bims-kimdis 2024-03-10 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒03‒10
twenty-one papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Substrate utilization and durability during prolonged intermittent exercise in elite road cyclists.
Lower GLUT1 and unchanged MCT1 in Alzheimer's disease cerebrovasculature.
Long-term outcomes of infantile spasms in children treated with ketogenic diet therapy in combination with anti-seizure medications in a resource-limited region.
Sodium butyrate alleviates experimental autoimmune prostatitis by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway.
Beta-Hydroxybutyrate Levels and Risk of Diabetic Ketoacidosis in Adults with Type 1 Diabetes Treated with Sotagliflozin.
A review of fatty acid oxidation disorder mouse models.
D-beta-hydroxybutyrate up-regulates Claudin-1 and alleviates the intestinal hyperpermeability in lipopolysaccharide-treated mice.
Molecular mechanisms underlying sarcopenia in heart failure.
Targeting mitochondrial dynamics and redox regulation in cardiovascular diseases.
Sarcopenia is linked to higher levels of B-type natriuretic peptide and its N-terminal fragment in heart failure: a systematic review and meta-analysis.
Exercise-induced potentiation of the acute hypoxic ventilatory response: Neural mechanisms and implications for cerebral blood flow.
Celecoxib attenuates hindlimb unloading-induced muscle atrophy via suppressing inflammation, oxidative stress and ER stress by inhibiting STAT3.
Protein combined with certain dietary fibers increases butyrate production in gut microbiota fermentation.
Salivary levels of NLRP3 protein are significantly raised in chronic periodontitis: A systematic review and meta-analysis of clinical studies.
Exercise Improves Heart Function after Myocardial Infarction: The Merits of AMPK.
Chronic stress alters hepatic metabolism and thermodynamic respiratory efficiency affecting epigenetics in C57BL/6 mice.
Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition.
Discovery of anti-inflammatory agents from 3, 4-dihydronaphthalene-1(2H)-one derivatives by inhibiting NLRP3 inflammasome activation.
How calorie restriction slows aging: an epigenetic perspective.
High intensity interval training vs. moderate intensity continuous training on aerobic capacity and functional capacity in patients with heart failure: a systematic review and meta-analysis.
Becoming a World Champion Powerlifter at 71 Years of Age: It Is Never Too Late to Start Exercising.

Eur J Appl Physiol. 2024 Mar 05.

Substrate utilization and durability during prolonged intermittent exercise in elite road cyclists.

Niels Ørtenblad, Magnus Zachariassen, Joachim Nielsen, Kasper Degn Gejl.

  PURPOSE: This study investigated the effects of prolonged intermittent cycling exercise on peak power output (PPO) and 6-min time-trial (6 min-TT) performance in elite and professional road cyclists. Moreover, the study aimed to determine whether changes in performance in the fatigued state could be predicted from substrate utilization during exercise and laboratory measures obtained in a fresh state.METHODS: Twelve cyclists (age: 23 years [21;25]; body mass: 71.5 kg [66.7;76.8]; height: 181 cm [178;185]; V˙ O2peak: 73.6 ml kg-1 min-1 [71.2;76.0]) completed a graded submaximal cycling test to determine lactate threshold (LT1), gross efficiency (GE), and maximal fat oxidation (MFO) as well as power output during a maximal 6 min-TT (MPO6 min) in a fresh condition. On a separate day, the cyclists completed a 4-h intermittent cycling protocol with a high CHO intake (100 g h-1). Substrate utilization and PPO was measured hourly during the protocol, which was followed by another 6 min-TT.
RESULTS: MPO6 min and PPO was reduced by 10% [4;15] and 6% [0;6], respectively, after the cycling protocol. These reductions were accompanied by reductions in the anaerobic energy contribution and V˙ O2peak, whereas the average V˙ O2 during the 6 min-TT was unchanged. Correlation analyses showed no strong associations between reductions in MPO6 min and PPO and laboratory measures (i.e., LT1, GE, MFO, V˙ O2peak) obtained in the fresh condition. Additionally, fat oxidation rates during the cycling protocol were not related to changes in neither PPO nor MPO6 min.
CONCLUSION: PPO and MPO6 min were reduced following prolonged intermittent cycling, but the magnitude of these reductions could not be predicted from laboratory measures obtained in the fresh condition.

Keywords:  Carbohydrate oxidation; Endurance; Fat oxidation; Fatigue; Oxygen uptake; Performance

DOI:  https://doi.org/10.1007/s00421-024-05437-y
J Cereb Blood Flow Metab. 2024 Mar 05. 271678X241237484

Lower GLUT1 and unchanged MCT1 in Alzheimer's disease cerebrovasculature.

Manon Leclerc, Cyntia Tremblay, Philippe Bourassa, Julie A Schneider, David A Bennett, Frédéric Calon.

  The brain is a highly demanding organ, utilizing mainly glucose but also ketone bodies as sources of energy. Glucose transporter-1 (GLUT1) and monocarboxylates transporter-1 (MCT1) respectively transport glucose and ketone bodies across the blood-brain barrier. While reduced glucose uptake by the brain is one of the earliest signs of Alzheimer's disease (AD), no change in the uptake of ketone bodies has been evidenced yet. To probe for changes in GLUT1 and MCT1, we performed Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders Study. Participants clinically diagnosed with AD had lower cerebrovascular levels of GLUT1, whereas MCT1 remained unchanged. GLUT1 reduction was associated with lower cognitive scores. No such association was found for MCT1. GLUT1 was inversely correlated with neuritic plaques and cerebrovascular β-secretase-derived fragment levels. No other significant associations were found between both transporters, markers of Aβ and tau pathologies, sex, age at death or apolipoprotein-ε4 genotype. These results suggest that, while a deficit of GLUT1 may underlie the reduced transport of glucose to the brain in AD, no such impairment occurs for MCT1. This study thus supports the exploration of ketone bodies as an alternative energy source for the aging brain.

Keywords:  Alzheimer’s disease; Glucose transporter; cerebrovasculature; cognitive impairment; monocarboxylate transporter

DOI:  https://doi.org/10.1177/0271678X241237484
Front Epidemiol. 2022 ;2 1080068

Long-term outcomes of infantile spasms in children treated with ketogenic diet therapy in combination with anti-seizure medications in a resource-limited region.

Jianxiang Liao, Zhanqi Hu, Sufang Lin, Xinguo Lu, Jialun Wen, Jing Duan, Dongfang Zou, Huafang Zou, Mei Yu, Liqin Liu, Xiaoying Qiao, Yuanzhen Ye.

  Objective: Despite numerous guidelines, the overall outcome of infantile spasms is poor, with only a small number of patients being able to attend school. The purpose of this study was to investigate long-term outcomes. Patients had poor access to the recommended first-line anti-seizure medications (ASMs), such as hormones (corticotropin or prednisolone/prednisone) and vigabatrin, and their alternative treatment was other ASMs and a ketogenic diet.Methods: Patients suffering from infantile spasms who had at least 2 years of medical records in the electronic medical record system between January 2014 and August 2022 were included in this study. Patient information was retrospectively reviewed. All patients had received ketogenic diet therapy (mainly classical ketogenic diet therapy). The ketogenic diet therapy was combined with ASMs not used as first-line therapies. The primary endpoint outcome measure was the number of patients with seizure freedom. The secondary measures included the duration of ketogenic diet therapy, choice of ASMs, and patient development at the last visit.
Results: A total of 177 patients with infantile spasms were included, and 152 (86%) of them had seizure freedom. The median duration from the first to the last hospital visit was 53.27 months, and the number of visits was 47.00. The median age at the initial hospital visit was 8.00 months, and the median age at initiation of the ketogenic diet was 17.73 months. At the last visit, the proportions of patients with neurodevelopmental delay, developmental epileptic encephalopathy, drug-resistant epilepsy, and generalized seizures increased significantly. The frequently used ASMs were topiramate, valproic acid, levetiracetam, nitrazepam, and vitamin B6 injection, while the recommended first-line drugs corticotropin and vigabatrin were rarely selected. The study duration of 9.5 years was divided into three periods but the prescription of ASMs did not change significantly between these periods.
Conclusions: Although the seizure freedom rate was high with ketogenic diet therapy combined with non-standard ASMs, the patients had a significant neurodevelopmental delay at the last visit, which was, however, similar to that of standard treatment. To improve the outcomes of infantile spasms, multicenter clinical trials of the ketogenic diet as a first-line treatment in combination with non-standard ASMs are needed.

Keywords:  anti-seizure medications; epilepsy; infantile spasms; ketogenic diet; outcome; real world study; seizure free; treatment

DOI:  https://doi.org/10.3389/fepid.2022.1080068
Prostate. 2024 Mar 05.

Sodium butyrate alleviates experimental autoimmune prostatitis by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway.

Xiaoliang Hua, Jiong Zhang, Juan Chen, Rui Feng, Li Zhang, Xianguo Chen, Qing Jiang, Cheng Yang, Chaozhao Liang.

  BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) leads to severe discomfort in males and loss of sperm quality. Current therapeutic options have failed to achieve satisfactory results. Sodium butyrate (NaB) plays a beneficial role in reducing inflammation, increasing antioxidant capacities, and improving organ dysfunction; additionally NaB has good safety prospects and great potential for clinical application. The purpose of the current research was to study the effect of NaB on CP/CPPS and the underlying mechanisms using a mouse model of experimental autoimmune prostatitis (EAP) mice.METHODS: The EAP mouse model was successfully established by subcutaneously injecting a mixture of prostate antigen and complete Freund's adjuvant. Then, EAP mice received daily intraperitoneal injections of NaB (100, 200, or 400 mg/kg/day) for 16 days, from Days 26 to 42. We then explored anti-inflammatory potential mechanisms of NaB by studying the effects of Nrf2 inhibitor ML385 and HO-1 inhibitor zinc protoporphyrin on prostate inflammation and pelvic pain using this model. On Day 42, hematoxylin-eosin staining and dihydroethidium staining were used to evaluate the histological changes and oxidative stress levels of prostate tissues. Chronic pelvic pain was assessed by applying Von Frey filaments to the lower abdomen. The levels of inflammation-related cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor were detected by enzyme-linked immunosorbent assay. The regulation of Nrf2/HO-1 signaling pathway and the expression of NLRP3 inflammasome-related protein in EAP mice were detected by western blot analysis assay.
RESULTS: Compared with the EAP group, chronic pain development, histological manifestations, and cytokine levels showed that NaB reduced the severity of EAP. NaB treatment could inhibit NLRP3 inflammasome activation. Mechanism studies showed that NaB intervention could alleviate oxidative stress in EAP mice through Nrf2/HO-1 signal pathway. Nrf2/HO-1 pathway inhibitors can inhibit NaB -mediated oxidative stress. The inhibitory effect of NaB on the activation of NLRP3 inflammasome and anti-inflammatory effect can also be blocked by Nrf2/HO-1 pathway.
CONCLUSIONS: NaB treatment can alleviates prostatic inflammation and pelvic pain associated with EAP by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway. NaB has the potential as an effective agent in the treatment of EAP.

Keywords:  NLRP3 inflammasome; chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS); inflammation; oxidative stress; sodium butyrate

DOI:  https://doi.org/10.1002/pros.24683
Diabetes Technol Ther. 2024 Mar 05.

Beta-Hydroxybutyrate Levels and Risk of Diabetic Ketoacidosis in Adults with Type 1 Diabetes Treated with Sotagliflozin.

Schafer Boeder, Michael J Davies, Janet B McGill, Richard E Pratley, Manon Girard, Phillip Banks, Jeremy Pettus, Satish K Garg.

INTRODUCTION: Sodium glucose cotransporter (SGLT) inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct.RESEARCH DESIGN AND METHODS: This post-hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N=1402) or with DKA events in a pooled analysis (inTandem1-3; N=2453).
RESULTS: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03-0.05; P<0.001) at 24 weeks with sotagliflozin vs. placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline .
CONCLUSION: Incremental increases in baseline BHB and ΔBHB were associated with higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.

DOI: https://doi.org/10.1089/dia.2023.0605
Mol Genet Metab. 2024 Feb 23. pii: S1096-7192(24)00236-1. [Epub ahead of print]142(1): 108351

A review of fatty acid oxidation disorder mouse models.

Shannon J Babcock, Sander M Houten, Melanie B Gillingham.

  Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients. The purpose of this review is to present the different FAOD mouse models and highlight the benefits and limitations of using these models. Specifically, we discuss the phenotypes of the available FAOD mouse models, the potential molecular causes of prominent FAOD phenotypes that have been studied using FAOD mouse models, and how FAOD mouse models have been used to evaluate treatments for patients.

Keywords:  Cardiomyopathy; Exercise; Fatty acid β-oxidation; Gene addition; Hypoglycemia; Inborn errors of metabolism; Mouse models

DOI:  https://doi.org/10.1016/j.ymgme.2024.108351
Tissue Cell. 2024 Mar 01. pii: S0040-8166(24)00044-2. [Epub ahead of print]87 102343

D-beta-hydroxybutyrate up-regulates Claudin-1 and alleviates the intestinal hyperpermeability in lipopolysaccharide-treated mice.

Ting Wang, Yuchen Zhuang, Chenglong Yu, Zhaobo Wang, Yuan Liu, Qian Xu, Kun Liu, Yanning Li.

  The hyperpermeability of intestinal epithelium is a key contributor to the occurrence and development of systemic inflammation. Although D-beta-hydroxybutyrate (BHB) exhibits various protective effects, whether it affects the permeability of intestinal epithelium in systemic inflammation has not been clarified. In this study, we investigated the effects of BHB on the intestinal epithelial permeability, the epithelial marker E-cadherin and the tight junction protein Claudin-1 in colon in the lipopolysaccharide (LPS)-induced systemic inflammation mouse model. Intraperitoneal injection of LPS was used to induce systemic inflammation and BHB was given by oral administration. The permeability of intestinal epithelium, the morphological changes of colonic epithelium, the distribution and generation of colon E-cadherin, and the Claudin-1 generation and its epithelial distribution in colon were detected. The results confirmed the intestinal epithelial hyperpermeability and inflammatory changes in colonic epithelium, with disturbed E-cadherin distribution in LPS-treated mice. Besides, colon Claudin-1 generation was decreased and its epithelial distribution in colon was weakened in LPS-treated mice. However, BHB treatments alleviated the LPS-induced hyperpermeability of intestinal epithelium, attenuated the colonic epithelial morphological changes and promoted orderly distribution of E-cadherin in colon. Furthermore, BHB up-regulated colon Claudin-1 generation and promoted its colonic epithelial distribution and content in LPS-treated mice. In conclusion, BHB may alleviate the hyperpermeability of intestinal epithelium via up-regulation of Claudin-1 in colon in LPS-treated mice.

Keywords:  Claudin-1; D-beta-hydroxybutyrate; E-cadherin; Intestinal epithelial permeability; Systemic inflammation

DOI:  https://doi.org/10.1016/j.tice.2024.102343
J Cardiovasc Aging. 2024 Jan;4(1): 7

Molecular mechanisms underlying sarcopenia in heart failure.

Cody A Rutledge.

  The loss of skeletal muscle, also known as sarcopenia, is an aging-associated muscle disorder that is disproportionately present in heart failure (HF) patients. HF patients with sarcopenia have poor outcomes compared to the overall HF patient population. The prevalence of sarcopenia in HF is only expected to grow as the global population ages, and novel treatment strategies are needed to improve outcomes in this cohort. Multiple mechanistic pathways have emerged that may explain the increased prevalence of sarcopenia in the HF population, and a better understanding of these pathways may lead to the development of therapies to prevent muscle loss. This review article aims to explore the molecular mechanisms linking sarcopenia and HF, and to discuss treatment strategies aimed at addressing such molecular signals.

Keywords:  Heart failure; inflammation; mitochondria; proteostasis; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.20517/jca.2023.40
Trends Pharmacol Sci. 2024 Mar 07. pii: S0165-6147(24)00028-2. [Epub ahead of print]

Targeting mitochondrial dynamics and redox regulation in cardiovascular diseases.

Mirza Ahmar Beg, Minqi Huang, Lance Vick, K N Shashanka Rao, Jue Zhang, Yiliang Chen.

  Accumulating evidence highlights the pivotal role of mitochondria in cardiovascular diseases (CVDs). Understanding the molecular mechanisms underlying mitochondrial dysfunction is crucial for developing targeted therapeutics. Recent years have seen substantial advancements in unraveling mitochondrial regulatory pathways in both normal and pathological states and the development of potent drugs. However, specific delivery of drugs into the mitochondria is still a challenge. We present recent findings on regulators of mitochondrial dynamics and reactive oxygen species (ROS), critical factors influencing mitochondrial function in CVDs. We also discuss advancements in drug delivery strategies aimed at overcoming the technical barrier in targeting mitochondria for CVD treatment.

Keywords:  atherosclerosis; cardiovascular disease; drug delivery; fission/fusion; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1016/j.tips.2024.02.001
Eur Geriatr Med. 2024 Mar 08.

Sarcopenia is linked to higher levels of B-type natriuretic peptide and its N-terminal fragment in heart failure: a systematic review and meta-analysis.

Konstantinos Prokopidis, Jordi Morwani-Mangnani, Garry McDowell, Gregory Y H Lip, Massimo Venturelli, Rajiv Sankaranarayanan, Masoud Isanejad.

  AIMS: Sarcopenia is linked to impaired physical function and exercise tolerance. The aim of this systematic review and meta-analysis was to examine the association of sarcopenia and low appendicular skeletal muscle (ASM) with biomarkers of cardiac function, B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP), in patients with heart failure (HF).METHODS AND RESULTS: From inception until May 2023, a systematic literature search of observational studies was undertaken utilizing the PubMed, Web of Science, Scopus, and Cochrane Library databases. A meta-analysis employing a random-effects model was used to compute the pooled effects (CRD42023418465). Overall, 16 studies were included in this systematic review and meta-analysis. Our main analysis showed that sarcopenia in HF was linked to significantly higher levels of BNP (MD: 87.76, 95% CI 20.74-154.78, I2 = 61%, P = 0.01) and NT-proBNP (MD: 947.45, 95% CI 98.97-1795.93, I2 = 35%, P = 0.03). Similarly, low ASM was associated with significantly higher levels of BNP (MD: 118.95, 95% CI 46.91-191.00, I2 = 93%, P < 0.01) and NT-proBNP (MD: 672.01, 95% CI 383.72-960.30, I2 = 2%, P < 0.01). The quality of the included cohort studies was considered moderate, using the binary AXIS checklist and the Cochrane Tool to Assess the Risk of Bias in Cohort Studies.
CONCLUSIONS: In patients with HF, sarcopenia and reduced ASM are associated with considerably higher plasma levels of BNP and NT-proBNP. Future research is required to investigate whether sarcopenia may express dysregulated biomarkers of cardiac function.

Keywords:  BNP; Biomarkers; Cardiac function; Heart failure; NT-proBNP; Sarcopenia

DOI:  https://doi.org/10.1007/s41999-024-00950-x
Exp Physiol. 2024 Mar 05.

Exercise-induced potentiation of the acute hypoxic ventilatory response: Neural mechanisms and implications for cerebral blood flow.

Diogo M Oliveira, Anas Rashid, Patrice Brassard, Bruno M Silva.

  A given dose of hypoxia causes a greater increase in pulmonary ventilation during physical exercise than during rest, representing an exercise-induced potentiation of the acute hypoxic ventilatory response (HVR). This phenomenon occurs independently from hypoxic blood entering the contracting skeletal muscle circulation or metabolic byproducts leaving skeletal muscles, supporting the contention that neural mechanisms per se can mediate the HVR when humoral mechanisms are not at play. However, multiple neural mechanisms might be interacting intricately. First, we discuss the neural mechanisms involved in the ventilatory response to hypoxic exercise and their potential interactions. Current evidence does not support an interaction between the carotid chemoreflex and central command. In contrast, findings from some studies support synergistic interactions between the carotid chemoreflex and the muscle mechano- and metaboreflexes. Second, we propose hypotheses about potential mechanisms underlying neural interactions, including spatial and temporal summation of afferent signals into the medulla, short-term potentiation and sympathetically induced activation of the carotid chemoreceptors. Lastly, we ponder how exercise-induced potentiation of the HVR results in hyperventilation-induced hypocapnia, which influences cerebral blood flow regulation, with multifaceted potential consequences, including deleterious (increased central fatigue and impaired cognitive performance), inert (unchanged exercise) and beneficial effects (protection against excessive cerebral perfusion).

Keywords:  brain; breathing; exertion; hypocapnia; hypoxia; reflex; synergism

DOI:  https://doi.org/10.1113/EP091330
Inflammopharmacology. 2024 Mar 07.

Celecoxib attenuates hindlimb unloading-induced muscle atrophy via suppressing inflammation, oxidative stress and ER stress by inhibiting STAT3.

Yanan Ji, Junfei Lin, Ruiqi Liu, Kexin Wang, Mengyuan Chang, Zihui Gao, Boya Liu, Yuntian Shen, Jianwei Zhu, Xinlei Yao, Lei Qi, Hualin Sun.

  Improving inflammation may serve as useful therapeutic interventions for the hindlimb unloading-induced disuse muscle atrophy. Celecoxib is a selective non-steroidal anti-inflammatory drug. We aimed to determine the role and mechanism of celecoxib in hindlimb unloading-induced disuse muscle atrophy. Celecoxib significantly attenuated the decrease in soleus muscle mass, hindlimb muscle function and the shift from slow- to fast-twitch muscle fibers caused by hindlimb unloading in rats. Importantly, celecoxib inhibited the increased expression of inflammatory factors, macrophage infiltration in damaged soleus muscle. Mechanistically, Celecoxib could significantly reduce oxidative stress and endoplasmic reticulum stress in soleus muscle of unloaded rats. Furthermore, celecoxib inhibited muscle proteolysis by reducing the levels of MAFbx, MuRF1, and autophagy related proteins maybe by inhibiting the activation of pro-inflammatory STAT3 pathway in vivo and in vitro. This study is the first to demonstrate that celecoxib can attenuate disuse muscle atrophy caused by hindlimb unloading via suppressing inflammation, oxidative stress and endoplasmic reticulum stress probably, improving target muscle function and reversing the shift of muscle fiber types by inhibiting STAT3 pathways-mediated inflammatory cascade. This study not only enriches the potential molecular regulatory mechanisms, but also provides new potential therapeutic targets for disuse muscle atrophy.

Keywords:  Celecoxib; Hindlimb unloading; Inflammation; Muscle atrophy; Proteolysis

DOI:  https://doi.org/10.1007/s10787-024-01454-7
Food Funct. 2024 Mar 05.

Protein combined with certain dietary fibers increases butyrate production in gut microbiota fermentation.

Rachel Jackson, Tianming Yao, Nuseybe Bulut, Thaisa M Cantu-Jungles, Bruce R Hamaker.

The modern diet delivers nearly equal amounts of carbohydrates and protein into the colon representing an important protein increase compared to past higher fiber diets. At the same time, plant-based protein foods have become increasingly popular, and these sources of protein are generally less digestible than animal protein sources. As a result, a significant amount of protein is expected to reach the colon and be available for fermentation by gut microbiota. While studies on diet-microbiota interventions have mainly focused on carbohydrate fermentation, limited attention has been given to the role of protein or protein-fiber mixtures as fermentation substrates for the colonic microbiota. In this study, we aimed to investigate: (1) how changing the ratio of protein to fiber substrates affects the types and quantities of gut microbial metabolites and bacteria; and (2) how the specific fermentation characteristics of different types of fiber might influence the utilization of protein by gut microbes to produce beneficial short chain fatty acids. Our results revealed that protein fermentation in the gut plays a crucial role in shaping the overall composition of microbiota communities and their metabolic outputs. Surprisingly, butyrate production was maintained or increased when fiber and protein were combined, and even when pure protein samples were used as substrates. These findings suggest that indigestible protein in fiber-rich substrates may promote the production of microbial butyrate perhaps including the later stages of fermentation in the large intestine.

DOI: https://doi.org/10.1039/d3fo04187e
J Indian Soc Periodontol. 2023 Nov-Dec;27(6):27(6): 552-558

Salivary levels of NLRP3 protein are significantly raised in chronic periodontitis: A systematic review and meta-analysis of clinical studies.

Dax Abraham, Arundeep Singh, Anjana Goyal.

  Background: To date, there is no confirmatory diagnostic test that can identify the type of periodontal disease and the disease progress. With the advent of "molecular biomarkers," this systematic review and meta-analysis were designed with the sole purpose of identifying a novel biomarker, namely, nucleotide leucine rich repeat pyrin protein-3 (NLRP3) inflammasome which has already been extensively researched for chronic inflammatory and autoimmune diseases.Types of Studies Reviewed: Only case observational studies that evaluated the presence of human NLRP3 inflammasome in the saliva of patients with chronic periodontitis with no overlying systemic disease and compared the same to healthy patients to obtain quantitative data that can be statistically analyzed were included. The confirmatory test used in all the studies was the enzyme-linked immunosorbent assay.
Results: The broad-based search led to a total of three articles that fulfilled the inclusion criteria so that a meta-analysis of the results could be carried out. Data reveal that NLRP3 levels are raised in chronic periodontitis cases (P = 0.05; relative risk = 1.05 [0.00-2.09]). The risk of bias assessment was carried out according to the Joanna Briggs Institute Critical Appraisal Checklist where ten-point criteria were outlined indicating a low risk of bias for three studies.
Clinical Implications: NLPR3 inflammasome could be tested as a reliable biomarker in saliva to identify the type and progress of the periodontal disease.

Keywords:  Chronic periodontitis; NLRP3 inflammasome; saliva

DOI:  https://doi.org/10.4103/jisp.jisp_185_23
Cardiovasc Drugs Ther. 2024 Mar 04.

Exercise Improves Heart Function after Myocardial Infarction: The Merits of AMPK.

Xiaodi Zhang, Yi Zhao, Dafen Guo, Mingxian Luo, Qing Zhang, Li Zhang, Dengshen Zhang.

  BACKGROUND: AMPK is considered an important protein signaling pathway that has been shown to exert prominent cardioprotective effects on the pathophysiological mechanisms of numerous diseases. Following myocardial infarction, severe impairment of cardiac function occurs, leading to complications such as heart failure and arrhythmia. Therefore, protecting the heart and improving cardiac function are important therapeutic goals after myocardial infarction. Currently, there is substantial ongoing research on exercise-centered rehabilitation training, positioning exercise training as a significant nonpharmacological approach for preventing and treating numerous cardiovascular diseases.OBJECTIVE: Previous studies have reported that exercise can activate AMPK phosphorylation and upregulate the AMPK signaling pathway to play a cardioprotective role in coronary artery disease, but the specific mechanism involved remains to be elucidated.
CONCLUSION: This review discusses the role and mechanism of the exercise-mediated AMPK pathway in improving postinfarction cardiac function through existing studies and describes the mechanism of exercise-induced myocardial repair of AMPK from multiple perspectives to formulate a reasonable and optimal exercise rehabilitation program for the prevention and treatment of myocardial infarction patients in the clinic.

Keywords:  AMPK; Exercise; Inflammatory response; Mitochondria; Myocardial infarction; Oxidative stress

DOI:  https://doi.org/10.1007/s10557-024-07564-2
iScience. 2024 Mar 15. 27(3): 109276

Chronic stress alters hepatic metabolism and thermodynamic respiratory efficiency affecting epigenetics in C57BL/6 mice.

Aleksandra Nikolic, Pia Fahlbusch, Nele-Kathrien Riffelmann, Natalie Wahlers, Sylvia Jacob, Sonja Hartwig, Ulrike Kettel, Martina Schiller, Matthias Dille, Hadi Al-Hasani, Jörg Kotzka, Birgit Knebel.

  Chronic stress episodes increase metabolic disease risk even after recovery. We propose that persistent stress detrimentally impacts hepatic metabolic reprogramming, particularly mitochondrial function. In male C57BL/6 mice chronic variable stress (Cvs) reduced energy expenditure (EE) and body mass despite increased energy intake versus controls. This coincided with decreased glucose metabolism and increased lipid β-oxidation, correlating with EE. After Cvs, mitochondrial function revealed increased thermodynamic efficiency (ƞ-opt) of complex CI, positively correlating with blood glucose and NEFA and inversely with EE. After Cvs recovery, the metabolic flexibility of hepatocytes was lost. Reduced CI-driving NAD+/NADH ratio, and diminished methylation-related one-carbon cycle components hinted at epigenetic regulation. Although initial DNA methylation differences were minimal after Cvs, they diverged during the recovery phase. Here, the altered enrichment of mitochondrial DNA methylation and linked transcriptional networks were observed. In conclusion, Cvs rapidly initiates the reprogramming of hepatic energy metabolism, supported by lasting epigenetic modifications.

Keywords:  Cell biology; Epigenetics; Molecular biology; Physiology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.109276
Mol Metab. 2024 Mar 06. pii: S2212-8778(24)00043-7. [Epub ahead of print] 101912

Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition.

Serge Ducommun, Paulo R Jannig, Igor Cervenka, Marta Murgia, Melanie J Mittenbühler, Ekaterina Chernogubova, José M Dias, Baptiste Jude, Jorge C Correia, Jonathan G Van Vranken, Gabriel Ocana-Santero, Margareta Porsmyr-Palmertz, Sarah McCann Haworth, Vicente Martínez-Redondo, Zhengye Liu, Mattias Carlström, Matthias Mann, Johanna T Lanner, Ana I Teixeira, Lars Maegdefessel, Bruce M Spiegelman, Jorge L Ruas.

  OBJECTIVE: Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory regeneration and hypertrophy, respectively.METHODS: We analyzed mouse skeletal muscle at the transition from hindlimb unloading to reloading for changes in transcriptome and extracellular fluid proteome. We then used qRT-PCR, immunohistochemistry, and bulk and single-cell RNA sequencing data to determine Mustn1 gene and protein expression, including changes in gene expression in mouse and human skeletal muscle with different challenges such as exercise and muscle injury. We generated Mustn1-deficient genetic mouse models and characterized them in vivo and ex vivo with regard to muscle function and whole-body metabolism. We isolated smooth muscle cells and functionally characterized them, and performed transcriptomics and proteomics analysis of skeletal muscle and aorta of Mustn1-deficient mice.
RESULTS: We show that Mustn1 (Musculoskeletal embryonic nuclear protein 1, also known as Mustang) is highly expressed in skeletal muscle during the early stages of hindlimb reloading. Mustn1 expression is transiently elevated in mouse and human skeletal muscle in response to intense exercise, resistance exercise, or injury. We find that Mustn1 expression is highest in smooth muscle-rich tissues, followed by skeletal muscle fibers. Muscle from heterozygous Mustn1-deficient mice exhibit differences in gene expression related to extracellular matrix and cell adhesion, compared to wild-type littermates. Mustn1-deficient mice have normal muscle and aorta function and whole-body glucose metabolism. Loss of Mustn1 in vascular smooth muscle cells does not affect their proliferative or migratory functions. We show that Mustn1 can be secreted from smooth muscle cells, and that it is present in arterioles of the muscle microvasculature and in muscle extracellular fluid, particularly during the hindlimb reloading phase. Proteomics analysis of muscle from Mustn1-deficient mice confirms differences in extracellular matrix composition, and female mice display higher collagen content after chemically induced muscle injury compared to wild-type littermates.
CONCLUSIONS: We show that, in addition to its previously reported intracellular localization, Mustn1 is a microprotein secreted from smooth muscle cells into the muscle extracellular space. We explore its role in muscle ECM deposition and remodeling in homeostasis and upon muscle injury. The role of Mustn1 in fibrosis and immune infiltration upon muscle injury and dystrophies remains to be investigated, as does its potential for therapeutic interventions.

Keywords:  Extracellular Matrix; Leiokine; Microprotein; Muscle regeneration; Mustn1; Smooth Muscle

DOI:  https://doi.org/10.1016/j.molmet.2024.101912
Eur J Med Chem. 2024 Feb 29. pii: S0223-5234(24)00164-8. [Epub ahead of print]268 116284

Discovery of anti-inflammatory agents from 3, 4-dihydronaphthalene-1(2H)-one derivatives by inhibiting NLRP3 inflammasome activation.

Wen-Xuan Li, Lu Yu, Jiang-Bo Chi, Ji-Peng Wang, Yong-Jun Liu, Chun-Hua Wang, Meng Zhang, Gui-Ge Hou.

  NLRP3 inflammatory vesicles are a polymer of cellular innate immunity composed of a pair of proteins. The continuous activation of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammatory vesicles induces the occurrence and enhancement of inflammatory response. In this study, a series of 3, 4-dihydronaphthalene-1(2H)-one derivatives (DHNs, 6a-u, 7a-e, 8a-n) were synthesized and characterized by NMR and HRMS. We evaluated the cytotoxicity and anti-inflammatory activity of all compounds in vitro, and selected 7a substituted by 7-Br in A-ring and 2-pyridylaldehyde in C-ring as effective lead compounds. Specifically, 7a can block the assembly and activation of NLRP3 inflammasome by down-regulating the expression of NLPR3 and apoptosis-associated speck-like protein containing a CARD (ASC), and inhibiting the production of reactive oxygen species (ROS) and other inflammatory mediators. In addition, 7a inhibits the phosphorylation of inhibitor kappa B alpha (IκBα) and NF-κB/p65 and the nuclear translocation of p65, thereby inhibiting nuclear factor kappa-B (NF-κB) signaling. Molecular docking analysis confirmed that 7a could reasonably bind the active sites of NLRP3, ASC and p65 proteins. Therefore, 7a is predicted as a potential NLRP3 inflammatory vesicle inhibitor and deserves further research and development.

Keywords:  3,4-Dihydronaphthalene-1(2H)-one; Anti-inflammatory; NF-κB pathway; NLRP3 inflammasome inhibitor

DOI:  https://doi.org/10.1016/j.ejmech.2024.116284
J Mol Med (Berl). 2024 Mar 08.

How calorie restriction slows aging: an epigenetic perspective.

Gyeong Min Lim, Nagarajan Maharajan, Gwang-Won Cho.

  Genomic instability and epigenetic alterations are some of the prominent factors affecting aging. Age-related heterochromatin loss and decreased whole-genome DNA methylation are associated with abnormal gene expression, leading to diseases and genomic instability. Modulation of these epigenetic changes is crucial for preserving genomic integrity and controlling cellular identity is important for slowing the aging process. Numerous studies have shown that caloric restriction is the gold standard for promoting longevity and healthy aging in various species ranging from rodents to primates. It can be inferred that delaying of aging through the main effector such as calorie restriction is involved in cellular identity and epigenetic modification. Thus, an understanding of aging through calorie restriction may seek a more in-depth understanding. In this review, we discuss how caloric restriction promotes longevity and healthy aging through genomic stability and epigenetic alterations. We have also highlighted how the effectors of caloric restriction are involved in modulating the chromatin-based barriers.

Keywords:  Aging; Caloric restriction; Chromosome stability; Epigenetic; Sirt1

DOI:  https://doi.org/10.1007/s00109-024-02430-y
Front Cardiovasc Med. 2024 ;11 1302109

High intensity interval training vs. moderate intensity continuous training on aerobic capacity and functional capacity in patients with heart failure: a systematic review and meta-analysis.

Changran Yang, Lizhuang Zhang, Yu Cheng, Manman Zhang, Yuxin Zhao, Tianzi Zhang, Jiawang Dong, Jun Xing, Yuzhi Zhen, Cuihua Wang.

  Background: Exercise training is commonly employed as a efficacious supplementary treatment for individuals suffering from heart failure, but the optimal exercise regimen is still controversial. The objective of the review was to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the exercise capacity, cardiac function, quality of life (QoL) and heart rate among patients with heart failure with reduced ejection fraction.Methods: A systematic search was performed using the following eight databases from their inception to July 5, 2023: PubMed, Web of Science, Embase, Cochrane Library, Clinical Trials, China Knowledge Network, Wan fang Data, and the China Biology Medicine databases. The meta-analysis results were presented as mean difference (MD) and 95% confidence interval (CI). The Cochrane Risk of Bias tool was used for the included studies. The Grading of Recommendations Assessment, Development, and Evaluations was used to assess the certainty of evidence.
Results: Thirteen randomized controlled trials were included in the study. The results showed that HIIT had a significant positive effect on peak oxygen uptake (MD = 1.78, 95% CI for 0.80-2.76), left ventricular ejection fraction (MD = 3.13, 95% CI for 1.25-5.02), six-minute walk test (MD = 28.13, 95% CI for 14.56-41.70), and Minnesota Living with Heart Failure Questionnaire (MD = -4.45, 95% CI for -6.25 to -2.64) compared to MICT. However, there were no statistically significant differences observed in resting heart rate and peak heart rate.
Conclusions: HIIT significantly improves peak oxygen uptake, left ventricular ejection fraction, six-minute walk test, and Minnesota Living with Heart Failure Questionnaire in patients with heart failure with reduced ejection fraction. Additionally, HIIT exhibits greater effectiveness in improving peak oxygen uptake among patients with lower body mass index.
Systematic Review Registration: https://www.doi.org/10.37766/inplasy2023.7.0100, identifier (INPLASY2023.7.0100).

Keywords:  exercise capacity; functional capacity; heart failure with reduced ejection fraction; high-intensity interval training; moderate-intensity continuous training

DOI:  https://doi.org/10.3389/fcvm.2024.1302109
Int J Sport Nutr Exerc Metab. 2024 Mar 07. 1-9

Becoming a World Champion Powerlifter at 71 Years of Age: It Is Never Too Late to Start Exercising.

Cas J Fuchs, Jorn Trommelen, Michelle E G Weijzen, Joey S J Smeets, Janneau van Kranenburg, Lex B Verdijk, Luc J C van Loon.

  This case study assessed body composition, muscle strength, cardiorespiratory fitness, and metabolic health of the present female world champion powerlifter in the 70+ age category who started resistance exercise training at 63 years of age with no prior experience with structured exercise training. Measures of body composition (magnetic resonance imaging, computed tomography, and dual-energy X-ray absorptiometry scanning, leg volume); strength (one-repetition maximum leg press and extension, maximum voluntary contraction, and handgrip strength); physical function (short physical performance battery); cardiorespiratory fitness (peak oxygen consumption); and metabolic health (oral glucose tolerance test) were assessed. In addition, a muscle biopsy was collected to assess muscle fiber type distribution and cross-sectional area (CSA). Where possible, data were compared with previously (un)published sex- and age-matched data using z scores. Skeletal muscle mass index was calculated by dividing limb muscle mass by height squared. Data from the control groups are expressed as mean ± 95% confidence interval. Our participant (age: 71 years; body mass: 64.5 kg; body mass index: 27.6 kg/m2) reported a good bone mineral density of 1.09 g/cm2 (T score between -1 and +1) and very low values of abdominal and organ body fat (i.e., between 20% and 70% lower compared with a reference group of postmenopausal women). In addition, she showed a 33% greater skeletal muscle mass index when compared with healthy, older female control subjects (7.9 vs. 5.9 [5.7-6.2] kg/m2; n = 61) as well as 37% greater muscle quadriceps CSA (63.8 vs. 46.6 [44.5-48.7] cm2; n = 48) and 46% greater Type II muscle fiber CSA (4,536 vs. 3,097 [2,707-3,488] μm2; n = 19). Absolute leg press muscle strength was 36% greater (190 vs. 140 [132-147] kg; n = 30) and handgrip strength was 33% greater (33 vs. 25 [23-26] kg; n = 48) when compared with healthy, age-matched controls. In conclusion, even for resistance exercise naïve individuals, starting exercise at an advanced age can lead to improvements in body composition and muscle strength allowing older adults to reduce the risk for developing metabolic syndrome, live independently, and even compete at a world class level.

Keywords:  aging; body composition; master athletes; muscle strength; resistance exercise

DOI:  https://doi.org/10.1123/ijsnem.2023-0230