bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023‒03‒26
28 papers selected by
Matías Javier Monsalves Álvarez
Universidad de O’Higgins

  1. Clin Nutr ESPEN. 2023 Apr;pii: S2405-4577(23)00032-3. [Epub ahead of print]54 277-287
      BACKGROUND: Single doses of exogenous ketone salts (KS) transiently increase circulating beta-hydroxybutyrate (BHB) (∼1 mM; 1-2 h) regardless of starting levels of ketosis; however, no studies have explored how sustained use of KS influences measures of ketonemia and glycemia.OBJECTIVES: To determine the response to a hypocaloric, well-formulated ketogenic diet (KD), with and without the inclusion of two daily racemic KS doses (6 g R-BHB + 6 g S-BHB per serving) on 1) daily fasting capillary R-BHB and glucose (R-BHB/GLUfast), 2) bi-weekly 13 h diurnal BHB and glucose (R-BHB/GLUdiur), 3) three-hours post-KS ingestion kinetics (R-BHBKS), and 4) bi-weekly fasting plasma enantiomer-specific BHB (R/S-BHBplasma).
    METHODS: Non-diabetic adults with overweight and obesity were randomized to receive a precisely measured hypocaloric KD (∼75 %en of maintenance) for six weeks, supplemented twice-daily with KS or placebo (PL). A non-randomized comparison group was provided an isonitrogenous/isoenergetic low-fat diet (LFD). All meals were provided to subjects. Capillary blood was collected daily to measure R-BHB/GLUfast and hourly for R-BHB/GLUdiur. Plasma was collected to measure R/S-BHBplasma, insulin, fasting glucose, and insulin resistance (HOMA-IR). Total AUC was calculated using the trapezoidal method.
    RESULTS: Mean R-BHBfast increased significantly during KD + PL (1.0 mM BHB), an effect enhanced 26% during KD + KS. GLUfast AUC was -6% lower during KD + KS versus LFD. Mean R-BHBdiur increased 40% in KD + KS versus KD + PL, whereas GLUdiur decreased 13% during both KDs versus LFD. R-BHBKS peaked (Δ: ∼1 mM) 1 h after the morning KS dose, but not following the afternoon dose. Both R/S-BHBplasma increased during KD independent of KS inclusion. R-BHBplasma was 50-times greater compared to S-BHBplasma, and the KS augmented S-BHBplasma 50% more than PL. Fasting insulin and HOMA-IR decreased after 14 days independent of diet.
    CONCLUSIONS: A hypocaloric KD was effective at reducing diurnal glucose compared to a LFD independent of weight loss, but twice-daily racemic KS ingestion during KD augmented ketonemia, both as R- and S-BHB, and decreased mean fasting glucose beyond a KD alone. The hypoglycemic effects of KD in combination with exogenous ketones merit further investigation.
    Keywords:  Beta-hydroxybutyrate; Glucose; Ketogenic diet; Ketone salts; Low-fat diet; Weight loss
  2. Adv Exp Med Biol. 2023 ;1411 537-554
      The ketogenic diet, known as a low-carbohydrate, high-protein, and high-fat diet, drastically restrains the major source of energy for the body, forcing it to burn all excess fat through a process called ketosis-the breaking down of fat into ketone bodies. First suggested as a medical treatment for children suffering from epilepsy, this diet has gained increased popularity as a rapid weight loss strategy. Over the past few years, there have been numerous studies suggesting that the ketogenic diet may provide therapeutic effects for several psychiatric conditions such as mood- and anxiety-related disorders. However, despite significant progress in research, the mechanisms underlying its therapeutic effects remain largely unexplored and are yet to be fully elucidated. This chapter provides an in-depth overview of preclinical and clinical evidence supporting the use of a ketogenic diet in the management of mood and anxiety disorders and discusses its relationship with inflammatory processes and potential mechanisms of actions for its therapeutic effects.
    Keywords:  Anxiety; Bipolar disorder; Inflammation; Ketogenic diet; Major depressive disorder; Mood disorders; Schizophrenia
  3. Front Nutr. 2023 ;10 1110291
      Glioblastoma Multiforme is an aggressive brain cancer affecting children and adults frequently resulting in a short life expectancy. Current cancer therapies include surgery and radiation followed by chemotherapy, which due to their ineffectiveness, requires repeated exposure to the same therapies. Since the 1990s, researchers and doctors have explored other therapies, such as diet therapies, to aid in combating gliomas. The ketogenic diet has gained popularity due to Otto Warburg's theory that tumor cells prefer "aerobic glycolysis" and cannot metabolize ketones. The inability of gliomas to use ketones provides an excellent opportunity to weaken the tumor while protecting healthy cells during cancer treatments. This review will examine some of the current research using the ketogenic diet as a form of cancer therapy to determine if this intervention is manageable and effective in patients with glioblastoma. Peer-reviewed articles from 2009 to 2019 were used. The primary objective is to distinguish differences between pre-clinical and clinical research to determine if the ketogenic diet is reproducible from mouse models into humans to determine its effectiveness. The analysis revealed several limitations of the ketogenic diet as an intervention. The effectiveness is more robust in mice than in human studies. Furthermore, tolerability is marginally supported in human studies requiring more reproducible research to validate that the intervention is manageable and effective in patients with glioblastoma.
    Keywords:  calorie restriction; diet intervention; glioblastoma; ketogenic diet; low carbohydrate diet
  4. J Neural Transm (Vienna). 2023 Mar 21.
      Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD) are often resistant to current pharmacological treatment. Therefore, various alternative therapeutic approaches including diets are, therefore, under investigation. Ketogenic diet (KD) is effective for treatment-resistant epilepsy and metabolic diseases, however, only a few clinical studies suggest its beneficial effect also for mental disorders. Animal models are a useful tool to uncover the underlying mechanisms of therapeutic effects. Women have a twice-higher prevalence of mood disorders but very little is known about sex differences in nutritional psychiatry. In this review, we aim to summarize current knowledge of the sex-specific effects of KD in mood disorders. Ketone bodies improve mitochondrial functions and suppress oxidative stress, inducing neuroprotective and anti-inflammatory effects which are both beneficial for mental health. Limited data also suggest KD-induced improvement of monoaminergic circuits and hypothalamus-pituitary-adrenal axis-the key pathophysiological pathways of mood disorders. Gut microbiome is an important mediator of the beneficial and detrimental effects of diet on brain functioning and mental health. Gut microbiota composition is affected in mood disorders but its role in the therapeutic effects of different diets, including KD, remains poorly understood. Still little is known about sex differences in the effects of KD on mental health as well as on metabolism and body weight. Some animal studies used both sexes but did not find differences in behavior, body weight loss or gut microbiota composition. More studies, both on a preclinical and clinical level, are needed to better understand sex-specific effects of KD on mental health.
    Keywords:  Bipolar disorder; Depression; Ketogenic diet; Neurogenesis; Neuroinflammation; Sex differences
  5. BMC Sports Sci Med Rehabil. 2023 Mar 20. 15(1): 37
      BACKGROUND: A ketogenic diet (KD) reduces daily carbohydrates (CHOs) ingestion by replacing most calories with fat. KD is of increasing interest among athletes because it may increase their maximal oxygen uptake (VO2max), the principal performance limitation at high-altitudes (1500-3500 m). We examined the tolerance of a 4-week isocaloric KD (ICKD) under simulated hypoxia and the possibility of evaluating ICKD performance benefits with a maximal graded exercise bike test under hypoxia and collected data on the effect of the diet on performance markers and arterial blood gases.METHODS: In a randomised single-blind cross-over model, 6 recreational mountaineers (age 24-44 years) completed a 4-week ICKD followed or preceded by a 4-week usual mixed Western-style diet (UD). Performance parameters (VO2max, lactate threshold [LT], peak power [Ppeak]) and arterial blood gases (PaO2, PaCO2, pH, HCO3-) were measured at baseline under two conditions (normoxia and hypoxia) as well as after a 4-week UD and 4-week ICKD under the hypoxic condition.
    RESULTS: We analysed data for all 6 participants (BMI 19.9-24.6 kg m-2). Mean VO2max in the normoxic condition was 44.6 ml kg-1 min-1. Hypoxia led to decreased performance in all participants. With the ICKD diet, median values for PaO2 decreased by - 14.5% and VO2max by + 7.3% and Ppeak by + 4.7%.
    CONCLUSION: All participants except one could complete the ICKD. VO2max improved with the ICKD under the hypoxia condition. Therefore, an ICKD is an interesting alternative to CHOs dependency for endurance performance at high-altitudes, including high-altitude training and high-altitude races. Nevertheless, decreased PaO2 with ICKD remains a significant limitation in very-high to extreme altitudes (> 3500 m). Trial registration Clinical trial registration Nr. NCT05603689 ( Ethics approval CER-VD, trial Nr. 2020-00427, registered 18.08.2020-prospectively registered.
    Keywords:  Endurance exercise; High-altitude; Hypoxia; Ketogenic diet; Low-carbohydrate; VO2max
  6. Clin Nutr ESPEN. 2023 Apr;pii: S2405-4577(23)00026-8. [Epub ahead of print]54 166-174
      Intermittent Fasting (IF) is the consumption of food and drinks within a defined time, while the ketogenic diet (KD) switches the metabolism from glucose to fats. Continuation of intermittent fasting leads to the generation of ketones, the exact mechanism for a ketogenic diet. This article discusses the types of IF and KD, the monitoring required, and the mechanisms underlying IF and KD, followed by disorders in which the combination strategy could be applied. The strategies for successfully applying combination therapy are included, along with recommendations for the primary care physicians (PCP) which could serve as a handy guide for patient management. This opinion article could serve as the baseline for future clinical studies since there is an utmost need for developing new wholesome strategies for managing chronic disorders.
    Keywords:  Chronic conditions; Intermittent fasting; Ketogenic diet; Neurological disorders; Nutrition
  7. Mol Metab. 2023 Mar 21. pii: S2212-8778(23)00045-5. [Epub ahead of print] 101711
      Heart diseases are the leading cause of deaths worldwide. Metabolic interventions via ketogenic diets (KDs) have been used for decades to treat epilepsy, and more recently, also diabetes and obesity, as common comorbidities of heart diseases. However, recent reports linked KDs, based on long-chain triglycerides (LCTs), to cardiac fibrosis and a reduction of heart function in rodents. As intervention using medium-chain triglycerides (MCTs) was recently shown to be beneficial in murine cardiac reperfusion injury, the question arises as to what extent the fatty acid (FA)-composition in a KD alters molecular markers of FA-oxidation (FAO) and modulates cardiac fibrotic outcome. Here, we show that eight weeks of feeding an LCT-KD as well as an LCT/MCT mix (8:1 ketogenic ratio) induces cardiac fibrosis in male C57/BL6NRJ mice. Despite the increased amount of collagen fibers, cardiac tissue was immunologically indistinguishable between groups. MCT supplementation resulted in i) profound changes in plasma metabolome, ii) reduced hydroxymethylglutaryl-CoA synthase upregulation, and mitofusin 2 downregulation, iii) abrogation of LCT-induced mitochondrial enlargement, and iv) enhanced FAO profile. Contrary to literature, mitochondrial biogenesis was unaffected by KDs. We propose that the tissue remodeling, which we observed, is caused by the accumulation of 4-hydroxy-2-nonenal protein adducts, despite an inconspicuous nuclear factor (erythroid-derived 2)-like 2 pathway. We conclude that in spite of the generally favorable effects of MCTs, they cannot inhibit 4-hydroxy-2-nonenal adduct formation and fibrotic tissue formation in this setting. Furthermore, we support the burgeoning concern about the effect of KDs on the cardiac safety profile.
    Keywords:  4-HNE; collagen deposition; diet composition; dietary therapeutics; heart diseases; low carbohydrate diets
  8. J Cardiovasc Med (Hagerstown). 2023 Apr 01. 24(4): 232-243
      AIMS: Inflammation in the epicardial adipose tissue (EAT) is a contributor to atrial fibrillation. Studies have reported that sodium glucose co-transporter 2 inhibitor (SGLT2i) can alleviate EAT inflammation. However, the mechanism remains elusive. This study aims to investigate the molecular mechanism of SGLT2i in reducing EAT inflammation and to explore the effects of SGLT2i on atrial fibrosis in atrial fibrillation.METHODS: Sprague-Dawley rats were injected with angiotensin II to induce atrial fibrillation and randomly assigned to receive SGLT2i ( n  = 6) or vehicle ( n  = 6). Macrophages (RAW264.7) were treated with ketone bodies; ACC1 knockdown/overexpression and malonyl-CoA overexpression were performed in vitro . The levels of inflammatory cytokines, ACC1, and malonyl-CoA were examined by ELISA. GAPDH malonylation was measured by co-immunoprecipitation.
    RESULTS: In atrial fibrillation rats, SGLT2i increased the ketone body levels and decreased the expression of ACC1 and alleviated EAT inflammation and atrial fibrosis. In RAW264.7 cells, ketone bodies decreased the levels of ACC1, malonyl-CoA, and GAPDH malonylation, accompanied by reduced inflammatory cytokines. ACC1 knockdown decreased the expression of malonyl-CoA and GAPDH malonylation and alleviated lipopolysaccharide (LPS)-induced macrophage inflammation; these effects were inhibited by malonyl-CoA overexpression. Furthermore, the protective effects of ketone bodies on macrophage inflammation were abrogated by ACC1 overexpression.
    CONCLUSION: SGLT2i alleviates EAT inflammation by reducing GAPDH malonylation via downregulating the expression of ACC1 through increasing ketone bodies, thus attenuating atrial fibrosis.
  9. Am J Clin Nutr. 2021 Jun;pii: S0002-9165(23)07238-6. [Epub ahead of print]113(6): 1398-1399
  10. J Nutr. 2023 Mar 22. pii: S0022-3166(23)35499-3. [Epub ahead of print]
      BACKGROUND: The role of fat-free mass loss (FFML) in modulating weight regain, in individuals with obesity, as well as the potential mechanisms involved, remain inconsistent.AIMS: To determine if % FFML following weight loss (WL) is a predictor of weight regain, and to investigate the association between %FFML and changes in appetite markers.
    METHODS: Seventy individuals with obesity (BMI: 36±4kg/m2; age: 44±9 years; 29 males) underwent 8 weeks of a very low-energy diet (550-660 kcal/day), followed by 4 weeks of gradual refeeding and weight stabilization, and a 9-month maintenance program (eucaloric diet). Body weight and body composition (fat mass (FM) and FFM) (primary outcomes), as well as ß-hydroxybutyrate (ßHB) plasma concentration (a marker of ketosis) in fasting and appetite-related hormones (ghrelin, glucagon-like peptide 1, peptide YY, and cholecystokinin) and subjective appetite feelings, in fasting and every 30 minutes after a fixed breakfast for 2.5h (secondary outcomes), were measured at baseline, week 9 and 1 year (and week 13 in 35 subjects (25 males)). The association between FFML, weight regain and changes in appetite was assessed by linear regression.
    RESULTS: WL at week 9 was 17.5±4.3kg and %FFML 20.4±10.6%. Weight regain at 1 year was 1.7±8.2kg (8.8±45.0%). After adjusting for WL and FM at baseline, %FFML at week 9 was not a significant predictor of weight regain. Similar results were seen at week 13. The greater the %FFML at week 9, but not 13, the smaller the reduction, or greater the increase in basal ghrelin concentration (ß:-3.2; 95% CI: -5.0, -1.1; P=0.003), even after adjusting for WL and ß-hydroxybutyrate.
    CONCLUSION: %FFML was not a significant predictor of weight regain at 1-year in individuals with obesity. However, a greater %FFML was accompanied by a greater increase in ghrelin secretion under ketogenic conditions, suggesting a link between FFM and appetite regulation.
    CLINICAL TRIAL REGISTRATION: identifier NCT01834859.
    Keywords:  appetite; fat-free mass; ghrelin; hunger; weight loss; weight regain
  11. Am J Clin Nutr. 2023 Mar 20. pii: S0002-9165(23)46271-5. [Epub ahead of print]
      BACKGROUND: Approximately 84% of fatty acids contained in coconut oil (CO) are saturated fatty acids (SFA), and approximately 47% of the SFA are lauric acid with 12 carbon atoms. Lauric acid carbon chain length is intermediate between medium and long chain fatty acids. We examined how CO acts on lipid-related substances in the blood to determine whether its properties were similar to medium-chain fatty acids (MCFA) or long-chain fatty acids (LCFA).METHODS: This is a randomized controlled single-blind crossover study. 15 females were enrolled, using three test meals containing 30-g each of three different oils: CO (CO-meal), medium-chain triacylglycerol-oil (MCT-meal), and long-chain triacylglycerol-oil (LCT-meal). Blood samples were collected at fasted baseline and every 2 h for 8 h after the intake of each test meal.
    RESULTS: Repeated measure analysis of variance (ANOVA) of the ketone bodies and triglyceride (TG) showed an interaction between time and the test meal (P < 0.01 and P < 0.001, respectively). In subsequent Tukey's honestly significant difference (HSD) test of the ketone bodies, statistically significant differences were observed between the CO-meal and the LCT-meal (P < 0.05) 83.8 (95% CI, 14.7,153.0) and between the MCT-meal and the LCT-meal (P < 0.05) 79.2 (95% CI, 10.0,148.4). The incremental area under the curve (iAUC) and maximum increase in very low-density lipoprotein cholesterol (VLDL-C) and intermediate-density lipoprotein cholesterol (IDL-C) were the lowest for CO-meal intakes.
    CONCLUSIONS: The characteristics of lauric acid contained in coconut oil, including the kinetics of β-oxidation and effects on blood TG, were very similar to those of MCFA. Moreover, regarding the iAUC and peak increment, VLDL-C and IDL-C were the lowest with the CO-meal. These results suggest that the intake of CO after fasting does not increase the TG, VLDL-C, and IDL-C, and may help prevent dyslipidemia. This trial was registered at UMIN as UMIN000019959.
    Keywords:  IDL-cholesterol; VLDL-cholesterol; coconut oil; free fatty acids (FFA); ketone bodies; lauric acid; long-chain fatty acid (LCFA); medium-chain fatty acid (MCFA); triglyceride (TG)
  12. Int J Mol Med. 2023 Apr;pii: 35. [Epub ahead of print]51(4):
      The inflammasome regulates innate immunity by serving as a signaling platform. The Nod‑like receptor protein 3 (NLRP3) inflammasome, equipped with NLRP3, the adaptor protein apoptosis‑associated speck‑like protein (ASC) and pro‑caspase‑1, is by far the most extensively studied and well‑characterized inflammasome. A variety of stimuli can activate the NLRP3 inflammasome. When activated, the NLRP3 protein recruits the adaptor ASC protein and activates pro‑caspase‑1, resulting in inflammatory cytokine maturation and secretion, which is associated with inflammation and pyroptosis. However, the aberrant activation of the NLRP3 inflammasome has been linked to various inflammatory diseases, including atherosclerosis, ischemic stroke, Alzheimer's disease, diabetes mellitus and inflammatory bowel disease. Therefore, the NLRP3 inflammasome has emerged as a promising therapeutic target for inflammatory diseases. In the present review, systematic searches were performed using 'NLRP3 inhibitor(s)' and 'inflammatory disease(s)' as key words. By browsing the literature from 2012 to 2022, 100 articles were retrieved, of which 35 were excluded as they were reviews, editorials, retracted or unavailable online, and 65 articles were included. According to the retrieved literature, the current understanding of NLRP3 inflammasome pathway activation in inflammatory diseases was summarize, and inhibitors of the NLRP3 inflammasome pathway targeting the NLRP3 protein and other inflammasome components or products were highlighted. Additionally, the present review briefly discusses the current novel efforts in clinical research.
    Keywords:  Nod‑like receptor protein 3 inflammasome inhibitors; clinical perspectives; inflammation; inflammatory diseases; pyroptosis
  13. CEN Case Rep. 2023 Mar 19.
      Metformin-associated lactic acidosis is a well-known metformin treatment complication; however, the development of euglycemic diabetic ketoacidosis (euDKA) has rarely been reported. Here we report a case of lactic acidosis and euDKA after metformin overdose. A 57-year-old female patient was transferred to our hospital with severe metabolic acidosis and acute kidney injury. She had type 2 diabetes mellitus and was on oral antidiabetic therapy of vildagliptin metformin hydrochloride daily. On the admission day, she had committed suicide by overdosing 50 tablets of vildagliptin metformin hydrochloride, which was equivalent to 25,000 mg of metformin and 2500 mg of vildagliptin. She had severe lactic acidosis 5 h after overdosing. However, after 34 h of overdosing, serum lactate levels decreased while serum anion gap levels increased. She received single hemodialysis treatment. Serum total ketone bodies, β-hydroxybutyrate acetoacetic acid, and acetone were increased even after hemodialysis treatment. Her blood glucose levels have never exceeded 250 mg/dL since admission. Therefore, we considered that the cause of metabolic acidosis in this patient was not only lactic acidosis but also euDKA. The causes of euDKA in our patient might be hepatic production of ketone bodies due to metformin overdose in addition to type 2 diabetes mellitus, starvation, infection, and stressful physical conditions such as vomiting and diarrhea. We propose that not only lactic acidosis but also ketoacidosis is one of the important pathological conditions in patients with metformin overdose.
    Keywords:  Acute kidney injury; Euglycemic diabetic ketoacidosis; Lactic acidosis; Metformin; Metformin-associated lactic acidosis (MALA); Overdose
  14. Ageing Res Rev. 2023 Mar 22. pii: S1568-1637(23)00074-0. [Epub ahead of print]87 101915
      Parkinson's disease (PD), a multifactorial movement disorder, is interlinked with numerous molecular pathways, including neuroinflammation, which is a critical factor in the development and progression of PD. Microglia play a central role in driving neuroinflammation through activation and overexpression of the M1 phenotype, which has a significant impact on mitochondria. Multiple regulators converge together, and among these, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes have been implicated in transmitting inflammatory and deleterious components to the mitochondria. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the NLRP3 inflammasome and acts as the saviour of the mitochondria. Together, the NLRP3-Nrf2 axis functions in regulating mitochondrial function in the case of PD. It regulates fundamental processes such as oxidative stress, mitochondrial respiratory function, and mitochondrial dynamics. In this review, we discuss the contributions that a variety of miRNAs make to the regulation of the NLRP3 inflammasome and Nrf2, which can be used to target this important axis and contribute to the preservation of mitochondrial integrity. This axis may prove to be a crucial target for extending the lives of Parkinson's patients by deferring neuroinflammatory damage to mitochondria.
    Keywords:  Innate immunity; Mitochondria; NLRP3; Neuroinflammation; Nrf2; Parkinson’s disease
  15. Nat Immunol. 2023 Mar 20.
      Upon detecting pathogens or cell stress, several NOD-like receptors (NLRs) form inflammasome complexes with the adapter ASC and caspase-1, inducing gasdermin D (GSDMD)-dependent cell death and maturation and release of IL-1β and IL-18. The triggers and activation mechanisms of several inflammasome-forming sensors are not well understood. Here we show that mitochondrial damage activates the NLRP10 inflammasome, leading to ASC speck formation and caspase-1-dependent cytokine release. While the AIM2 inflammasome can also sense mitochondrial demise by detecting mitochondrial DNA (mtDNA) in the cytosol, NLRP10 monitors mitochondrial integrity in an mtDNA-independent manner, suggesting the recognition of distinct molecular entities displayed by the damaged organelles. NLRP10 is highly expressed in differentiated human keratinocytes, in which it can also assemble an inflammasome. Our study shows that this inflammasome surveils mitochondrial integrity. These findings might also lead to a better understanding of mitochondria-linked inflammatory diseases.
  16. Front Neurol. 2023 ;14 1113954
      Introduction: Five to eight percent of the world population currently suffers from at least one autoimmune disorder. Despite multiple immune modulatory therapies for autoimmune demyelinating diseases of the central nervous system, these treatments can be limiting for subsets of patients due to adverse effects and expense. To circumvent these barriers, we investigated a nutritional intervention in mice undergoing experimental autoimmune encephalomyelitis (EAE), a model of autoimmune-mediated demyelination that induces visual and motor pathologies similar to those experienced by people with multiple sclerosis (MS).Methods: EAE was induced in female and male mice and the impact of limiting dietary carbohydrates by feeding a ketogenic diet (KD) enriched in medium chain triglycerides (MCTs), alpha-linolenic acid (an omega-3 fatty acid), and fiber was evaluated in both a preventive regimen (prior to immunization with MOG antigen) and an interventional regimen (following the onset of symptoms). Motor scores were assigned daily and visual acuity was measured using optokinetic tracking. Immunohistochemical analyses of optic nerves were done to assess inflammatory infiltrates and myelination status. Fatty acid and cytokine profiling from blood were performed to evaluate systemic inflammatory status.
    Results: The KD was efficacious when fed as a preventive regimen as well as when initiated as an interventional regimen following symptom onset. The KD minimally impacted body weight during the experimental time course, increased circulating ketones, prevented motor and ocular deficits, preserved myelination of the optic nerve, and reduced infiltration of immune cells to optic nerves. The KD also increased anti-inflammatory-associated omega-3 fatty acids in the plasma and reduced select cytokines in the circulation associated with EAE-mediated pathological inflammation.
    Discussion: In light of ongoing clinical trials using dietary strategies to treat people with MS, these findings support that a KD enriched in MCTs, omega-3 fatty acids, and fiber promotes a systemic anti-inflammatory milieu and ameliorates autoimmune-induced demyelinating visual and motor deficits.
    Keywords:  experimental autoimmune encephalomyelitis; ketogenic diet; multiple sclerosis; optic nerve; optic neuritis; retinal ganglion cells
  17. Cell Rep. 2023 Mar 21. pii: S2211-1247(23)00305-4. [Epub ahead of print]42(4): 112294
      Stroke is a leading cause of adult disability worldwide, and better drugs are needed to promote functional recovery after stroke. Growing evidence suggests the critical role of network excitability during the repair phase for stroke recovery. Here, we show that β-hydroxybutyrate (β-HB), an essential ketone body (KB) component, is positively correlated with improved outcomes in patients with stroke and promotes functional recovery in rodents with stroke during the repair phase. These beneficial effects of β-HB depend on HDAC2/HDAC3-GABA transporter 1 (GAT-1) signaling-mediated enhancement of excitability and phasic GABA inhibition in the peri-infarct cortex and structural and functional plasticity in the ipsilateral cortex, the contralateral cortex, and the corticospinal tract. Together with available clinical approaches to elevate KB levels, our results offer a clinically translatable means to promote stroke recovery. Furthermore, GAT-1 can serve as a pharmacological target for developing drugs to promote functional recovery after stroke.
    Keywords:  CP: Neuroscience
  18. Int J Sports Med. 2023 Mar 21.
      Resistance training is employed for pursuing muscle strength characterized by activation of mammalian target of rapamycin (mTOR)-mediated hypertrophic signaling for protein production. Endurance training elevates peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling of mitochondrial adaptations for oxidative phosphorylation. Now, emerging evidence suggests that, like endurance training, resistance training also elicits profound effects on mitochondrial adaptations in skeletal muscle, which means that resistance training yields both strength and endurance phenotypes in myofibers, which has treatment value for the muscle loss and poor aerobic capacity in humans. Our review outlines a brief overview of muscle hypertrophic signals with resistance training and focused on the effects of resistance training on mitochondrial biogenesis and respiration in skeletal muscle, providing novel insights into the therapeutic strategy of resistance training for the metabolically dysfunctional individuals with declined mitochondrial function.
  19. Biol Res. 2023 Mar 25. 56(1): 14
      The endocannabinoid system (ECS) regulates energy metabolism, has been implicated in the pathogenesis of metabolic diseases and exerts its actions mainly through the type 1 cannabinoid receptor (CB1). Likewise, autophagy is involved in several cellular processes. It is required for the normal development of muscle mass and metabolism, and its deregulation is associated with diseases. It is known that the CB1 regulates signaling pathways that control autophagy, however, it is currently unknown whether the ECS could regulate autophagy in the skeletal muscle of obese mice. This study aimed to investigate the role of the CB1 in regulating autophagy in skeletal muscle. We found concomitant deregulation in the ECS and autophagy markers in high-fat diet-induced obesity. In obese CB1-KO mice, the autophagy-associated protein LC3 II does not accumulate when mTOR and AMPK phosphorylation levels do not change. Acute inhibition of the CB1 with JD-5037 decreased LC3 II protein accumulation and autophagic flux. Our results suggest that the CB1 regulates autophagy in the tibialis anterior skeletal muscle in both lean and obese mice.
    Keywords:  Autophagy; Endocannabinoid receptor; High-fat diet; Skeletal muscle
  20. Circulation. 2023 Mar 21.
    American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and American College of Cardiology
      Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure; its prevalence is increasing, and outcomes are worsening. Affected patients often experience severe exertional dyspnea and debilitating fatigue, as well as poor quality of life, frequent hospitalizations, and a high mortality rate. Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life. This success may be attributed, at least in part, to the pleiotropic effects of exercise, which may favorably affect the full range of abnormalities-peripheral vascular, skeletal muscle, and cardiovascular-that contribute to exercise intolerance in HFpEF. Accordingly, this scientific statement critically examines the currently available literature on the effects of exercise-based therapies for chronic stable HFpEF, potential mechanisms for improvement of exercise capacity and symptoms, and how these data compare with exercise therapy for other cardiovascular conditions. Specifically, data reviewed herein demonstrate a comparable or larger magnitude of improvement in exercise capacity from supervised exercise training in patients with chronic HFpEF compared with those with heart failure with reduced ejection fraction, although Medicare reimbursement is available only for the latter group. Finally, critical gaps in implementation of exercise-based therapies for patients with HFpEF, including exercise setting, training modalities, combinations with other strategies such as diet and medications, long-term adherence, incorporation of innovative and more accessible delivery methods, and management of recently hospitalized patients are highlighted to provide guidance for future research.
    Keywords:  AHA Scientific Statements; aged; cardiac rehabilitation; exercise therapy; exercise tolerance; heart failure
  21. Cell Mol Neurobiol. 2023 Mar 23.
      Chronic cerebral ischaemia (CCI) is a high-incidence cardiovascular and cerebrovascular disease that is very common in clinical practice. Although many pathogenic mechanisms have been explored, there is still great controversy among neuroscientists regarding the pathogenesis of CCI. Therefore, it is important to elucidate the mechanisms of CCI occurrence and progression for the prevention and treatment of ischaemic cerebrovascular disorders. Autophagy and inflammation play vital roles in CCI, but the relationship between these two processes in this disease remains unknown. Here, we review the progression and discuss the functions, actions and pathways of autophagy and inflammation in CCI, including a comprehensive view of the transition from acute disease to CCI through ischaemic repair mechanisms. This review may provide a reference for future research and treatment of CCI. Schematic diagram of the interplay between autophagy and inflammation in CCI. CCI lead to serious, life-threatening complications. This review summarizes two factors in CCI, including autophagy and inflammation, which have been focused for the mechanisms of CCI. In short, the possible points of intersection are shown in the illustration. CCI, Chronic cerebral ischaemia; ER stress, Endoplasmic reticulum stress; ROS, Reactive oxygen species.
    Keywords:  Autophagy; Chronic cerebral ischaemia; Inflammation
  22. bioRxiv. 2023 Mar 11. pii: 2023.03.10.532020. [Epub ahead of print]
      Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, deficiency of coenzyme Q (CoQ), mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells results in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial Ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.
  23. J Coll Physicians Surg Pak. 2023 Mar;33(3): 308-313
      OBJECTIVE: To investigate the effect of SGLT2-i and GLP-1RA as an add-on therapy to metformin on weight loss and body composition, and to compare their effects on glucose and lipid parameters.STUDY DESIGN: A descriptive study. Place and Duration of the Study: Goztepe Prof Dr Suleyman Yalcin City Hospital, from January 2016 to May 2021.
    METHODOLOGY:  The study included 50 patients with diabetes on metformin+SGLT2-i (dapagliflozin or empagliflozin, group 1) and 50 patients with diabetes on metformin+GLP-1 receptor agonist (RA, exenatide, group 2).
    RESULTS: The reduction in weight, BMI, total body, abdominal, leg, and arm fat percentage, and the improvement in body fat-free and muscle mass percentage were significantly higher in Group 2 (p<0.001, p<0.001, p=0.014; p=0.031, p<0.001; p=0.002 and p=0.014, p=0.014, respectively). The decline in abdominal fat mass in the GLP-1 RA group was also significant (p=0.031). There was a significant decrease in HbA1c, fasting glucose, and triglyceride levels (p<0.001, p<0.001, and p=0.036) with a significant increase in HDL-C (p=0.015). There was no significant difference between groups for glucose, HbA1c, and lipid parameters (p>0.05).
    CONCLUSION: Both SGLT2 inhibitors and exenatide, when added to metformin therapy, were effective in reducing weight and body fat, more by the GLP-agonist. SGLT2-i had no significant impact on decreasing abdominal fat depicting that these agents do not have any benefit in treating visceral adiposity.
    KEY WORDS: Type 2 diabetes mellitus, Obesity, GLP-1 receptor, SGLT2 inhibitor, Body fat distribution, Visceral adiposity.
  24. Front Cardiovasc Med. 2023 ;10 1055069
      Background: Epicardial and pericardial adipose tissue (EAT and PAT) surround and protect the heart, with EAT directly sharing the microcirculation with the myocardium, possibly presenting a distinct macrophage phenotype that might affect the inflammatory environment in coronary heart disease (CHD). This study aims to investigate the expression of genes in different AT compartments driving the polarization of AT macrophages toward an anti-inflammatory (L-Galectin 9; CD206) or pro-inflammatory (NOS2) phenotype.Methods: EAT, PAT, and subcutaneous (SAT) biopsies were collected from 52 CHD patients undergoing coronary artery bypass grafting, and from 22 CTRLs undergoing aortic valve replacement. L-Galectin9 (L-Gal9), CD206, and NOS2 AT gene expression and circulating levels were analyzed through RT-PCR and ELISA, respectively.
    Results: L-Gal9, CD206, and NOS2 gene expression was similar in all AT compartments in CHD and CTRLs, as were also L-Gal9 and CD206 circulating levels, while NOS2 serum levels were higher in CHD (p = 0.012 vs. CTRLs). In CTRLs, NOS2 expression was lower in EAT vs. SAT (p = 0.007), while in CHD patients CD206 expression was lower in both SAT and EAT as compared to PAT (p = 0.003, p = 0.006, respectively), suggestive of a possible macrophage reprogramming toward a pro-inflammatory phenotype in EAT. In CHD patients, NOS2 expression in SAT correlated to that in PAT and EAT (p = 0.007, both), CD206 expression correlated positively to L-Gal9 (p < 0.001) only in EAT, and CD206 expression associated with that of macrophage identifying markers in all AT compartments (p < 0.001, all). In CHD patients, subjects with LDL-C above 1.8 mmol/L showed significantly higher NOS2 expression in PAT and EAT as compared to subjects with LDL-C levels below (p < 0.05), possibly reflecting increased cardiac AT pro-inflammatory activation. In SAT and PAT, CD206 expression associated with BMI in both CHD and CTRLs (p < 0.05, all), and with L-Gal9 in EAT, however only in CTRLs (p = 0.002).
    Conclusion: CHD seems to be accompanied by an altered cardiac, and especially epicardial AT macrophage polarization. This may represent an important pathophysiological mechanism and a promising field of therapy targeting the excessive AT inflammation, in need of further investigation.
    Keywords:  LDL-C; adipose tissue; body mass index; coronary heart disease; inflammation; macrophage polarization
  25. Med Sci Sports Exerc. 2023 Mar 20.
      PURPOSE: We investigated short-term (9 d) exposure to low energy availability (LEA) in elite endurance athletes during a block of intensified training on self-reported well-being, body composition and performance.METHODS: Twenty-three highly trained race walkers undertook a ~ 3 w research-embedded training camp during which they undertook baseline testing and 6 d of high energy/carbohydrate (CHO) availability (40 kcal·kg FFM-1·d-1) before being allocated to 9 d continuation of this diet (HCHO: n = 10 M, 2F) or a significant decrease in energy availability to 15 kcal·kg FFM-1·d-1 (LEA: n = 10 M, 1F). A real-world 10,000 m race walking event was undertaken before (Baseline) and after (Adaptation) these phases, with races being preceded by standardized CHO fueling (8 g·kg BM-1 for 24 h and 2 g·kg BM-1 pre-race meal).
    RESULTS: DXA-assessed body composition showed BM loss (2.0 kg; p < 0.001), primarily due to a 1.6 kg fat mass reduction (p < 0.001) in LEA, with smaller losses (BM: 0.9 kg; p = 0.008; fat mass: 0.9 kg; p < 0.001) in HCHO. The Recovery-Stress Questionnaire for Athletes (RESTQ-76), undertaken at the end of each dietary phase showed significant Diet*Trial effects for Overall Stress (p = 0.021), Overall Recovery (p = 0.024), Sport-Specific Stress (p = 0.003) and Sport-Specific Recovery (p = 0.012). However, improvements in race performance were similar: 4.5 ± 4.1% and 3.5 ± 1.8% for HCHO and LEA, respectively (p < 0.001). The relationship between changes in performance and pre-race BM was not significant (r = -0.08 [-0.49, 0.35]; p = 0.717).
    CONCLUSIONS: A series of strategically timed but brief phases of substantially restricted energy availability might achieve ideal race weight as part of a long-term periodization of physique by high performance athletes, but the relationship between BM, training quality and performance in weight-dependent endurance sports is complicated.