bims-kimdis 2024-07-07 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–07–07
28 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Metagenomic and metabolomic analysis showing the adverse risk-benefit trade-off of the ketogenic diet.
Effects of ketogenic diet on cognitive function of patients with Alzheimer's disease: a systematic review and meta-analysis.
Long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin trafficking and secretion in mice.
Amino acids regulating skeletal muscle metabolism: mechanisms of action, physical training dosage recommendations and adverse effects.
Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
Low thiamine status in adults following low-carbohydrate / ketogenic diets: a cross-sectional comparative study of micronutrient intake and status.
Does BMI moderate the LDL cholesterol response to low-carbohydrate diets?
UK5099 Inhibits the NLRP3 Inflammasome Independently of its Long-Established Target Mitochondrial Pyruvate Carrier.
Proteins change when skeletal muscle regenerates.
Bioenergetic myths of energy transduction in eukaryotic cells.
NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis.
Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects.
Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence.
Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.
Intermittent fasting modulates human gut microbiota diversity in a phenotype-dependent manner: a systematic review.
Chronic Endurance Exercise Impairs Niacin Nutritional Status in Mice.
A mitochondrial checkpoint to NF-κB signaling.
Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure.
Measurement of energy availability in highly trained male endurance athletes and examination of its associations with bone health and endocrine function.
Ribosomal proteins: the missing piece in the inflammation puzzle?
Cannabis in Combat Sports: position statement of the association of ringside physicians.
Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.
MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.
Mitochondrial dysfunction and NLRP3 inflammasome: key players in kidney stone formation.
Why do some individuals with obesity remain metabolically healthy?
The effects of intermittent fasting on body composition and cardiometabolic health in adults with prediabetes or type 2 diabetes: A systematic review and meta-analysis.
Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism.
Production and Characterization of Melt-Spun Poly(3-hydroxybutyrate)/Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) Blend Monofilaments.

Lipids Health Dis. 2024 Jun 29. 23(1): 207

Metagenomic and metabolomic analysis showing the adverse risk-benefit trade-off of the ketogenic diet.

Hongyan Qiu, Chengxia Kan, Fang Han, Youhong Luo, Na Qu, Kexin Zhang, Yanhui Ma, Ningning Hou, Di Wu, Xiaodong Sun, Junfeng Shi.

   BACKGROUND: Ketogenic diets are increasingly popular for addressing obesity, but their impacts on the gut microbiota and metabolome remain unclear. This paper aimed to investigate how a ketogenic diet affects intestinal microorganisms and metabolites in obesity.
METHODS: Male mice were provided with one of the following dietary regimens: normal chow, high-fat diet, ketogenic diet, or high-fat diet converted to ketogenic diet. Body weight and fat mass were measured weekly using high-precision electronic balances and minispec body composition analyzers. Metagenomics and non-targeted metabolomics data were used to analyze differences in intestinal contents.
RESULTS: Obese mice on the ketogenic diet exhibited notable improvements in weight and body fat. However, these were accompanied by a significant decrease in intestinal microbial diversity, as well as an increase in Firmicutes abundance and a 247% increase in the Firmicutes/Bacteroidetes ratio. The ketogenic diet also altered multiple metabolic pathways in the gut, including glucose, lipid, energy, carbohydrate, amino acid, ketone body, butanoate, and methane pathways, as well as bacterial secretion and colonization pathways. These changes were associated with increased intestinal inflammation and dysbiosis in obese mice. Furthermore, the ketogenic diet enhanced the secretion of bile and the synthesis of aminoglycoside antibiotics in obese mice, which may impair the gut microbiota and be associated with intestinal inflammation and immunity.
CONCLUSIONS: The study suggest that the ketogenic diet had an unfavorable risk-benefit trade-off and may compromise metabolic homeostasis in obese mice.

Keywords:  Gut microbiota; High-fat diet; Ketogenic diet; Metabolome; Metagenome; Obesity

DOI:  https://doi.org/10.1186/s12944-024-02198-7
J Nutr Health Aging. 2024 Jun 28. pii: S1279-7707(24)00393-2. [Epub ahead of print]28(8): 100306

Effects of ketogenic diet on cognitive function of patients with Alzheimer's disease: a systematic review and meta-analysis.

Liyang Rong, Yating Peng, Qi Shen, Keying Chen, Bangjiang Fang, Weirong Li.

   BACKGROUND: Ketogenic diets (KD) have shown remarkable effects in many disease areas. It has been demonstrated in numerous animal experiments that KD is effective in the treatment of Alzheimer's disease (AD). But the clinical effect of treating AD is uncertain.
OBJECTIVE: To systematically review the impact of KD on cognitive function in AD.
METHODS: We conducted a search of three international databases-PubMed, Cochrane Library, and Embase-to retrieve RCTs on the KD intervention for AD from the inception of the databases through October 2023. Two reviewers searched and screened the literature, extracted and checked relevant data independently, and assessed the risk of bias of the included studies. The meta-analysis was carried out utilizing RevMan 5.3 software.
RESULTS: A total of 10 RCTS involving 691 patients with AD were included. There were 357 participants in the intervention group and 334 participants in the control group. The duration of the KD intervention ranged from a minimum of 3 months to a maximum of 15 months. Meta-analysis results showed that KD could effectively improve the mental state of the elderly (NM scale) [MD = 7.56, 95%CI (3.02, 12.10), P = 0.001], MMSE [MD = 1.25, 95%CI (0.46, 2.04), P = 0.002], and ADAS-Cog [MD = -3.43, 95%CI (-5.98, -0.88), P = 0.008]. The elevation of ketone body (β-hydroxybutyric) [MD = 118.84, 95%CI (15.20, 222.48), P = 0.02] may also lead to the elevation of triglyceride [MD = 0.19, 95%CI (0.03, 0.35), P = 0.02] and low density lipoprotein [MD = 0.31, 95%CI (0.04, 0.58), P = 0.02].
CONCLUSION: Research conducted has indicated that the KD can enhance the mental state and cognitive function of those with AD, albeit potentially leading to an elevation in blood lipid levels. In summary, the good intervention effect and safety of KD are worthy of promotion and application in clinical treatment of AD.

Keywords:  Alzheimer's disease; Ketogenic diet; Meta-analysis; Mild cognitive impairment; Systematic review

DOI:  https://doi.org/10.1016/j.jnha.2024.100306
bioRxiv. 2024 Jun 17. pii: 2024.06.14.599117. [Epub ahead of print]

Long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin trafficking and secretion in mice.

Molly R Gallop, Renan F L Vieira, Elijah T Matsuzaki, Peyton D Mower, Willisa Liou, Faith E Smart, Seth Roberts, Kimberley J Evason, William L Holland, Amandine Chaix.

A ketogenic diet (KD) is a very low-carbohydrate, very high-fat diet proposed to treat obesity and type 2 diabetes. While KD grows in popularity, its effects on metabolic health are understudied. Here we show that, in male and female mice, while KD protects against weight gain and induces weight loss, over long-term, mice develop hyperlipidemia, hepatic steatosis, and severe glucose intolerance. Unlike high fat diet-fed mice, KD mice are not insulin resistant and have low levels of insulin. Hyperglycemic clamp and ex vivo GSIS revealed cell-autonomous and whole-body impairments in insulin secretion. Major ER/Golgi stress and disrupted ER-Golgi protein trafficking was indicated by transcriptomic profiling of KD islets and confirmed by electron micrographs showing a dilated Golgi network likely responsible for impaired insulin granule trafficking and secretion. Overall, our results suggest long-term KD leads to multiple aberrations of metabolic parameters that caution its systematic use as a health promoting dietary intervention.

DOI: https://doi.org/10.1101/2024.06.14.599117
Nutr Metab (Lond). 2024 Jul 02. 21(1): 41

Amino acids regulating skeletal muscle metabolism: mechanisms of action, physical training dosage recommendations and adverse effects.

Guangqi Li, Zhaojun Li, Junyi Liu.

  Maintaining skeletal muscle mass is important for improving muscle strength and function. Hence, maximizing lean body mass (LBM) is the primary goal for both elite athletes and fitness enthusiasts. The use of amino acids as dietary supplements is widespread among athletes and physically active individuals. Extensive literature analysis reveals that branched-chain amino acids (BCAA), creatine, glutamine and β-alanine may be beneficial in regulating skeletal muscle metabolism, enhancing LBM and mitigating exercise-induced muscle damage. This review details the mechanisms of these amino acids, offering insights into their efficacy as supplements. Recommended dosage and potential side effects are then outlined to aid athletes in making informed choices and safeguard their health. Lastly, limitations within the current literature are addressed, highlighting opportunities for future research.

Keywords:  Amino acid supplementation; Branched-chain amino acids; Creatine; Glutamine; Muscle protein synthesis; β-alanine

DOI:  https://doi.org/10.1186/s12986-024-00820-0
Aging Cell. 2024 Jul 02. e14262

Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.

Annika Traa, Allison Keil, Abdelrahman AlOkda, Suleima Jacob-Tomas, Aura A Tamez González, Shusen Zhu, Zenith Rudich, Jeremy M Van Raamsdonk.

  The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.

Keywords:   C. elegans ; aging; biological resilience; genetics; lifespan; mitochondria; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.1111/acel.14262
Eur J Nutr. 2024 Jul 05.

Low thiamine status in adults following low-carbohydrate / ketogenic diets: a cross-sectional comparative study of micronutrient intake and status.

Chaitong Churuangsuk, Anthony Catchpole, Dinesh Talwar, Paul Welsh, Naveed Sattar, Michael E J Lean, Emilie Combet.

   BACKGROUND: Low-carbohydrate diets (LCD) are popular for weight loss but lack evidence about micronutrient sufficiency in real-life use. This study assessed the intake and biochemical status of selected micronutrients in people voluntarily following LCDs.
METHODS: A cross-sectional study was conducted (2018-20) among 98 adults recruited as self-reporting either LCD (n = 49) or diets not restricting carbohydrates (controls; n = 49). Diets were assessed using the 130-item EPIC-Norfolk food-frequency questionnaire. Red-blood-cell thiamine diphosphate (TDP) was measured for thiamine status using HPLC. Plasma magnesium, zinc, copper, and selenium were measured using inductively coupled plasma mass spectrometry. Between-group biomarker comparisons were conducted using ANCOVA and adjusted for age, sex, body mass index (BMI), and diabetes status.
RESULTS: LCD-followers (26% male, median age 36 years, median BMI 24.2 kg/m2) reported adhering to LCDs for a median duration of 9 months (IQR 4-36). The most followed LCD type was 'their own variations of LCD' (30%), followed by ketogenic (23%), 'palaeolithic' (15%), and Atkins diets (8%). Among controls, 41% were male (median age 27 years, median BMI 23 kg/m2). Median macronutrient intakes for LCD vs control groups were carbohydrate 16%Energy (E) vs. 50%E; protein 25%E vs. 19%E; and fat 55%E vs 34%E (saturated fat 18%E vs. 11%E). Two-thirds of LCD followers (32/49) and half of the controls (24/49) reported some use of dietary supplements (p = 0.19). Among LCD-followers, assessing from food data only, 21 (43%) failed to meet the reference nutrient intake (RNI) for thiamine (vs.14% controls, p = 0.002). When thiamine from supplementation (single- or multivitamin) was included, there appeared to be no difference in thiamine intake between groups. Still, red-blood-cell TDP was lower in LCD-followers than controls (407 ± 91 vs. 633 ± 234 ng/gHb, p < 0.001). Three LCD-followers were thiamine-deficient (RBC thiamine < 275 ng/gHb) vs. one control. There were no significant differences in dietary intakes or plasma concentrations of magnesium, zinc, copper, and selenium between groups.
CONCLUSIONS: Following LCDs is associated with lower thiamine intake and TDP status than diets without carbohydrate restriction, incompletely corrected by supplement use. These data, coupled with a lack of RCT evidence on body weight control, do not support recommending LCDs for weight management without appropriate guidance and diet supplementation.

Keywords:  Ketogenic diet; Low carbohydrate; Magnesium; Micronutrient; Obesity; Thiamine

DOI:  https://doi.org/10.1007/s00394-024-03459-y
Am J Clin Nutr. 2024 Jul;pii: S0002-9165(24)00478-7. [Epub ahead of print]120(1): 274-275

Does BMI moderate the LDL cholesterol response to low-carbohydrate diets?

Javier T Gonzalez, Lorenzo Lolli, Greg Atkinson.

DOI: https://doi.org/10.1016/j.ajcnut.2024.04.039
Adv Sci (Weinh). 2024 Jul 01. e2307224

UK5099 Inhibits the NLRP3 Inflammasome Independently of its Long-Established Target Mitochondrial Pyruvate Carrier.

Linyu Ran, Miao Chen, Jihui Ye, Song Zhang, Zhibing Luo, Tengfei Bai, Chenchen Qian, Quan Zhou, Mengtian Shan, Yong Chu, Joerg Herrmann, Qiang Li, Feilong Wang.

  Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long-established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC-independent. Mechanistically, UK5099 abrogates mitochondria-NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL-1β production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3-driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies.

Keywords:  NLRP3; UK5099; macrophage; metabolism; mitochondrial pyruvate carrier

DOI:  https://doi.org/10.1002/advs.202307224
Lab Anim (NY). 2024 Jul;53(7): 177

Proteins change when skeletal muscle regenerates.

Jorge Ferreira.

DOI: https://doi.org/10.1038/s41684-024-01407-1
Front Mol Biosci. 2024 ;11 1402910

Bioenergetic myths of energy transduction in eukaryotic cells.

Guy C Brown.

  The study of energy transduction in eukaryotic cells has been divided between Bioenergetics and Physiology, reflecting and contributing to a variety of Bioenergetic myths considered here: 1) ATP production = energy production, 2) energy transduction is confined to mitochondria (plus glycolysis and chloroplasts), 3) mitochondria only produce heat when required, 4) glycolysis is inefficient compared to mitochondria, and 5) mitochondria are the main source of reactive oxygen species (ROS) in cells. These myths constitute a 'mitocentric' view of the cell that is wrong or unbalanced. In reality, mitochondria are the main site of energy dissipation and heat production in cells, and this is an essential function of mitochondria in mammals. Energy transduction and ROS production occur throughout the cell, particularly the cytosol and plasma membrane, and all cell membranes act as two-dimensional energy conduits. Glycolysis is efficient, and produces less heat per ATP than mitochondria, which might explain its increased use in muscle and cancer cells.

Keywords:  Warburg effect; bioenergetics; cancer; cell metabolism; energetics; glycolysis; mitochondria; oxidative stress

DOI:  https://doi.org/10.3389/fmolb.2024.1402910
medRxiv. 2024 Jun 16. pii: 2024.06.15.24308845. [Epub ahead of print]

NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis.

Elie Naddaf, Thi Kim Oanh Nguyen, Jens O Watzlawik, Huanyao Gao, Xu Hou, Fabienne C Fiesel, Jay Mandrekar, Eileen Kokesh, William S Harmsen, Ian R Lanza, Wolfdieter Springer, Eugenia Trushina.

Background: Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients, highlighting sex differences.
Methods: We included 38 IBM patients and 22 age- and sex-matched controls without myopathy. Bulk RNA sequencing, Meso Scale Discovery ELISA, western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.
Results: We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated. On muscle histopathology, there is increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction-NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy, most significantly in males, with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction. NLRP3 RNA levels correlated with p-S65-Ubiquitin levels in both sexes but with loss of in muscle strength only in males. Finally, we identified sex-specific molecular pathways in IBM, with females having activation of pathways that could offset some of the pathomechanisms of IBM.
Conclusions: NLRP3 inflammasome is activated in IBM, along with altered mitophagy particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.

DOI: https://doi.org/10.1101/2024.06.15.24308845
Biomed Pharmacother. 2024 Jul 02. pii: S0753-3322(24)00873-4. [Epub ahead of print]177 116989

Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects.

Jinlan Deng, Danyang Wang, Yanmei Shi, Lin Lin, Weihan Gao, Yu Sun, Xiayinan Song, Yunlun Li, Jie Li.

  The mitochondrial unfolded protein response (UPRmt) is a cytoprotective response in response to cellular stress that is activated in response to mitochondrial stress to maintain intra-protein homeostasis, thereby protecting the cell from a variety of stimuli. The activation of this response has been linked to cardiovascular diseases. Here, we reviewed the current understanding of UPRmt and discussed its specific molecular mechanism, mainly in mammals, as well as addressing its protective role against cardiovascular diseases, so as to provide direction for further research on UPRmt and therapies targeting cardiovascular diseases in the future.

Keywords:  Cardiovascular diseases; Factors; Molecular mechanism; UPR(mt)

DOI:  https://doi.org/10.1016/j.biopha.2024.116989
World J Exp Med. 2024 Jun 20. 14(2): 91519

Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence.

Raúl Lelio Sanz, Sebastián García Menéndez, Felipe Inserra, Leon Ferder, Walter Manucha.

  Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II, the main mediator of the renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity of sirtuins (SIRTs), a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High SIRT levels and 5' adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increase mitochondrial efficiency, reduce oxidative stress and inflammation, and strengthen tissues. These findings suggest that SGLT2i hold great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research is needed to validate these preliminary findings.

Keywords:  Cardiovascular diseases; Inflammation; Mitochondrial dysfunction; Oxidative stress; Sirtuins; Sodium-glucose cotransporter-2 inhibitors

DOI:  https://doi.org/10.5493/wjem.v14.i2.91519
PLoS Biol. 2024 Jul;22(7): e3002671

Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.

Noga Preminger, Maya Schuldiner.

Mitochondrial shape and network formation have been primarily associated with the well-established processes of fission and fusion. However, recent research has unveiled an intricate and multifaceted landscape of mitochondrial morphology that extends far beyond the conventional fission-fusion paradigm. These less-explored dimensions harbor numerous unresolved mysteries. This review navigates through diverse processes influencing mitochondrial shape and network formation, highlighting the intriguing complexities and gaps in our understanding of mitochondrial architecture. The exploration encompasses various scales, from biophysical principles governing membrane dynamics to molecular machineries shaping mitochondria, presenting a roadmap for future research in this evolving field.

DOI: https://doi.org/10.1371/journal.pbio.3002671
Biosci Microbiota Food Health. 2024 ;43(3): 170-182

Intermittent fasting modulates human gut microbiota diversity in a phenotype-dependent manner: a systematic review.

Adriyan Pramono, Martha Ardiaria, Edward Kurnia Setiawan Limijadi, Etika Ratna Noer, Endang Sri Lestari, Ferbian Milas Siswanto.

  Cumulative evidence suggests that intermittent fasting (IF) has beneficial effects on human metabolic health. It has been indicated that its impact on the gut microbiota may mediate these beneficial effects. As a result, we hypothesized that IF may impact the human gut microbiota. A systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol using the PubMed, Scopus, and CINAHL databases. We registered our systematic review protocol in PROSPERO under registration number CRD42021270050. Human intervention studies published until April 30, 2023, were included. The quality of the included studies was assessed using National Institutes of Health (NIH) quality assessment study tools for intervention studies. The search in the database returned 166 studies, of which 13 matched all criteria for the final qualitative analysis. The body of evidence suggests that IF modulates human gut microbiota alpha and beta diversity in lean (relatively healthy) and relatively healthy overweight/obese individuals but not in individuals with metabolic syndrome. Furthermore, IF also alters human gut microbiota composition in all phenotypes. Of interest, the gut microbiota taxa or microbial metabolites after an IF intervention are associated with metabolic markers. According to this review, IF influences the diversity and taxonomic levels of the human gut microbiota. Individual metabolic phenotypes may alter the effect of IF on the diversity and taxonomic levels of the gut microbiota.

Keywords:  diversity; gut microbiota; human; intermittent fasting; systematic review

DOI:  https://doi.org/10.12938/bmfh.2023-111
J Nutr Sci Vitaminol (Tokyo). 2024 ;70(3): 185-192

Chronic Endurance Exercise Impairs Niacin Nutritional Status in Mice.

Amane Mizutani, Tatsumasa Nishikawa, Hidetsugu Fujigaki, Yasuko Yamamoto, Kuniaki Saito, Sho Hatayama, Tsutomu Fukuwatari.

  Niacin is a cofactor in many biological reactions related to energy metabolism, redox reactions, DNA repair and longevity. Although it has been considered that increasing energy expenditure increases NAD consumption, little study has directly demonstrated the effect of exercise on niacin nutritional status. We have recently established the niacin insufficient model mice using kynurenine 3-monooxygenase knock out (KMO-/-) mice with niacin-limited diet, which lack the de novo NAD synthesis pathway from tryptophan. To evaluate the effects of chronic endurance exercise on niacin nutritional status, 4 wk old KMO-/- mice were fed 4 or 30 mg/kg nicotinic acid containing diets, and forced to swim in a running water pool every other day for 35 d. The swim-exercised mice fed 4 mg/kg nicotinic acid diet showed lower body weight gain and niacin nutritional markers such as liver and blood NAD, and urine nicotinamide metabolites than the sedentary mice. These animals did not show any difference in the NAD synthesis, NAD salvage and nicotinamide catabolic pathways. Chronic endurance exercise failed to affect any indices in the mice fed the 30 mg/kg nicotinic acid diet. When the diet was exchanged the 4 mg/kg for 30 mg/kg nicotinic acid diet to the mice showed chronic endurance exercise-induced growth retardation, their body weight rapidly increased. These results show that chronic endurance exercise impairs niacin nutritional status in the niacin insufficient mice, and enough niacin intake can prevent this impairment. Our findings also suggest that chronic endurance exercise increases niacin requirement by increase of NAD consumption.

Keywords:  NAD; deficiency; exercise; insufficiency; niacin; tryptophan

DOI:  https://doi.org/10.3177/jnsv.70.185
Cell Death Dis. 2024 Jul 03. 15(7): 477

A mitochondrial checkpoint to NF-κB signaling.

Emma Guilbaud, Lorenzo Galluzzi.

Mitochondrial dysfunction can elicit multiple inflammatory pathways, especially when apoptotic caspases are inhibited. Such an inflammatory program is negatively regulated by the autophagic disposal of permeabilized mitochondria. Recent data demonstrate that the ubiquitination of mitochondrial proteins is essential for NEMO-driven NF-kB activation downstream of mitochondrial permeabilization.

DOI: https://doi.org/10.1038/s41419-024-06868-3
Cardiovasc Diabetol. 2024 Jun 28. 23(1): 223

Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure.

Barbora Judita Kasperova, Milos Mraz, Petr Svoboda, Daniel Hlavacek, Helena Kratochvilova, Istvan Modos, Nikola Vrzackova, Peter Ivak, Petra Janovska, Tatyana Kobets, Jakub Mahrik, Martin Riecan, Lenka Steiner Mrazova, Viktor Stranecky, Ivan Netuka, Tomas Cajka, Ondrej Kuda, Vojtech Melenovsky, Sona Stemberkova Hubackova, Martin Haluzik.

   BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure.
METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed.
RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects.
CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

Keywords:  Adipose tissue; Ether lipids; Heart failure; Inflammation; Sodium-glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1186/s12933-024-02298-9
Eur J Nutr. 2024 Jul 02.

Measurement of energy availability in highly trained male endurance athletes and examination of its associations with bone health and endocrine function.

Amy McGuire, Giles Warrington, Adam Walsh, Thomas Byrne, Lorna Doyle.

   PURPOSE: Despite the introduction of Relative Energy Deficiency in Sport (RED-s) in 2014, there is evidence to suggest that male endurance athletes still present with a high prevalence of low energy availability (LEA). Previous findings suggest that energy availability (EA) status is strongly correlated with impairments in endocrine function such as reduced leptin, triiodothyronine (T3), and insulin, and elevated bone loss. This study aimed to report the current EA status, endocrine function and bone health of highly trained Irish male endurance athletes.
METHODS: In this cross-sectional study, participants (n = 3 triathletes; n = 10 runners) completed a 7-day testing period during the competition season using lab-based measures, to ascertain EA status, hormone level and rates of bone metabolism. Serum blood samples were obtained to assess hormone levels and markers of bone metabolism.
RESULTS: Mean EA was < 30 kcal/kg lean body mass (LBM)/day in 76.9% of athletes. There was a strong association between LEA and low carbohydrate intake, and lower LBM. Mean levels of insulin, IGF-1 and leptin were significantly lower than their reference ranges. Elevated mean concentrations of β-CTX and a mean P1NP: β-CTX ratio < 100, indicated a state of bone resorption.
CONCLUSION: The EA level, carbohydrate intake, hormone status and bone metabolism status of highly trained male endurance athletes are a concern. Based on the findings of this study, more frequent assessment of EA across a season is recommended to monitor the status of male endurance athletes, in conjunction with nutritional education specific to EA and the associated risks.

Keywords:  Bone metabolism; Endocrine function; Energy availability

DOI:  https://doi.org/10.1007/s00394-024-03433-8
Mol Cell Biochem. 2024 Jul 01.

Ribosomal proteins: the missing piece in the inflammation puzzle?

Anindhya Sundar Das, Anandita Basu, Rupak Mukhopadhyay.

  Ribosomal proteins (RPs) are constituents of macromolecular machinery, ribosome that translates genetic information into proteins. Besides ribosomal functions, RPs are now getting appreciated for their 'moonlighting'/extra-ribosomal functions modulating many cellular processes. Accumulating evidence suggests that a number of RPs are involved in inflammation. Though acute inflammation is a part of the innate immune response, uncontrolled inflammation is a driving factor for several chronic inflammatory diseases. An in-depth understanding of inflammation regulation has always been valued for the better management of associated diseases. Hence, this review first outlines the common livelihood of RPs and then provides a comprehensive account of five RPs that significantly contribute to the inflammation process. Finally, we discuss the possible therapeutic uses of RPs against chronic inflammatory diseases.

Keywords:  Extra-ribosomal function; Immunity; Inflammation; Inflammatory diseases; Ribosomal proteins

DOI:  https://doi.org/10.1007/s11010-024-05050-9
Phys Sportsmed. 2024 Jul 01.

Cannabis in Combat Sports: position statement of the association of ringside physicians.

Samuel J Stellpflug, Andrew Stolbach, Joe Ghorayeb, Erik Magraken, Eric Twohey, Jeff Lapoint, Kevin deWeber.

  and ARP Position StatementBased on the available body of scientific evidence and with the goals of promoting safety of combat sports athletes and striving for the advancement of clean sport, the Association of Ringside Physicians recommends the following regarding cannabis:●Use of marijuana or synthetic cannabinoids by combat sports athletes is discouraged due to unproven benefits and many known adverse effects. Acute use can impair cognition and complex motor function, which likely leads to reduced performance in combat sports. Chronic use can increase risk for heart and lung disease, several cancers, schizophrenia, and can reduce testosterone in men and impair fertility. Benefits from cannabis in most contexts, including athletic performance, have not been proven.●Use of topical purified CBD is neither encouraged nor discouraged.●Since acute cannabis intoxication can impair complex cognitive and motor function, any athlete suspected of acute intoxication at the time of competition - based on clinical judgment - should be banned from that competition.●Wide-scale regulation of cannabis based on quantitative testing has limited usefulness in combat sports, for the following reasons:○Cannabis is not ergogenic and is likely ergolytic.○Concentrations in body fluids correlate poorly with clinical effects and timing of use.○Access to testing resources varies widely across sporting organizations.

Keywords:  Cannabinoid; THC; drug testing; marijuana; regulations; toxicology

DOI:  https://doi.org/10.1080/00913847.2024.2375788
Physiol Rep. 2024 Jul;12(13): e16103

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.

Brian A Hain, Scot R Kimball, David L Waning.

  Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.

Keywords:  cancer cachexia; mitochondria; nicotinic acid; oxidative stress; sirtuin‐1

DOI:  https://doi.org/10.14814/phy2.16103
FEBS J. 2024 Jun 30.

MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.

Eddie Tam, Khang Nguyen, Hye Kyoung Sung, Gary Sweeney.

  Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the CDGSH iron-sulfur domain-containing protein 1 (CISD1, also known as mitoNEET) (mitoN) protein, we examined the potential role of MitoN in preventing IO-induced insulin resistance. In L6 control cells, IO resulted in insulin resistance which could be prevented by MitoN as demonstrated by western blot of p-Akt and Akt biosensor cells. Mechanistically, IO increased; mitochondrial iron accumulation, mitochondrial reactive oxygen species (ROS), Fis1-dependent mitochondrial fission, mitophagy, FUN14 domain-containing protein 1 (FUNDC1) expression, and decreased Parkin. MitoN overexpression was able to reduce increases in mitochondrial iron accumulation, mitochondrial ROS, mitochondrial fission, mitophagy and FUNDC1 upregulation due to IO. MitoN did not have any effect on the IO-induced downregulation of Parkin. MitoN alone also upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) protein levels, a master regulator of mitochondrial biogenesis. The use of mitochondrial antioxidant, Skq1, or fission inhibitor, Mdivi-1, prevented IO-induced insulin resistance implying both mitochondrial ROS and fission play a causal role in the development of insulin resistance. Taken together, MitoN is able to confer protection against IO-induced insulin resistance in L6 skeletal muscle cells through regulation of mitochondrial iron content, mitochondrial ROS, and mitochondrial fission.

Keywords:  insulin resistance; iron overload; mitoNEET; mitochondria; mitochondrial dynamics; reactive oxygen species

DOI:  https://doi.org/10.1111/febs.17214
BJU Int. 2024 Jul 05.

Mitochondrial dysfunction and NLRP3 inflammasome: key players in kidney stone formation.

Boyan Su, YaLin Ren, Weimin Yao, Yue Su, Qiqi He.

  The mitochondrion serves as a critical intracellular organelle, engaging in essential roles in the regulation of energy production, oxidative stress management, calcium homeostasis, and apoptosis. One such disease that has been particularly associated with these functions is kidney stone disease (KSD), specifically calcium oxalate (CaOx). It is underpinned by oxidative stress and tissue inflammation. Recent studies have shed light on the vital involvement of mitochondrial dysfunction, the nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) inflammasome, endoplasmic reticulum stress and subsequent cell death in CaOx crystal retention and aggregation. These processes are pivotal in the pathogenesis of kidney stone formation. This review focuses on the pivotal roles of mitochondria in renal cell functions and provides an overview of the intricate interconnectedness between mitochondrial dysfunction and NLRP3 inflammasome activation in the context of KSD. It is essential to recognise the utmost significance of gaining a comprehensive understanding of the mechanisms that safeguard mitochondrial function and regulate the NLRP3 inflammasome. Such knowledge carries significant scientific implications and opens up promising avenues for the development of innovative strategies to prevent the formation of kidney stones.

Keywords:  NLRP3; calcium oxalate; mitochondria; nephrolithiasis; oxidative stress

DOI:  https://doi.org/10.1111/bju.16454
Trends Endocrinol Metab. 2024 Jul 02. pii: S1043-2760(24)00176-0. [Epub ahead of print]

Why do some individuals with obesity remain metabolically healthy?

Christoph Buettner, Kenichi Sakamoto, Mary A Butera.

  A recent study by Peterson et al. that characterized individuals with metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO) in depth provides insights into the potential pathogenesis of MUO that accounts for much of the cardiometabolic disease and excess mortality caused by the obesity epidemic.

Keywords:  cardiometabolic health; insulin resistance; metabolically healthy obesity (MHO); metabolically unhealthy obesity (MUO)

DOI:  https://doi.org/10.1016/j.tem.2024.06.015
Diabetes Obes Metab. 2024 Jul 02.

The effects of intermittent fasting on body composition and cardiometabolic health in adults with prediabetes or type 2 diabetes: A systematic review and meta-analysis.

Mousa Khalafi, Aref Habibi Maleki, Michael E Symonds, Sara K Rosenkranz, Hadi Rohani, Mahsa Ehsanifar.

   AIM: To perform a meta-analysis to investigate the effects of intermittent fasting (IF), as compared with either a control diet (CON) and/or calorie restriction (CR), on body composition and cardiometabolic health in individuals with prediabetes and type 2 diabetes (T2D).
METHODS: PubMed, Web of Science, and Scopus were searched from their inception to March 2024 to identify original randomized trials with parallel or crossover designs that studied the effects of IF on body composition and cardiometabolic health. Weighted mean differences (WMDs) or standardized mean differences with 95% confidence intervals (CIs) were calculated using random-effects models.
RESULTS: Overall, 14 studies involving 1101 adults with prediabetes or T2D were included in the meta-analysis. IF decreased body weight (WMD -4.56 kg [95% CI -6.23 to -2.83]; p = 0.001), body mass index (BMI; WMD -1.99 kg.m2 [95% CI -2.74 to -1.23]; p = 0.001), glycated haemoglobin (HbA1c; WMD -0.81% [95% CI -1.24 to -0.38]; p = 0.001), fasting glucose (WMD -0.36 mmol/L [95% CI -0.63 to -0.09]; p = 0.008), total cholesterol (WMD -0.31 mmol/L [95% CI -0.60 to -0.02]; p = 0.03) and triglycerides (WMD -0.14 mmol/L [95% CI -0.27 to -0.01]; p = 0.02), but did not significantly decrease fat mass, insulin, low-densitiy lipoprotein, high-density lipoprotein, or blood pressure as compared with CON. Furthermore, IF decreased body weight (WMD -1.14 kg [95% CI -1.69 to -0.60]; p = 0.001) and BMI (WMD -0.43 kg.m2 [95% CI -0.58 to -0.27]; p = 0.001), but did not significantly affect fat mass, lean body mass, visceral fat, insulin, HbA1c, lipid profiles or blood pressure.
CONCLUSION: Intermittent fasting is effective for weight loss and specific cardiometabolic health markers in individuals with prediabetes or T2D. Additionally, IF is associated with a reduction in body weight and BMI compared to CR, without effects on glycaemic markers, lipid profiles or blood pressure.

Keywords:  body composition; cardiovascular disease; dietary intervention; dyslipidaemia; insulin resistance; type 2 diabetes

DOI:  https://doi.org/10.1111/dom.15730
Mol Metab. 2024 Jul 01. pii: S2212-8778(24)00114-5. [Epub ahead of print] 101983

Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism.

Alexis Diaz-Vegas, Kristen C Cooke, Harry B Cutler, Belinda Yau, Stewart W C Masson, Dylan Harney, Oliver K Fuller, Meg Potter, Søren Madsen, Niamh R Craw, Yiju Zhang, Cesar L Moreno, Melkam Kebede, G Gregory Neely, Jacqueline Stöckli, James G Burchfield, David E James.

  Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP. To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance. We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, these phenotypes vanished when mice were housed at thermoneutrality, suggesting that metabolic protection conferred by miPEP deletion hinges upon a thermoregulatory process. Tissue specific analysis of miPEP deficient mice revealed an increment in muscle metabolism, and upregulation of the protein FBP2 that is involved in ATP hydrolysis in the gluconeogenic pathway. These findings suggest that miPEP deletion initiates a compensatory increase in skeletal muscle metabolism acting as a protective mechanism against diet-induced obesity and insulin resistance.

Keywords:  Adipose Tissue; Insulin Resistance; Metabolism; Mitochondria; Peptidases; Skeletal Muscle

DOI:  https://doi.org/10.1016/j.molmet.2024.101983
ACS Omega. 2024 Jun 25. 9(25): 27415-27427

Production and Characterization of Melt-Spun Poly(3-hydroxybutyrate)/Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) Blend Monofilaments.

Sabrina Kopf, Andrew Root, Ivo Heinmaa, Juliana Aristéia de Lima, Dan Åkesson, Mikael Skrifvars.

We investigated the melt-spinning potential of a poly(3-hydroxybutyrate)/poly(3-hydroxybutyrate-co-4-hydroxybutyrate) blend using a piston spinning machine with two different spinneret diameters (0.2 and 0.5 mm). Results from the differential scanning calorimetry, dynamic mechanical thermal analysis, and tensile testing showed distinct filament properties depending on the monofilaments' cross-sectional area. Finer filaments possessed different melting behaviors compared to the coarser filaments and the neat polymer, indicating the formation of a different type of polymer crystal. Additionally, the mechanical properties of the finer filament (tensile strength: 21.5 MPa and elongation at break: 341%) differed markedly from the coarser filament (tensile strength: 11.7 MPa, elongation at break: 12.3%). The hydrolytic stability of the filaments was evaluated for 7 weeks in a phosphate-buffered saline solution and showed a considerably reduced elongation at break of the thinner filaments. Overall, the results indicate considerable potential for further filament improvements to facilitate textile processing.

DOI: https://doi.org/10.1021/acsomega.4c02241