël Carrier, Katherine Picard, Nathalie Vernoux, Kanchan Bisht, Jessica Deslauriers, Maciej Lalowski, Marie-Ève Tremblay.

  Psychological stress confers an increased risk for several diseases including psychiatric conditions. The susceptibility to psychological stress is modulated by various factors, many of them being modifiable lifestyle choices. The ketogenic diet (KD) has emerged as a dietary regime that offers positive outcomes on mood and health status. Psychological stress and elevated inflammation are common features of neuropsychiatric disorders such as certain types of major depressive disorder. KD has been attributed anti-inflammatory properties that could underlie its beneficial consequences on the brain and behavior. Microglia are the main drivers of inflammation in the central nervous system. They are known to respond to both dietary changes and psychological stress, notably by modifying their production of cytokines and relationships among the brain parenchyma. To assess the interactions between KD and the stress response, including effects on microglia, we examined adult male mice on control diet (CD) versus KD that underwent 10 days of repeated social defeat (RSD) or remained non-stressed (controls; CTRLs). Through a social interaction test, stressed mice were classified as susceptible (SUS) or resistant (RES) to RSD. The mouse population fed a KD tended to have a higher proportion of individuals classified as RES following RSD. Microglial morphology and ultrastructure were then analyzed in the ventral hippocampus CA1, a brain region known to present structural alterations as a response to psychological stress. Distinct changes in microglial soma and arborization linked to the KD, SUS and RES phenotypes were revealed. Ultrastructural analysis by electron microscopy showed a clear reduction of cellular stress markers in microglia from KD fed animals. Furthermore, ultrastructural analysis showed that microglial contacts with synaptic elements were reduced in the SUS compared to the RES and CTRL groups. Hippocampal lipidomic analyses lastly identified a distinct lipid profile in SUS animals compared to CTRLs. These key differences, combined with the distinct microglial responses to diet and stress, indicate that unique metabolic changes may underlie the stress susceptibility phenotypes. Altogether, our results reveal novel mechanisms by which a KD might improve the resistance to psychological stress.

Keywords:  Electron microscopy; Hippocampus; Ketogenic diet; Lipidomics; Microglia; Psychological stress; Repeated social defeat

DOI:  https://doi.org/10.1016/j.bbi.2023.09.006
Genes Dis. 2024 Mar;11(2): 819-829

Fantastic voyage: The journey of NLRP3 inflammasome activation.

Xiangyong Que, Sihao Zheng, Qibin Song, Huadong Pei, Pingfeng Zhang.

  NLRP3 inflammasome, an intracellular multiprotein complex, can be activated by a range of pathogenic microbes or endogenous hazardous chemicals. Its activation results in the release of cytokines such as IL-1β and IL-18, as well as Gasdermin D which eventually causes pyroptosis. The activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and mechanisms. Its excessive activation can lead to a persistent inflammatory response, which is linked to the onset and progression of severe illnesses. Recent studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation process. In this review, we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation, focusing on the subcellular localization of NLRP3 and the associated regulatory mechanisms. We aim to provide a comprehensive understanding of the dynamic transportation, activation, and degradation processes of NLRP3.

Keywords:  Inflammasome activation; Innate immunity; NLRP3; NLRP3 inflammasome; Subcellular localization

DOI:  https://doi.org/10.1016/j.gendis.2023.01.009
J Endocr Soc. 2023 Aug 28. 7(10): bvad112

Effects of Ketogenic Diet on Reproductive Hormones in Women With Polycystic Ovary Syndrome.

Karniza Khalid, Saraswathy Apparow, Irma Liyana Mushaddik, Amalina Anuar, Syed A A Rizvi, Anasufiza Habib.

  Context: Ketogenic diet has recently made a comeback as a part of lifestyle and dietary modifications in patients with polycystic ovary syndrome (PCOS). Despite studies suggesting its beneficial effects in reversing hormonal imbalance in women with PCOS, evidence has been patchy and derived from small populations under varying conditions.Objective: To pool evidence from clinical trials to study the effects of ketogenic diet on reproductive hormones (LH/FSH ratio, free testosterone, serum progesterone) and observe evidence of weight change.
Methods: PubMed, ScienceDirect, Scopus, and Web of Science core collection were searched for clinical trials evaluating the effects of ketogenic diet in established PCOS women consistent with the Rotterdam classification. Single- or double-arm studies that included an outcome of interest were included. Two investigators worked independently to screen potential articles and a designated investigator extracted data on study characteristics and evaluated the outcomes. Data were pooled using a random-effects model. The quality of selected studies was assessed using the Cochrane Risk of Bias Tool.
Results: Following ≥45 days of intervention with ketogenic diet among women with PCOS, significant improvement was observed in reproductive hormone levels, with reduced LH/FSH ratio (d -0.851; 95% CI -1.015, -0.686; P < .001), reduced serum free testosterone (d -0.223; 95% CI -0.328, -0.119; P < .001), and an increased in serum sex hormone binding globulin (SHBG) (d 9.086; 95% CI 3.379, 14.792; P = .002). Significant weight loss was unanimously observed in all included studies (d -11.56; 95% CI -14.97, -8.15; P < .001).
Conclusion: Short-term ketogenic diet potentially improved hormonal imbalances commonly associated with PCOS.

Keywords:  clinical trial; ketogenic diet; lifestyle; meta-analysis; polycystic ovary syndrome

DOI:  https://doi.org/10.1210/jendso/bvad112
Brain Res. 2023 Sep 07. pii: S0006-8993(23)00338-4. [Epub ahead of print]1821 148567

Infusions of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produce antidepressant-like effects on learned helplessness rats through BDNF-TrkB signaling and AMPA receptor activation, and strengthen learning ability.

Yukihiko Shirayama, Masaaki Iwata, Kanako Miyano, Yuki Hirose, Yasunori Oda, Yuko Fujita, Kenji Hashimoto.

  Beta-hydroxybutyrate (BHB), an endogenous NLRP3 inflammasome inhibitor, has been shown to be associated with the pathophysiology of depression in rodents. However its active mechanism has not been revealed. Herein, we probed both the pathways and brain regions involved in BHB's antidepressant-like effects in a learned helplessness (LH) rat model of depression. A single bilateral infusion of BHB into the cerebral ventricles induced the antidepressant-like effects on the LH rats. The antidepressant-like effects of BHB were blocked by the TrkB inhibitor ANA-12 and the AMPA receptor antagonist NBQX, indicating that the antidepressant-like effects of BHB involve BDNF-TrkB signaling and AMPA receptor activation. Further, infusions of BHB into the prelimbic and infralimbic portions of medial prefrontal cortex, the dentate gyrus of hippocampus, and the basolateral region of amygdala produced the antidepressant-like effects on LH rats. However, infusions of BHB into the central region of amygdala, the CA3 region of hippocampus, and the shell and core regions of nucleus accumbens had no effect. Finally, a single bilateral infusion of BHB into the cerebral ventricles of naive rats strengthened learning ability on repeated active avoidance test where saline-infused animals failed to increase avoidance responses.

Keywords:  AMPA receptor; BDNF; Beta-hydroxybutyrate (BHB); Depression; Learned helplessness (LH); Learning

DOI:  https://doi.org/10.1016/j.brainres.2023.148567
Mol Biol Rep. 2023 Sep 13.

β-hydroxybutyrate ameliorates sepsis-induced acute kidney injury.

Min Jeong Kim, Young Suk Kim, Seo Rin Kim, Dong Won Lee, Soo Bong Lee, Il Young Kim.

  BACKGROUND: Sepsis is a major cause of acute kidney injury (AKI). Recent studies have demonstrated that β-hydroxybutyrate (β-HB) alleviates renal ischemia-reperfusion injury and cisplatin-induced renal injury in murine models. This study aimed to investigate whether β-HB ameliorates sepsis-induced AKI (SIAKI) in a lipopolysaccharide (LPS)-induced mouse sepsis model.METHODS AND RESULTS: SIAKI was induced by intraperitoneally injecting LPS to C57BL/6 male mice. β-HB was administrated intraperitoneally before LPS injection. The mice were divided into sham, β-HB, LPS, and β-HB + LPS groups. The histological damage score and serum creatinine level were significantly increased in the LPS group mice, but attenuated in the β-HB + LPS group mice. The expression of phosphorylated nuclear factor-κB tumor necrosis factor-α/interleukin-6 and the number of F4/80-positive macrophages in the β-HB + LPS group mice were lower than those in the LPS group mice. The number of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells, cleaved caspase-3 expression, and Bax/Bcl-2 ratio in the β-HB + LPS group mice were lower than those in the LPS group mice.
CONCLUSION: β-HB pre-treatment ameliorates SIAKI by reducing tubular apoptosis and inflammatory responses. Thus, β-HB pre-treatment could be a potential prophylactic strategy against SIAKI.

Keywords:  Acute kidney injury; Apoptosis; Inflammation; Sepsis; β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s11033-023-08713-w
Int J Biol Macromol. 2023 Sep 08. pii: S0141-8130(23)03681-4. [Epub ahead of print] 126784

Alleviative effect of poly-β-hydroxybutyrate on lipopolysaccharide-induced oxidative stress, inflammation and cell apoptosis in Cyprinus carpio.

Liang Li, Xiao-Fang Wei, Zhi-Yong Yang, Rui Zhu, Deng-Lai Li, Guo-Jun Shang, Hao-Tong Wang, Si-Tong Meng, Yin-Tao Wang, Si-Ying Liu, Li-Fang Wu.

  In this study, the alleviative effects of poly-β-hydroxybutyrate (PHB) in bioflocs on oxidative stress, inflammation and apoptosis of common carp (Cyprinus carpio) induced by lipopolysaccharide (LPS) were evaluated. Common carp were irregularity divided into 5 groups and fed five diets with 0 % (CK), 2 %, 4 %, 6 % and 8 % PHB. After 8-week feeding trial, LPS challenge was executed. Results showed that appropriate level of PHB enhanced serum immune function by reversing LPS-induced the decrease of C3, C4, IgM, AKP, ACP and LZM in serum, alleviated LPS-induced intestinal barrier dysfunction by decreasing the levels of 5-HT, D-LA, ET-1 and DAO in serum, increasing ZO-1, Occludin, Claudin-3 and Claudin-7 mRNA, improving intestinal morphology. Moreover, dietary PHB reversed LPS-induced the decrease of AST and ALT in hepatopancreas, while in serum exhibited the opposite trend. Suitable level of PHB reversed LPS-induced the reduction of GSH-PX, CAT, T-SOD and T-AOC in intestines and hepatopancreas, whereas MDA showed the opposite result. PHB alleviated LPS-induced the decrease of Nrf2, HO-1, CAT, SOD and GSH-PX mRNA, the increase of Keap1 mRNA. Appropriate level of PHB alleviated LPS-induced inflammation and apoptosis by up-regulating TGF-β, IL-10 and Bcl-2 mRNA, down-regulating NF-κB, TNF-α, IL-6, Bax, Caspase-3, Caspase-8 and Caspase-9 mRNA. Furthermore, PHB inhibited activation of NLRP3 inflammasomes by reducing the levels of NLRP3, Caspase-1, ASC, IL-1β and IL-18 mRNA and protein. In addition, the increases of dietary PHB linearly and quadratically affected LPS-induced adverse effects on common carp. Summary, this study suggested that appropriate level of dietary PHB alleviated LPS-induced oxidative stress, inflammation, apoptosis and the activation of NLRP3 inflammasome in common carp. And the appropriate level of PHB in common carp diets was 4 %.

Keywords:  Antioxidant capacity; Cyprinus carpio; Immunity; Lipopolysaccharide; NLRP3 inflammasome; Poly-β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.126784
Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]

Mitochondrial degradation: Mitophagy and beyond.

Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.

  Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.

Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
FASEB J. 2023 10;37(10): e23184

Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high-intensity interval training.

Macsue Jacques, Shanie Landen, Javier Alvarez Romero, Danielle Hiam, Ralf B Schittenhelm, Iresha Hanchapola, Anup D Shah, Sarah Voisin, Nir Eynon.

  Exercise is a major beneficial contributor to muscle metabolism, and health benefits acquired by exercise are a result of molecular shifts occurring across multiple molecular layers (i.e., epigenome, transcriptome, and proteome). Identifying robust, across-molecular level targets associated with exercise response, at both group and individual levels, is paramount to develop health guidelines and targeted health interventions. Sixteen, apparently healthy, moderately trained (VO2 max = 51.0 ± 10.6 mL min-1 kg-1 ) males (age range = 18-45 years) from the Gene SMART (Skeletal Muscle Adaptive Responses to Training) study completed a longitudinal study composed of 12-week high-intensity interval training (HIIT) intervention. Vastus lateralis muscle biopsies were collected at baseline and after 4, 8, and 12 weeks of HIIT. DNA methylation (~850 CpG sites) and proteomic (~3000 proteins) analyses were conducted at all time points. Mixed models were applied to estimate group and individual changes, and methylome and proteome integration was conducted using a holistic multilevel approach with the mixOmics package. A total of 461 proteins significantly changed over time (at 4, 8, and 12 weeks), whilst methylome overall shifted with training only one differentially methylated position (DMP) was significant (adj.p-value < .05). K-means analysis revealed cumulative protein changes by clusters of proteins that presented similar changes over time. Individual responses to training were observed in 101 proteins. Seven proteins had large effect-sizes >0.5, among them are two novel exercise-related proteins, LYRM7 and EPN1. Integration analysis showed bidirectional relationships between the methylome and proteome. We showed a significant influence of HIIT on the epigenome and more so on the proteome in human muscle, and uncovered groups of proteins clustering according to similar patterns across the exercise intervention. Individual responses to exercise were observed in the proteome with novel mitochondrial and metabolic proteins consistently changed across individuals. Future work is required to elucidate the role of these proteins in response to exercise.

Keywords:  DNA methylation; epigenetics; exercise; proteomics; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202300840RR
Cell Commun Signal. 2023 Sep 15. 21(1): 232

Divergent functions of NLRP3 inflammasomes in cancer: a review.

Alireza Shadab, Mohamad Mahjoor, Mohammad Abbasi-Kolli, Hamed Afkhami, Parisa Moeinian, Amir-Reza Safdarian.

  The cancer is a serious health problem, which is The cancer death rate (cancer mortality) is 158.3 per 100,000 men and women per year (based on 2013-2017 deaths). Both clinical and translational studies have demonstrated that chronic inflammation is associated with Cancer progression. However, the precise mechanisms of inflammasome, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the "inflammasome" a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in cancer pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the malignancy condition consequences of the inflammation. Video Abstract.

Keywords:  Caspase; Immunosuppression; Immunotherapy; Inflammasome; Metastasis; NLRP3; Pyroptosis; Tumor

DOI:  https://doi.org/10.1186/s12964-023-01235-9
Gene Ther. 2023 Sep 12.

Long-term effects of a fat-directed FGF21 gene therapy in aged female mice.

Jacqueline M Anderson, W David Arnold, Wei Huang, Alissa Ray, Gregory Owendoff, Lei Cao.

Fibroblast growth factor 21 (FGF21) has been developed as a potential therapeutic agent for metabolic syndromes. Moreover, FGF21 is considered a pro-longevity hormone because transgenic mice overexpressing FGF21 display extended lifespan, raising the possibility of using FGF21 to promote healthy aging. We recently showed that visceral fat directed FGF21 gene therapy improves metabolic and immune health in insulin resistant BTBR mice. Here, we used a fat directed rAAV-FGF21 vector in 17-month-old female mice to investigate whether long-term FGF21 gene transfer could mitigate aging-related functional decline. Animals with FGF21 treatment displayed a steady, significant lower body weight over 7-month of the study compared to age-matched control mice. FGF21 treatment reduced adiposity and increased relative lean mass and energy expenditure associated with almost 100 folds higher serum level of FGF21. However, those changes were not translated into benefits on muscle function and did not affect metabolic function of liver. Overall, we have demonstrated that a single dose of fat-directed AAV-FGF21 treatment can provide a sustainable, high serum level of FGF21 over long period of time, and mostly influences adipose tissue homeostasis and energy expenditure. High levels of FGF21 alone in aged mice is not sufficient to improve liver or muscle functions.

DOI: https://doi.org/10.1038/s41434-023-00422-0
Front Aging. 2023 ;4 1256844

Aging, adaptation and maladaptation.

Thomas Lissek.

  Aging is accompanied by a dysregulation of adaptive processes. On the one hand, physiological adaptation mechanisms such as learning and memory, immune system plasticity and exercise-dependent muscle remodeling are blunted. On the other hand, several maladaptive processes increase with age including cancer, pathological cardiovascular remodeling and metabolic dysregulation. With increasing age the quotient of beneficial adaptation (Ab) to harmful adaptation (Ah), Ab/Ah, decreases. The adaptation-maladaptation framework of aging entails that there are age-related pathological phenotypes that are the result of activation of physiological adaptation mechanisms (e.g., maladaptation as a result of misdirection of adaptive cascades and molecular damage incurred by adaptation processes) and their occurrence over time might, to some degree, be inevitable. Aging might hence result from the organism's inability to solve the adaptation-maladaptation dilemma. The present work explores the concept of counteracting aging through adaptation and proposes that interventions such as exercise, environmental enrichment and dietary restriction work in counteracting aging because they increase the ratio Ab/Ah by both raising Ab (e.g., by inducing metaplasticity in cells, meaning they raise the adaptability of cells to future stimuli) and decreasing Ah (e.g., through desensitizing certain potentially harmful adaptive mechanisms). Molecules whose aging-related expression changes can explain aspects of dysfunctional adaptation such as CREB and certain immediate early genes are examined and it is delineated how a better understanding of the dynamical organization of adaptation cascades could elucidate the seemingly complex role of adaptation in driving aging as well as protecting against it.

Keywords:  adaptation; age; aging; longevity; maladaptation; plasticity; transcription

DOI:  https://doi.org/10.3389/fragi.2023.1256844
J Nephrol. 2023 Sep 14.

Sodium-glucose cotransporter-2 inhibition in a CKD patient with severe heart failure treated by high-dose diuretics and peritoneal ultrafiltration: lesson for the clinical nephrologist.

Silvio Borrelli, Carlo Garofalo, Maria Elena Liberti, Chiara Ruotolo, Federica Capozzi, Pavlo Yavorskiy, Luca De Nicola.



Keywords:  Heart failure; Peritoneal dialysis; SGLT2-inhibitors

DOI:  https://doi.org/10.1007/s40620-023-01766-x
Phytother Res. 2023 Sep 10.

Targeting the NLRP3 inflammasome for the treatment of hypertensive target organ damage: Role of natural products and formulations.

Xiaolin Liao, Yuanshan Han, Chuanpu Shen, Jianjun Liu, Yuhong Wang.

  BACKGROUND AND AIM: Hypertension is a major global health problem that causes target organ damage (TOD) in the heart, brain, kidney, and blood vessels. The mechanisms of hypertensive TOD are not fully understood, and its treatment is challenging. This review provides an overview of the current knowledge on the role of Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome in hypertensive TOD and the natural products and formulations that inhibit it.METHODS: We searched PubMed, Web of Science, Google Scholar, and CNKI for relevant articles using the keywords "hypertension," "target organ damage," "NLRP3 inflammasome," "natural products," and "formulations." We reviewed the effects of the NLRP3 inflammasome on hypertensive TOD in different organs and discussed the natural products and formulations that modulate it.
KEY RESULTS: In hypertensive TOD, the NLRP3 inflammasome is activated by various stimuli such as oxidative stress and inflammation. Activation of NLRP3 inflammasome leads to the production of pro-inflammatory cytokines that exacerbate tissue damage and dysfunction. Natural products and formulations, including curcumin, resveratrol, triptolide, and allicin, have shown protective effects against hypertensive TOD by inhibiting the NLRP3 inflammasome.
CONCLUSIONS AND IMPLICATIONS: The NLRP3 inflammasome is a promising therapeutic target in hypertensive TOD. Natural products and formulations that inhibit the NLRP3 inflammasome may provide novel drug candidates or therapies for hypertensive TOD. Further studies are needed to elucidate the molecular mechanisms and optimize the dosages of these natural products and formulations and evaluate their clinical efficacy and safety.

Keywords:  NLRP3 inflammasome; formulations; hypertension; natural products; target organ damage

DOI:  https://doi.org/10.1002/ptr.8009
Food Funct. 2023 Sep 13.

Low-carbohydrate diet and risk of cardiovascular disease, cardiovascular and all-cause mortality: a systematic review and meta-analysis of cohort studies.

Pei Qin, Xiangying Suo, Shanquan Chen, Cuihong Huang, Wanyi Wen, Xiaoyan Lin, Dongsheng Hu, Yacong Bo.

Background: Evidence for the long-term health effect of low-carbohydrate diets (LCDs) is inconsistent. Herein, we aimed to examine the associations of LCDs with cardiovascular disease (CVD) and all-cause and cause-specific mortality. Methods: We searched PubMed, EMBASE, and the Web of Science up to 26 July 2023 for eligible publications. Random-effect models were used to pool the summary relative risks (RRs) and 95% confidence intervals (CIs). Results: A total of 44 studies (17 articles) were included in the systematic review and 38 in the meta-analysis, including 223 657 all-cause deaths (771 609 participants), 14 046 cardiovascular deaths (274 807 participants), 18 264 CVD cases (405 631 participants), and 3634 coronary heart disease (CHD) cases (151 023 participants). Subsequently, the highest LCD score was compared with the lowest one and the pooled RRs (95% CIs) were 1.05 (0.96, 1.14; I2 = 65.1%; n = 13) for CVD, 1.43 (1.18, 1.72; I2 = 25.4%; n = 3) for CHD, 0.93 (0.81, 1.06; I2 = 0.0%; n = 2) for stroke, 1.03 (0.96, 1.10; I2 = 86.6%; n = 13) for all-cause mortality and 1.09 (0.99, 1.19; I2 = 65.1%; n = 10) for cardiovascular mortality. Conclusion: Our analysis showed positive associations of LCDs with CHD. Thus, vigilance is recommended for long-term adherence to this dietary pattern.

DOI: https://doi.org/10.1039/d3fo01374j
Mol Metab. 2023 Sep 08. pii: S2212-8778(23)00136-9. [Epub ahead of print] 101802

Partial Skeletal Muscle-Specific Drp1 Knockout Enhances Insulin Sensitivity in Diet-Induced Obese Mice, But Not in Lean Mice.

Benjamin A Kugler, Jared Lourie, Nicolas Berger, Nana Lin, Paul Nguyen, Edzana DosSantos, Abir Ali, Amira Sesay, H Grace Rosen, Baby Kalemba, Gregory M Hendricks, Joseph A Houmard, Hiromi Sesaki, Philimon Gona, Tongjian You, Zhen Yan, Kai Zou.

  OBJECTIVE: Dynamin-related protein 1 (Drp1) is the key regulator of mitochondrial fission. We and others have reported a strong correlation between enhanced Drp1 activity and impaired skeletal muscle insulin sensitivity. This study aimed to determine whether Drp1 directly regulates skeletal muscle insulin sensitivity and whole-body glucose homeostasis.METHODS: We employed tamoxifen-inducible skeletal muscle-specific heterozygous Drp1 knockout mice (mDrp1+/-). Male mDrp1+/- and wildtype (WT) mice were fed with either a high-fat diet (HFD) or low-fat diet (LFD) for four weeks, followed by tamoxifen injections for five consecutive days, and remained on their respective diet for another four weeks. In addition, we used primary human skeletal muscle cells (HSkMC) from lean, insulin-sensitive, and severely obese, insulin-resistant humans and transfected the cells with either a Drp1 shRNA (shDrp1) or scramble shRNA construct. Skeletal muscle and whole-body insulin sensitivity, skeletal muscle insulin signaling, mitochondrial network morphology, respiration, and H2O2 production were measured.
RESULTS: Partial deletion of the Drp1 gene in skeletal muscle led to improved whole-body glucose tolerance and insulin sensitivity (P<0.05) in diet-induced obese, insulin-resistant mice but not in lean mice. Analyses of mitochondrial structure and function revealed that the partial deletion of the Drp1 gene restored mitochondrial dynamics, improved mitochondrial morphology, and reduced mitochondrial Complex I- and II-derived H2O2 (P<0.05) under the condition of diet-induced obesity. In addition, partial deletion of Drp1 in skeletal muscle resulted in elevated circulating FGF21 (P<0.05) and in a trend towards increase of FGF21 expression in skeletal muscle tissue (P=0.095). In primary myotubes derived from severely obese, insulin-resistant humans, ShRNA-induced-knockdown of Drp1 resulted in enhanced insulin signaling, insulin-stimulated glucose uptake and reduced cellular reactive oxygen species (ROS) content compared to the shScramble-treated myotubes from the same donors (P<0.05).
CONCLUSION: These data demonstrate that partial loss of skeletal muscle-specific Drp1 expression is sufficient to improve whole-body glucose homeostasis and insulin sensitivity under obese, insulin-resistant conditions, which may be, at least in part, due to reduced mitochondrial H2O2 production. In addition, our findings revealed divergent effects of Drp1 on whole-body metabolism under lean healthy or obese insulin-resistant conditions in mice.

Keywords:  Insulin sensitivity; Mitochondrial H (2)O(2); Mitochondrial dynamics; Mitochondrial fission

DOI:  https://doi.org/10.1016/j.molmet.2023.101802
JIMD Rep. 2023 Sep;64(5): 360-366

Fasting and non-fasting plasma levels of monomethyl branched chain fatty acids: Implications for maple syrup urine disease.

Trine Tangeraas, Erle Kristensen, Lars Mørkrid, Elisabeth Elind, Yngve Thomas Bliksrud, Lars Eide.

  The branched-chain amino acids (BCAA) leucine, valine, and isoleucine provide precursors for monomethyl branched-chain fatty acids (BCFA). Established reference ranges for BCFAs are lacking. In maple syrup urine disease (MSUD), a rare inborn error of BCAA metabolism, the endogen production is impaired and MSUD patients are treated with a low protein (low BCAA) diet. The protein restriction may affect the dietary intake of BCFA, depending on the dietary choices made. Patients with MSUD are prescribed a more or less protein-restricted diet depending on the severity of the disease. The combination of a protein-restricted diet and subsequent impaired endogenous synthesis may render MSUD patients sensitive to BCFA deficiency, with yet unknown implications. To investigate the possibility of lower circulatory BCFA levels in MSUD that favors dietary BCFA supplementation, we first established fasting-state reference ranges for selected BCFAs and saturated/unsaturated fatty acids in plasma. Then, the effect of fasting on BCFA levels was evaluated by comparing the distribution in a fasting versus a non-fasting cohort. To test the hypothesis that BCFA deficiency could contribute to MSUD pathophysiology, we recruited patients with intermittent, intermediate, and classical form of MSUD and analyzed the corresponding BCFA z-scores. None of the BCFA species had |z-scores| > 2 relative to the reference range. Our findings do not support the requirement of BCFA supplementation in MSUD patients. The origin of BCFAs is discussed. Impaired capacity to synthesize BCFA do not manifest as reduced plasma levels in MSUD, suggesting that endogenous synthesis is dispensable for plasma levels.

Keywords:  MSUD; fasting; isoleucine; leucine; monomethyl branched‐chain fatty acids; valine

DOI:  https://doi.org/10.1002/jmd2.12380