bims-kimdis 2022-11-20 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022‒11‒20
twenty-two papers selected by
Matías Javier Monsalves Álvarez

Fat not so bad? The role of ketone bodies and ketogenic diet in the treatment of endothelial dysfunction and hypertension.
Experience with the ketogenic diet in premature neonates.
Ketogenic diet containing medium-chain triglyceride ameliorates transcriptome disruption in skeletal muscles of rat models of duchenne muscular dystrophy.
A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.
How Can SGLT2 Inhibitors Stimulate Erythrocytosis in Patients Who Are Iron Deficient? Implications for Understanding Iron Hemostasis in Heart Failure.
Detection of Euglycemic Diabetic Ketoacidosis During Thoracic Surgery 75 Hours After Empagliflozin Discontinuation.
Attenuation of hepatic fibrosis by p-Coumaric acid via modulation of NLRP3 inflammasome activation in C57BL/6 mice.
Effect of 30 days of ketogenic Mediterranean diet with phytoextracts on athletes' gut microbiome composition.
A Case of SGLT2 Inhibitor-Induced Euglycemic Diabetic Ketoacidosis.
Short-time effects of ketogenic diet or modestly hypocaloric Mediterranean diet on overweight and obese women with polycystic ovary syndrome.
NLRP3 inflammasome in digestive diseases: From mechanism to therapy.
Metabolic Flexibility During Exercise in Children with Overweight/Obesity Versus Children who are Lean.
Intermittent fasting and time-restricted eating role in dietary interventions and precision nutrition.
Incidence of diabetic ketoacidosis during Ramadan compared with non-fasting months in King Saud Medical City, Riyadh, Saudi Arabia.
Potential therapeutic role of pyroptosis mediated by the NLRP3 inflammasome in type 2 diabetes and its complications.
Low skeletal muscle mass Accompanied by Abdominal Obesity Additively Increases the Risk of Incident Type 2 Diabetes.
Parkin deficiency exacerbates fasting-induced skeletal muscle wasting in mice.
Mitochondrial quality control mechanisms as therapeutic targets in doxorubicin-induced cardiotoxicity.
[Low-fat cheese in the focus of dietary nutrition].
Sulforaphane reduces lipopolysaccharide-induced inflammation and enhances myogenic differentiation of mouse embryonic myoblasts via the toll-like receptor 4 and NLRP3 pathways.
Medicine & Science in Sports & Exercise 2021 Paper of the Year: The Role of Steps per Day in Preventing "Exercise Resistance".
Inflammasomes and their roles in arthritic disease pathogenesis.

Biochem Pharmacol. 2022 Nov 13. pii: S0006-2952(22)00440-3. [Epub ahead of print] 115346

Fat not so bad? The role of ketone bodies and ketogenic diet in the treatment of endothelial dysfunction and hypertension.

Luciano Pirola, Oskar Ciesielski, Aneta Balcerczyk.

  The ketogenic diet (KD), a high-fat, low-carbohydrate dietary approach that is based on the induction of extensive ketone bodies (KB) metabolism, is recently receiving a lot of attention due to its application as effective intervention for multiple metabolic disorders including cardiovascular diseases. Despite its already established clinical use, especially in the treatment of drug-resistant epilepsy, GLUT1 deficiency syndromes and, in selected cases, obesity; the systemic impact of is not yet fully understood. Here, we discuss the evidence for and against the application of ketogenic diets, or ketone bodies precursors, in the etiology of hypertension and endothelial cells dysfunction. We attempt to identify the benefits and potential risks of chronic use of the ketogenic diet, also considering the molecular effects that KB exerts at multiple levels.

Keywords:  acetoacetate; endothelium; hypertension; inflammatory response; ketogenic diet; ketone bodies; lipid metabolism; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.bcp.2022.115346
Epilepsia Open. 2022 Nov 18.

Experience with the ketogenic diet in premature neonates.

Chalongchai Phitsanuwong, Jeong-A Kim, Stephanie Schimpf, Douglas R Nordli.

  The ketogenic diet is a time-tested, potent, non-pharmacological treatment of epilepsy. However, the use of the ketogenic diet in premature neonates with epilepsy has not been previously reported. We share our experience with use of the ketogenic diet therapy in two premature neonates. Two identical twin premature neonates with SCN2A related developmental and epileptic encephalopathy, whose seizures were refractory to multiple anti-seizure medications, were started on the classic ketogenic diet at the conceptual age of 35 weeks Ketosis was achieved and maintained (range 2-5 mmol/L of serum beta-hydroxybutyrate level). Seizure frequency was significantly reduced (> 90% reduction in both patients), and some anti-seizure medications were able to be discontinued. Initial transient weight loss and one episode of asymptomatic hypoglycemia were observed and corrected. The ketogenic diet was found to be safe, well-tolerated, and effective treatment for seizures in two premature neonates. The side effects are tolerable and correctable. The ketogenic diet, therefore, is a treatment option for refractory seizures in this age group, when administered under expert guidance.

Keywords:  epilepsy; ketogenic diet; neonate; newborn; premature; preterm

DOI:  https://doi.org/10.1002/epi4.12673
Biochem Biophys Rep. 2022 Dec;32 101378

Ketogenic diet containing medium-chain triglyceride ameliorates transcriptome disruption in skeletal muscles of rat models of duchenne muscular dystrophy.

Yuri Fujikura, Keitaro Yamanouchi, Hidetoshi Sugihara, Masaki Hatakeyama, Tomoki Abe, Satoru Ato, Katsutaka Oishi.

  Duchenne muscular dystrophy (DMD) is a myopathy characterized by progressive muscle weakness caused by a mutation in the dystrophin gene on the X chromosome. We recently showed that a medium-chain triglyceride-containing ketogenic diet (MCTKD) improves skeletal muscle myopathy in a CRISPR/Cas9 gene-edited rat model of DMD. We examined the effects of the MCTKD on transcription profiles in skeletal muscles of the model rats to assess the underlying mechanism of the MCTKD-induced improvement in DMD. DMD rats were fed MCTKD or normal diet (ND) from weaning to 9 months, and wild-type rats were fed with the ND, then tibialis anterior muscles were sampled for mRNA-seq analysis. Pearson correlation heatmaps revealed a one-node transition in the expression profile between DMD and wild-type rats. A total of 10,440, 11,555 and 11,348 genes were expressed in the skeletal muscles of wild-type and ND-fed DMD rats the MCTKD-fed DMD rats, respectively. The MCTKD reduced the number of DMD-specific mRNAs from 1624 to 1350 and increased the number of mRNAs in common with wild-type rats from 9931 to 9998. Among 2660 genes were differentially expressed in response to MCTKD intake, the mRNA expression of 1411 and 1249 of them was respectively increased and decreased. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses suggested that the MCTKD significantly suppressed the mRNA expression of genes associated with extracellular matrix organization and inflammation. This suggestion was consistent with our previous findings that the MCTKD significantly suppressed fibrosis and inflammation in DMD rats. In contrast, the MCTKD significantly increased the mRNA expression of genes associated with oxidative phosphorylation and ATP production pathways, suggesting altered energy metabolism. The decreased and increased mRNA expression of Sln and Atp2a1 respectively suggested that Sarco/endoplasmic reticulum Ca2+-ATPase activation is involved in the MCTKD-induced improvement of skeletal muscle myopathy in DMD rats. This is the first report to examine transcription profiles in the skeletal muscle of CRISPR/Cas9 gene-edited DMD model rats and the effect of MCTKD feeding on it.

Keywords:  DAPC, dystrophin-associated glycoprotein complex; DEG, differentially expressed gene; DMD, Duchenne muscular dystrophy; Duchenne muscular dystrophy; FPKM, fragments per kilobase of exons per million mapped reads; GO, gene ontology; KD, ketogenic diet; KR, ketogenic ratio; Ketogenic diet; Ketone bodies; MCT, medium-chain triglycerides; MCTKD, medium-chain triglycerides containing ketogenic diet; ND, normal diet; PC, principal component; SERCA, sarco/endoplasmic reticulum (SR) Ca2+ ATPase; Skeletal muscle; TA, tibialis anterior; Transcriptome; WT, wild type

DOI:  https://doi.org/10.1016/j.bbrep.2022.101378
Cancer Res Commun. 2022 Sep;2(9): 951-965

A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.

Natalia E Cortez, Cecilia Rodriguez Lanzi, Brian V Hong, Jihao Xu, Fangyi Wang, Shuai Chen, Jon J Ramsey, Matthew G Pontifex, Michael Müller, David Vauzour, Payam Vahmani, Chang-Il Hwang, Karen Matsukuma, Gerardo G Mackenzie.

  Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.

Keywords:  ERK and AKT signaling pathways; Ketogenic diet; Lipid metabolism; gemcitabine; microbiome; pancreatic cancer; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1158/2767-9764.crc-22-0256
Eur J Heart Fail. 2022 Nov 14.

How Can SGLT2 Inhibitors Stimulate Erythrocytosis in Patients Who Are Iron Deficient? Implications for Understanding Iron Hemostasis in Heart Failure.

Milton Packer.

Many patients with heart failure have an iron-deficient state, which can limit erythropoiesis in erythroid precursors and ATP production in cardiomyocytes. Yet, treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors produce consistent increases in hemoglobin and hematocrit, even in patients who are iron-deficient before treatment, and this effect remains unattenuated throughout treatment even though SGLT2 inhibitors further aggravate biomarkers of iron deficiency. Heart failure is often accompanied by systemic inflammation, which activates hepcidin, thus impairing the duodenal absorption of iron and the release of iron from macrophages and hepatocytes, leading to a decline in circulating iron. Inflammation and oxidative stress also promote the synthesis of ferritin and suppress ferritinophagy, thus impairing the release of intracellular iron stores and leading to the depletion of bioreactive cytosolic Fe2+ . By alleviating inflammation and oxidative stress, SGLT2 inhibitors down-regulate hepcidin, upregulate transferrin receptor protein 1 and reduce ferritin; the net result is to increase the levels of cytosolic Fe2+ available to mitochondria, thus enabling the synthesis of heme (in erythroid precursors) and ATP (in cardiomyocytes). The finding that SGLT2 inhibitors can induce erythro-cytosis without iron supplementation suggests that the abnormalities in iron diagnostic tests in patients with mild-to-moderate heart failure are likely to be functional, rather than absolute, i.e., they are related to inflammation-mediated trapping of iron by hepcidin and ferritin, which is reversed by treatment with SGLT2 inhibitors. An increase in bioreactive cytosolic Fe2+ is also likely to augment mitochondrial production of ATP in cardiomyocytes, thus retarding the progression of heart failure. These effects on iron metabolism are consistent with (1) proteomics analyses of placebo-controlled trials, which have shown that biomarkers of iron homeostasis represent the most consistent effect of SGLT2 inhibitors; and (2) statistical mediation analyses, which have reported striking parallelism of the effect of SGLT2 inhibitors to promote erythrocytosis and reduce heart failure events. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ejhf.2731
Cureus. 2022 Oct;14(10): e29974

Detection of Euglycemic Diabetic Ketoacidosis During Thoracic Surgery 75 Hours After Empagliflozin Discontinuation.

Ai Nishida, Osamu Ogawa, Hiroki Takizawa.

  Euglycemic diabetic ketoacidosis (eDKA) has been increasingly reported as an adverse event of sodium-glucose cotransporter 2 inhibitors (SGLT2i), and the accompanying information on the drug recommends discontinuation three days prior to scheduled surgery. We present a case of a 50-year-old woman who developed eDKA during surgery for a metastatic lung tumor 75 hours after discontinuing SGLT2i. In this case, the onset of eDKA was detected using intraoperative blood gas analysis and urinary ketone measurements. Hence, perioperative eDKA can occur even after three or more days of SGLT2i withdrawal.

Keywords:  blood gas analysis; blood ketone measurement; empagliflozin; euglycemic diabetic ketoacidosis; sglt2i

DOI:  https://doi.org/10.7759/cureus.29974
J Nutr Biochem. 2022 Nov 15. pii: S0955-2863(22)00272-8. [Epub ahead of print] 109204

Attenuation of hepatic fibrosis by p-Coumaric acid via modulation of NLRP3 inflammasome activation in C57BL/6 mice.

Thi My Tien Truong, Seok Hee Seo, Soonkyu Chung, Inhae Kang.

  A prolonged high-fat and high-sucrose (HFHS) diet induces hepatic inflammation and mediates hepatic stellate cell (HSC) activation, which result in hepatic fibrosis. Aberrant activation of the innate immune system components, such as the NOD-like receptor protein 3 (NLRP3) inflammasome, has been implicated in HSC activation and hepatic fibrosis. We have previously shown that p-coumaric acid (PCA)-enriched peanut sprout extracts exert anti-inflammatory effects. However, it is unknown whether PCA reduces hepatic fibrosis by modulating innate immunity and HSC activation. To test this hypothesis, C57BL/6 male mice were randomly assigned to three groups and fed low-fat (LF) diet (11% calories from fat), high-fat (HF) diet (60% calories from fat, 0.2% cholesterol) with sucrose drink (20% sucrose, HFHS), or HFHS diet with PCA treatment (HFHS+PCA, 50 mg/kg body weight, intraperitoneally) for 13 weeks. The results showed that PCA treatment 1) partly improved systemic insulin sensitivity without altering adiposity, 2) attenuated hepatic signaling pathways associated with NLRP3 inflammasome activation, including toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFκB), and endoplasmic reticulum/oxidative stress, and 3) reduced circulating interleukin (IL)-1β levels. More importantly, PCA ameliorated hepatic fibrosis compared to that in the HFHS group, and the anti-fibrogenic effects of PCA were confirmed in vitro in transforming growth factor β (TGFβ) treated-LX-2 HSCs. The role of PCA in decreased NLRP3 activation and caspase-1 cleavage was recapitulated in primary bone marrow‒derived macrophages. These findings indicate that PCA contributes to the prevention of HFHS diet‒mediated liver fibrosis, partly by attenuating the activation of the NLRP3 inflammasome.

Keywords:  HSC activation; NLRP3 inflammasome; hepatic fibrosis; p-coumaric acid

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109204
Front Nutr. 2022 ;9 979651

Effect of 30 days of ketogenic Mediterranean diet with phytoextracts on athletes' gut microbiome composition.

Laura Mancin, Stefano Amatori, Massimiliano Caprio, Eleonora Sattin, Loris Bertoldi, Lorenzo Cenci, Davide Sisti, Antonino Bianco, Antonio Paoli.

  Background: Recent research suggest that gut microbiome may play a fundamental role in athlete's health and performance. Interestingly, nutrition can affect athletic performance by influencing the gut microbiome composition. Among different dietary patterns, ketogenic diet represents an efficient nutritional approach to get adequate body composition in athletes, however, some concerns have been raised about its potential detrimental effect on gut microbiome. To the best of our knowledge, only one study investigated the effect of ketogenic diet on the gut microbiome in athletes (elite race walkers), whilst no studies are available in a model of mixed endurance/power sport such as soccer. This study aimed to investigate the influence of a ketogenic Mediterranean diet with phytoextracts (KEMEPHY) diet on gut microbiome composition in a cohort of semi-professional soccer players.Methods: 16 male soccer players were randomly assigned to KEMEPHY diet (KDP n = 8) or western diet (WD n = 8). Body composition, performance measurements and gut microbiome composition were measured before and after 30 days of intervention by 16S rRNA amplicon sequencing. Alpha-diversity measures and PERMANOVA was used to investigate pre-post differences in the relative abundance of all taxonomic levels (from phylum to genus) and Spearman's correlations was used to investigate associations between microbial composition and macronutrient intake. Linear discriminant analysis was also performed at the different taxonomic levels on the post-intervention data.
Results: No differences were found between pre and post- dietary intervention for microbial community diversity: no significant effects of time (p = 0.056, ES = 0.486 and p = 0.129, ES = 0.388, respectively for OTUs number and Shannon's ENS), group (p = 0.317, ES = 0.180 and p = 0.809, ES = 0.047) or time × group (p = 0.999, ES = 0.01 and p = 0.230, ES = 0.315). Post-hoc paired Wilcoxon test showed a significant time × group effect for Actinobacteriota (p = 0.021, ES = 0.578), which increased in the WD group (median pre: 1.7%; median post: 2.3%) and decreased in the KEMEPHY group (median pre: 4.3%; median post: 1.7%). At genus level, the linear discriminant analysis in the post intervention differentiated the two groups for Bifidobacterium genus (pertaining to the Actinobacteria phylum), Butyricicoccus and Acidaminococcus genera, all more abundant in the WD group, and for Clostridia UCG-014 (order, family, and genus), Butyricimonas, Odoribacterter genera (pertaining to the Marinifilaceae family), and Ruminococcus genus, all more abundant in the KEMEPHY group.
Conclusions: Our results demonstrate that 30 days of KEMEPHY intervention, in contrast with previous research on ketogenic diet and gut microbiome, do not modify the overall composition of gut microbiome in a cohort of athletes. KEMEPHY dietary pattern may represent an alternative and safety tool for maintaining and/or regulating the composition of gut microbiome in athletes practicing regular exercise. Due to the fact that not all ketogenic diets are equal, we hypothesized that each version of ketogenic diet, with different kind of nutrients or macronutrients partitioning, may differently affect the human gut microbiome.

Keywords:  athletes; exercise; gut microbiota; ketogenic diet; sport nutrition

DOI:  https://doi.org/10.3389/fnut.2022.979651
Cureus. 2022 Oct;14(10): e30106

A Case of SGLT2 Inhibitor-Induced Euglycemic Diabetic Ketoacidosis.

Shiavax J Rao, Kaushik Kumar, Nahar Saleh.

  While rare, serious adverse effects including euglycemic diabetic ketoacidosis (EDKA) have been associated with sodium-glucose cotransporter-2 inhibitor (SGLT2i) use. We present an interesting case of SGLT2i-induced EDKA occurring two years after initiation of therapy. Most patients with EDKA recover with prompt recognition and treatment. Patient education about identifying early signs remains a cornerstone of early identification and response to SGLT2i-induced EDKA.

Keywords:  diabetic keto acidosis; euglycemic dka; high anion gap metabolic acidosis; sglt-2 inhibitor; sodium-glucose cotransporter-2 inhibitors

DOI:  https://doi.org/10.7759/cureus.30106
J Endocrinol Invest. 2022 Nov 19.

Short-time effects of ketogenic diet or modestly hypocaloric Mediterranean diet on overweight and obese women with polycystic ovary syndrome.

I R Cincione, C Graziadio, F Marino, C Vetrani, F Losavio, S Savastano, A Colao, D Laudisio.

  INTRODUCTION: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during reproductive age. It is characterized clinically by oligo-ovulation or anovulation, hyper-androgenism, and the presence of polycystic ovaries. Often comorbid with insulin resistance, dyslipidemia, and obesity, it also carries significant risk for the development of cardio-vascular and metabolic sequelae, including diabetes and metabolic syndrome. In light of these evidences, the most therapeutic option prescribed to PCOS women with obesity, regardless of the phenotype from the severity of clinical expression, is lifestyle correction by diet and physical activity.PURPOSE: The aim of this study was to evaluate the association between PCOS with KD in overweight and/or obese women with PCOS, and evaluate the possible beneficial effects on metabolic and endocrine parameters, compared to a standard, balanced hypocaloric diet such as Mediterranean diet (MD).
METHODS: Participants were assigned to receive, in a 1:1 ratio, one of the two following dietary sequences: KD or MD. In all subjects anthropometric parameters, body composition and metabolic and endocrine parameters were obtained at baseline and after dietetic treatment.
RESULTS: Our results showed a significant change in the anthropometric and biochemical parameters in both groups after both diet therapies, with statistically significant differences (p < 0.001). Though, the reductions of all parameters were significantly greater in KD group than in MD group.
CONCLUSION: Our results suggest that a reduction of dietary intake of carbohydrates by KD may be considered as a valuable non-pharmacological treatment for PCOS.

Keywords:  Insulin resistance; Ketogenic diet; Nutrition; Obesity; PCOS

DOI:  https://doi.org/10.1007/s40618-022-01943-y
Front Immunol. 2022 ;13 978190

NLRP3 inflammasome in digestive diseases: From mechanism to therapy.

Rui Qiang, Yanbo Li, Xincan Dai, Wenliang Lv.

  Digestive system diseases remain a formidable challenge to human health. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most characteristic multimeric protein complex and is involved in a wide range of digestive diseases as intracellular innate immune sensors. It has emerged as a research hotspot in recent years. In this context, we provide a comprehensive review of NLRP3 inflammasome priming and activation in the pathogenesis of digestive diseases, including clinical and preclinical studies. Moreover, the scientific evidence of small-molecule chemical drugs, biologics, and phytochemicals, which acts on different steps of the NLRP3 inflammasome, is reviewed. Above all, deep interrogation of the NLRP3 inflammasome is a better insight of the pathomechanism of digestive diseases. We believe that the NLRP3 inflammasome will hold promise as a novel valuable target and research direction for treating digestive disorders.

Keywords:  NLRP3 inflammasome; biologics; digestive system diseases; phytochemicals; small-molecule chemical drugs

DOI:  https://doi.org/10.3389/fimmu.2022.978190
Pediatr Exerc Sci. 2022 Nov 11. 1-7

Metabolic Flexibility During Exercise in Children with Overweight/Obesity Versus Children who are Lean.

Brandon Dykstra, Dillon Kuszmaul, Anthony D Mahon.

  PURPOSE: This study examined metabolic flexibility with respect to fat metabolism during exercise in children who are lean (n=11; 10.9[0.9] y) and overweight/obese (OW/OB; n=9; 10.3[1.2] y).METHOD: Participants were grouped based on body mass index percentiles for age and sex. Groups were mixed in age and sex. Participants completed two 20-minute exercise bouts on a cycle ergometer, separated by a 10-minute rest. Bout 1 consisted of 10 minutes at 50% VO2peak and 10 minutes at 75% VO2peak. Bout 2 was 20 minutes at 50% VO2peak. Absolute fat oxidation rate (FOR), FOR relative to body mass, FOR relative to fat-free mass, and proportional fat use were measured at 10 minutes of bout 1 and 5, 10, 15, and 20 minutes of bout 2.
RESULTS: Absolute FOR was higher in the OW/OB group (range: 117.8 [55.1]-206.2 [48.3] mg·min-1) than in the lean group (81.1 [32.2]-152.2 [38.2] mg·min-1); however, there were no significant main effects for group or significant interactions for proportional fat use, FOR relative to body mass, or FOR relative to fat-free mass.
CONCLUSION: Children in this age range who are overweight/obese do not display impaired metabolic flexibility with respect to fat metabolism during exercise.

Keywords:  fat metabolism; metabolic flexibility; obesity

DOI:  https://doi.org/10.1123/pes.2021-0229
Front Public Health. 2022 ;10 1017254

Intermittent fasting and time-restricted eating role in dietary interventions and precision nutrition.

Ghada A Soliman.

  Intermittent fasting (IF), time-restricted eating (TRE) and fasting-mimicking diets (FMD) are gaining popularity as weight loss programs. As such, the timing and frequency of meals have been recognized as essential contributors to improving cardiometabolic health and a role as adjuvant therapy in cancer. Randomized controlled trials suggested that the weight loss associated with IF is due to a reduced energy intake due to time restriction. Although the supervised TRE clinical trials documented the dietary caloric intake, many free-living studies focused on the timing of meals without a complete characterization of the dietary intake, caloric density, or macronutrient composition. It is possible that both caloric-restriction diets and time-restriction protocols could work synergistically or additively to improve metabolic health outcomes. Like personalized medicine, achieving precision nutrition mandates the provision of the right nutrients to the right patient at the right time. To accomplish this goal, future studies need to evaluate the benefits of IF and TRE. Randomized controlled trials were conducted in different populations, ethnic groups, ages, geographic distribution, physical activity levels, body composition and in patients with obesity, diabetes, and cardiovascular diseases. Also, it is crucial to analyze the dietary composition and caloric density as related to circadian rhythm and timing of meals. It is conceivable that IF and TRE may contribute to precision nutrition strategies to achieve optimal health. However, more research is needed to evaluate IF and TRE effects on health outcomes and any side effects.

Keywords:  alternative day modified fasting (ADMF); fasting-mimicking diets (FMD); intermittent fasting (IF); precision nutrition; time-restricted eating (TRE)

DOI:  https://doi.org/10.3389/fpubh.2022.1017254
J Family Med Prim Care. 2022 Jul;11(7): 3905-3908

Incidence of diabetic ketoacidosis during Ramadan compared with non-fasting months in King Saud Medical City, Riyadh, Saudi Arabia.

Mohsin Alshahrani, Ahmad Alraddadi.

  Background: Ramadan in Islam is the ninth month of the Muslim calendar and the holy month of fasting. In the fasting state, there is the danger of the blood glucose levels becoming too high when normal levels of medication are not taken. This can lead to diabetic ketoacidosis (DKA). The risk of diabetic emergencies, including DKA, is thought to be higher during Ramadan fasting due to metabolic changes and alterations in food habits. We aim to assess the incidence of DKA during Ramadan and perform a comparison pre and post month of Ramadan.Methods: This is a retrospective study that involves all adults who were admitted with DKA to King Saud Medical City in Riyadh, Saudi Arabia. We explored the relationship of admissions to Ramadan and compared it to the month before (Sha'aban) and the month after (Shawwal).
Results: During the duration of the study, 51 patients with DKA were admitted to the hospital. Nineteen patients in Ramadan (37.3%), eight patients in Sha'aban (15.7%), and 24 patients in Shawwal (47%). This shows a significant increment in Ramadan compared to Sha'aban, and more increment in Shawwal (P = 0.019). The most common precipitating factor for diabetic ketoacidosis during Ramadan and Sha'aban is missing insulin dose, while infections are considered the main stimulating agent in Shawwal.
Conclusion: There was an increase in the incidence of DKA episodes in Ramadan compared with the preceding month, but fewer DKA events compared to Shawwal, which might indicate that Ramadan fasting is a potential risk factor for DKA.

Keywords:  Diabetic ketoacidosis; KSA; Ramadan; fasting; incidence

DOI:  https://doi.org/10.4103/jfmpc.jfmpc_2004_21
Front Endocrinol (Lausanne). 2022 ;13 986565

Potential therapeutic role of pyroptosis mediated by the NLRP3 inflammasome in type 2 diabetes and its complications.

Xiang Li, Gui-Ying Xiao, Tao Guo, Yu-Jie Song, Qiu-Mei Li.

  As a new way of programmed cell death, pyroptosis plays a vital role in many diseases. In recent years, the relationship between pyroptosis and type 2 diabetes (T2D) has received increasing attention. Although the current treatment options for T2D are abundant, the occurrence and development of T2D appear to continue, and the poor prognosis and high mortality of patients with T2D remain a considerable burden in the global health system. Numerous studies have shown that pyroptosis mediated by the NLRP3 inflammasome can affect the progression of T2D and its complications; targeting the NLRP3 inflammasome has potential therapeutic effects. In this review, we described the molecular mechanism of pyroptosis more comprehensively, discussed the most updated progress of pyroptosis mediated by NLRP3 inflammasome in T2D and its complications, and listed some drugs and agents with potential anti-pyroptosis effects. Based on the available evidence, exploring more mechanisms of the NLRP3 inflammasome pathway may bring more options and benefits for preventing and treating T2D and drug development.

Keywords:  NLRP3 inflammasome; complications; pyroptosis; therapy; type 2 diabetes

DOI:  https://doi.org/10.3389/fendo.2022.986565
J Clin Endocrinol Metab. 2022 Nov 17. pii: dgac662. [Epub ahead of print]

Low skeletal muscle mass Accompanied by Abdominal Obesity Additively Increases the Risk of Incident Type 2 Diabetes.

Ji Eun Jun, Seung-Eun Lee, You-Bin Lee, Gyuri Kim, Sang-Man Jin, Jae Hwan Jee, Jae Hyeon Kim.

  CONTEXT: Low skeletal muscle mass often accompanies abdominal obesity in the aging process.OBJECTIVE: We aimed to investigate the effect of reduced skeletal muscle mass and its interaction with abdominal obesity on incident type 2 diabetes.
METHODS: This retrospective longitudinal study included a total of 36,304 diabetes-free Koreans who underwent two or more health check-ups annually or biennially. Appendicular skeletal muscle mass was measured by bioelectrical impedance analysis and was presented as a skeletal muscle mass index (SMI) adjusted for body weight. Pre-sarcopenia was defined as an SMI <1 standard deviation of the sex-specific mean for a healthy young reference group. Abdominal obesity was defined using waist circumference ≥ 90 cm for men and ≥ 85 cm for women. Participants were classified into four groups of normal, pre-sarcopenia alone, abdominal obesity alone, and pre-sarcopenic obesity according to initial body composition.
RESULTS: The cumulative incidence of diabetes was 9.1% during the 7-year follow-up. Compared with the highest tertile, the lowest sex-specific SMI tertile was significantly associated with a greater risk of incident type 2 diabetes (adjusted hazard ratio [HR] = 1.31, 95% confidence interval [CI] 1.18-1.45) in a fully adjusted model. Pre-sarcopenic obesity significantly increased incident diabetes risk (adjusted HR = 1.57, 95% CI 1.42-1.73) compared with normal body composition, pre-sarcopenia alone, or abdominal obesity alone.
CONCLUSIONS: Low skeletal muscle mass and its coexistence with abdominal obesity additively increased the risk of incident type 2 diabetes independent of the glycometabolic parameters.

Keywords:  abdominal obesity; pre-sarcopenia; pre-sarcopenic obesity; skeletal muscle; type 2 diabetes

DOI:  https://doi.org/10.1210/clinem/dgac662
NPJ Parkinsons Dis. 2022 Nov 17. 8(1): 159

Parkin deficiency exacerbates fasting-induced skeletal muscle wasting in mice.

Nesibe Peker, Mridula Sharma, Ravi Kambadur.

Parkinson's Disease (PD) is a chronic and progressive neurodegenerative disease manifesting itself with tremors, muscle stiffness, bradykinesia, dementia, and depression. Mutations of mitochondrial E3 ligase, PARKIN, have been associated with juvenile PD. Previous studies have characterized muscle atrophy and motor deficits upon loss of functional Parkin in fly and rodent models. However, the mechanisms behind pathophysiology of Parkin deficient muscle remains to be elusive. Here, results suggested that knock down of Parkin significantly increases proteolytic activities in skeletal muscle cell line, the C2C12 myotubes. However, the atrogene levels increase moderately in Parkin deficient cell line. To further investigate the role of Parkin in skeletal muscle atrophy, Parkin knock out (KO) and wild type mice were subjected to 48 h starvation. After 48 h fasting, a greater reduction in skeletal muscle weights was observed in Parkin KO mice as compared to age matched wild type control, suggesting elevated proteolytic activity in the absence of Parkin. Subsequent microarray analyses revealed further enhanced expression of FOXO and ubiquitin pathway in fasted Parkin KO mice. Furthermore, a greater reduction in the expression of cytoskeleton genes was observed in Parkin KO mice following 48 h fasting. Collectively, these results suggest that Parkin deficiency exacerbates fasting-induced skeletal muscle wasting, through upregulating genes involved in catabolic activities in skeletal muscle.

DOI: https://doi.org/10.1038/s41531-022-00419-3
Trends Pharmacol Sci. 2022 Nov 14. pii: S0165-6147(22)00229-2. [Epub ahead of print]

Mitochondrial quality control mechanisms as therapeutic targets in doxorubicin-induced cardiotoxicity.

Lin Wu, Litao Wang, Yuxin Du, Yingmei Zhang, Jun Ren.

  Doxorubicin (DOX) is a chemotherapeutic drug that is utilized for solid tumors and hematologic malignancies, but its clinical application is hampered by life-threatening cardiotoxicity including cardiac dilation and heart failure. Mitochondrial quality control processes, including mitochondrial proteostasis, mitophagy, and mitochondrial dynamics and biogenesis, serve to maintain mitochondrial homeostasis in the cardiovascular system. Importantly, recent advances have unveiled a major role for defective mitochondrial quality control in the etiology of DOX cardiomyopathy. Moreover, specific interventions targeting these quality control mechanisms to preserve mitochondrial function have emerged as potential therapeutic strategies to attenuate DOX cardiotoxicity. However, clinical translation is challenging because of obscure mechanisms of action and potential adverse effects. The purpose of this review is to provide new insights regarding the role of mitochondrial quality control in the pathogenesis of DOX cardiotoxicity, and to explore promising therapeutic approaches targeting these mechanisms to aid clinical management.

Keywords:  doxorubicin-induced cardiotoxicity; mitochondria; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control

DOI:  https://doi.org/10.1016/j.tips.2022.10.003
Vopr Pitan. 2022 ;91(5): 105-115

[Low-fat cheese in the focus of dietary nutrition].

G M Sviridenko, D S Vakhrusheva, Yu Ya Sviridenko, V A Mordvinova, I N Delitskaya.

  Currently, products with a reduced content of saturated fatty acids and a high protein content occupy an important place in the structure of a balanced diet, which leads to an increasing demand for cheeses with a low content of milk fat and high organoleptic properties. As a result of the growing trend towards the consumption of products with a reduced calorie content, there is a scientific interest in the development of technologies for low-fat cheeses with high consumer characteristics that are not inferior to analogues with a fat content of 45-50%. However, low-fat cheeses produced using existing technologies, as a rule, are characterized by low organoleptic properties, including an unexpressed taste and aroma and a rough, rubbery texture. The purpose of the research was to develop a low-fat cheese with high organoleptic characteristics, produced using not only the main acid-forming microflora, but also adjunct bacterial cultures that enhance enzymatic processes during cheese ripening and have probiotic properties. Material and methods. The production of low-fat cheeses (options 2 and 3) with a fat mass fraction of 20% in terms of dry matter was carried out according to a single technological scheme, which ensures the manufacture of cheese after pressing with a mass fraction of moisture of 53-54%. As a control option (1), Dutch cheese was produced with a fat mass fraction of 45%. Bulk starter containing a mixture of lactococci of the Lactococcus lactis species was used as the main acid-forming starter microflora in all cheese options (1, 2, 3); in low-fat cheese option 3, adjunct cultures of Lactobacillus casei and Propionibacterium freudenreichii were added. During ripening, cheeses were subjected to microbiological (total quantity of viable cells of lactic acid microorganisms, Lactobacillus casei and Propionibacterium freudenreichii), physicochemical (mass fraction of lactose, fat, moisture, solids, protein) and organoleptic studies. The total quantity of viable cells of the mesophilic lactic acid microflora was determined by the quantity of mesophilic aerobic and facultative anaerobic microorganisms. In cheeses after the end of the ripening process, the molecular mass distribution of soluble nitrogenous compounds and the content of flavoring substances in the vapor phase were additionally evaluated. Results. It has been established that in low-fat cheeses, the mass fraction of protein increases by 5.9±0.1% with a decrease in the proportion of fat to 20.0%. In this regard, the calorie content of low-fat cheese reduced by a third. It has been demonstrated that differences in the composition of the starter microflora had a significant impact on the depth and direction of biochemical processes, the formation of flavoring substances, which lead to an improvement in the organoleptic characteristics of cheeses. Conclusion. The addition of adjunct cultures of Lactobacillus casei mesophilic rods and Propionibacterium freudenreichii propionic acid bacteria, together with technological methods, contributes to the formation of a pronounced cheese taste and aroma, improves the flavor profile and deepens the process of proteolysis in cheeses with a fat mass fraction of 20% and brings their consumer properties closer to those of cheese with a fat content of 45%.

Keywords:  adjunct cultures; dietary nutrition; low-fat cheese; main acid-forming microflora; organoleptic indicators; proteolysis

DOI:  https://doi.org/10.33029/0042-8833-2022-91-5-105-115
Adv Clin Exp Med. 2022 Nov 18.

Sulforaphane reduces lipopolysaccharide-induced inflammation and enhances myogenic differentiation of mouse embryonic myoblasts via the toll-like receptor 4 and NLRP3 pathways.

Manfeng Wang, Meiling Liu, Wanzhen Xu, Zongyan Teng, Xiaowei Wu, Lu Gan, Yina Zhang.

  BACKGROUND: Muscle loss and muscle weakness are manifestations of infection-induced sepsis, a condition that can lead to organ failure and death. Toll-like receptor 4 (TLR4) signaling and the NLRP3 inflammasome are involved in the inflammatory storm and the development of sarcopenia during sepsis. They are also potential targets for sepsis treatment.OBJECTIVES: To explore the effects and molecular mechanisms of sulforaphane (SFN) on sepsis-associated inflammation and sarcopenia.
MATERIAL AND METHODS: Mouse C2C12 embryonic myoblasts were treated with lipopolysaccharide (LPS) to simulate sepsis-induced sarcopenia. Molecular mechanisms were investigated using quantitative real-time polymerase chain reaction (qRT-PCR), western blot, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA).
RESULTS: Sulforaphane significantly reduced the secretion of the inflammatory cytokine interleukin-1β (IL-1β) by C2C12 cells after LPS treatment, and inhibited the production of intracellular reactive oxygen species (ROS). It also increased the expression of E-myosin heavy chain, myosin ID heavy chain, and myogenin, and induced myogenic differentiation of LPS-treated C2C12 cells. Mechanistically, SFN reduced messenger ribonucleic acid and protein levels of TLR4, NLRP3, apoptosis-associated speck-like protein, and Caspase-1 in C2C12 cells, thereby inhibiting the inflammatory response and promoting myogenic differentiation. In addition, the TLR4 inhibitor TAK-242 induced myogenic differentiation in LPS-pretreated C2C12 cells in a similar manner.
CONCLUSIONS: Sulforaphane can reduce sepsis-induced inflammatory responses and enhance myogenic differentiation by regulating the TLR4 and NLRP3 inflammasome pathways.

Keywords:  C2C12; LPS; TLR4-NLRP3 pathway; sepsis; sulforaphane

DOI:  https://doi.org/10.17219/acem/155342
Med Sci Sports Exerc. 2022 Dec 01. 54(12): 2227-2228

Medicine & Science in Sports & Exercise 2021 Paper of the Year: The Role of Steps per Day in Preventing "Exercise Resistance".

David R Bassett.

DOI: https://doi.org/10.1249/MSS.0000000000003036
Front Mol Biosci. 2022 ;9 1027917

Inflammasomes and their roles in arthritic disease pathogenesis.

Gabsik Yang, Han Chang Kang, Yong-Yeon Cho, Hye Suk Lee, Joo Young Lee.

  The inflammasome is a molecular platform that is created in the cytosolic compartment to mediate the host immunological response to cellular injury and infection. Caspase-1 may be activated by the inflammasome, which leads to the generation of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and the beginning of pyroptosis, which is a type of proinflammatory cell death. Scientists have identified a number of different inflammasomes in the last 2 decades. The NLRP3 inflammasome has been studied the most, and its activity may be triggered by a broad range of different inducers. However, activation of the NLRP3 inflammasome in a manner that is not properly controlled is also a factor in the etiology of many human illnesses. Accumulating evidence indicates that the NLRP3 inflammasome plays a significant role in the innate and adaptive immune systems and the development of various arthritic illnesses, such as rheumatoid arthritis, ankylosing spondylitis, and gout. The present review provides a concise summary of the biological properties of the NLRP3 inflammasome and presents the fundamental processes behind its activation and control. We discuss the role of the inflammasome in the pathogenesis of arthritic diseases, such as rheumatoid arthritis, ankylosing spondylitis, and gout, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases, with a particular emphasis on treatment and clinical application.

Keywords:  immunity; inflammation; pattern recognition receptors; pharmacological inhibitors; therapeutic targets

DOI:  https://doi.org/10.3389/fmolb.2022.1027917