bims-kimdis 2024-08-04 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–08–04
twenty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE.
β-hydroxybutyrate and ischemic stroke: roles and mechanisms.
Histone β-hydroxybutyrylation is critical in reversal of sarcopenia.
Low-Carbohydrate High-Fat Diets, Lipid Levels, and Cardiovascular Risk.
Nutritional Ketosis as a Therapeutic Approach in Critical Illness: A Systematic Review.
Ketogenic effect of coconut oil in ALS patients.
Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review.
Alterations to the copulatory sequence in young adult male Sprague-Dawley rats administered a ketogenic diet.
Mitochondrial calcium signaling and redox homeostasis in cardiac health and disease.
Inflammation- and Tissue Remodeling-Related Gene Responses in Skeletal Muscle of Heart Failure Patients Following High-Intensity Interval Training.
Impact of short-term vegan versus ketogenic diets on human immunity and microbiome.
Mitochondria can substitute for parvalbumin to lower cytosolic calcium levels in the murine fast skeletal muscle.
The Effect of Creatine Supplementation on Resistance Training-Based Changes to Body Composition: A Systematic Review and Meta-analysis.
Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure with a Preserved Ejection Fraction: A Meta-Analysis of Randomized Controlled Trials.
Cardiovascular Mechanisms of Exercise Intolerance in Older Patients with Heart Failure.
SGLT2 Inhibition in Heart Failure with Preserved Ejection Fraction - The New Frontier.
The Discovery of Mitochondria-Endoplasmic Reticulum Contact Sites (MERCs) as Mitochondria-Associated Membranes (MAMs).
Carbon monoxide and mitochondria: Cell energy and fate control.
Counting hours or calories? Metabolic regulatory role of time-restricted eating in adults with overweight and obesity: a systematic review and meta-analysis.
Does the Addition of Strength Training to a High-Intensity Interval Training Program Benefit More the Patients with Chronic Heart Failure.
Molecular Editing of Ketones through N-Heterocyclic Carbene and Photo Dual Catalysis.
A systematic review and meta-analysis comparing outcomes between using subcutaneous insulin and continuous insulin infusion in managing adult patients with diabetic ketoacidosis.

bioRxiv. 2024 Jul 22. pii: 2024.01.23.576931. [Epub ahead of print]

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE.

Rocío Rojas, Christian Griñán-Ferré, Aida Castellanos, Ernesto Griego, Marc Martínez, Juan de Dios Navarro-López, Lydia Jiménez-Díaz, José Rodríguez-Álvarez, David Soto Del Cerro, Pablo E Castillo, Mercè Pallàs, Rut Fadó, Núria Casals.

The ketogenic diet, characterized by high fat and low carbohydrates, has gained popularity not only as a strategy for managing body weight but also for its efficacy in delaying cognitive decline associated with neurodegenerative diseases and the aging process. Since this dietary approach stimulates the liver's production of ketone bodies, primarily β-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons, we investigated whether BHB could mitigate impaired AMPA receptor trafficking, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as saturated fatty acids. Here, we observe that, in cultured primary cortical neurons, exposure to palmitic acid (200μM) decreased surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids, such as oleic acid and ω-3 docosahexaenoic acid (200μM), and BHB (5mM) increased them. Furthermore, BHB countered the adverse effects of palmitic acid on synaptic GluA1 levels in hippocampal neurons, as well as excitability and plasticity in hippocampal slices. Additionally, daily intragastric administration of BHB (100 mg/kg/day) for two months reversed cognitive impairment induced by a saturated high-fat diet (49% of calories from fat) in a mouse experimental model of obesity. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptors abundance, synaptic function and neuroplasticity, shedding light on the potential use of BHB to delay cognitive impairments associated with metabolic diseases.

DOI: https://doi.org/10.1101/2024.01.23.576931
Mol Brain. 2024 Jul 29. 17(1): 48

β-hydroxybutyrate and ischemic stroke: roles and mechanisms.

Ge Feng, Zongkai Wu, Leyi Yang, Kaimeng Wang, Hebo Wang.

  Stroke is a significant global burden, causing extensive morbidity and mortality. In metabolic states where glucose is limited, ketone bodies, predominantly β-hydroxybutyrate (BHB), act as alternative fuel sources. Elevated levels of BHB have been found in the ischemic hemispheres of animal models of stroke, supporting its role in the pathophysiology of cerebral ischemia. Clinically, higher serum and urinary BHB concentrations have been associated with adverse outcomes in ischemic stroke, highlighting its potential utility as a prognostic biomarker. In both animal and cellular models, exogenous BHB administration has exhibited neuroprotective effects, reduction of infarct size, and improvement of neurological outcomes. In this review, we focus on the role of BHB before and after ischemic stroke, with an emphasis on the therapeutic potential and mechanisms of ketone administration after ischemic stroke.

Keywords:  Ischemic stroke; Neuroprotective effect; Prognostic biomarker; β-hydroxybutyrate

DOI:  https://doi.org/10.1186/s13041-024-01119-0
Aging Cell. 2024 Jul 30. e14284

Histone β-hydroxybutyrylation is critical in reversal of sarcopenia.

Qiquan Wang, Xinqiang Lan, Hao Ke, Siman Xu, Chunping Huang, Jiali Wang, Xiang Wang, Tiane Huang, Xia Wu, Mengxin Chen, Yingqi Guo, Lin Zeng, Xiao-Li Tian, Yang Xiang.

  Sarcopenia, a leading cause for global disability and mortality, is an age-related muscular disorder, characterized by accelerated muscle mass loss and functional decline. It is known that caloric restriction (CR), ketogenic diet or endurance exercise lessen sarcopenia and elevate circulating β-hydroxybutyrate (β-HB) levels. Whether the elevated β-HB is essential to the reversal of sarcopenia, however, remains unclear. Here we show in both Caenorhabditis elegans and mouse models that an increase of β-HB reverse myofiber atrophy and improves motor functions at advanced ages. β-HB-induced histone lysine β-hydroxybutyrylation (Kbhb) is indispensable for the reversal of sarcopenia. Histone Kbhb enhances transcription of genes associated with mitochondrial pathways, including oxidative phosphorylation, ATP metabolic process and aerobic respiration. This ultimately leads to improve mitochondrial integrity and enhance mitochondrial respiration. The histone Kbhb are validated in mouse model with CR. Thus, we demonstrate that β-HB induces histone Kbhb, increases mitochondrial function, and reverses sarcopenia.

Keywords:  mitochondria; sarcopenia; skeletal muscle; β‐hydroxybutyrate; β‐hydroxybutyrylation

DOI:  https://doi.org/10.1111/acel.14284
JACC Adv. 2024 Jun;3(6): 100975

Low-Carbohydrate High-Fat Diets, Lipid Levels, and Cardiovascular Risk.

Moriah P Bellissimo, W Gregory Hundley.



Keywords:  atherogenic; cardiac; cholesterol; ketogenic diet; nutrition

DOI:  https://doi.org/10.1016/j.jacadv.2024.100975
Cureus. 2024 Jul;16(7): e65455

Nutritional Ketosis as a Therapeutic Approach in Critical Illness: A Systematic Review.

Rana A Abdelrahim, Sai Rohit R Mekala, Krishna V Polepalli, Vemparala Priyatha, Chimezirim Ezeano, Esraa M AlEdani, Sondos T Nassar.

  Critical illness encompasses the dysfunction of vital organs, the risk of death, and potential reversibility; it is a major cause of morbidity and mortality globally. The pathophysiology underlying many critical illnesses includes bioenergetic failure, inflammation, and oxidative stress. This systematic review aims to explore the use of nutritional ketosis (ketogenic feeds and exogenous ketone body administration) as a potential therapy, affecting the aforementioned pathways in patients with critical illnesses. This study was conducted, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The search was conducted, systematically using PubMed, PubMed Central (PMC), Google Scholar, and the ScienceDirect databases in February 2024. The inclusion criteria were set to free full-text articles published within the past five years: human and animal studies, literature reviews, systematic reviews, meta-analyses, observational studies, randomized controlled trials, case reports, book chapters, gray literature, studies investigating adult samples, and articles in the English language. Exclusion criteria included pediatric studies as the topic has been studied more extensively in children, and this review aims to explore potential benefits in adult patients. The search was conducted through four databases; after the screening process, the remaining studies were assessed through quality appraisal tools appropriate to each study type. In the end, 11 studies were selected, including eight narrative reviews, one cohort study, one animal study, and one randomized controlled trial. The results of this review demonstrated that nutritional ketosis has potential safe and effective benefits for humans and animals. Nutritional ketosis shows therapeutic benefits for a vast variety of complications commonly associated with critical illness, status epilepticus, sepsis, viral infections, and glycemic control. In the end, both randomized and nonrandomized clinical trials are necessary for more conclusive findings.

Keywords:  critical illness; high-fat very low-carbohydrate diet; icu; intensive care; ketogenic diet; ketone bodies; ketosis; nutrition; nutritional ketosis; therapeutic ketosis

DOI:  https://doi.org/10.7759/cureus.65455
Front Nutr. 2024 ;11 1429498

Ketogenic effect of coconut oil in ALS patients.

Sandra Carrera-Juliá, Elena Obrador, Rafael López-Blanch, María Oriol-Caballo, Paz Moreno-Murciano, José M Estrela.

  A recent pilot study in amyotrophic lateral sclerosis (ALS) patients analyzed the effect of a Mediterranean diet (MeDi) supplemented with nicotinamide riboside (NR, a NAD+ promoter), pterostilbene (PTER, a natural antioxidant) and/or coconut oil on anthropometric variables in ALS patients. The results suggested that the MeDi supplemented with NR, PTER and coconut oil is the nutritional intervention showing the greatest benefits at anthropometric levels. Over the last 30 years, glucose intolerance has been reported in ALS patients. Thus, suggesting that an alternative source of energy may be preferential for motor neurons to survive. Ketone bodies (KBs), provided through a MeDi with a lower carbohydrate content but enriched with medium chain triglycerides, could be a therapeutic alternative to improve the neuromotor alterations associated with the disease. Nevertheless, the use of a coconut oil-supplemented diet, as potentially ketogenic, is a matter of controversy. In the present report we show that a MeDi supplemented with coconut oil increases the levels of circulating KBs in ALS patients.

Keywords:  amyotrophic lateral sclerosis; coconut oil; ketogenic diet; nicotinamide riboside; pterostilbene

DOI:  https://doi.org/10.3389/fnut.2024.1429498
Epilepsia Open. 2024 Aug;9(4): 1176-1191

Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review.

Mathilde Gras, David Bearden, Justin West, Rima Nabbout.

   OBJECTIVE: KCNT1-related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep-related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients present with drug-resistant seizures and global developmental delays. In addition to conventional anti-seizure medications (ASM), multiple alternative therapies have been tested including the ketogenic diet (KD), cannabidiol (CBD-including Epidyolex © and other CBD derivatives) and quinidine (QUIN). We aimed to clarify the current state of the art concerning the benefits of those therapies administered to the three groups of patients.
METHODS: We performed a literature review on PubMed and EMBase with the keyword "KCNT1" and selected articles reporting qualitative and/or quantitative information on responses to these treatments. A treatment was considered beneficial if it improved seizure frequency and/or intensity and/or quality of life. Patients were grouped by phenotype.
RESULTS: A total of 43 studies including 197 patients were reviewed. For EIMFS patients (32 studies, 135 patients), KD resulted in benefit in 62.5% (25/40), all types of CBD resulted in benefit in 50% (6/12), and QUIN resulted in benefit in 44.6% (25/56). For (AD)SHE patients (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was trialed in 8 patients with no reported benefit. For DEE patients (10 studies, 30 patients), KD resulted in benefit for 4/7, CBD for 1/2, and QUIN for 6/9. In all groups, conventional ASM are rarely reported as beneficial (in 5%-25% of patients).
SIGNIFICANCE: Ketogenic diet, CBD, and QUIN treatments appear to be beneficial in a subset of patient with drug-resistant epilepsy. The KD and CBD are reasonable to trial in patients with KCNT1-related epilepsy. Further studies are needed to identify optimal treatment strategies and to establish predictive response factors.
PLAIN LANGUAGE SUMMARY: We performed an extensive review of scientific articles providing information about the therapeutic management of epilepsy in patients with epilepsy linked to a mutation in the KCNT1 gene. Conventional anti-seizure treatments were rarely reported to be beneficial. The ketogenic diet (a medical diet with very high fat, adequate protein and very low carbohydrate intake) and cannabidiol appeared to be useful, but larger studies are needed to reach a conclusion.

Keywords:  CBD; developmental and epileptic encephalopathy; epilepsy; ketogenic diet; pediatrics; therapy

DOI:  https://doi.org/10.1002/epi4.12975
Physiol Behav. 2024 Jul 27. pii: S0031-9384(24)00198-7. [Epub ahead of print] 114650

Alterations to the copulatory sequence in young adult male Sprague-Dawley rats administered a ketogenic diet.

Christina Tzianabos, Grace Chouinard, Luis Martinez.

  Ketogenic diets (KDs) have shown therapeutic potential for a range of neuropsychiatric disorders; however, there is insufficient data regarding the behavioral impacts of KDs in healthy populations. Here, we examined the impact of a KD on sexual behavior in young adult male Sprague-Dawley rats maintained on either a KD or standard chow diet (SD). We found that KD males exhibited higher mount rates, higher intromission rates (third and fourth tests only), and lower ejaculation likelihood (second test only) compared to SD males. Consequently, it may be that experience-dependent changes in the processing of sexual stimuli are not occurring as efficiently in KD males, thereby yielding the observed copulatory sequence alterations.

Keywords:  Copulation; Ketogenic; Metabolic therapies; Sexual behavior

DOI:  https://doi.org/10.1016/j.physbeh.2024.114650
Front Mol Med. 2023 ;3 1235188

Mitochondrial calcium signaling and redox homeostasis in cardiac health and disease.

Tudor-Alexandru Popoiu, Christoph Maack, Edoardo Bertero.

  The energy demand of cardiomyocytes changes continuously in response to variations in cardiac workload. Cardiac excitation-contraction coupling is fueled primarily by adenosine triphosphate (ATP) production by oxidative phosphorylation in mitochondria. The rate of mitochondrial oxidative metabolism is matched to the rate of ATP consumption in the cytosol by the parallel activation of oxidative phosphorylation by calcium (Ca2+) and adenosine diphosphate (ADP). During cardiac workload transitions, Ca2+ accumulates in the mitochondrial matrix, where it stimulates the activity of the tricarboxylic acid cycle. In this review, we describe how mitochondria internalize and extrude Ca2+, the relevance of this process for ATP production and redox homeostasis in the healthy heart, and how derangements in ion handling cause mitochondrial and cardiomyocyte dysfunction in heart failure.

Keywords:  calcium; cardiomyocyte; heart failure; mitochondria; reactive oxygen species; redox homeostasis

DOI:  https://doi.org/10.3389/fmmed.2023.1235188
Rev Cardiovasc Med. 2023 Feb;24(2): 46

Inflammation- and Tissue Remodeling-Related Gene Responses in Skeletal Muscle of Heart Failure Patients Following High-Intensity Interval Training.

Andrea Tryfonos, Georgios Tzanis, Εleftherios Karatzanos, Michael Koutsilieris, Serafim Nanas, Anastassios Philippou.

   Background: Peripheral myopathy consists a hallmark of heart failure (HF) and has been associated with poor prognosis. Inflammation has been suggested to dominate this pathology, while exercise training is typically associated with the induction of anti-inflammatory mechanisms. However, the current knowledge regarding the involvement of inflammation-related genes in the exercise training-induced muscle adaptations in HF patients is very limited. Given that high-intensity interval training (HIIT) alone or combined with strength training (COM) has gained ground in HF cardiac rehabilitation, this study aimed to investigate the local muscle expression of inflammatory and tissue remodeling factors in HF patients, who underwent 3 months of these training schemes. In addition, we examined whether these exercise training-induced gene expression responses are associated with changes in exercise capacity in those patients.
Methods: Thirteen male patients with chronic HF (age: 51 ± 13 y; body mass index (BMI): 27 ± 4 kg/ m2 ) were randomly assigned to a 3-month exercise program consisted of either HIIT (N = 6) or COM training (N = 7). Muscle tissue biopsies were obtained from vastus lateralis pre- and post-training and transcriptional changes in interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-1 alpha (TNF-1 α ), urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), and transforming growth factor-beta 1 (TGF- β 1) were quantified by RT-PCR.
Results: An overall increase in the expression levels of selected inflammatory (IL-8, TNF-1 α ) and remodeling factors (uPAR) was found post-training (p < 0.05), while IL-6, uPA and TGF- β 1 gene expression remained unchanged (p > 0.05). The observed alterations did not differ between training groups. Additionally, IL-8 changes were found to be correlated with the improvement in exercise capacity post-training (p < 0.05).
Conclusions: This is the first study demonstrating an increase in intramuscular inflammatory and remodeling key factors induced by HIIT or COM training in HF patients. Combining these observations with our previous findings of improved muscle hypertrophy and capillarization post-training in these patients, the findings of the present study may suggest that inflammatory responses are part of an ongoing remodeling process in the exercising skeletal muscle.
Clinical Trial Registration: NCT02387411.

Keywords:  cardiac rehabilitation; heart failure; inflammation; skeletal muscle remodelling

DOI:  https://doi.org/10.31083/j.rcm2402046
Am J Transplant. 2024 Jul 31. pii: S1600-6135(24)00459-3. [Epub ahead of print]

Impact of short-term vegan versus ketogenic diets on human immunity and microbiome.

Nolan K Horner, Eva M Gillis-Buck, James M Gardner.

DOI: https://doi.org/10.1016/j.ajt.2024.07.032
Acta Physiol (Oxf). 2024 Jul 30. e14208

Mitochondria can substitute for parvalbumin to lower cytosolic calcium levels in the murine fast skeletal muscle.

Lorenzo Marcucci, Leonardo Nogara, Marta Canato, Elena Germinario, Anna Raffaello, Michela Carraro, Paolo Bernardi, Laura Pietrangelo, Simona Boncompagni, Feliciano Protasi, Nazareno Paolocci, Carlo Reggiani.

   AIM: Parvalbumin (PV) is a primary calcium buffer in mouse fast skeletal muscle fibers. Previous work showed that PV ablation has a limited impact on cytosolic Ca2+ ([Ca2+]cyto) transients and contractile response, while it enhances mitochondrial density and mitochondrial matrix-free calcium concentration ([Ca2+]mito). Here, we aimed to quantitatively test the hypothesis that mitochondria act to compensate for PV deficiency.
METHODS: We determined the free Ca2+ redistribution during a 2 s 60 Hz tetanic stimulation in the sarcoplasmic reticulum, cytosol, and mitochondria. Via a reaction-diffusion Ca2+ model, we quantitatively evaluated mitochondrial uptake and storage capacity requirements to compensate for PV lack and analyzed possible extracellular export.
RESULTS: [Ca2+]mito during tetanic stimulation is greater in knock-out (KO) (1362 ± 392 nM) than in wild-type (WT) (855 ± 392 nM), p < 0.05. Under the assumption of a non-linear intramitochondrial buffering, the model predicts an accumulation of 725 μmoles/Lfiber (buffering ratio 1:11 000) in KO, much higher than in WT (137 μmoles/Lfiber, ratio 1:4500). The required transport rate via mitochondrial calcium uniporter (MCU) reaches 3 mM/s, compatible with available literature. TEM images of calcium entry units and Mn2+ quenching showed a greater capacity of store-operated calcium entry in KO compared to WT. However, levels of [Ca2+]cyto during tetanic stimulation were not modulated to variations of extracellular calcium.
CONCLUSIONS: The model-based analysis of experimentally determined calcium distribution during tetanic stimulation showed that mitochondria can act as a buffer to compensate for the lack of PV. This result contributes to a better understanding of mitochondria's role in modulating [Ca2+]cyto in skeletal muscle fibers.

Keywords:  calcium; mitochondria; mouse skeletal muscle fibers; parvalbumin; reaction–diffusion model

DOI:  https://doi.org/10.1111/apha.14208
J Strength Cond Res. 2024 Jul 23.

The Effect of Creatine Supplementation on Resistance Training-Based Changes to Body Composition: A Systematic Review and Meta-analysis.

Imtiaz Desai, Michael A Wewege, Matthew D Jones, Briana K Clifford, Anurag Pandit, Nadeem O Kaakoush, David Simar, Amanda D Hagstrom.

ABSTRACT: Desai, I, Wewege, MA, Jones, MD, Clifford, BK, Pandit, A, Kaakoush, NO, Simar, D, and Hagstrom, AD. The effect of creatine supplementation on resistance training-based changes to body composition: A systematic review and meta-analysis. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this review was to determine the added effect of creatine supplementation on changes in body composition with resistance training in adults younger than 50 years. The review protocol was preregistered on the Open Science Framework (osf.io/x48a6/). Our primary outcome was lean body mass (LBM); secondary outcomes were body fat percentage (%) and body fat mass (kg). We performed a random-effects meta-analysis in R using the metafor package. Subgroup analyses were conducted to examine the effects of training status and use of a carbohydrate drink with creatine. We conducted a meta-regression to examine the moderating effect of total training volume. Statistical significance was set at p < 0.05. One thousand six hundred ninety-four records were screened, and 67 full-text articles were assessed for eligibility. Twelve studies were included in the meta-analysis. Fifty-two percentages of the studies had low risk, 41% some concerns, and 7% high risk of bias. Compared with resistance training (RT) alone, creatine supplementation increased LBM by 1.14 kg (95% CI 0.69 to 1.59), and reduced body fat percentage by -0.88% (95% CI -1.66 to -0.11) and body fat mass by -0.73 kg (95% CI -1.34 to -0.11). There were no differences between training status or carbohydrate subgroups. Training volume was not associated with effect size in all outcomes; 7 g or 0.3 g/kg of body mass of creatine per day is likely to increase LBM by 1 kg and reduce fat mass by 0.7 kg more than RT alone. Concurrent carbohydrate ingestion did not enhance the hypertrophy benefits of creatine.

DOI: https://doi.org/10.1519/JSC.0000000000004862
Rev Cardiovasc Med. 2022 Nov;23(11): 374

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure with a Preserved Ejection Fraction: A Meta-Analysis of Randomized Controlled Trials.

Yake Lou, Qi Yang, Weicong Zhang, Ying Yu, Jing Huang.

   Background: Heart failure is prevalent worldwide. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective in heart failure patients with reduced ejection fraction, whether SGLT2i are effective in heart failure with preserved ejection fraction (HFpEF) remains to be determined.
Methods: All relevant citations in the PubMed, Embase and Cochrane databases were identified from inception to September, 2022. The primary outcome was a composite endpoint of cardiovascular death and hospitalization for heart failure (HHF). A subgroup analysis was performed according to diabetes mellitus status and the ejection fraction. Secondary endpoints were cardiovascular death, hospitalization for heart failure and all cause death.
Results: Seven studies involving 11,604 patients were included in the meta-analysis. Compared with placebo, sodium-glucose cotransporter 2 inhibitors reduced the incidence of the primary outcome by 24%, with an odds ratio (OR) and 95% confidence interval (CI) 0.76 [0.69, 0.84]. For secondary outcomes, sodium-glucose cotransporter 2 inhibitors were associated with a lower incidence of hospitalization for heart failure, but not cardiovascular or all-cause death; the OR and 95% CI were 0.73 [0.66, 0.82], 0.92 [0.81, 1.04], 0.96 [0.88, 1.05], respectively.
Conclusions: This study proves the clinical efficacy of SGLT2i for treatment of HFpEF patients with or without diabetes, which was mainly driven by prevention of HHF rather than cardiovascular or all-cause death.

Keywords:  canagliflozin; dapagliflozin; empagliflozin; heart failure; preserved ejection fraction; reduced ejection fraction; sodium-glucose cotransporter 2 inhibitors; sotagliflozin

DOI:  https://doi.org/10.31083/j.rcm2311374
Rev Cardiovasc Med. 2022 Sep;23(9): 313

Cardiovascular Mechanisms of Exercise Intolerance in Older Patients with Heart Failure.

Narayana Sarma V Singam, Meir Tabi, Jerome L Fleg.

  Exercise intolerance, measured by peak oxygen consumption (V̇O2), is a hallmark feature of heart failure (HF). The effect is compounded in the elderly HF patient by aging-associated changes such as a reduction in lean muscle mass, an increase in adiposity, and a reduction in maximal heart rate and peripheral blood flow with exercise. There is a non-linear reduction in peak V̇O2 with age that accelerates in the later decades of life. Peak V̇O2 is further reduced due to central and peripheral maladaptation from HF. Central mechanisms include impaired peak heart rate, stroke volume, contractility, increased filling pressures, and a blunted vasodilatory response. Peripheral mechanisms include endothelial dysfunction, reduced blood flow to muscles, and impaired skeletal muscle oxidative capacity. This review presents a focused update on mechanisms leading to impaired aerobic capacity in older HF patients.

Keywords:  elderly patient; exercise intolerance; heart failure; peak oxygen consumption

DOI:  https://doi.org/10.31083/j.rcm2309313
Rev Cardiovasc Med. 2023 Jan;24(1): 1

SGLT2 Inhibition in Heart Failure with Preserved Ejection Fraction - The New Frontier.

Inês Aguiar-Neves, Diogo Santos-Ferreira, Ricardo Fontes-Carvalho.

  Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with high morbidity and increasing socio-economic burden, compounded by the lack of effective treatment options available to treat this disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have previously been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes and patients with heart failure with reduced ejection fraction (HFrEF). Recent major clinical trials with SGLT2 inhibitors, both empagliflozin and dapagliflozin, have now demonstrated improved cardiovascular outcomes in patients with HFpEF and a significant reduction in heart failure hospitalization. Current evidence shows a potential for cardiovascular benefits with SGLT2 inhibition that is consistent across the spectrum of ejection fraction, age, New York Heart Association (NYHA) functional class, natriuretic peptide levels and diabetes status. Although the cardioprotective mechanisms behind SGLT2 inhibition remain unclear, ongoing clinical studies aim to clarify the role of SGLT2 inhibitors on biomarkers of cardiac metabolism, diastolic function and exercise capacity in HFpEF. This article analyzes current clinical evidence from randomized controlled trials and meta-analyses and explores the potential cardioprotective mechanisms of SGLT2 inhibitors, while also looking towards the future of SGLT2 inhibition in HFpEF.

Keywords:  HFpEF; SGLT2 inhibitor; diabetes; gliflozin; heart failure

DOI:  https://doi.org/10.31083/j.rcm2401001
Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241261228

The Discovery of Mitochondria-Endoplasmic Reticulum Contact Sites (MERCs) as Mitochondria-Associated Membranes (MAMs).

Tadashi Makio, Thomas Simmen.

  Mitochondria-endoplasmic reticulum contacts (MERCs), also called endoplasmic reticulum (ER)-mitochondria contact sites (ERMCS), are the membrane domains, where these two organelles exchange lipids, Ca2+ ions, and reactive oxygen species. This crosstalk is a major determinant of cell metabolism, since it allows the ER to control mitochondrial oxidative phosphorylation and the Krebs cycle, while conversely, it allows the mitochondria to provide sufficient ATP to control ER proteostasis. MERC metabolic signaling is under the control of tethers and a multitude of regulatory proteins. Many of these proteins have recently been discovered to give rise to rare diseases if their genes are mutated. Surprisingly, these diseases share important hallmarks and cause neurological defects, sometimes paired with, or replaced by skeletal muscle deficiency. Typical symptoms include developmental delay, intellectual disability, facial dysmorphism and ophthalmologic defects. Seizures, epilepsy, deafness, ataxia, or peripheral neuropathy can also occur upon mutation of a MERC protein. Given that most MERC tethers and regulatory proteins have secondary functions, some MERC protein-based diseases do not fit into this categorization. Typically, however, the proteins affected in those diseases have dominant functions unrelated to their roles in MERCs tethering or their regulation. We are discussing avenues to pharmacologically target genetic diseases leading to MERC defects, based on our novel insight that MERC defects lead to common characteristics in rare diseases. These shared characteristics of MERCs disorders raise the hope that they may allow for similar treatment options.

Keywords:  endoplasmic reticulum; mitochondria; mutation; rare disease

DOI:  https://doi.org/10.1177/25152564241261228
Biochim Biophys Acta Mol Basis Dis. 2024 Jul 29. pii: S0925-4439(24)00439-3. [Epub ahead of print] 167446

Carbon monoxide and mitochondria: Cell energy and fate control.

Catarina Cardoso-Pires, Helena L A Vieira.

  Carbon monoxide (CO) is a ubiquitously produced endogenous gas in mammalian cells and is involved in stress response being considered as a cytoprotective and homeostatic factor. In the present review, the underlying mechanisms of CO are discussed, in particular CO's impact on cellular metabolism affecting cell fate and function. One of the principal signaling molecules of CO is reactive oxygen species (ROS), particularly hydrogen peroxide, which is mainly generated at the mitochondrial level. Likewise, CO acts on mitochondria modulating oxidative phosphorylation and mitochondria quality control, namely mitochondrial biogenesis (mitobiogenesis) and mitophagy. Other metabolic pathways are also involved in CO's mode of action such as glycolysis and pentose phosphate pathway. The review ends with some new perspectives on CO Biology research. Carboxyhemoglobin (COHb) formation can also be implicated in the CO mode of action, as well as its potential biological role. Finally, other organelles such as peroxisomes hold the potential to be targeted and modulated by CO.

Keywords:  Glycolysis; Mitochondria; Mitochondrial quality control; Oxidative phosphorylation; Pentose phosphate pathway; ROS signaling

DOI:  https://doi.org/10.1016/j.bbadis.2024.167446
Crit Rev Food Sci Nutr. 2024 Jul 28. 1-15

Counting hours or calories? Metabolic regulatory role of time-restricted eating in adults with overweight and obesity: a systematic review and meta-analysis.

Xin Jin, Yan Deng, Wenxue Zhang, Xintian Xu, Shuang Rong.

  Time-restricted eating (TRE) effectively improves healthspan, including controlling obesity and improving metabolic health. To date, few meta-analyses have been conducted to explore the effects of various protocols of TRE in participants with overweight/obesity. PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched up until October 15, 2022. Randomized and non-randomized clinical trials that investigated the effect of TRE on body weight, body composition and cardiometabolic parameters in participants with overweight/obesity were included. Mean differences of changes from the baseline were used for all analyses between the two groups. Prespecified subgroup analyses based on different protocols of TRE were performed. Twenty-three studies were included in the meta-analysis with 1867 participants. TRE interventions led to significant changes in body weight. When energy restriction strategies were conducted in both the TRE and control groups, the weight-loss effect of TRE remained significant. TRE with 4 ∼ 8h feeding window, morning or late eating strategies, led to reduction in body weight and fat mass for at least 8 wk. Hence TRE is a potential and effective approach for weight loss for participants with overweight/obesity. An 8h-TRE intervention with a morning eating strategy for at least eight weeks might be the optimum TRE intervention mode.

Keywords:  Time-restricted eating; body weight; meta-analysis; obesity; overweight

DOI:  https://doi.org/10.1080/10408398.2024.2382344
Rev Cardiovasc Med. 2023 Jan;24(1): 29

Does the Addition of Strength Training to a High-Intensity Interval Training Program Benefit More the Patients with Chronic Heart Failure.

Manal Alshamari, Christos Kourek, Despina Sanoudou, Dimitrios Delis, Stavros Dimopoulos, Nikoletta Rovina, Serafim Nanas, Eleftherios Karatzanos, Anastassios Philippou.

   Background: Aerobic exercise, either continuous or high intensity interval training (HIIT), induces important benefits in chronic heart failure (CHF) patients. Resistance training has been also shown to be beneficial in CHF. However, data regarding combined aerobic exercise and muscle strength training is still limited. The aim of this study was to investigate whether adding strength training to a HIIT protocol within a cardiac rehabilitation (CR) program has a cumulative beneficial effect on the functional capacity (FC) and quality of life (QoL) in patients with CHF.
Methods: Forty-four consecutive patients [35 males, ejection fraction (EF) < 50%] with CHF under medication enrolled in a 36-session CR program and were randomized in two exercise groups; HIIT (HIIT group) or HIIT combined with strength training (high intensity interval training combined with strength training (COM) group). All patients underwent baseline and endpoint outcome measures of a symptom-limited maximal cardiopulmonary exercise testing (CPET), 1 repetition maximum (1RM) test, muscular endurance test, echocardiography, and Minnesota Living with Heart Failure Questionnaire (MLWHFQ).
Results: Most of the CPET indices, EF, 1RM test, muscular endurance and QoL were improved after the CR program in each exercise training group (p < 0.05). However, COM group demonstrated a further improvement in chest muscle testing and workload at anaerobic threshold (AT) compared to HIIT group.
Conclusions: An exercise-based CR program, consisted of either HIIT or HIIT combined with strength training, improves FC and QoL of patients with CHF. However, the addition of strength training to HIIT seems to have further beneficial effects on chest muscle strength and endurance, as well as workload at AT.
Clinical Trial Registration: The study was registered in ClinicalTrials.gov with number NCT02387411.

Keywords:  cardiac rehabilitation; chronic heart failure (CHF); functional capacity; high-intensity interval training (HIIT); quality of life; strength training

DOI:  https://doi.org/10.31083/j.rcm2401029
J Am Chem Soc. 2024 Jul 31.

Molecular Editing of Ketones through N-Heterocyclic Carbene and Photo Dual Catalysis.

Qing-Zhu Li, Mei-Hao He, Rong Zeng, Yuan-Yuan Lei, Zhao-Yuan Yu, Min Jiang, Xiang Zhang, Jun-Long Li.

The molecular editing of ketones represents an appealing strategy due to its ability to maximize the structural diversity of ketone compounds in a straightforward manner. However, developing efficient methods for the arbitrary modification of ketonic molecules, particularly those integrated within complex skeletons, remains a significant challenge. Herein, we present a unique strategy for ketone recasting that involves radical acylation of pre-functionalized ketones facilitated by N-heterocyclic carbene and photo dual catalysis. This protocol features excellent substrate tolerance and can be applied to the convergent synthesis and late-stage functionalization of structurally complex bioactive ketones. Mechanistic investigations, including experimental studies and density functional theory (DFT) calculations, shed light on the reaction mechanism and elucidate the basis of the regioselectivity.

DOI: https://doi.org/10.1021/jacs.4c08163
BMC Endocr Disord. 2024 Aug 01. 24(1): 133

A systematic review and meta-analysis comparing outcomes between using subcutaneous insulin and continuous insulin infusion in managing adult patients with diabetic ketoacidosis.

Ahmed Alnuaimi, Tiffany Mach, Pauline Reynier, Kristian B Filion, Jed Lipes, Oriana Hoi Yun Yu.

   BACKGROUND: The purpose of this systematic review and meta-analysis was to synthesize the current literature to determine the safety and efficacy of using subcutaneous insulin compared to an intravenous (IV) insulin infusion in managing diabetic ketoacidosis (DKA).
METHODS: We searched Ovid-Medline, EMBASE, SCOPUS, BIOSIS and CENTRAL from inception to April 26, 2024. Randomized controlled trials (RCTs) and observational studies that assessed the use of subcutaneous compared to intravenous insulin for the treatment of mild to moderate DKA were included. Data extraction and quality assessment were performed by two independent reviewers and disagreements were resolved through further discussion or by a third reviewer. The Cochrane Risk of Bias tool version 2.0 was used to evaluate the RCTs and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS)-I tool was used to evaluate the observational studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Meta-analyses were conducted using random-effects models. We followed the PRISMA guidelines for reporting our findings.
RESULTS: Six RCTs (245 participants) and four observational studies (8444 patients) met our inclusion criteria. Some studies showed a decreased length of stay (Mean Difference [MD] in days: -0.39; 95% CI: -2.83 to 2.08; I2: 0%) among individuals treated with subcutaneous insulin compared to intravenous insulin. There was no difference in the risk of all-cause mortality, time to resolution of DKA (MD in hours: 0.17; 95% confidence interval [CI]: -3.45 to 3.79; I2: 0%) and hypoglycemia (Risk Ratio [RR]: 1.02; 95% CI: 0.88 to 1.19; I2: 0%) between the two groups.
CONCLUSION: Treatment of DKA with subcutaneous insulin may be a safe and effective alternative to IV insulin in selected patients. The limited available evidence underscores the need for further studies to explore optimal dosing, patient selection criteria and long-term outcomes.

Keywords:  Diabetes; Diabetic ketoacidosis; Subcutaneous insulin; Systematic review

DOI:  https://doi.org/10.1186/s12902-024-01666-6