bims-kimdis 2022-10-16 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–10–16
25 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Effects of the Ketogenic Diet on Muscle Hypertrophy in Resistance-Trained Men and Women: A Systematic Review and Meta-Analysis.
Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future.
Ketone Body Infusion abrogates Growth Hormone Induced Lipolysis and Insulin Resistance.
The Therapeutic Role of Short-Chain Fatty Acids Mediated Very Low-Calorie Ketogenic Diet-Gut Microbiota Relationships in Paediatric Inflammatory Bowel Diseases.
Effect of Ketogenic Diets on Body Composition and Metabolic Parameters of Cancer Patients: A Systematic Review and Meta-Analysis.
Hyperinsulinemia impairs the metabolic switch to ketone body utilization in proximal renal tubular epithelial cells under energy crisis via the inhibition of the SIRT3/SMCT1 pathway.
Glucose 6-P Dehydrogenase-An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise.
Pyroptosis and Insulin Resistance in Metabolic Organs.
2-Deoxy-D-glucose Alleviates Cancer Cachexia-Induced Muscle Wasting by Enhancing Ketone Metabolism and Inhibiting the Cori Cycle.
NLRP3: Role in ischemia/reperfusion injuries.
Glucose-Lowering and Metabolic Effects of SGLT2 Inhibitors.
Sarcopenia and Endocrine Ageing: Are They Related?
Effect of a low carbohydrate, high fat diet versus a high carbohydrate diet on exercise efficiency and economy in recreational male athletes.
The ketogenic diet could improve the efficacy of curcumin and Oldenlandia diffusa extract in the treatment of gastric cancer by increasing miR340 expression and apoptosis mediated by autophagy, oxidative stress, and angiogenesis.
Aging is associated with an altered macrophage response during human skeletal muscle regeneration.
Exogenous glucose oxidation during endurance exercise under low energy availability.
Effect of intermittent fasting 5:2 on body composition and nutritional intake among employees with obesity in Jakarta: a randomized clinical trial.
Implications of notch signaling in duchenne muscular dystrophy.
The role of Sirt3 in the changes of skeletal muscle mitophagy induced by hypoxic training.
Changes in plasma fatty acids profile in hyperketonemic ewes during early lactation: a preliminary study.
The Ketogenic Diet: Considerations for Cancer Survivorship.
Endocrine responses of the stress system to different types of exercise.
Phytochemicals in Skeletal Muscle Health: Effects of Curcumin (from Curcuma longa Linn) and Sulforaphane (from Brassicaceae) on Muscle Function, Recovery and Therapy of Muscle Atrophy.
Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing.
Role of Sirtuins in Diabetes and Age-Related Processes.

Int J Environ Res Public Health. 2022 Oct 03. pii: 12629. [Epub ahead of print]19(19):

Effects of the Ketogenic Diet on Muscle Hypertrophy in Resistance-Trained Men and Women: A Systematic Review and Meta-Analysis.

Salvador Vargas-Molina, José L Gómez-Urquiza, Jerónimo García-Romero, Javier Benítez-Porres.

  Reviews focused on the ketogenic diet (KD) based on the increase in fat-free mass (FFM) have been carried out with pathological populations or, failing that, without population differentiation. The aim of this review and meta-analysis was to verify whether a ketogenic diet without programmed energy restriction generates increases in fat-free mass (FFM) in resistance-trained participants. We evaluated the effect of the ketogenic diet, in conjunction with resistance training, on fat-free mass in trained participants. Boolean algorithms from various databases (PubMed, Scopus. and Web of Science) were used, and a total of five studies were located that related to both ketogenic diets and resistance-trained participants. In all, 111 athletes or resistance-trained participants (87 male and 24 female) were evaluated in the studies analyzed. We found no significant differences between groups in the FFM variables, and more research is needed to perform studies with similar ketogenic diets and control diet interventions. Ketogenic diets, taking into account the possible side effects, can be an alternative for increasing muscle mass as long as energy surplus is generated; however, their application for eight weeks or more without interruption does not seem to be the best option due to the satiety and lack of adherence generated.

Keywords:  body building; body composition; ketosis; muscle mass; muscle protein synthesis; strength

DOI:  https://doi.org/10.3390/ijerph191912629
Sports Med. 2022 Oct 10.

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future.

Mark Evans, Tyler S McClure, Andrew P Koutnik, Brendan Egan.

The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by serving as an alternative substrate for energy provision, and by modulating inflammation, oxidative stress, catabolic processes, and gene expression. Of particular relevance to athletes are the metabolic actions of ketone bodies to alter substrate utilisation through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. There has been long-standing interest in the development of ingestible forms of ketone bodies that has recently resulted in the commercial availability of exogenous ketone supplements (EKS). These supplements in the form of ketone salts and ketone esters, in addition to ketogenic compounds such as 1,3-butanediol and medium chain triglycerides, facilitate an acute transient increase in circulating AcAc and βHB concentrations, which has been termed 'acute nutritional ketosis' or 'intermittent exogenous ketosis'. Some studies have suggested beneficial effects of EKS to endurance performance, recovery, and overreaching, although many studies have failed to observe benefits of acute nutritional ketosis on performance or recovery. The present review explores the rationale and historical development of EKS, the mechanistic basis for their proposed effects, both positive and negative, and evidence to date for their effects on exercise performance and recovery outcomes before concluding with a discussion of methodological considerations and future directions in this field.

DOI: https://doi.org/10.1007/s40279-022-01756-2
J Clin Endocrinol Metab. 2022 Oct 14. pii: dgac595. [Epub ahead of print]

Ketone Body Infusion abrogates Growth Hormone Induced Lipolysis and Insulin Resistance.

Morten Lyng Høgild, Astrid Johannesson Hjelholt, Jakob Hansen, Steen Bønløkke Pedersen, Niels Møller, Jørgen F P Wojtaszewski, Mogens Johannsen, Niels Jessen, Jens Otto Lunde Jørgensen.

   BACKGROUND: Exogenous ketone body administration lowers circulating glucose levels but the underlying mechanisms are uncertain. We tested the hypothesis that administration of the ketone body β-hydroxybutyrate (βOHB) acutely increases insulin sensitivity via feedback suppression of circulating free fatty acid (FFA) levels.
DESIGN: In a randomized, single-blinded crossover design, eight healthy men were studied twice with a GH infusion to induce lipolysis in combination with infusion of either βOHB or saline. Each study day comprised a basal period and a hyperinsulinemic-euglycemic clamp combined with a glucose tracer and adipose tissue and skeletal muscle biopsies.
RESULTS: βOHB administration profoundly suppressed FFA levels concomitantly with a significant increase in glucose disposal and energy expenditure. This was accompanied by a many-fold increase in skeletal muscle content of both βOHB and its derivative acetoacetate.
CONCLUSION: Our data unravel an insulin sensitizing effect of βOHB, which we suggest is mediated by concomitant suppression of lipolysis.

Keywords:  Ketone bodies; free fatty acids; glucose metabolism; growth hormone; insulin sensitivity; β-hydroxybutyrate

DOI:  https://doi.org/10.1210/clinem/dgac595
Nutrients. 2022 Oct 03. pii: 4113. [Epub ahead of print]14(19):

The Therapeutic Role of Short-Chain Fatty Acids Mediated Very Low-Calorie Ketogenic Diet-Gut Microbiota Relationships in Paediatric Inflammatory Bowel Diseases.

Naser A Alsharairi.

  The very low-calorie ketogenic diet (VLCKD) has been recognized as a promising dietary regimen for the treatment of several diseases. Short-chain fatty acids (SCFAs) produced by anaerobic bacterial fermentation of indigestible dietary fibre in the gut have potential value for their underlying epigenetic role in the treatment of obesity and asthma-related inflammation through mediating the relationships between VLCKD and the infant gut microbiota. However, it is still unclear how VLCKD might influence gut microbiota composition in children, and how SCFAs could play a role in the treatment of inflammatory bowel disease (IBD). To overcome this knowledge gap, this review aims to investigate the role of SCFAs as key epigenetic metabolites that mediate VLCKD-gut microbiota relationships in children, and their therapeutic potential in IBD.

Keywords:  children; gut microbiota; inflammatory bowel disease; short chain fatty acids; very low-calorie ketogenic diet

DOI:  https://doi.org/10.3390/nu14194113
Nutrients. 2022 Oct 08. pii: 4192. [Epub ahead of print]14(19):

Effect of Ketogenic Diets on Body Composition and Metabolic Parameters of Cancer Patients: A Systematic Review and Meta-Analysis.

Haobin Zhao, Han Jin, Junfang Xian, Zhifu Zhang, Junling Shi, Xiaosu Bai.

  A ketogenic diet characterized by high fat and low carbohydrate can drive the body to produce a large number of ketone bodies, altering human metabolism. Unlike normal cells, tumor cells have difficulty in consuming ketone bodies. Therefore, the application of ketogenic diets in cancer therapy is gaining attention. However, the effect of ketogenic diets on body parameters of cancer patients is not well established. This meta-analysis aimed to summarize the effects of ketogenic diets on cancer patients in earlier controlled trials. PubMed, Embase, and Cochrane Library were searched for clinical trials that enrolled cancer patients who received ketogenic diets intervention. Ten controlled trials were included in this meta-analysis. Data were extracted and checked by three authors independently. Pooled effect sizes revealed a significant effect of ketogenic diets on body weight (SMD -1.83, 95% CI -2.30 to -1.35; p < 0.00001) and fat mass (SMD -1.52, 95% CI -1.92 to -1.07; p < 0.00001). No significant effect on blood glucose, insulin, or lipid profile except triglycerides was found in the analysis. It had no effect on liver and kidney function except that GGT were decreased a little. There were no significant changes in IGF-1 and TNF-α related to tumor growth. Mental health improvement of cancer patients was supported by several trials. Taken together, findings in this study confirmed that the ketogenic diet was a safe approach for cancer patients reducing body weight and fat mass. In addition, cancer treatment-related indicators changed insignificantly. Ketogenic diets may be beneficial to the quality of life of cancer patients. However, intervention duration in most studies is shorter than 6 months, and the effect of a long-term ketogenic diet is still required further validation. More trials with a larger sample size are necessary to give a more conclusive result; PROSPERO registration number: CRD42021277559.

Keywords:  body composition; cancer patients; food function; ketogenic diets; metabolic parameters; nutrition

DOI:  https://doi.org/10.3390/nu14194192
Front Endocrinol (Lausanne). 2022 ;13 960835

Hyperinsulinemia impairs the metabolic switch to ketone body utilization in proximal renal tubular epithelial cells under energy crisis via the inhibition of the SIRT3/SMCT1 pathway.

Jinlan Xie, Feifei Zhong, Zhenhong Guo, Xinran Li, Jingyu Wang, Zhongai Gao, Baocheng Chang, Juhong Yang.

   Objective: To investigate the effects and mechanism of hyperinsulinemia on the metabolic switch to β-hydroxybutyrate (BHB) absorption and utilization under a starvation or hypoxic environment in proximal tubular epithelial cells.
Methods: A high-fat diet-induced hyperinsulinemia model in ZDF rats was used to test the expression of key enzymes/proteins of ketone body metabolism in the kidney. Notably, 12-week-old renal tubule SMCT1 specific knockout mice (SMCT1 flox/floxCre+) and control mice (SMCT1 flox/floxCre-) were used to confirm the roles of SMCT1 in kidney protection under starvation. The changes of key enzymes/proteins of energy metabolism, mitochondrial function, and albumin endocytosis in HK2 cells under low glucose/hypoxic environments with or without 50 ng/mL insulin were studied. Silent information regulation 2 homolog 3 (SIRT3) was overexpressed to evaluate the effect of hyperinsulinemia on the metabolic switch to BHB absorption and utilization through the SIRT3/SMCT1 pathway in HK2 cells.
Results: In ZDF rats, the expression of HMGCS2 increased, the SMCT1 expression decreased, while SCOT remained unchanged. In renal tubule SMCT1 gene-specific knockout mice, starvation for 48 h induced an increase in the levels of urine retinol-binding protein, N-acetyl-β-glucosaminidase, and transferrin, which reflected tubular damages. In HK2 cells under an environment of starvation and hypoxia, the levels of key enzymes related to fatty acid oxidation and ketone body metabolism were increased, whereas glucose glycolysis did not change. The addition of 2 mmol/l BHB improved ATP production, mitochondrial biosynthesis, and endocytic albumin function, while cell apoptosis was reduced in HK2 cells. The addition of 50 ng/ml insulin resulted in the decreased expression of SMCT1 along with an impaired mitochondrial function, decreased ATP production, and increased apoptosis. The overexpression of SIRT3 or SMCT1 reversed these alterations induced by a high level of insulin both in low-glucose and hypoxic environments.
Conclusions: The increased absorption and utilization of BHB is part of the metabolic flexibility of renal tubular epithelial cells under starvation and hypoxic environments, which exhibits a protective effect on renal tubular epithelial cells by improving the mitochondrial function and cell survival. Moreover, hyperinsulinemia inhibits the absorption of BHB through the inhibition of the SIRT3/SMCT1 pathway.

Keywords:  Hyperinsulinemia; metabolic flexibility; mitochondria; proximal tubular epithelial cells; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fendo.2022.960835
Cells. 2022 Sep 28. pii: 3041. [Epub ahead of print]11(19):

Glucose 6-P Dehydrogenase-An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise.

Esther García-Domínguez, Aitor Carretero, Aurora Viña-Almunia, Julio Domenech-Fernandez, Gloria Olaso-Gonzalez, Jose Viña, Mari Carmen Gomez-Cabrera.

  Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.

Keywords:  G6PD; NADPH; aging; pentose phosphate pathway; physical training; skeletal muscle

DOI:  https://doi.org/10.3390/cells11193041
Int J Mol Sci. 2022 Oct 01. pii: 11638. [Epub ahead of print]23(19):

Pyroptosis and Insulin Resistance in Metabolic Organs.

Huiting Wei, Di Cui.

  Skeletal muscle serves as the optimal effective organ to balance glucose homeostasis, but insulin resistance (IR) in skeletal muscle breaks this balance by impeding glucose uptake and causes metabolic disorders. IR in skeletal muscle is caused by multiple factors, and it has been reported that systemic low-grade inflammation is related to skeletal muscle IR, though its molecular mechanisms need to be ulteriorly studied. Pyroptosis is a novel inflammatory-mediated type of cell death. It has recently been reported that pyroptosis is associated with a decline in insulin sensitivity in skeletal muscle. The appropriate occurrence of pyroptosis positively eliminates pathogenic factors, whereas its excessive activation may aggravate inflammatory responses and expedite disease progression. The relationship between pyroptosis and IR in skeletal muscle and its underlined mechanism need to be further illustrated. The role of pyroptosis during the process of IR alleviation induced by non-drug interventions, such as exercise, also needs to be clarified. In this paper, we review and describe the molecular mechanisms of pyroptosis and further comb the roles of its relevant key factors in skeletal muscle IR, aiming to propose a novel theoretical basis for the relationship between pyroptosis and muscle IR and provide new research targets for the improvement of IR-related diseases.

Keywords:  GSDMs; IR; NLRP3; caspase; pyroptosis; skeletal muscle

DOI:  https://doi.org/10.3390/ijms231911638
Cells. 2022 Sep 25. pii: 2987. [Epub ahead of print]11(19):

2-Deoxy-D-glucose Alleviates Cancer Cachexia-Induced Muscle Wasting by Enhancing Ketone Metabolism and Inhibiting the Cori Cycle.

Lulu Wei, Ranran Wang, Junaid Wazir, Kai Lin, Shiyu Song, Li Li, Wenyuan Pu, Chen Zhao, Yong Wang, Zhonglan Su, Hongwei Wang.

  Cachexia is characterized by progressive weight loss accompanied by the loss of specific skeletal muscle and adipose tissue. Increased lactate production, either due to the Warburg effect from tumors or accelerated glycolysis effects from cachectic muscle, is the most dangerous factor for cancer cachexia. This study aimed to explore the efficiency of 2-deoxy-D-glucose (2-DG) in blocking Cori cycle activity and its therapeutic effect on cachexia-associated muscle wasting. A C26 adenocarcinoma xenograft model was used to study cancer cachectic metabolic derangements. Tumor-free lean mass, hindlimb muscle morphology, and fiber-type composition were measured after in vivo 2-DG administration. Activation of the ubiquitin-dependent proteasome pathway (UPS) and autophagic-lysosomal pathway (ALP) was further assessed. The cachectic skeletal muscles of tumor-bearing mice exhibited altered glucose and lipid metabolism, decreased carbohydrate utilization, and increased lipid β-oxidation. Significantly increased gluconeogenesis and decreased ketogenesis were observed in cachectic mouse livers. 2-DG significantly ameliorated cancer cachexia-associated muscle wasting and decreased cachectic-associated lean mass levels and fiber cross-sectional areas. 2-DG inhibited protein degradation-associated UPS and ALP, increased ketogenesis in the liver, and promoted ketone metabolism in skeletal muscle, thus enhancing mitochondrial bioenergetic capacity. 2-DG effectively prevents muscle wasting by increasing ATP synthesis efficiency via the ketone metabolic pathway and blocking the abnormal Cori cycle.

Keywords:  Cori cycle; cancer cachexia; glucose metabolism; ketone; muscle wasting

DOI:  https://doi.org/10.3390/cells11192987
Front Immunol. 2022 ;13 926895

NLRP3: Role in ischemia/reperfusion injuries.

Soudeh Ghafouri-Fard, Hamed Shoorei, Yadollah Poornajaf, Bashdar Mahmud Hussen, Yasaman Hajiesmaeili, Atefe Abak, Mohammad Taheri, Ahmad Eghbali.

  NLR family pyrin domain containing 3 (NLRP3) is expressed in immune cells, especially in dendritic cells and macrophages and acts as a constituent of the inflammasome. This protein acts as a pattern recognition receptor identifying pathogen-associated molecular patterns. In addition to recognition of pathogen-associated molecular patterns, it recognizes damage-associated molecular patterns. Triggering of NLRP3 inflammasome by molecules ATP released from injured cells results in the activation of the inflammatory cytokines IL-1β and IL-18. Abnormal activation of NLRP3 inflammasome has been demonstrated to stimulate inflammatory or metabolic diseases. Thus, NLRP3 is regarded as a proper target for decreasing activity of NLRP3 inflammasome. Recent studies have also shown abnormal activity of NLRP3 in ischemia/reperfusion (I/R) injuries. In the current review, we have focused on the role of this protein in I/R injuries in the gastrointestinal, neurovascular and cardiovascular systems.

Keywords:  NLRP3; biomarker; diagnosis; expression; ischemia/reperfusion

DOI:  https://doi.org/10.3389/fimmu.2022.926895
Heart Fail Clin. 2022 Oct;pii: S1551-7136(22)00029-0. [Epub ahead of print]18(4): 529-538

Glucose-Lowering and Metabolic Effects of SGLT2 Inhibitors.

Ify R Mordi, Chim C Lang.

  Sodium-glucose cotransporter 2 (SGLT2) inhibitors have consistently demonstrated improved outcomes in patients with heart failure with or without type 2 diabetes; however, the mechanisms contributing to these benefits remain poorly understood. Although SGLT2 inhibitors do have glucose-lowering effects, it is unlikely that their cardiovascular benefits are solely due to improved glycemic control. This improved glycemia leads to consequent metabolic effects that could provide further explanation for their action. This review discusses the glucose-lowering and metabolic effects of SGLT2 inhibitors and how these might lead to improved cardiovascular outcomes in patients with heart failure.

Keywords:  Cardiometabolic; Glycemia; Heart failure; SGLT2 inhibitors

DOI:  https://doi.org/10.1016/j.hfc.2022.03.004
Cureus. 2022 Sep;14(9): e28787

Sarcopenia and Endocrine Ageing: Are They Related?

Prishita Gupta, Sunil Kumar.

  Sarcopenia is an illness of the elderly defined by a widespread and gradual decline of skeletal muscle mass and function, with the possibility of negative effects such as poor physical performance, decreased quality of life, and death. Sarcopenia has complicated and multiple pathogeneses. The shift in pathways necessary for muscle regeneration, inflammatory process, and protein synthesis appears to be one of the leading causes of loss of strength and muscle due to age. Researchers have discussed the effects of hypothalamic-pituitary dysfunction in this condition. Lifestyle factors like diet and exercise significantly influence body composition, physical function, and metabolic consequences. The effectiveness and tolerability of hormone replacement in treating sarcopenia will be determined through large-scale clinical trials. In this article, we present a summary of our current knowledge regarding the role of the endocrine system in sarcopenia and an overview of hormonal therapy to address endocrine abnormalities.

Keywords:  exercise; hormones; igf-1; muscle loss; replacement; testosterone

DOI:  https://doi.org/10.7759/cureus.28787
J Sports Med Phys Fitness. 2022 Oct 14.

Effect of a low carbohydrate, high fat diet versus a high carbohydrate diet on exercise efficiency and economy in recreational male athletes.

A Mireille Baart, Hennes Schaminee, Marco Mensink, Rieneke Terink.

BACKGROUND: Exercise efficiency and economy are key determinants of endurance exercise performance. In this cross-over intervention trial, we investigated the effect of adherence to a low carbohydrate, high fat (LCHF) diet versus a high carbohydrate (HC) diet on gross efficiency (GE) and oxygen cost (OC) during exercise, both after 2 days and after 14 days of adherence.
METHODS: Fourteen recreational male athletes followed a two week LCHF diet (<10 energy % carbohydrate) and a two week HC diet (>50 energy % carbohydrate), in random order, with a wash-out period of three weeks in between. After 2 and 14 days on each diet, the athletes performed a 90 minutes submaximal exercise session on a bicycle ergometer. Indirect calorimetry measurements were done after 60 minutes of exercise to calculate GE and OC.
RESULTS: GE was significantly lower on the LCHF diet compared to the HC diet, after 2 days (17.6 ± 1.9 vs 18.8 ± 1.2 %, p=0.011, for the LCHF and HC diet respectively), not after 14 days. OC was significantly higher on the LCHF diet compared to the HC diet, after 2 days (1191 ± 138 vs 1087 ± 72 ml O2/kCal, p=0.003, for the LCHF and HC diet respectively), and showed a strong tendency to remain higher after 14 days, p=0.018.
CONCLUSIONS: Although LCHF diets are popular strategies to increase fat oxidation during exercise, adherence to a LCHF diet was associated with a lower exercise efficiency and economy compared to a HC diet.

DOI: https://doi.org/10.23736/S0022-4707.22.14066-1
J Food Biochem. 2022 Oct 11. e14407

The ketogenic diet could improve the efficacy of curcumin and Oldenlandia diffusa extract in the treatment of gastric cancer by increasing miR340 expression and apoptosis mediated by autophagy, oxidative stress, and angiogenesis.

Qiuju Xiao, Bo Deng, Abolfazl Akbari, Qisheng Liu, Bisheng Zhu.

  The pathogenesis of gastric cancer is a multistage process that involves glucose metabolism, inflammation, oxidative damage, angiogenesis, autophagy, and apoptosis. Moreover, microRNA-340 (miR340) also plays a vital role in tumorigenesis and the biology of gastric cancer as an epigenetic factor. It seems that the use of ketogenic diets (KDs) and plant extracts that have antitumor, anti-inflammatory, and antioxidant properties can be good treatment options to cure gastric cancer. The aim of this study was to investigate the role of miR-340 on pathways involved in the pathogenesis of gastric cancer and the improving effects of the KD, Oldenlandia diffusa extract (ODE), and curcumin in the animal model of gastric cancer. One hundred and ten male Wistar rats were divided into control and treatment groups. The expression of miR-340 along with genes involved in inflammation, oxidative damage, angiogenesis, and apoptosis were assessed. The results showed that the KD and different doses of curcumin and ODE in a dose-dependent behavior could induce apoptosis and the expression of the Akt/mTORC1 pathway and inhibit inflammation, oxidative damage, and angiogenesis in the gastric tissue of rats with cancer. In addition, there was no significant difference between cancer groups receiving ODE and curcumin. These results also showed that consumption of KD could significantly increase the efficacy of ODE and curcumin which may be due to increasing miR-340 expression. The results of this study suggested well that the KD along with conventional therapies in traditional medicine can be a useful solution for the prevention and treatment of gastric cancer. PRACTICAL APPLICATIONS: Gastric cancer is the third leading cause of cancer death, and genetic and epigenetic factors, including miR-340, are involved in its pathogenesis. However, the use of ketogenic diets (KDs) and plant products such as curcumin and Oldenlandia diffusa extract (ODE) can play an effective role in inhibiting tumorigenesis in some cancers. Our results showed that the KD and different doses of curcumin and ODE could induce apoptosis and the expression of the Akt/mTORC1 pathway and inhibit inflammation, oxidative damage, and angiogenesis in the gastric tissue. Moreover, the KD could significantly increase the efficacy of ODE and curcumin which may be due to an increase in miR-340 expression. These findings provide novel perceptions about the mechanisms of the KD, curcumin, and ODE to cure gastric cancer. It suggested that the KD as adjunctive therapy along with conventional therapies in traditional medicine could be considered a useful solution to prevent and treat gastric cancer.

Keywords:   Oldenlandia diffusa ; curcumin; gastric cancer; ketogenic diet; miR340

DOI:  https://doi.org/10.1111/jfbc.14407
Exp Gerontol. 2022 Oct 10. pii: S0531-5565(22)00282-0. [Epub ahead of print] 111974

Aging is associated with an altered macrophage response during human skeletal muscle regeneration.

Mohadeseh Ahmadi, Anders Karlsen, Jack Mehling, Casper Soendenbroe, Abigail L Mackey, Robert D Hyldahl.

  Skeletal muscle injury in aged rodents is characterized by an asynchronous infiltration of pro- and anti-inflammatory macrophage waves, leading to improper and incomplete regeneration. It is unclear whether this aberration also occurs in aged human muscle. In this study, we quantified the macrophage responses in a human model of muscle damage and regeneration induced by electrical stimulation in 7 young and 21 older adults. At baseline, total resident macrophage (CD68+/DAPI+) content was not different between young and old subjects, but pro-inflammatory (CD206-/CD68+/DAPI+) macrophage content was lower in the old. Following damage, muscle Infiltration of CD206-/CD68+/DAPI+ macrophages was lower in old relative to young subjects. Further, only the increase in CD206-/CD68+ macrophages correlated with the change in muscle satellite cell content. Our data show that older individuals have a compromised macrophage response during muscle regeneration, pointing to an altered inflammatory response as a potential mechanism for reduced muscle regenerative efficacy in aged humans.

Keywords:  Aging; Immunosenescence; Inflammation; Muscle damage; Muscle regeneration; Satellite cell

DOI:  https://doi.org/10.1016/j.exger.2022.111974
PLoS One. 2022 ;17(10): e0276002

Exogenous glucose oxidation during endurance exercise under low energy availability.

Chihiro Kojima, Aya Ishibashi, Kumiko Ebi, Kazushige Goto.

The present study was conducted to determine the effect of endurance exercise under low energy availability (EA) on exogenous glucose oxidation during endurance exercise. Ten active males (21.4 ± 0.6 years, 170.4 ± 1.4 cm, 62.4 ± 1.5 kg, 21.5 ± 0.4 kg/m2) completed two trials, consisting of two consecutive days (days 1 and 2) of endurance training under low EA (19.9 ± 0.2 kcal/kg fat free mass [FFM]/day, LEA trial) or normal EA (46.4 ± 0.1 kcal/kg FFM/day, NEA trial). The order of these two trials was randomized with at least a 1-week interval between trials. As an endurance training, participants performed 60 min of treadmill running at 70% of maximal oxygen uptake ([Formula: see text]) during two consecutive days (on days 1 and 2). On day 1, the endurance training was performed with consumed individually manipulated meals. During the endurance exercise on day 2, exogenous glucose oxidation was evaluated using 13C-labeled glucose, and respiratory gas samples were collected. In addition, blood glucose and lactate concentrations were measured immediately after exercise on day 2. Body composition, blood parameters, and resting respiratory gas variables were evaluated under overnight fasting on days 1 and 2. Body weight was significantly reduced in the LEA trial on day2 (day1: 61.8 ± 1.4 kg, day 2: 61.3 ± 1.4 kg, P < 0.001). There were no significant differences between trials in 13C excretion (P = 0.33) and area under the curve during the 60 min of exercise (LEA trial: 40.4 ± 3.1 mmol•60min, NEA trial: 40.4 ± 3.1 mmol•60min, P = 0.99). However, the respiratory exchange ratio (RER, LEA trial: 0.88 ± 0.01, NEA trial: 0.90 ± 0.01) and carbohydrate oxidation (LEA trial: 120.1 ± 8.8 g, NEA trial: 136.8 ± 8.6 g) during endurance exercise showed significantly lower values in the LEA trial than in the NEA trial (P = 0.01 for RER and carbohydrate oxidation). Serum insulin and total ketone body concentrations were significantly changed after a day of endurance training under low EA (P = 0.04 for insulin, P < 0.01 for total ketone). In conclusion, low EA during endurance exercise reduced systemic carbohydrate oxidation; however, exogenous glucose oxidation (evaluated by 13C excretion) remained unchanged during exercise under low EA.

DOI: https://doi.org/10.1371/journal.pone.0276002
BMC Res Notes. 2022 Oct 12. 15(1): 323

Effect of intermittent fasting 5:2 on body composition and nutritional intake among employees with obesity in Jakarta: a randomized clinical trial.

Fiastuti Witjaksono, Erfi Prafiantini, Anni Rahmawati.

   OBJECTIVE: This study aimed to determine the effect of intermittent fasting 5:2 on body composition in employees with obesity in Jakarta.
RESULTS: Fifty participants were included; 25 were allocated to the fasting group and 25 to the control group. There was no significant change in fat mass, fat-free mass, skeletal muscle, and BMI (p > 0.05). Significant in-group changes were observed in body weight (p = 0.023) and BMI (p = 0.018) in the fasting group. Dietary intake was similar before and during the intervention. The reduction in macronutrient intake resulted in a statistically significant difference in carbohydrate, protein, and fat intake in the two groups (p < 0.05). Intermittent fasting 5:2 results in weight loss but does not affect fat mass and fat-free mass reductions. None of the between-group differences were clinically relevant.
TRIAL REGISTRATION: ClinicalTrials.gov with ID: NCT04319133 registered on 24 March 2020.

Keywords:  Body composition; Employees; Fat mass; Fat-free mass; Intermittent fasting 5:2; Obesity

DOI:  https://doi.org/10.1186/s13104-022-06209-7
Front Physiol. 2022 ;13 984373

Implications of notch signaling in duchenne muscular dystrophy.

Lily Den Hartog, Atsushi Asakura.

  This review focuses upon the implications of the Notch signaling pathway in muscular dystrophies, particularly Duchenne muscular dystrophy (DMD): a pervasive and catastrophic condition concerned with skeletal muscle degeneration. Prior work has defined the pathogenesis of DMD, and several therapeutic approaches have been undertaken in order to regenerate skeletal muscle tissue and ameliorate the phenotype. There is presently no cure for DMD, but a promising avenue for novel therapies is inducing muscle regeneration via satellite cells (muscle stem cells). One specific target using this approach is the Notch signaling pathway. The canonical Notch signaling pathway has been well-characterized and it ultimately governs cell fate decision, cell proliferation, and induction of differentiation. Additionally, inhibition of the Notch signaling pathway has been directly implicated in the deficits seen with muscular dystrophies. Here, we explore the connection between the Notch signaling pathway and DMD, as well as how Notch signaling may be targeted to improve the muscle degeneration seen in muscular dystrophies.

Keywords:  muscle regeneration; muscle stem cell; muscular dystrophy; notch; satellite cell

DOI:  https://doi.org/10.3389/fphys.2022.984373
Gen Physiol Biophys. 2022 Sep;41(5): 447-455

The role of Sirt3 in the changes of skeletal muscle mitophagy induced by hypoxic training.

Chunwei Ma, Yongcai Zhao, Xiaoqing Ding, Binghong Gao.

We aimed to explore the role of Sirt3 in the regulation of skeletal muscle mitophagy with hypoxic training. C57BL/6J mice were randomly divided into four groups: C group (control), HT group (mice performed a hypoxic training of living in an environment with an oxygen concentration of 13.8% and treadmill exercise under normoxia for 6 weeks), T group (mice were subjected to an intraperitoneal (i.p.) injection of the Sirt3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP) 50 mg/kg three times per week for 6 weeks) and THT group (the hypoxic training of HT group with i.p. injection of 3-TYP in T group). The results showed that 6 weeks of hypoxic training could improve ATP synthesis in skeletal muscle. After the combined intervention of 3-TYP injection and hypoxic training, Sirt3, FOXO3a, and SOD2 protein contents were still lower than those in hypoxic training group. Hypoxic training cannot improve the negative effect of Sirt3 inhibition on muscle PINK1/Parkin signal. This study demonstrated that Sirt3 plays a key role in mediating skeletal muscle mitophagy by hypoxic training. The results of our study also provided the first evidence that mitophagy caused by hypoxic training might be transduced through the Sirt3-FOXO3a signaling pathway.

DOI: https://doi.org/10.4149/gpb_2022023
Sci Rep. 2022 Oct 11. 12(1): 17017

Changes in plasma fatty acids profile in hyperketonemic ewes during early lactation: a preliminary study.

Anastasia Lisuzzo, Filippo Fiore, Kevin Harvatine, Elisa Mazzotta, Michele Berlanda, Nicoletta Spissu, Tamara Badon, Barbara Contiero, Livia Moscati, Enrico Fiore.

The transition from late pregnancy to early lactation is characterized by marked changes in energy balance of dairy ruminants. The mobilization of adipose tissue led to an increase in plasma non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHB). The aim of this study was to analyze the total plasma fatty acids of healthy and hyperketonemic dairy ewes in early lactation through gas chromatography (GC) to evaluate metabolic alterations. An observational study was used with a cross-sectional experimental design. Forty-six Sarda dairy ewes were enrolled in the immediate post-partum (7 ± 3 days in milk) and divided into two groups according to serum BHB concentration: non-hyperketonemic group (n = 28; BHB < 0.86 mmol/L) and hyperketonemic group (n = 18; BHB ≥ 0.86 mmol/L). A two-way ANOVA included the effect of group and parity was used to evaluate differences in fatty acids (FA) concentrations. A total of 34 plasma FA was assessed using GC. 12 out of 34 FA showed a significant different between groups and 3 out of 34 were tended to significance. Only NEFA concentration and stearic acid were influenced by parity. The results may suggest possible links with lipid metabolism, inflammatory and immune responses in hyperketonemic group. In conclusion, GC represents a useful tool in the study of hyperketonemia and primiparous dairy ewes might show a greater risk to develop this condition.

DOI: https://doi.org/10.1038/s41598-022-21088-5
Curr Nutr Rep. 2022 Oct 13.

The Ketogenic Diet: Considerations for Cancer Survivorship.

Cara Miller, Karina Austin, Lawren Fischer, Eleah Stringer, Satnam Sidhu.

   PURPOSE OF REVIEW: This article aims to evaluate the current practice of the ketogenic diet (KD) in oncology by discussing feasibility, impact on quality of life, and implications for dietetic practice. Articles discussed were selected based on an adult oncology population with emphasis on publications from the last 5 years.
RECENT FINDINGS: There is a paucity of randomized prospective trials and articles reviewed were heterogeneous in nature, limiting the ability to draw conclusions about the KDs role in cancer care and survivorship. Despite the lack of evidence, patients with cancer are interested in KD. The authors highlight barriers to supporting implementation of KD and recommend the inclusion of a registered dietitian with experience in KD to ensure safety and support the nutrition goals of patients with cancer. Thorough, well-designed randomized control trials are needed to elucidate the potential advantages of this diet therapy in cancer care and survivorship.

Keywords:  Cancer; Feasibility; Ketogenic diet; Nutrition; Oncology; Quality of life; Safety; Survivorship

DOI:  https://doi.org/10.1007/s13668-022-00439-8
Rev Endocr Metab Disord. 2022 Oct 15.

Endocrine responses of the stress system to different types of exercise.

Nikolaos Athanasiou, Gregory C Bogdanis, George Mastorakos.

  Physical activity is an important part of human lifestyle although a large percentage of the population remains sedentary. Exercise represents a stress paradigm in which many regulatory endocrine systems are involved to achieve homeostasis. These endocrine adaptive responses may be either beneficial or harmful in case they exceed a certain threshold. The aim of this review is to examine the adaptive endocrine responses of hypothalamic-pituitary-adrenal axis (HPA), catecholamines, cytokines, growth hormone (GH) and prolactin (PRL) to a single bout or regular exercise of three distinct types of exercise, namely endurance, high-intensity interval (HIIE) and resistance exercise. In summary, a single bout of endurance exercise induces cortisol increase, while regular endurance exercise-induced activation of the HPA axis results to relatively increased basal cortisolemia; single bout or regular exercise induce similar GH peak responses; regular HIIE training lowers basal cortisol concentrations, while catecholamine response is reduced in regular HIIE compared with a single bout of HIIE. HPA axis response to resistance exercise depends on the intensity and volume of the exercise. A single bout of resistance exercise is characterized by mild HPA axis stimulation while regular resistance training in elderly results in attenuated inflammatory response and decreased resting cytokine concentrations. In conclusion, it is important to consider which type of exercise and what threshold is suitable for different target groups of exercising people. This approach intends to suggest types of exercise appropriate for different target groups in health and disease and subsequently to introduce them as medical prescription models.

Keywords:  Catecholamines; Cortisol; Exercise; GH; HPA; IL-6

DOI:  https://doi.org/10.1007/s11154-022-09758-1
Plants (Basel). 2022 Sep 26. pii: 2517. [Epub ahead of print]11(19):

Phytochemicals in Skeletal Muscle Health: Effects of Curcumin (from Curcuma longa Linn) and Sulforaphane (from Brassicaceae) on Muscle Function, Recovery and Therapy of Muscle Atrophy.

Nancy Vargas-Mendoza, Eduardo Madrigal-Santillán, Isela Álvarez-González, Eduardo Madrigal-Bujaidar, Liliana Anguiano-Robledo, José Leopoldo Aguilar-Faisal, Mauricio Morales-Martínez, Luis Delgado-Olivares, Elda Victoria Rodríguez-Negrete, Ángel Morales-González, José A Morales-González.

  The mobility of the human body depends on, among other things, muscle health, which can be affected by several situations, such as aging, increased oxidative stress, malnutrition, cancer, and the lack or excess of physical exercise, among others. Genetic, metabolic, hormonal, and nutritional factors are intricately involved in maintaining the balance that allows proper muscle function and fiber recovery; therefore, the breakdown of the balance among these elements can trigger muscle atrophy. The study from the nutrigenomic perspective of nutritional factors has drawn wide attention recently; one of these is the use of certain compounds derived from foods and plants known as phytochemicals, to which various biological activities have been described and attributed in terms of benefiting health in many respects. This work addresses the effect that the phytochemicals curcumin from Curcuma longa Linn and sulforaphane from Brassicaceae species have shown to exert on muscle function, recovery, and the prevention of muscle atrophy, and describes the impact on muscle health in general. In the same manner, there are future perspectives in research on novel compounds as potential agents in the prevention or treatment of medical conditions that affect muscle health.

Keywords:  curcumin; phytochemicals; skeletal muscle; sulforaphane

DOI:  https://doi.org/10.3390/plants11192517
Int J Mol Sci. 2022 Sep 27. pii: 11391. [Epub ahead of print]23(19):

Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing.

Veronica Bazzani, Mara Equisoain Redin, Joshua McHale, Lorena Perrone, Carlo Vascotto.

  Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that can exist in multiple copies within the organelle. Both strands are translated and encode for 22 tRNAs, 2 rRNAs, and 13 proteins. mtDNA molecules are anchored to the inner mitochondrial membrane and, in association with proteins, form a structure called nucleoid, which exerts a structural and protective function. Indeed, mitochondria have evolved mechanisms necessary to protect their DNA from chemical and physical lesions such as DNA repair pathways similar to those present in the nucleus. However, there are mitochondria-specific mechanisms such as rapid mtDNA turnover, fission, fusion, and mitophagy. Nevertheless, mtDNA mutations may be abundant in somatic tissue due mainly to the proximity of the mtDNA to the oxidative phosphorylation (OXPHOS) system and, consequently, to the reactive oxygen species (ROS) formed during ATP production. In this review, we summarise the most common types of mtDNA lesions and mitochondria repair mechanisms. The second part of the review focuses on the physiological role of mtDNA damage in ageing and the effect of mtDNA mutations in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Considering the central role of mitochondria in maintaining cellular homeostasis, the analysis of mitochondrial function is a central point for developing personalised medicine.

Keywords:  Alzheimer’s disease; DNA damage; DNA repair pathways; Parkinson’s disease; mitochondria; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms231911391
Cureus. 2022 Sep;14(9): e28774

Role of Sirtuins in Diabetes and Age-Related Processes.

Nimisha Lingappa, Harvey N Mayrovitz.

  The practice of intermittent fasting continues to grow as a widely practiced diet trend due to its feasibility and reported high success rate. By practicing intermittent fasting, levels of sirtuin proteins (SIRTs), also known as the longevity protein, rise in the body and bring numerous health benefits. Currently, seven SIRTs have been described in humans in different locations of the cell with a wide variety of corresponding functions including gene transcription, DNA repair, and protection against oxidative damage. SIRT activators, such as resveratrol found in red wine, are also commonly consumed to amplify the health benefits associated with protection against diabetes and age-related disease processes. The purpose of this review is to explore the interaction of intermittent fasting on SIRT levels and how the increase in these proteins impacts age-related disease processes. The understanding of SIRTs is continuously evolving as more interactions and SIRT-specific activators are being revealed. New discoveries are crucial for forming potential therapeutics that delay many common diseases and promote healthy living.

Keywords:  aging; caloric restriction; intermittent fasting; sirtuin proteins; type 2 diabetes mellitus

DOI:  https://doi.org/10.7759/cureus.28774