bims-kimdis 2024-09-29 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–09–29
nineteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.
The potential protective effect of 3-Hydroxybutyrate against aortic dissection: a mendelian randomization analysis.
β-hydroxybutyrate recapitulates the beneficial effects of ketogenic metabolic therapy in polycystic kidney disease.
Exogenous ketosis attenuates acute mountain sickness and mitigates normobaric high-altitude hypoxemia.
Ketogenic diet improves fertility in patients with polycystic ovary syndrome: a brief report.
From fat to fire: The lipid-inflammasome connection.
No Effects of Carbohydrate Ingestion on Muscle Metabolism or Performance During Short-Duration High-Intensity Intermittent Exercise.
Continuous ketone monitoring: Exciting implications for clinical practice.
Comparing caloric restriction regimens for effective weight management in adults: a systematic review and network meta-analysis.
Infusion of sodium DL-3-ß-hydroxybutyrate decreases cerebral injury biomarkers after resuscitation in experimental cardiac arrest.
Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center.
From tradition to science: Possible mechanisms of ghee in supporting bone and joint health.
Effect of different forms of high-intensity interval training on V̇O2max, strength, flexibility, and body fat percentage among middle-aged males.
The NLRP3 inflammasome in allergic diseases: mechanisms and therapeutic implications.
Exercise and nutrition benefit skeletal muscle: From influence factor and intervention strategy to molecular mechanism.
The role of mitochondria in cytokine and chemokine signalling during ageing.
Every-other-day fasting inhibits pyroptosis while regulating bile acid metabolism and activating TGR5 signaling in spinal cord injury.
Interleukin-15 and high-intensity exercise: relationship with inflammation, body composition and fitness in cancer survivors.
Exercise training alleviates cholesterol and lipid accumulation in mice with non-alcoholic steatohepatitis: reduction of KMT2D-mediated histone methylation of IDI1.

bioRxiv. 2024 Sep 09. pii: 2024.09.09.612087. [Epub ahead of print]

A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.

Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.

β-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.

DOI: https://doi.org/10.1101/2024.09.09.612087
Nutr Metab (Lond). 2024 Sep 20. 21(1): 75

The potential protective effect of 3-Hydroxybutyrate against aortic dissection: a mendelian randomization analysis.

Shi Qiu, Zhen Liu, Chun-Ting Wang, Xiao-di Sun, Zeng-Qiang Liu, Wen Liu.

   BACKGROUND: 3-Hydroxybutyrate, also called β-hydroxybutyrate, is a significant constituent of ketone bodies. Previous observational and experimental studies have suggested that ketogenic diet, especially 3-hydroxybutyrate, may have a protective effect against cardiovascular disease. However, the relationship between ketone bodies, especially 3-hydroxybutyrate, and aortic dissection remains uncertain.
MATERIALS AND METHODS: Publicly accessible data from genome-wide association study (GWAS) was utilized to obtain information on ketone bodies, including 3-hydroxybutyrate, acetoacetate and acetone as exposure respectively, while GWAS data on aortic dissection was used as outcome. Subsequently, two-sample Mendelian randomization (MR) analysis was conducted to examine the potential relationship between ketone bodies and aortic dissection. Then, reverse and multivariate Mendelian randomization analyses were performed. Additionally, sensitivity tests were conducted to assess the robustness of MR study.
RESULTS: The inverse-variance weighted (IVW) method of Mendelian randomization analysis of gene prediction observed a negative correlation between 3-hydroxybutyrate and risk of aortic dissection (OR 0.147, 95% CI 0.053-0.410). Furthermore, consistent findings were obtained through the implementation of the weighted median, simple mode, Mendelian randomization-Egger (MR-Egger), and weighted mode methods. After adjusting acetoacetate (OR 0.143, 95% CI 0.023-0.900) or acetone (OR 0.100, 95% CI 0.025-0.398), MR analysis of gene prediction still observed a negative correlation between 3-hydroxybutyrate and risk of aortic dissection. No indications of heterogeneity or pleiotropy among the SNPs were detected.
CONCLUSION: The findings from the MR analysis demonstrated that genetically predicted 3-hydroxybutyrate exhibits a protective effect against aortic dissection.

Keywords:  3-hydroxybutyrate; Aortic dissection; Genome-wide association study (GWAS); Ketone bodies; Mendelian randomization (MR)

DOI:  https://doi.org/10.1186/s12986-024-00853-5
iScience. 2024 Sep 20. 27(9): 110773

β-hydroxybutyrate recapitulates the beneficial effects of ketogenic metabolic therapy in polycystic kidney disease.

Jacob A Torres, Nickolas Holznecht, David A Asplund, Bradley C Kroes, Tselmeg Amarlkhagva, Matthias M Haeffner, Elizabeth H Sharpe, Stella Koestner, Sebastian Strubl, Margaret F Schimmel, Samantha Kruger, Shagun Agrawal, Brina A Aceves, Muthusamy Thangaraju, Thomas Weimbs.

  Autosomal-dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by the formation of fluid-filled renal cysts, loss of mitochondrial function, decreased fatty acid oxidation, increased glycolysis, and likely renal failure. We previously demonstrated that inducing a state of ketosis ameliorates or reverses PKD progression in multiple animal models. In this study, we compare time-restricted feeding and 48-h periodic fasting regimens in both juvenile and adult Cy/+ rats. Both fasting regimens potently prevent juvenile disease progression and partially reverse PKD in adults. To explore the mechanism of fasting, we administered β-hydroxybutyrate (BHB) to Cy/+ rats and orthologous mouse models of PKD (Pkd1 RC/RC , Pkd1-Ksp:Cre). BHB recapitulated the effects of fasting in these models independent of stereoisomer, suggesting the effects of BHB are largely due to its signaling functions. These findings implicate the use of ketogenic metabolic therapy and BHB supplementation as potential disease modifiers of PKD and point toward underlying mechanisms.

Keywords:  Diet; Pathophysiology; Therapy

DOI:  https://doi.org/10.1016/j.isci.2024.110773
J Appl Physiol (1985). 2024 Sep 26.

Exogenous ketosis attenuates acute mountain sickness and mitigates normobaric high-altitude hypoxemia.

Myrthe Stalmans, Domen Tominec, Wout Lauriks, Ruben Robberechts, Tadej Debevec, Chiel Poffé.

   BACKGROUND: Acute mountain sickness (AMS) represents a considerable issue for individuals sojourning to high altitudes with systemic hypoxemia known to be intimately involved in its development. Based on recent evidence that ketone ester (KE) intake attenuates hypoxemia, we investigated whether exogenous ketosis might mitigate AMS development and to identify underlying physiological mechanisms.
METHODS: Fourteen healthy, male participants were enrolled in two 29h protocols (simulated altitude of 4,000-4,500m) receiving either KE or a placebo (CON) at regular timepoints throughout the protocol in a randomized, crossover manner. Physiological responses were characterized after 15min and 4h in hypoxia, and the protocol was terminated prematurely upon development of severe AMS (Lake Louise Score ≥ 10).
RESULTS: KE ingestion induced a consistent diurnal ketosis ([ßHB] of ~3 mM), whereas blood [ßHB] remained low (<0.6 mM) in CON. Each participant tolerated the protocol equally long or longer (n=6 or n=8, resp.) in KE. Protocol duration increased by 32% on average with KE, and doubled upon KE for severe AMS-developing participants (n=9). Relative to CON, KE induced a mild metabolic acidosis, hyperventilation, and relative sympathetic dominance. KE also inhibited the progressive hypoxemia that was observed between 15min and 4h in hypoxia in CON, while concomitantly increasing cerebral oxygenation and capillary pO2 within this timeframe despite a KE-induced reduction in cerebral oxygen supply.
CONCLUSIONS: These data indicate that exogenous ketosis attenuates AMS development. The key underlying mechanisms include improved arterial and cerebral oxygenation, in combination with lowered cerebral blood flow and oxygen delivery, and increased sympathetic dominance.

Keywords:  acute mountain sickness (AMS); cerebral oxygenation; hypoxia; ketones; oxygen saturation

DOI:  https://doi.org/10.1152/japplphysiol.00190.2024
Front Nutr. 2024 ;11 1395977

Ketogenic diet improves fertility in patients with polycystic ovary syndrome: a brief report.

Yumiko Tsushima, Noura Nachawi, Kevin M Pantalone, Marcio L Griebeler, Ula Abed Alwahab.

   Introduction: Polycystic ovary syndrome (PCOS) affects up to 20 % of reproductive-age individuals and is strongly linked to obesity. The impacts of ketogenic diet on fertility in people with PCOS are unknown. This study aims to determine the effect of a ketogenic diet on restoration of regular menstrual cycles and fertility.
Methods: After approval from the Institutional Review Boards of Cleveland Clinic, a retrospective analysis was conducted using the electronic health record system. We analyzed data from thirty patients (n = 30) with polycystic ovary syndrome who followed a ketogenic diet for at least 3 months at the Cleveland Clinic, Cleveland, Ohio, USA. Main outcomes were percentage of women with restoration of regular menstrual cycles and pregnancy rate.
Results: All women (n = 30) had restoration of regular menstrual cycles. The overall pregnancy rate of women desiring pregnancy (n = 18) was 55.6% (n = 10). Pregnancy rate was 38.5% for women on metformin and 100% for those who were not (P = 0.036). Pregnancy rate was 62.5% for women using ovulation induction agents and 50.0% for those who did not (P = 0.66). Percent weight change between the pregnant and non-pregnant groups did not significantly differ [-8.1 ± 6.2, vs -6.4 ± 8.4, P = 0.64, respectively].
Conclusion: This study reports a higher rate of pregnancy with the ketogenic diet in women with PCOS compared to existing literature.

Keywords:  fertility; ketogenic diet; obesity; ovulation; polycystic ovary syndrome; pregnancy

DOI:  https://doi.org/10.3389/fnut.2024.1395977
Immunol Rev. 2024 Sep 27.

From fat to fire: The lipid-inflammasome connection.

Paras K Anand.

  Inflammasomes are multiprotein complexes that play a crucial role in regulating immune responses by governing the activation of Caspase-1, the secretion of pro-inflammatory cytokines, and the induction of inflammatory cell death, pyroptosis. The inflammasomes are pivotal in effective host defense against a range of pathogens. Yet, overt activation of inflammasome signaling can be detrimental. The most well-studied NLRP3 inflammasome has the ability to detect a variety of stimuli including pathogen-associated molecular patterns, environmental irritants, and endogenous stimuli released from dying cells. Additionally, NLRP3 acts as a key sensor of cellular homeostasis and can be activated by disturbances in diverse metabolic pathways. Consequently, NLRP3 is considered a key player linking metabolic dysregulation to numerous inflammatory disorders such as gout, diabetes, and atherosclerosis. Recently, compelling studies have highlighted a connection between lipids and the regulation of NLRP3 inflammasome. Lipids are integral to cellular processes that serve not only in maintaining the structural integrity and subcellular compartmentalization, but also in contributing to physiological equilibrium. Certain lipid species are known to define NLRP3 subcellular localization, therefore directly influencing the site of inflammasome assembly and activation. For instance, phosphatidylinositol 4-phosphate plays a crucial role in NLRP3 localization to the trans Golgi network. Moreover, new evidence has demonstrated the roles of lipid biosynthesis and trafficking in activation of the NLRP3 inflammasome. This review summarizes and discusses these emerging and varied roles of lipid metabolism in inflammasome activation. A deeper understanding of lipid-inflammasome interactions may open new avenues for therapeutic interventions to prevent or treat chronic inflammatory and autoimmune conditions.

Keywords:  FASN; NLRP3; cholesterol; cholesterol trafficking; fatty acid biosynthesis; inflammasomes; lipid metabolism; lipids; phosphatidylinositol

DOI:  https://doi.org/10.1111/imr.13403
Scand J Med Sci Sports. 2024 Sep;34(9): e14731

No Effects of Carbohydrate Ingestion on Muscle Metabolism or Performance During Short-Duration High-Intensity Intermittent Exercise.

Jeppe F Vigh-Larsen, Daniel Z Kruse, Maja B Moseholt, Laura G B Hansen, Ann-Louise L Christensen, Amanda Bæk, Ole E Andersen, Magni Mohr, Kristian Overgaard.

  Carbohydrates are critical for high-intensity exercise performance. However, the effects of carbohydrate supplementation on muscle metabolism and performance during short-duration high-intensity intermittent exercise remain inadequately explored. Our aim was to address this aspect in a randomized, counterbalanced, double-blinded crossover design. Eleven moderately-to-well-trained males performed high-intensity intermittent cycling receiving carbohydrate (CHO, ~55 g/h) or placebo (PLA) fluid supplementation. Three exercise periods (EX1-EX3) were completed comprising 10 × 45 s at ~105% Wmax interspersed with 135 s rest between bouts and ~20 min between periods. Repeated sprint ability (5 × 6 s sprints with 24 s recovery) was assessed at baseline and after each period. Thigh muscle biopsies were obtained at baseline and before and after EX3 to determine whole-muscle and fiber-type-specific glycogen depletion. No differences were found in muscle glycogen degradation at the whole-muscle (p = 0.683) or fiber-type-specific level (p = 0.763-0.854) with similar post-exercise whole-muscle glycogen concentrations (146 ± 20 and 122 ± 15 mmol·kg-1 dw in CHO and PLA, respectively). Repeated sprint ability declined by ~9% after EX3 with no between-condition differences (p = 0.971) and no overall differences in ratings of perceived exertion (p = 0.550). This was despite distinctions in blood glucose concentrations throughout exercise, reaching post-exercise levels of 5.3 ± 0.2 and 4.1 ± 0.2 mmol·L-1 (p < 0.001) in CHO and PLA, respectively, accompanied by fivefold higher plasma insulin levels in CHO (p < 0.001). In conclusion, we observed no effects of carbohydrate ingestion on net muscle glycogen breakdown or sprint performance during short-duration high-intensity intermittent exercise despite elevated blood glucose and insulin levels. These results therefore question the efficacy of carbohydrate supplementation strategies in high-intensity intermittent sports.

Keywords:  ergogenic aids; fiber type; glycogen; sprint ability; substrate

DOI:  https://doi.org/10.1111/sms.14731
Diabetes Obes Metab. 2024 Sep 24.

Continuous ketone monitoring: Exciting implications for clinical practice.

Yee Wen Kong, Dale Morrison, Jean C Lu, Melissa H Lee, Alicia J Jenkins, David N O'Neal.

  Diabetic ketoacidosis (DKA) is a life-threatening complication usually affecting people with type 1 diabetes (T1D) and, less commonly, people with type 2 diabetes. Early identification of ketosis is a cornerstone in DKA prevention and management. Current methods for ketone measurement by people with diabetes include capillary blood or urine testing. These approaches have limitations, including the need to carry testing strips that have a limited shelf life and a requirement for the user to initiate a test. Recent studies have shown the feasibility of continuous ketone monitoring (CKM) via interstitial fluid with a sensor inserted subcutaneously employing an enzymatic electrochemical reaction. Ketone readings can be updated every 5 minutes. In the future, one would expect that commercialized devices will incorporate alarms linked with standardized thresholds and trend arrows. Ideally, to minimize the burden on users, CKM functionality should be integrated with other devices used to implement glucose management, including continuous glucose monitors and insulin pumps. We suggest CKM provision to all at risk of DKA and recommend that the devices should be worn continuously. Those who may particularly benefit are individuals who have T1D, are pregnant, on medications such as sodium-glucose linked transporter (SGLT) inhibitors that increase DKA, people with recurrent DKA, those with T1D undertaking high intensity exercise, are socially or geographically isolated, or those on low carbohydrate diets. The provision of ketone profiles will provide important clinical insights that have previously been unavailable to people living with diabetes and their healthcare professionals.

Keywords:  clinical physiology; continuous glucose monitoring; glycaemic control; type 1 diabetes

DOI:  https://doi.org/10.1111/dom.15921
Int J Behav Nutr Phys Act. 2024 Sep 26. 21(1): 108

Comparing caloric restriction regimens for effective weight management in adults: a systematic review and network meta-analysis.

Jinming Huang, Yi Li, Maohua Chen, Zhaolun Cai, Zhen Cai, Zhiyuan Jiang.

   BACKGROUND: Randomized controlled trials have confirmed the effectiveness of four prevalent caloric restriction regimens in reducing obesity-related health risks. However, there is no consensus on the optimal regimen for weight management in adults.
METHODS: We systematically searched PubMed, Embase, Web of Science, and Cochrane CENTRAL up to January 15, 2024, for randomized controlled trials (RCT) involving adults, evaluating the weight-loss effects of alternate day fasting (ADF), short-term fasting (STF), time-restricted eating (TRE), and continuous energy restriction (CER). The primary outcome was body weight, with secondary outcomes including BMI, fat mass, lean mass, waist circumference, fasting glucose, HOMA-IR, and adverse events. Bayesian network meta-analysis was conducted, ranking regimens using the surface under the cumulative ranking curve and the probability of being the best. Study quality was assessed using the Confidence in Network Meta-Analysis tool.
RESULTS: Data from 47 RCTs (representing 3363 participants) were included. ADF showed the most significant body weight loss (Mean difference (MD): -3.42; 95% Confidence interval (CI): -4.28 to -2.55), followed by TRE (MD: -2.25; 95% CI: -2.92 to -1.59). STF (MD: -1.87; 95% CI: -3.32 to -0.56) and CER (MD: -1.59; 95% CI: -2.42 to -0.79) rank third and fourth, respectively. STF lead to decline in lean mass (MD: -1.26; 95% CI: -2.16, -0.47). TRE showed benefits on fasting glucose (MD: -2.98; 95% CI: -4.7, -1.26). Subgroup analysis revealed all four caloric restriction regimens likely lead to modest weight loss after 1-3 months, with ADF ranked highest, but by 4-6 months, varying degrees of weight regain occur, particularly with CER, while interventions lasting 7-12 months may result in effective weight loss, with TRE potentially ranking first during both the 4-6 months and 7-12 months periods. ADF showing fewer and shorter-lasting physical symptoms.
CONCLUSION: All four included regiments were effective in reducing body weight, with ADF likely having the most significant impact. Each regimen likely leads to modest weight loss after 1-3 months, followed by weight regain by 4-6 months. However, interventions lasting 7-12 months achieve greater weight loss overall.
TRIAL REGISTRATION: PROSPERO: CRD42022382478.

Keywords:  Alternate day fasting; Body weight; Calorie restriction; Intermittent fasting; Short-term fasting; Time restrict eating

DOI:  https://doi.org/10.1186/s12966-024-01657-9
Crit Care. 2024 Sep 20. 28(1): 314

Infusion of sodium DL-3-ß-hydroxybutyrate decreases cerebral injury biomarkers after resuscitation in experimental cardiac arrest.

Filippo Annoni, Fuhong Su, Lorenzo Peluso, Ilaria Lisi, Enrico Caruso, Francesca Pischiutta, Elisa Gouvea Bogossian, Bruno Garcia, Hassane Njimi, Jean-Louis Vincent, Nicolas Gaspard, Lorenzo Ferlini, Jacques Creteur, Elisa R Zanier, Fabio Silvio Taccone.

   AIMS: Cerebral complications after cardiac arrest (CA) remain a major problem worldwide. The aim was to test the effects of sodium-ß-hydroxybutyrate (SBHB) infusion on brain injury in a clinically relevant swine model of CA.
RESULTS: CA was electrically induced in 20 adult swine. After 10 min, cardiopulmonary resuscitation was performed for 5 min. After return of spontaneous circulation (ROSC), the animals were randomly assigned to receive an infusion of balanced crystalloid (controls, n = 11) or SBHB (theoretical osmolarity 1189 mOsm/l, n = 8) for 12 h. Multimodal neurological and cardiovascular monitoring were implemented in all animals. Nineteen of the 20 animals achieved ROSC. Blood sodium concentrations, osmolarity and circulating KBs were higher in the treated animals than in the controls. SBHB infusion was associated with significantly lower plasma biomarkers of brain injury at 6 (glial fibrillary acid protein, GFAP and neuron specific enolase, NSE) and 12 h (neurofilament light chain, NFL, GFAP and NSE) compared to controls. The amplitude of the stereoelectroencephalograph (sEEG) increased in treated animals after ROSC compared to controls. Cerebral glucose uptake was lower in treated animals.
CONCLUSIONS: In this experimental model, SBHB infusion after resuscitated CA was associated with reduced circulating markers of cerebral injury and increased sEEG amplitude.

Keywords:  Anoxic injury; Beta hydroxybutyrate; Cardiac arrest; Ischemia–reperfusion; Ketone bodies

DOI:  https://doi.org/10.1186/s13054-024-05106-8
bioRxiv. 2024 Sep 15. pii: 2024.09.12.612739. [Epub ahead of print]

Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center.

Jue Wang, Man Wu, Venkat G Magupalli, Peter D Dahlberg, Hao Wu, Grant J Jensen.

The NLRP3 inflammasome is a multi-protein molecular machine that mediates inflammatory responses in innate immunity. Its dysregulation has been linked to a large number of human diseases. Using cryogenic fluorescence-guided focused-ion-beam (cryo-FIB) milling and electron cryo-tomography (cryo-ET), we obtained 3-D images of the NLRP3 inflammasome in situ at various stages of its activation at macromolecular resolution. The cryo-tomograms unexpectedly reveal dense condensates of the human macrophage NLRP3 inflammasome that form within and around the microtubule organizing center (MTOC). We also find that following activation, the trans-Golgi network disperses and 50-nm NLRP3-associated vesicles appear which likely ferry NLRP3 to the MTOC. At later time points after activation, the electron-dense condensates progressively solidify and the cells undergo pyroptosis with widespread damaged mitochondria and autophagasomal structures.

DOI: https://doi.org/10.1101/2024.09.12.612739
Prostaglandins Other Lipid Mediat. 2024 Sep 21. pii: S1098-8823(24)00096-0. [Epub ahead of print]175 106902

From tradition to science: Possible mechanisms of ghee in supporting bone and joint health.

Maryam Falahatzadeh, Kianoosh Najafi, Kaveh Bashti.

  Ghee, a traditional form of clarified butter, has been used for centuries in Ayurvedic medicine for its numerous health benefits. Recent scientific studies have begun to elucidate the molecular mechanisms by which ghee may support bone and joint health. This review explores the bioactive components of ghee, including short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), and fat-soluble vitamins (A, D, E, K2), and their potential therapeutic effects on bone density, joint lubrication, and inflammation. SCFAs in ghee can potentially improve joint lubrication and reduce inflammation. MCFAs and conjugated linoleic acid (CLA) exhibit anti-inflammatory properties, modulating cytokine production and oxidative stress pathways. Vitamins D and K2 in ghee can play potentially crucial roles in calcium metabolism and bone mineralization, while vitamin A supports immune regulation and cartilage health. This review integrates traditional knowledge with contemporary scientific research, highlighting the potential of ghee as a complementary therapy for conditions such as osteoporosis and arthritis. By understanding the molecular mechanisms involved, future studies can focus on this field to shed a light on different effects of ghee on bone and joint health.

Keywords:  Arthritis; Bone health; Ghee; Joint health; Osteoporosis

DOI:  https://doi.org/10.1016/j.prostaglandins.2024.106902
J Sports Med Phys Fitness. 2024 Sep 25.

Effect of different forms of high-intensity interval training on V̇O2max, strength, flexibility, and body fat percentage among middle-aged males.

Abdul L Shaikh, Zuhair A Al Salim, Abdul A Al Rafati, Mohammad Ahsan.

BACKGROUND: High-intensity interval training (HIIT) has become a popular exercise approach due to its potential to elicit significant physiological adaptations. However, limited research has compared the effects of different HIIT modalities on fitness parameters in middle-aged males. This study aimed to determine the effect of different HIIT on V̇O<inf>2max</inf>, strength, flexibility, and body fat percentage among middle-aged males.
METHODS: Thirty sedentary males aged 40-50 years were randomly assigned to HIIT-Weight Training Circuit (WTC), HIIT-Shuttle Run (SR), or HIIT-Bodyweight Exercise (BWE) groups. Training consisted of 20 sessions over 5 weeks of 4×4 minutes at 90-95% HR<inf>max</inf> with 3 minutes recovery at 70% HR<inf>max</inf> between intervals. Outcome measures including V̇O<inf>2max</inf>, strength, flexibility, and body fat percentage were assessed pre- and postintervention.
RESULTS: The result for the Two-Way Mixed ANOVA indicated there was no significant interaction effect between the three training groups. There was no significant main effect for the three training groups, whereas there was a significant effect for the repeated measure time existed. A significant improvement in V̇O<inf>2max</inf>, strength, flexibility has been shown between post-test and pre-test for the HIIT-SR, HIIT-WTC, and HIIT-BWE group. Whereas A significant decrease has been shown between post and pretest for all the groups in body fat percentage.
CONCLUSIONS: This research findings suggested that different forms of HIIT can elicit differential adaptation in middle-aged males. Incorporating different form of HIIT as HITT-SR, HITT-WTC, and HITT-BWE into exercise program may be an effective way to systematically improve V̇O<inf>2max</inf>, strength, flexibility, and body composition in middle-age male population. These findings provide guidance on HIIT prescription according to fitness goals.

DOI: https://doi.org/10.23736/S0022-4707.24.16121-X
Clin Exp Med. 2024 Sep 26. 24(1): 231

The NLRP3 inflammasome in allergic diseases: mechanisms and therapeutic implications.

Huiqin Zhou, Li Wang, Wei Lv, Hongmeng Yu.

  In recent years, there has been a global increase in the prevalence of allergic diseases, including allergic rhinitis, chronic rhinosinusitis, allergic asthma, atopic dermatitis, allergic conjunctivitis, and food allergies. Since the pathogenic mechanisms of these allergic diseases are not yet fully understood, targeted and effective therapies are lacking. The NLRP3 inflammasome, a multiprotein complex implicated in various inflammatory diseases, can be activated by diverse stimuli. It assembles into NLRP3 inflammasome complexes through conformational changes, initiating the proteolytic cleavage of dormant procaspase-1 into active caspase-1 and promoting the maturation of inflammatory cytokines, including IL-1β and IL-18. Dysfunction of the NLRP3 inflammasome may serve as a key driver of inflammatory diseases, leading to pyroptosis and amplifying the local inflammatory response. As preliminarily demonstrated, specific NLRP3 inflammatory vesicle inhibitors play refectory roles in animal models of allergic diseases, and it is believed that specific NLRP3 inflammasome inhibitors may be potential therapeutic agents for allergic diseases. This review highlights the progress of research on the NLRP3 inflammasome in allergic diseases, explores its contribution to different types of allergic diseases, and identifies promising clinical targets for intervention.

Keywords:  Allergic asthma; Allergic conjunctivitis; Allergic rhinitis; Atopic dermatitis; Chronic rhinosinusitis; Food allergy

DOI:  https://doi.org/10.1007/s10238-024-01492-z
Sports Med Health Sci. 2024 Dec;6(4): 302-314

Exercise and nutrition benefit skeletal muscle: From influence factor and intervention strategy to molecular mechanism.

Lili Feng, Bowen Li, Su Sean Yong, Xiaonan Wu, Zhenjun Tian.

  Sarcopenia is a progressive systemic skeletal muscle disease induced by various physiological and pathological factors, including aging, malnutrition, denervation, and cardiovascular diseases, manifesting as the decline of skeletal muscle mass and function. Both exercise and nutrition produce beneficial effects on skeletal muscle growth and are viewed as feasible strategies to prevent sarcopenia. Mechanisms involve regulating blood flow, oxidative stress, inflammation, apoptosis, protein synthesis and degradation, and satellite cell activation through exerkines and gut microbiomes. In this review, we summarized and discussed the latest progress and future development of the above mechanisms for providing a theoretical basis and ideas for the prevention and treatment of sarcopenia.

Keywords:  Diet; Exercise; Exerkines; Sarcopenia; Satellite cells; Signaling pathway; Skeletal muscle

DOI:  https://doi.org/10.1016/j.smhs.2024.02.004
Mech Ageing Dev. 2024 Sep 20. pii: S0047-6374(24)00093-9. [Epub ahead of print]222 111993

The role of mitochondria in cytokine and chemokine signalling during ageing.

Maria Kalykaki, Teresa Rubio-Tomás, Nektarios Tavernarakis.

  Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPRmt, in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.

Keywords:  Age-related disease; Chemokine; Cytokine; Inflammageing; Mitochondrial dysfunction; Senescence

DOI:  https://doi.org/10.1016/j.mad.2024.111993
Front Mol Neurosci. 2024 ;17 1466125

Every-other-day fasting inhibits pyroptosis while regulating bile acid metabolism and activating TGR5 signaling in spinal cord injury.

Honghu Song, Rizhao Pang, Zhixuan Chen, Linjie Wang, Xiaomin Hu, Jingzhi Feng, Wenchun Wang, Jiancheng Liu, Anren Zhang.

  Every-other-day fasting (EODF) is a form of caloric restriction that alternates between periods of normal eating and fasting, aimed at preventing and treating diseases. This approach has gained widespread usage in basic research on neurological conditions, including spinal cord injury, and has demonstrated significant neuroprotective effects. Additionally, EODF is noted for its safety and feasibility, suggesting broad potential for application. This study aims to evaluate the therapeutic effects of EODF on spinal cord injury and to investigate and enhance its underlying mechanisms. Initially, the SCI rat model was utilized to evaluate the effects of EODF on pathological injury and motor function. Subsequently, considering the enhancement of metabolism through EODF, bile acid metabolism in SCI rats was analyzed using liquid chromatography-mass spectrometry (LC-MS), and the expression of the bile acid receptor TGR5 was further assessed. Ultimately, it was confirmed that EODF influences the activation of microglia and NLRP3 inflammasomes associated with the TGR5 signaling, along with the expression of downstream pyroptosis pathway related proteins and inflammatory cytokines, as evidenced by the activation of the NLRP3/Caspase-1/GSDMD pyroptosis pathway in SCI rats. The results demonstrated that EODF significantly enhanced the recovery of motor function and reduced pathological damage in SCI rats while controlling weight gain. Notably, EODF promoted the secretion of bile acid metabolites, activated TGR5, and inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway and inflammation in these rats. In summary, EODF could mitigate secondary injury after SCI and foster functional recovery by improving metabolism, activating the TGR5 signaling and inhibiting the NLRP3 pyroptosis pathway.

Keywords:  NLRP3/Caspase-1/GSDMD pathway; every-other-day fasting; pyroptosis; spinal cord injury; trans-membrane G protein-coupled receptor 5

DOI:  https://doi.org/10.3389/fnmol.2024.1466125
J Physiol. 2024 Sep 20.

Interleukin-15 and high-intensity exercise: relationship with inflammation, body composition and fitness in cancer survivors.

Morgan J Farley, Alexander N Boytar, Kirsten N Adlard, Chloe E Salisbury, Nicolas H Hart, Mia A Schaumberg, David G Jenkins, Tina L Skinner.

  Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti-oncogenic effects of exercise were associated with the exercise-mediated release of myokines such as interleukin (IL)-15. However, no study has quantified the acute IL-15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high-intensity interval exercise (HIIE) [4×4 min at 85-95% heart rate (HR) peak, 3 min at 50-70% HR peak] before and after 7 months of three times weekly high-intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL-15, IL-6, IL-10, IL-1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL-15 concentrations (pre-intervention: 113%; P = 0.013, post-intervention: 102%; P = 0.005). Post-exercise IL-15 concentrations were associated with all other post-exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute V̇O2${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre- or post-HIIE IL-15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL-15 and other myokines including IL-6, IL-10 and IL-1ra which may be clinically relevant in the anti-oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. KEY POINTS: Exercise has been demonstrated to reduce the risk of cancer recurrence. Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise-induced myokines (IL-6 and IL-15). High-intensity interval exercise significantly increased myokines associated with the anti-oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response. Given IL-15 has been implicated in the anti-oncogenic effect of exercise and is being explored as an immunotherapy agent, high-intensity interval exercise may improve outcomes for people living beyond cancer through IL-15-mediated pathways. Interventions that increase lean mass may also enhance this response.

Keywords:  exercise; high‐intensity interval training; immunology; interleukins; myokines; neoplasm

DOI:  https://doi.org/10.1113/JP286043
Exp Cell Res. 2024 Sep 25. pii: S0014-4827(24)00356-2. [Epub ahead of print] 114265

Exercise training alleviates cholesterol and lipid accumulation in mice with non-alcoholic steatohepatitis: reduction of KMT2D-mediated histone methylation of IDI1.

Xiuqin Fan, Hongshi Wang, Weiwei Wang, Jiayan Shen, Zejun Wang.

  Exercise training is a cornerstone treatment for non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the effects of exercises on lipid accumulation in non-alcoholic steatohepatitis (NASH) and to explore the molecular mechanism. Established NASH mice were remained sedentary or subjected to moderate-intensity continuous training or high-intensity interval training (HIIT). The two training regimens, especially the latter one, reduced liver weight, steatosis, inflammation, lipid accumulation, collagen deposition, and cholesterol content in the mouse liver. Similarly, the HIIT regimen improved clinical presentation of NAFLD patients. RNA sequencing analysis revealed lysine methyltransferase 2D (Kmt2d) and isopentenyl-diphosphate delta isomerase 1 (Idi1) as two important genes downregulated in mice underwent HIIT. By using mouse hepatocytes AML12, we found that KMT2D promoted Idi1 expression by catalyzing H3K4me1 modification near its promoter. Upregulation of either KMT2D or IDI1 blocked the ameliorating effects of HIIT on mice. Meanwhile, in AML12 cells modeled by palmitic acid and oleic acid treatment, KMT2D and IDI1 were found to be correlated with lipid accumulation, cholesterol content, inflammation, and cell death and senescence. In conclusion, this study demonstrates that the ameliorating effects of exercise training on NASH might involve the downregulation of the KMT2D/IDI1 axis.

Keywords:  Cholesterol; Exercise training; Hepatic cell damage; KMT2D; Non-alcoholic steatohepatitis

DOI:  https://doi.org/10.1016/j.yexcr.2024.114265