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Solar ultraviolet B (UVB) radiation-induced DNA damage is a well-known initiator of skin carcinomas. The UVB-induced DNA damage response (DDR) involves series of signaling cascades that are activated to maintain cell integrity. Among the different biological processes, little is known about the role of energy metabolism in the DDR. We sought to determine whether UVB-induced nuclear and/or mitochondrial cyclobutane pyrimidine dimers (CPDs) alter cellular energy metabolism. To gain insight into this question, we took advantage of keratinocytes expressing nuclear or mitochondrial CPD photolyase. Applying a quantitative proteomic approach and targeted metabolomics, we observed biphasic alterations in multiple metabolic pathways and in the abundance of various metabolites, largely influenced by the presence of genomic CPDs. The heightened oxygen consumption rate post-irradiation, along with mitochondrial structural rearrangements, was found to be dependent on both mitochondrial and nuclear CPDs. Understanding the influence of nuclear and mitochondrial DNA damage on keratinocyte responses to UVB irradiation deepens current knowledge regarding skin cancer prevention, initiation, and therapy. [Display omitted] • Biphasic variations in energy metabolism pathways result from UVB-induced gDNA and mtDNA damage. • Dynamic morphological and structural remodeling of the mitochondrial network following UVB exposure. • Energy metabolism rewiring following UVB irradiation is predominantly influenced by nuclear DNA damage. [ABSTRACT FROM AUTHOR]

The positive role of melatonin in obesity control and skeletal muscle (SKM) preservation is well known. We recently showed that melatonin improves vastus lateralis muscle (VL) fiber oxidative phenotype. However, fiber type characterization, mitochondrial function, and molecular mechanisms that underlie VL fiber switching by melatonin are still undefined. Our study aims to investigate whether melatonin induces fiber switching by NRF2/RCAN/MEF2 pathway activation and mitochondrial oxidative metabolism modulation in the VL of both sex Zücker diabetic fatty (ZDF) rats. 5-Weeks-old male and female ZDF rats (N = 16) and their age-matched lean littermates (ZL) were subdivided into two subgroups: control (C) and orally treated with melatonin (M) (10 mg/kg/day) for 12 weeks. Interestingly, melatonin increased oxidative fibers amounts (Types I and IIa) counteracting the decreased levels found in the VL of obese-diabetic rats, and upregulated NRF2, calcineurin and MEF2 expression. Melatonin also restored the mitochondrial oxidative capacity increasing the respiratory control ratio (RCR) in both sex and phenotype rats through the reduction of the proton leak component of respiration (state 4). Melatonin also improved the VL mitochondrial phosphorylation coefficient and modulated the total oxygen consumption by enhancing complex I, III and IV activity, and fatty acid oxidation (FAO) in both sex obese-diabetic rats, decreasing in male and increasing in female the complex II oxygen consumption. These findings suggest that melatonin treatment induces fiber switching in SKM improving mitochondrial functionality by NRF2/RCAN/MEF2 pathway activation. [Display omitted] • Melatonin induces Skeletal Muscle (SKM) fiber switching in both sex obese-diabetic rats. • Melatonin increases the number of type I and IIa oxidative fibers and decreases the number of type IIb glycolytic ones. • Melatonin treatment recovers mitochondrial lipid β-oxidation and oxidative capacity of SKM impaired by obesity. • Melatonin ameliorates SKM mitochondrial respiratory function and complexes I-IV activities. • Melatonin activates NRF2/RCAN/Calcineurin/MEF2 pathway improving mitochondrial oxidative metabolism and SKM fiber switching. [ABSTRACT FROM AUTHOR]

Down Syndrome (DS) is a genetic disorder caused by the presence of an extra copy of chromosome 21, and leading to various developmental and cognitive defects. A critical feature of DS is the occurrence of oxidative distress particularly in the brain, which exacerbates neurodevelopmental processes. Mitochondria play a crucial role in cell energy metabolism and their impairment is one of the major causes of oxidative distress in several pathologies. Hence, this study investigates mitochondrial proteostasis by the mean of the mitochondrial Unfolded Protein Response (UPRmt) and the mitochondrial protein quality control (MQC) mechanisms in the context of DS, focusing on their implications in redox homeostasis in brain development. We analyzed key UPRmt markers and mitochondrial function in the frontal cortex isolated fromTs2Cje mice, a model for DS, across different developmental stages. Our results demonstrate significant alterations in UPRmt markers, particularly at postnatal day 0 (P0) and 1 month (1M). These changes indicate early UPRmt activation, primarily driven by the ATF5/GRP75 axis, although compromised by reduced levels of other components. Impaired UPRmt correlates with decreased mitochondrial activity, evidenced by reduced oxygen consumption rates and altered expression of OXPHOS complexes. Additionally, elevated oxidative stress markers such as 3-nitrotyrosine (3-NT), 4-hydroxynonenal (HNE), and protein carbonyls (PC) were observed, linking mitochondrial dysfunction to increased oxidative damage. Defects of MQC, including disrupted biogenesis, increased fission, and the activation of mitophagy were evident mostly at P0 and 1M consistent with UPRmt activation. Principal Component Analysis revealed distinct phenotypic differences between Ts2Cje and control mice, driven by these molecular alterations. Our findings underscore the critical role of UPRmt and MQC in DS brain development, highlighting potential therapeutic targets to mitigate mitochondrial dysfunction and oxidative distress, thereby alleviating some of the neurodevelopmental and cognitive impairments associated with DS. [Display omitted] • UPRmt activation is compromised in Ts2Cje mice brain. • Defects of Mitochodrial Quality Control (MQC) occur in Ts2Cje mice brain. • Dysfunctional UPRmt and MQC alter mitochondrial energy production. • Mitochondrial damage is responsible for oxidative distress in Ts2Cje mice brain. • These alterations are evident since P0 likely affecting brain development. [ABSTRACT FROM AUTHOR]

• Effects of ovariectomy on mitochondrial function and synaptic proteins were examined in rat entorhinal cortex. • Ovariectomy reduced respiration and the expression of the mitochondrial membrane protein VDAC1. • Ovariectomy increased cytochrome c and superoxide dismutase, suggesting an increase in oxidative stress. • Synaptic markers PSD95 and synaptophysin were reduced by ovariectomy. • Estradiol supplementation in ovariectomized animals prevented changes in mitochondial and synaptic proteins. Reductions in circulating estrogens can contribute to cognitive decline, in part by impairing mitochondrial function within the hippocampal region. The entorhinal cortex provides the hippocampus with its main cortical inputs. To assess the impact of estrogen deficiency on mitochondrial respiration and synaptic proteins in the entorhinal cortex, female wildtype rats received either sham surgery, bilateral ovariectomy, or ovariectomy with implantation of a subdermal capsule to maintain low levels of circulating 17β-estradiol (E2). Mitochondrial respiration in the entorhinal cortex was not significantly affected two weeks following ovariectomy, but there was a reduction in oxygen consumption four weeks after ovariectomy that was prevented by E2 supplementation. The expression of mitochondrial membrane integrity element voltage-dependent anion channel protein (VDAC1) was also reduced four weeks after ovariectomy, suggesting that respiration was reduced due to a decline in mitochondrial density. Ovariectomy also increased mitochondrial and cytoplasmic cytochrome c and upregulated superoxide dismutase 2 (SOD2) both two and four weeks after ovariectomy, reflecting mitochondrial electron leakage and oxidative redox imbalance. Further, the ovariectomy-induced changes in mitochondrial proteins were associated with reductions in postsynaptic density protein 95 (PSD95) and the presynaptic protein synaptophysin. There were no changes in mitochondrial or synaptic proteins in ovariectomized animals that received E2 supplementation. Our findings indicate that reductions in circulating 17β-estradiol induced by ovariectomy disrupt mitochondrial functions in the entorhinal cortex, and suggest that a resulting increase in oxidative stress contributes to the degradation in synaptic proteins that may affect cognitive functions mediated by the hippocampal region. [ABSTRACT FROM AUTHOR]

[Display omitted] • Arsenic-exposed differentiated cells displayed greater tolerance and reduced respiration. • Arsenic caused more extensive deregulation of miRNAs and proteins in differentiated cells. • Differentiated cells displayed increased neurotoxicity and greater miRNA-protein interactions. SH-SY5Y human neuroblastoma cells have been extensively used as an in vitro model system in a diverse range of studies involving neurodevelopment, neurotoxicity, neurodegeneration, and neuronal ageing. Both naïve and differentiated phenotypes of SH-SY5Y cells are utilized to model human neurons under in vitro conditions. The process of differentiation causes extensive remodeling of neuronal cells at multiple omic levels, including the epigenome and proteome. In the present investigation, the miRNAome and proteome profiles of arsenic-treated naïve and differentiated SH-SY5Y cells were generated using the miRNA OpenArray technology and high-resolution mass spectrometry. Our findings demonstrated that differentiation dramatically affected the response of SH-SY5Y cells to toxicant exposure, as indicated by increased tolerance of differentiated cells against arsenic exposure compared to naïve cells in cell viability assay. Arsenic-exposed naïve and differentiated SH-SY5Y cells possess distinct miRNA and protein profiles with few similarities. Compared to naïve cells, differentiated cells have undergone higher deregulation in the expression of brain-enriched miRNAs and proteins and have shown a more drastic decrease in oxygen consumption rate, which is a measure of mitochondrial respiration after exposure to arsenic. Proteins identified in arsenic-treated differentiated SH-SY5Y cells were more enriched in pathways underlying multifactorial neurotoxic events. Additionally, more functional regulatory modules have been identified between the miRNAs and proteins differentially expressed in arsenic-treated differentiated SH-SY5Y cells relative to naïve cells. Collectively, our studies have shown that differentiated SH-SY5Y cells displayed alterations in the expression of a greater number of miRNAs and proteins following neurotoxicant exposure, indicating their higher responsivity. [ABSTRACT FROM AUTHOR]

The pituitary gonadotropin luteinizing hormone (LH) is the primary stimulus for ovulation, luteal formation, and progesterone synthesis, regardless of species. Despite increased awareness of intracellular signaling events initiating the massive production of progesterone during the reproductive cycle and pregnancy, critical gaps exist in our knowledge of the metabolic and lipidomic pathways required for initiating and maintaining luteal progesterone synthesis. Using untargeted metabolomics and metabolic flux analysis in primary steroidogenic luteal cells, evidence is provided for rapid LHCGRstimulation of metabolic pathways leading to increased glycolysis and oxygen consumption. Treatment with LH stimulated posttranslational modifications of enzymes involved in de novo lipogenesis. Mechanistic studies implicated a crucial role for de novo fatty acid synthesis and fatty acid oxidation in energy homeostasis, LHCGR/PKA signaling, and, consequently, progesterone production. These findings reveal novel hormone-sensitive metabolic pathways essential for maintaining LHCGR/PKA signaling and steroidogenesis. Understanding hormonal control of metabolic pathways in steroidogenic cells may help elucidate approaches for improving ovarian function and successful reproduction or identifying metabolic targets for developing nonhormonal contraceptives. [ABSTRACT FROM AUTHOR]

The inherent susceptibility to oxidation limits the application of carbon fibre/phenolic resin composites (CF/Ph) in the thermal protection of hypersonic vehicle engines. Herein, TiB 2 -B 4 C modified Al-coated carbon fibre/boron phenolic resin ceramizable composites were fabricated. The optimal ceramizable composite (T 30 C 10) exhibited excellent ablation resistance and high-temperature insulation capacity at a linear ablation rate and bottom-surface temperature of −0.00768 mm/s and 129.8 °C, respectively. Oxygen consumption and inhibition, carbon fixation, and self-healing effects contributed to the excellent ablation resistance, and the effects of the Al coatings and carbothermal reduction reactions led to excellent high-temperature insulation capacities. [Display omitted] [ABSTRACT FROM AUTHOR]

To test the reliability of the VO 2 Master Pro and to compare it to the Cosmed Quark. Eight recreational cyclists participated in two different trials which consisted of graded cycling exercise stages at 50%, 70%, and 85% of their critical power. The VO 2 Master Pro was used during the first visit, while both the VO 2 Master Pro and Cosmed Quark were used during the second visit. Equivalence testing of the trials was done by TOST analysis while test of difference was done by ANOVA. The results indicated equivalence of the VO 2 Master Pro in the measurement of VO 2 (35.1 ± 10.4 mL·kg−1·min−1 vs. 35.4 ± 10.2 mL·kg−1·min−1) and V E (72.4 ± 20.5 L·min−1 vs 73.8 ± 22.3 L·min−1) across repeated visits indicating good reliability of the device. However, neither significant equivalence nor difference was detected when comparing the VO 2 Master Pro to the Cosmed Quark across the same variables indicating that the two devices were similar to each other. [ABSTRACT FROM AUTHOR]

To explore if individuals living with obesity participate, have interest, and benefit from circuit resistance training (RT+) and evaluate if the RT+ reaches moderate aerobic intensity and the association between oxygen consumption and heart rate while performing the RT+. Ten inactive adults living with obesity participated in the RT+ program for 12 weeks. Participants performed 150 min of the RT+ program using four exercises (squats, chest press, lunges and lat-pull down) for three sessions of 50 min each week. Measured outcomes included attendance, fitness, lipids, anthropometrics body composition. Oxygen consumption and heart rate were captured during a single session of the RT+ program using portable indirect calorimetry. Participants attended 90% of offered sessions (32.5/36.0 sessions). A significant improvement was observed in the body mass index (P = 0.03). The RT+ program was permitted to reach moderate intensity regardless of the indicator used to establish moderate intensity (3METs, 46%VO 2peak , 40%VO 2reserve , 64%HR max and 40%HR reserve). The association between HR and VO 2 while performing the RT+ program was 0.27; P < 0.01. This study suggests that people with obesity achieve moderate intensity when performing RT+. As a result, performing RT in a circuit manner could contribute to the aerobic portion of the guidelines for adults living with obesity. [ABSTRACT FROM AUTHOR]

Regulatory authorities in biopharmaceutical industry emphasize process design by process understanding but applicable tools that are easy to implement are still missing. Soft sensors are a promising tool for the implementation of the Quality by Design (QbD) approach and Process Analytical Technology (PAT). In particular, the correlation between viable cell counting and oxygen consumption was investigated, but problems remained: Either the process had to be modified for excluding CO 2 in pH control, or complex k L a models had to be set up for specific processes. In this work, a non-invasive soft sensor for simplified on-line cell counting based on dynamic oxygen uptake rate was developed with no need of special equipment. The dynamic oxygen uptake rates were determined by automated and periodic interruptions of gas supply in DASGIP® bioreactor systems, realized by a programmed Visual Basic script in the DASware® control software. With off-line cell counting, the two parameters were correlated based on linear regression and led to a robust model with a correlation coefficient of 0.92. Avoidance of oxygen starvation was achieved by gas flow reactivation at a certain minimum dissolved oxygen concentration. The soft sensor model was established in the exponential growth phase of a Chinese Hamster Ovary fed-batch process. Control studies showed no impact on cell growth by the discontinuous gas supply. This soft sensor is the first to be presented that does not require any specialized additional equipment as the methodology relies solely on the direct measurement of oxygen consumed by the cells in the bioreactor. • Non-invasive soft sensor method for simplified on-line cell counting. • Implemented in exponential growth phase of CHO cells. • Dynamic oxygen uptake rate as only predictor resulted in a correlation coefficient of 0.92. • No negative influences on cell growth as oxygen starvation was prevented. • 5-k cross validation showed RMSE of 0.7 × 106 cells/mL. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is driven by oxidative stress-mitochondrial damage. Activation of ROS producing cytosolic NADPH oxidase 2 (Nox2) in diabetes precedes retinal mitochondrial damage, initiating a vicious cycle of free radicals. Elevated ROS levels peroxidize membrane lipids increasing damaging lipid peroxides (LPOs). While glutathione peroxidase 4 (GPx4) neutralizes LPOs, an imbalance in its generation-neutralization leads to ferroptosis, which is characterized by increased LPOs, free iron and decreased GPx4 activity. Mitochondria are rich in polyunsaturated fatty acids and iron and have mitochondrial isoform of GPx4. Our aim was to investigate mitochondrial ferroptosis in diabetic retinopathy, focusing on Nox2 mediated ROS production. Using human retinal endothelial cells, incubated in 5 mM or 20 mM D-glucose for 12–96 h, with or without Nox2 inhibitors (100 μM apocynin, 5 μM EHop-016 or 5 μM Gp91 ds-tat), or ferroptosis inhibitors (1 μM ferrostatin-1, 50 μM deferoxamine) or activator (0.1 μM RSL3), cytosolic and mitochondrial ROS, LPOs, iron, GPx4 activity, mitochondrial integrity (membrane permeability, oxygen consumption rate, mtDNA copy numbers) and cell death were quantified. High glucose significantly increased ROS, LPOs and iron levels and inhibited GPx4 activity in cytosol, and while Nox2 and ferroptosis inhibitors prevented glucose-induced increase in ferroptosis markers, mitochondrial damage and cell death, RSL3, further worsened them. Furthermore, high glucose also increased ferroptosis markers in the mitochondria, which followed their increase in the cytosol, suggesting a role of cytosolic ROS in mitochondrial ferroptosis. Thus, targeting Nox2-ferroptosis should help break down the self-perpetuating vicious cycle of free radicals, initiated by the damaged mitochondria, and could provide novel therapeutics to prevent/retard the development of diabetic retinopathy. [Display omitted] • NADPH oxidase 2 activation in diabetes elevates cytosolic ROS and lipid peroxides. • Increase in LPOs and iron and inhibition of GPx4 leads to ferroptosis. • Cytosolic ROS damage mitochondria increasing mitochondrial ROS and LPOs. • Elevated mitochondrial LPOs and iron and GPx4 inhibition results in ferroptosis. • Mitochondrial ferroptosis/damage culminates in diabetic retinopathy development. [ABSTRACT FROM AUTHOR]

Mitochondrial abnormalities in lung epithelial cells have been associated with chronic obstructive pulmonary disease (COPD) pathogenesis. Cigarette smoke (CS) can induce alterations in the molecular pathways regulating mitochondrial function in lung epithelial cells. Recently, heated tobacco products (HTPs) have been marketed as harm reduction products compared with regular cigarettes. However, the effects of HTP emissions on human alveolar epithelial cell metabolism and on the molecular mechanisms regulating mitochondrial content and function are unclear. In this study, human alveolar epithelial cells (A549) were exposed to cigarette or HTP emissions in the form of liquid extracts. The oxygen consumption rate of differently exposed cells was measured, and mRNA and protein abundancy of key molecules involved in the molecular regulation of mitochondrial metabolism were assessed. Furthermore, we used a mitophagy detection probe to visualize mitochondrial breakdown over time in response to the extracts. Both types of extracts induced increases in basal-, maximal- and spare respiratory capacity, as well as in cellular ATP production. Moreover, we observed alterations in the abundancy of regulatory molecules controlling mitochondrial biogenesis and mitophagy. Mitophagy was not significantly altered in response to the extracts, as no significant differences compared to vehicle-treated cells were observed. • cigarette smoke extract (CSE) and heated tobacco product extract (HTPE) induce an increase in cellular respiration in human alveolar epithelial cells. • CSE and HTPE affect the transcriptional program driving mitochondrial biogenesis. • Mitophagy was not induced by CSE or HTPE treatment. • Our study suggests a similar impact of cigarette and HTP emission on mitochondrial energy metabolism and on the molecular mechanisms regulating mitochondrial activity and content. [ABSTRACT FROM AUTHOR]

The field of vascularized composite allograft (VCA) transplantation has seen steady, rapid growth, with new innovations driving the evolution from experimental procedures to more standardized therapies. With this expansion comes challenges with graft allocation, preservation, and postoperative graft rejection. Here, we outline the first example of subzero nonfreezing (SZNF), supercooled storage of a whole rat hindlimb with orthotopic transplantation. Rat hindlimbs were procured, loaded, and supercooled for 48 hours at –4°C (n = 4), after which, they were recovered. The loading and recovery phase were performed using subnormothermic machine perfusion (SNMP) during which viability markers (glucose and oxygen consumption, lactate, and resistance) were tracked. Control limbs underwent static cold storage (SCS). After ex vivo validation, the model was piloted in a transplant model, comparing 48 hours of SZNF (n = 1), 48 hours of SCS (n = 1), and 72 hours of SCS (n = 1), which demonstrated no survival beyond postoperative day 4 in the SCS models, and survival until the end of study (postoperative day [POD] 28) in the SZNF model. This study demonstrates the promise of this model in future studies on long-term VCA preservation. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. The inability of dairy calves to fully respond to immune stimuli until they reach maturity at 6 mo of age severely limits the use of parenteral vaccines to protect calves against disease. Immune responses are metabolically demanding, and immune cells rely on mitochondrial metabolites for their functionality. Due to the essential role of mitochondria in driving T-cell responses necessary for vaccine efficacy, we hypothesized that the mitochondrial function of dairy calf lymphocytes changes with age, from birth to immunologic maturity. In this cross-sectional study, groups of dairy calves (n = 4/group) were blood sampled at birth before colostrum intake and at 1, 2, 3, 4, 6, 8, 16, and 24 wk of age. Mid-lactation adult cows (n = 4) were also sampled to reference fully mature immune cell populations. B, CD4+, CD8+, and γδ T lymphocytes were enriched using magnetic-activated cell sorting, and their mitochondrial function was assessed with an extracellular flux analyzer. Nonmitochondrial oxygen consumption, basal respiration, maximal respiration, spare respiratory capacity, proton leak, and the oxygen consumption rate (OCR) to extracellular acidification rate (ECAR) ratio were reported. Results were compared among groups using a Kruskal-Wallis test. The OCR to ECAR ratio is an indicator of the relative proportions of oxidative phosphorylation and aerobic glycolysis which is associated with effector functions in lymphocytes. The ratio was lower in 0 wk than adults in CD4+ T-cells. For CD8+ T-cells, the OCR to ECAR ratio for the 2-wk group was lower than the 3-wk group. A lower OCR to ECAR ratio indicates more reliance on glycolytic metabolism than oxidative phosphorylation. Maximal respiration is an indication of mitochondrial efficiency and is often associated with mitochondrial mass. For γδ T-cells, the 3-wk group had higher maximal respiration than the 16-wk group, whereas for B-cells maximal respiration was higher in the 1 wk compared with the 16-wk group. Basal respiration indicates all cell functions that require oxygen and was lower in the 0-wk group than the 1- and 3-wk groups for CD4+ T-cells. γδ T-cells exhibited lower basal respiration in the 2-wk group than the 24-wk one. Although we found minimal differences in the mitochondrial outcomes reported from nonstimulated lymphocytes from birth through 6 mo of age and mid-lactation adults who served as mature immune cell populations, these results align with previous reports from weaning aged calf and adult CD4+ T-cells. In conclusion, insufficient evidence exists to suggest that the mitochondria in the lymphocytes of dairy calves from birth through immunologic maturity had functional changes associated with age. The capacity of unstimulated calf mitochondria to perform oxidative phosphorylation is not associated with age. [ABSTRACT FROM AUTHOR]

Hypoxic tumor microenvironments pose a significant challenge in cancer treatment. Hypoxia-activated prodrugs like evofosfamide aim to specifically target and eliminate these resistant cells. However, their effectiveness is often limited by reoxygenation after cell death. We hypothesized that ascorbate's pro-oxidant properties could be harnessed to induce transient hypoxia, enhancing the efficacy of evofosfamide by overcoming reoxygenation. To test this hypothesis, we investigated the sensitivity of MIA Paca-2 and A549 cancer cells to ascorbate in vitro and in vivo. Ascorbate induced a cytotoxic effect at 5 mM that could be alleviated by endogenous administration of catalase, suggesting a role for hydrogen peroxide in its cytotoxic mechanism. In vitro, Seahorse experiments indicated that the generation of hydrogen peroxide consumes oxygen, which is offset at later time points by a reduction in oxygen consumption due to hydrogen peroxide's cytotoxic effect. In vivo, photoacoustic imaging showed pharmacologic ascorbate treatment at sublethal levels triggered a complex, multi-phasic response in tumor oxygenation across both cell lines. Initially, ascorbate generated transient hypoxia within minutes through hydrogen peroxide production, via reactions that consume oxygen. This initial hypoxic phase peaked at around 150 s and then gradually subsided. However, at longer time scales (approximately 300 s) a vasodilation effect triggered by ascorbate resulted in increased blood flow and subsequent reoxygenation. Combining sublethal levels of i. p. Ascorbate with evofosfamide significantly prolonged tumor doubling time in MIA Paca-2 and A549 xenografts compared to either treatment alone. This improvement, however, was only observed in a subpopulation of tumors, highlighting the complexity of the oxygenation response. [Display omitted] • Hypoxia targeting drugs like evofosfamide target tumors resistant to radiation and other treatments. • Transiently increasing hypoxia can increase the effectiveness of hypoxia targeting drugs. • Hydrogen peroxide production from ascorbate transiently consumes oxygen. • At longer time scales, ascorbate causes vasodilation reversing the temporary hypoxia. • Ascorbate with evofosfamide significantly slowed tumor growth compared to either treatment alone. [ABSTRACT FROM AUTHOR]

The skin is made up of different layers with various gradients, which maintain a complex microenvironment, particularly in terms of oxygen levels. However, all types of skin cells are cultured in conventional incubators that do not reproduce physiological oxygen levels. Instead, they are cultured at atmospheric oxygen levels, a condition that is far removed from physiology and may lead to the generation of free radicals known to induce skin ageing. This review aims to summarize the current literature on the effect of physiological oxygen levels on skin cells, highlight the shortcomings of current in vitro models, and demonstrate the importance of respecting skin oxygen levels. We begin by clarifying the terminology used about oxygen levels and describe the specific distribution of oxygen in the skin. We review and discuss how skin cells adapt their oxygen consumption and metabolism to oxygen levels environment, as well as the changes that are induced, particularly, their redox state, life cycle and functions. We examine the effects of oxygen on both simple culture models and more complex reconstructed skin models. Finally, we present the implications of oxygen modulation for a more therapeutic approach. [Display omitted] • Skin cells are physiologically in a microenvironment poor in oxygen called physioxia. • Skin physioxia is not taken into account in in vitro models. • Physioxia affects cutaneous cell metabolism. • Physioxia impacts skin cell proliferation, differentiation and senescence. • Physioxia modulates skin cell migration, pigmentation and angiogenesis. [ABSTRACT FROM AUTHOR]

The number of people who run to achieve competitive performance has increased, encouraging the scientific community to analyze the association of factors that can affect a runner performance. Is there association between running spatiotemporal and angular kinematics with the physiological markers of endurance performance during a cardiorespiratory exercise test? This was an observational cross-sectional study with 40 distance runners simultaneously submitted to a running biomechanical analysis and cardiorespiratory exercise test on a treadmill. Mixed models were developed to verify the association between angular kinematic data obtained by the Movement Deviation Profile and the running spatiotemporal data with oxygen consumption and ventilatory thresholds. Spatiotemporal variables [.e., step frequency Odds Ratio 0.09 [0.06–0.12 95 % Confidence Interval], center of mass vertical displacement Odds Ratio 0.10 [0.07–0.14 95 % Confidence Interval], and step length [Odds Ratio −0.01 [-0.01 to −0.00 95 % Confidence Interval]] were associated with VO 2. Also, step frequency Odds Ratio 1.03 [1.01–1.05 95 % Confidence Interval] was associated with the first ventilatory threshold, and angular running kinematics [Movement Deviation Profile analysis] Odds Ratio 1.47 [1.13–1.91 95 % Confidence Interval] was associated with peak of exercise during the cardiorespiratory exercise test. Our findings demonstrated that: both higher step frequency and center of mass vertical displacement are associated with the increase of oxygen demand; step frequency is associated with the first ventilatory threshold, due to the entrainment mechanism and angular kinematic parameters are associated with peak aerobic speed. Future studies could also compare the biomechanical and physiological characteristics of different groups of distance runners. This could help identify the factors that contribute to oxygen demands during running and performance across different ages, genders, and levels of competition. • Study examines running kinematics and endurance performance. • Spatiotemporal variables affect oxygen consumption and VT1. • Angular kinematics (MDP analysis) was associated with peak of exercise and speed. • Findings suggest ways to improve running economy and performance. [ABSTRACT FROM AUTHOR]

A structural homolog of the mammalian TSPO has been identified in the human pathogen Bacillus cereus. BcTSPO, in its recombinant form, has previously been shown to bind and degrade porphyrins. In this study, we generated a Δ tspO mutant strain in B. cereus ATCC 14579 and assessed the impact of the absence of BcTSPO on cellular proteomics and physiological characteristics. The proteomic analysis revealed correlations between the lack of BcTSPO and the observed growth defects, increased oxygen consumption, ATP deficiency, heightened tryptophan catabolism, reduced motility, and impaired biofilm formation in the Δ tspO mutant strain. Our results also suggested that BcTSPO plays a crucial role in regulating intracellular levels of metabolites from the coproporphyrin-dependent branch of the heme biosynthetic pathway. This regulation potentially underlies alterations in the metabolic landscape, emphasizing the pivotal role of BcTSPO in B. cereus aerobic metabolism. Notably, our study unveils, for the first time, the involvement of TSPO in tryptophan metabolism. These findings underscore the multifaceted role of TSPO, not only in metabolic pathways but also potentially in the microorganism's virulence mechanisms. [Display omitted] • BcTSPO plays a pivotal role energy metabolism. • BcTSPO plays a crucial role in tryptophan metabolism. • BcTSPO contributes significantly to the oxidative stress response. • BcTSPO is involved in physiological processes such as motility and biofilm formation. • BcTSPO regulates the levels of free porphyrins. [ABSTRACT FROM AUTHOR]

Ischemic stroke-induced mitochondrial dysfunction in the blood-brain barrier-forming brain endothelial cells (BECs) results in long-term neurological dysfunction post-stroke. We previously reported data from a pilot study where intravenous administration of human BEC (hBEC)-derived mitochondria-containing extracellular vesicles (EVs) showed a potential efficacy signal in a mouse middle cerebral artery occlusion (MCAo) model of stroke. We hypothesized that EVs harvested from donor species homologous to the recipient species (e.g. , mouse) may improve therapeutic efficacy, and therefore, use of mouse BEC (mBEC)-derived EVs may improve post-stroke outcomes in MCAo mice. We investigated potential differences in the mitochondria transfer of EVs derived from the same species as the recipient cell (mBEC-EVs and recipient mBECs or hBECs-EVs and recipient hBECs) vs. cross-species EVs and recipient cells (mBEC-EVs and recipient hBECs or vice versa). Our results showed that while both hBEC- and mBEC-EVs transferred EV mitochondria, mBEC-EVs outperformed hBEC-EVs in increasing ATP levels and improved recipient mBEC mitochondrial function via increasing oxygen consumption rates. mBEC-EVs significantly reduced brain infarct volume and neurological deficit scores compared to vehicle-injected MCAo mice. The superior therapeutic efficacy of mBEC-EVs in MCAo mice support the continued use of mBEC-EVs to optimize the therapeutic potential of mitochondria-containing EVs in preclinical mouse models. [Display omitted] [ABSTRACT FROM AUTHOR]

Iron homeostasis is essential for maintaining metabolic health and iron disorder has been linked to chronic metabolic diseases. Increasing thermogenic capacity in adipose tissue has been considered as a potential approach to regulate energy homeostasis. Both mitochondrial biogenesis and mitochondrial function are iron-dependent and essential for adipocyte thermogenic capacity, but the underlying relationships between iron accumulation and adipose thermogenesis is unclear. Firstly, we confirmed that iron homeostasis and the iron regulatory markers (e.g., Tfr1 and Hfe) are involved in cold-induced thermogenesis in subcutaneous adipose tissues using RNA-seq and bioinformatic analysis. Secondly, an Hfe (Hfe−/−)-deficient mouse model, in which tissues become overloaded with iron, was employed. We found iron accumulation caused by Hfe deficiency enhanced mitochondrial respiratory chain expression in subcutaneous white adipose in vivo and resulted in enhanced tissue thermogenesis with upregulation of PGC-1α and adipose triglyceride lipase, mitochondrial biogenesis and lipolysis. To investigate the thermogenic capacity in vitro, stromal vascular fraction from adipose tissues was isolated, followed with adipogenic differentiation. Primary adipocyte from Hfe−/− mice exhibited higher cellular oxygen consumption, associated with enhanced expression of mitochondrial oxidative respiratory chain protein, while primary adipocytes or stromal vascular fractions from WT mice supplemented with iron citrate) exhibited similar effect in thermogenic capacity. Taken together, these findings indicate iron supplementation and iron accumulation (Hfe deficiency) can regulate adipocyte thermogenic capacity, suggesting a potential role for iron homeostasis in adipose tissues. [ABSTRACT FROM AUTHOR]

Podocytes are crucial for regulating glomerular permeability. They have foot processes that are integral to the renal filtration barrier. Understanding their energy metabolism could shed light on the pathogenesis of filtration barrier injury. Lactate has been increasingly recognized as more than a waste product and has emerged as a significant metabolic fuel and reserve. The recent identification of lactate transporters in podocytes, the expression of which is modulated by glucose levels and lactate, highlights lactate's relevance. The present study investigated the impact of lactate on podocyte respiratory efficiency and mitochondrial dynamics. We confirmed lactate oxidation in podocytes, suggesting its role in cellular energy production. Under conditions of glucose deprivation or lactate supplementation, a significant shift was seen toward oxidative phosphorylation, reflected by an increase in the oxygen consumption rate/extracellular acidification rate ratio. Notably, lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB) isoforms, which are involved in lactate conversion to pyruvate, were detected in podocytes for the first time. The presence of lactate led to higher intracellular pyruvate levels, greater LDH activity, and higher LDHB expression. Furthermore, lactate exposure increased mitochondrial DNA-to-nuclear DNA ratios and resulted in upregulation of the mitochondrial biogenesis markers peroxisome proliferator-activated receptor coactivator-1α and transcription factor A mitochondrial, regardless of glucose availability. Changes in mitochondrial size and shape were observed in lactate-exposed podocytes. These findings suggest that lactate is a pivotal energy source for podocytes, especially during energy fluctuations. Understanding lactate's role in podocyte metabolism could offer insights into renal function and pathologies that involve podocyte injury. [Display omitted] • Lactate serves as an important precursor for cellular energy production in podocytes. • Lactate stimulation alters mitochondrial dynamics and respiratory efficiency. • Lactate augments mitochondrial biogenesis in podocytes. • Lactate regulates LDH isoforms expression and activity in podocytes. [ABSTRACT FROM AUTHOR]

Cancer of the head and neck encompasses a wide range of cancers, including oral and oropharyngeal cancers. Oral cancer is often diagnosed at advanced stages and has a dismal prognosis. Piscidin-1, a marine antimicrobial peptide (AMP) containing approximately 22 amino acids, also exhibits significant anticancer properties. We investigated the possible anti-oral cancer effects of piscidin-1 and clarified the mechanisms underlying these effects. We treated the oral squamous cell carcinoma cell lines OC2 and SCC4 with piscidin-1. Cell viability and the expression of different hallmark apoptotic molecules, including reactive oxygen species (ROS), were tested using the appropriate MTT assay, flow cytometry and western blotting assays, and human umbilical vein endothelial cell (HUVEC) wound healing, migration, and tube formation (angiogenesis) assays. Piscidin-1 increases cleaved caspase 3 levels to induce apoptosis. Piscidin-1 also increases ROS levels and intensifies oxidative stress in the endoplasmic reticulum and mitochondria, causing mitochondrial dysfunction. Additionally, it decreases the oxygen consumption rates and activity of mitochondrial complexes I–V. As expected, the antioxidants MitoTEMPOL and N-acetylcysteine reduce piscidin-1–induced ROS generation and intracellular calcium accumulation. Piscidin-1 also inhibits matrix metalloproteinase (MMP)-2/-9 expression in HUVECs, affecting migration and tube formation angiogenesis. We demonstrated that piscidin-1 can promote apoptosis via both intrinsic and extrinsic apoptotic pathways and findings indicate that piscidin-1 has anti-proliferative and anti-angiogenic properties in oral cancer treatment. Our study on piscidin-1 thus provides a basis for future translational anti-oral cancer drug research and a new theoretical approach for anti-oral cancer clinical research. [Display omitted] • Piscidin-1 cleaves caspase 3 and induces apoptosis via intrinsic/extrinsic pathways. • Piscidin-1 decreased mitochondrial function, ΔΨ m , and the OXPHOS complex protein. • In OSCC cells, piscidin-1 raises intracellular Ca2+ and causes ER stress. • MitoTEMPOL and NAC mitigated the mtROS and Ca2+ caused by piscidin-1. • Piscidin-1 reduces angiogenesis in HUVECs, which is anti-tumor. [ABSTRACT FROM AUTHOR]

Loss of glycogen myophosphorylase (PYGM) expression results in an inability to break down muscle glycogen, leading to McArdle disease—an autosomal recessive metabolic disorder characterized by exercise intolerance and muscle cramps. While previously considered relatively benign, this condition has recently been associated with pattern dystrophy in the retina, accompanied by variable sight impairment, secondary to retinal pigment epithelial (RPE) cell involvement. However, the pathomechanism of this condition remains unclear. In this study, we generated a PYGM-null induced pluripotent stem cell line and differentiated it into mature RPE to examine structural and functional defects, along with metabolite release into apical and basal media. Mutant RPE exhibited normal photoreceptor outer segment phagocytosis but displayed elevated glycogen levels, reduced transepithelial resistance, and increased cytokine secretion across the epithelial layer compared to isogenic WT controls. Additionally, decreased expression of the visual cycle component, RDH11, encoding 11-cis-retinol dehydrogenase, was observed in PYGM-null RPE. While glycolytic flux and oxidative phosphorylation levels in PYGM-null RPE were near normal, the basal oxygen consumption rate was increased. Oxygen consumption rate in response to physiological levels of lactate was significantly greater in WT than PYGM-null RPE. Inefficient lactate utilization by mutant RPE resulted in higher glucose dependence and increased glucose uptake from the apical medium in the presence of lactate, suggesting a reduced capacity to spare glucose for photoreceptor use. Metabolic tracing confirmed slower 13C-lactate utilization by PYGM-null RPE. These findings have key implications for retinal health since they likely underlie the vision impairment in individuals with McArdle disease. [ABSTRACT FROM AUTHOR]

• Water-insoluble CoQ 10 was selectively delivered to the mitochondria in rat skeletal muscle cells. • CoQ 10 delivery to skeletal muscle cell mitochondria enhanced mitochondrial respiratory capacity. • The increased mitochondrial respiratory capacity may be associated with antioxidative effects. • The CoQ 10 , for the first time, has been delivered to the mitochondria of skeletal muscle cells for mitochondrial functional activation. Numerous mitochondria are present in skeletal muscle cells. Muscle disease and aging impair mitochondrial functioning in the skeletal muscle. However, there have been few reports of therapeutic intervention via drug delivery to mitochondria owing to methodological difficulties. We surmised that mitochondrial activation is associated with improved skeletal muscle function. In this study, we attempted to activate the mitochondrial respiratory capacity in rat skeletal muscle cells (L6 cells) by delivering Coenzyme Q 10 (CoQ 10), a mitochondrial functional activator, to mitochondria using MITO-Porter, a nanoparticle that facilitates mitochondria-targeted drug delivery. Cellular uptake was confirmed by measuring the amount of fluorescence-modified MITO-Porter taken up by cells using flow cytometry. Intracellular dynamics of MITO-Porter was observed using confocal laser scanning microscopy. Mitochondrial function was assessed by measuring the mitochondrial oxygen consumption rate using an extracellular flux analyzer. The results indicated MITO-Porter-assisted delivery of CoQ 10 to the mitochondria activated mitochondrial respiratory capacity in L6 cells. We believe that our results indicate the possibility of skeletal muscle therapy using mitochondrial drug delivery. [ABSTRACT FROM AUTHOR]

The next-generation energy economy relies heavily on hydrogen. Handling hydrogen during production, storage, and transportation requires risk mitigation. In this regard, the application of halide-free additives is very crucial. The present study experimentally and theoretically investigates the individual and combined inhibiting effect of propane and propene on hydrogen-air explosions. The experiments are carried out at 298 K and 1 bar, with additives ranging from 0.5 to 5% for the individual and 1–2% each for the combined effect in the 20–50% hydrogen-air mixture. Experimentally, the additive content in the stoichiometric and rich mixture decreases the explosion pressure, maximum pressure rise (MPR) rate, laminar burning velocity (LBV), and flame temperature, while increasing minimum ignition energy. For instance, the addition of 2% propane in a 50% hydrogen-air mixture, reduces the MPR rate by 98%, whereas such an effect is observed with 2.5% propene. Theoretical study shows that 3% equivalent additive augments inhibiting reactions, countering the main flame-promoting reaction R1 (H + O 2 O + OH) and thereby reducing LBV. Due to its low activation energy, propene consumes the active radicals twice the rate of propane, while propane not only scavenges the active radicals but also promotes oxygen consumption in the prior phase of combustion, weakening flame propagation. Overall, this approach exhibits a significant step forward in harnessing the potential of hydrogen while mitigating the safety risks associated with its use. [Display omitted] • The effect of C 3 -Hydrocarbons and their Mixtures on H2-air explosion is explored. • The additives decrease explosion pressure, MPR rate and LBV while increasing MIE. • Propene increases the consumption rate of active radicals in the additive mixtures. • Propane promotes oxygen consumption in the prior phase of combustion, countering R1. [ABSTRACT FROM AUTHOR]

Because of its advantageous band gap and band edge, BiVO 4 is thought to be a viable photoanode for photoelectrochemical (PEC) water splitting. However, its photoelectrochemical water splitting capability is primarily restricted by photogenerated carrier recombination. In order to address this issue, a hole storage layer (HSL) VO 2 was deposited onto a W-doped BiVO 4 photoanode through photoelectric deposition in this study. During PEC water oxidation, the ultrathin VO 2 layer's reversible V4+ species can regulate the hole-storage process, improving hole extraction capacity and reducing charge recombination. As expected, under AM 1.5 G illumination, the optimized W–BiVO 4 /VO 2 /Co-Pi photoanode exhibits a photocurrent density of 5.6 mA/cm2 at 1.23 V vs. RHE with an onset potential of 0.28 V. This value exceeds pure BiVO 4 (1.1 mA/cm2) by around 409%. Based on results from experiments, the charge transfer efficiency of the W–BiVO 4 /VO 2 /Co-Pi photoanode reaches 96.3%, showing excellent PEC water splitting performance. • Preparation of VO 2 particles on BiVO 4 photoanodes by photoelectric deposition for the first time. • Cyclic voltammetry demonstrates that V4+ redox in VO 2 significantly enhances hole stroage and transfer. • W–BiVO 4 /VO 2 exhibits a leading 1.54% ABPE value, showing its superiority among HSL-modified photoanodes. • The W–BiVO 4 /VO 2 /Co-Pi photoelectrode's current density was 5.6 mA cm−2 at 1.23 V vs. RHE. [ABSTRACT FROM AUTHOR]

This study aimed to contribute towards improving athletic performance by comparing the effects of highly concentrated hydrogen intake before and during exercise on soccer players' metabolic and athletic performance. This study followed a single-blind crossover design involving 10 male college soccer players. Before this experiment, the V max measurement and experimental familiarization stage were performed through pretesting. The exercise load test in this experiment involved a long-term intermittent high-intensity exercise protocol that reflects the specificity of soccer. It consisted of seven cycles taking about 120 minutes. Placebo (mineral water) or highly concentrated hydrogen water was administered 30 min before the exercise load test. The study revealed that, regarding the respiratory gas variable Respiratory Exchange Ratio (RER), the placebo intake experiment at exercise awareness was higher than that of the hydrogen water intake experiment (P < 0.05). There was no difference between the two experiments in terms of oxygen consumption (VO 2) and carbon dioxide production (VCO 2) (P > 0.05). Fat oxidation during exercise (P < 0.05), and running distance were higher after hydrogen water intake than after placebo, while running time, carbohydrate oxidation, active oxygen, and heart rate (P < 0.05) were higher after placebo than hydrogen water. The hydrogen water intake experiment in running distance and running time of exercise performance was higher than that of the placebo intake experiment (P < 0.05). The results of this study suggest that the intake of highly concentrated hydrogen water improves the ability to perform global motion and reduces the oxidative damage caused by active oxygen. [ABSTRACT FROM AUTHOR]

There is a paucity of experimental and mathematical models that take the extracellular and cellular components of the tumour microenvironment into account. Basic models only integrate cancer cells in isolation of the stromal and matrix surrounding and are flawed due to the lack of cancer-supporting cells and factors of the extracellular matrix, which are both essential for cell–cell and cell–matrix interactions and to produce metabolites that fuel cancer cells. The tumour microenvironment has a poor oxygen diffusion, low nutrient levels, and high interstitial pressure and, as a consequence, to exist in this nutrient-limiting conditions, cancer cells reprogram their metabolism, uptake of glucose, and mitochondrial pathways. We summarise approaches to model the metabolic crosstalk within the tumour microenvironment from a biological, engineering, and mathematical perspective, by discussing the perspectives and limitations. Biomaterial-based platforms and tumour-engineered systems are better approaches to model the tumour metabolism. Tumours are heterogeneous tissues containing diverse populations of cells and an abundant extracellular matrix (ECM). This tumour microenvironment prompts cancer cells to adapt their metabolism to survive and grow. Besides epigenetic factors, the metabolism of cancer cells is shaped by crosstalk with stromal cells and extracellular components. To date, most experimental models neglect the complexity of the tumour microenvironment and its relevance in regulating the dynamics of the metabolism in cancer. We discuss emerging strategies to model cellular and extracellular aspects of cancer metabolism. We highlight cancer models based on bioengineering, animal, and mathematical approaches to recreate cell–cell and cell–matrix interactions and patient-specific metabolism. Combining these approaches will improve our understanding of cancer metabolism and support the development of metabolism-targeting therapies. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the tubular function in an alloxan-induced type 1 diabetes mellitus (DM) rabbit model measured by renal oxygenation (R2*), oxygen extraction fraction (OEF), and renal blood flow (RBF) using blood oxygenation level dependent, asymmetric spin echo, and arterial spin labeling MRI. Methods Twenty-six rabbits were randomized into the 3-day DM group (n = 13) and the 7-day DM group (n = 13). We performed pairs of multiparametric MRIs (before and after furosemide injection) at baseline and 3/7 days post-DM, and scored pathological kidney injury. We performed statistical analyses using non-parametric, chi-square, and Spearman correlation tests. Results At baseline, medullary R2* significantly decreased by 24.97% and 16.74% in the outer and inner stripes of the outer medulla (OS and IS, p = 0.006 and 0.003, respectively) after furosemide administration. While the corresponding OEF decreased by 15.91% for OS and 16.67% for IS (both p = 0.003), and no significant change in medullary RBF was observed (p > 0.05). In the 3-day DM group, the decrease of medullary R2* and OEF post-furosemide became unremarkable, suggesting tubular dysfunction. We noticed similar changes in the 7-day DM group. Correlation analysis showed pathological tubular injury score significantly correlated with medullary ∆ R 2 * (post-furosemide – pre-furosemide difference, r = 0.82 for OS and 0.82 for IS) and ∆ OEF (r = 0.82 for OS and 0.82 for IS) (p < 0.001, respectively). Conclusion: The combination of medullary OEF and R2* in response to furosemide could detect renal tubular dysfunction in early DM. [ABSTRACT FROM AUTHOR]

In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better V E /V co 2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of −2.1 (95% CI: −3.6 to −0.6; P = 0.006), with no significant difference in peak VO 2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: −2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study. [Display omitted] [ABSTRACT FROM AUTHOR]

Due to its high energy density, safety and low-cost, zinc ion batteries are considered as one of the alternatives to lithium-ion batteries. The metastable phase VO 2 (B) is a highly sought-after active material due to its high discharge specific capacity, remarkable rate performance, and rapid diffusion kinetics. Herein, VO 2 (B) nanorod materials are prepared using a novel solvothermal approach coupled with mechanical force assistance. The developed VO 2 (B) nanorod synthesized at 200 rpm (V@200 rpm) exhibit a substantial specific capacity of 300 mAh g−1 at 0.1 A g−1, excellent rate capability of 171 mAh g−1 at 2 A g−1 and prolonged cyclic stability (capacity fading rate of 0.025 per cycle after 1000 cycles), providing a straightforward and efficient approach to enhancing the capacity, rate performance, and cycle stability of ZIBs. [ABSTRACT FROM AUTHOR]

At work rate corresponds to heavy or severe exercise, a slowly developing component of the V ˙ O 2 response, named V ˙ O 2 slow component appear. A clear picture of the mechanism underlying the slow-component rise in V ˙ O 2 remains to be described. We argue in this article that the V ˙ O 2 slow component could be explained by a progressive lactate and pyruvate availability for mitochondria observed only when oxidative capacity of muscle is challenged (above lactate threshold). In this kind of exercise, the work rate requires the use of a large number of mitochondria that could only be involved when the pyruvate/lactate concentration in the cells is increased. This mechanism would then operate according to the law of mass action. The resynthesize of ATP should become progressively more aerobic than anaerobic. The hypothesis of a pyruvate/lactate concentration mechanism of V ˙ O 2 slow component needs further experimental validation. [ABSTRACT FROM AUTHOR]

Although VO 2 possesses an attractive theoretical specific capacity and a shear-type structure to resist lattice shear during repeated Zn2+ insertion/extraction, its poor electrical conductivity, easy self-aggregation, and inferior stability lead to sluggish reaction kinetics and unsatisfactory Zn2+ storage performance. In this work, we successfully constructed novel 2D VO 2 nanoplates embedded in a carbon matrix (VO 2 /carbon) utilizing a straightforward hydrothermal approach without using any template or calcination procedure. The thickness of the carbon layer can be tuned by modulating the experimental conditions. Impressively, the obtained 2D VO 2 /carbon with the optimal thickness of the carbon layer displayed satisfactory cyclic stability (63 % capacity maintained after 2500 cycles at 3 A g-1), excellent rate capability (202 mAh g-1 at 5 A g-1), and high specific capacity (501 mAh g-1 at 0.1 A g-1) as cathode material for aqueous zinc ion batteries (ZIBs), attributed to the desirable 2D nanoplate structure that offers effective pathways for Zn2+ diffusion together with sufficient electroactive sites for redox reactions and moderate carbon coating that buffers the volume changes in the course of repeated insertion/extraction of Zn2+ and accelerates charge/ion transfer. Furthermore, two assembled Zn//VO 2 /carbon coin cells successfully lit an orange light-emitting diode (LED) light for over 5 h, highlighting their potential as ideal candidates for low-cost, high-performance, environmentally friendly, and intrinsically safe energy storage devices. [ABSTRACT FROM AUTHOR]

Rechargeable Mg-ion batteries (MIBs) have attracted much more attentions by virtue of the high capacity from the two electrons chemistry. However, the reversible Mg2+ diffusion in cathode materials is restricted by the strong interactions between the high-polarized bivalent Mg2+ ions and anionic lattice. Herein, we design and propose a hetero-structural VO 2 (R)-VS 4 cathode, in which the re-delocalized d -electrons can effectively shield the polarity of Mg2+ ions. Theoretically, the electrons should spontaneously transfer from VS 4 to VO 2 (R) through the interfaces of hetero-structure due to the lower work function value of VS 4. Furthermore, the internal electrons transfer lead to the electronic injection into VO 2 (R) from VS 4 and the partially broken V-V dimers, indicating the presence of lone pair electrons and charge re-delocalization. Benefiting from the shield effect of re-delocalized electrons, and the weakened attraction between cations and O/S anions enables more S2−-S 2 2− redox groups to participate the electrochemical reactions and compensate the double charge of Mg2+ ions. Accordingly, VO 2 (R)-VS 4 hetero-structure exhibits a high specific capacity of 554 mA h g−1 at 50 mA g−1. It is believed that the charge re-delocalization of cathode extremely boost the Mg2+ ions migration for the high-capacity of MIBs. [ABSTRACT FROM AUTHOR]

[Display omitted] Sublethal levels of antibiotics commonly fail to directly inhibit the growth of pathogenic bacteria due to the distribution, metabolism, and excretion in vivo. However, certain antibiotics at such sublethal levels potentiate the bactericidal activity of host macrophages to accelerate the clearance of intracellular pathogens, contributing to the understanding of the post-antibiotic effect. • Immunoregulation of antibiotics on macrophages was investigated to develop a mechanistic understanding of postantibiotic leukocyte enhancement (PALE). • Enrofloxacin reduced the intracellular burden of diverse bacterial pathogens by promoting the accumulation of reactive oxygen species (ROS) and regulating the spatiotemporal localization of myeloperoxidase (MPO). • Enrofloxacin upregulated oxidative stress of macrophages by modulating the electron transport chain and reducing the expression of catalase. • Dysfunctional topoisomerase II downregulated the expression of ATF4 in macrophages. Potentiation of the bactericidal activities of leukocytes, including macrophages, upon antibacterial agent administration has been observed for several decades and is summarized as the postantibiotic leukocyte enhancement (PALE) theory. Antibiotics-induced bacterial sensitization to leukocytes is commonly recognized as the mechanism of PALE. However, the degree of sensitization drastically varies with antibiotic classes, and little is known about whether and how the potentiation of leukocytes contributes to PALE. In this study, we aim to develop a mechanistic understanding of PALE by investigating the immunoregulation of traditional antibiotics on macrophages. Interaction models between bacteria and macrophages were constructed to identify the effects of different antibiotics on the bactericidal activities of macrophages. Oxygen consumption rate, expression of oxidases, and antioxidants were then measured to evaluate the effects of fluoroquinolones (FQs) on the oxidative stress of macrophages. Furthermore, the modulation in endoplasmic reticulum stress and inflammation upon antibiotic treatment was detected to analyze the mechanisms. At last, the peritoneal infection model was utilized to verify the PALE in vivo. Enrofloxacin significantly reduced the intracellular burden of diverse bacterial pathogens through promoting the accumulation of reactive oxygen species (ROS). The upregulated oxidative response accordingly reprograms the electron transport chain with decreased production of antioxidant enzymes to reduce internalized pathogens. Additionally, enrofloxacin modulated the expression and spatiotemporal localization of myeloperoxidase (MPO) to facilitate ROS accumulation to target invaded bacteria and downregulated inflammatory response to alleviate cellular injury. Our findings demonstrate the crucial role of leukocytes in PALE, shedding light on the development of new host-directed antibacterial therapies and the design of rational dosage regimens. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by elevated circulating blood metabolites such as glucose, insulin, and branched chain amino acids (BCAA), which often coincide with reduced mitochondrial function. 4-Phenylbutyrate (PBA), an ammonia scavenger, has been shown to activate BCAA metabolism, resolve endoplasmic reticulum (ER) stress, and rescue BCAA-mediated insulin resistance. To determine the effect of PBA on the altered metabolic phenotype featured in type 2 diabetes, the present study investigated the effect of PBA on various metabolic parameters including mitochondrial metabolism and mitochondrial biogenesis. C2C12 myotubes were treated with PBA at 0.5 mM (representing physiologically attainable blood concentrations) or 10 mM (representing physiologically unattainable/proof-of-concept levels) for up to 24 h. Mitochondrial and glycolytic metabolism were assessed via oxygen consumption and extracellular acidification rate, respectively. Mitochondrial content, lipid content, and ER stress were measured by fluorescent staining. Metabolic gene expression was measured by qRT-PCR. Both doses of PBA increased expression of indicators of mitochondrial biogenesis, though only PBA at 0.5 mM increased mitochondrial function and content while 10 mM PBA reduced mitochondrial function and content. PBA at 0.5 mM also rescued reduced mitochondrial function during insulin resistance, though PBA also caused a reduced insulin stimulated pAkt expression during insulin resistance. PBA treatment also increased extracellular BCAA accumulation during insulin resistance despite unchanged pBCKDH expression. Taken together, PBA may increase mitochondrial biogenesis, content, and function in a dose-dependent fashion which may have implications for prevention or treatment of metabolic disease such as insulin resistance. • 4-Phenylbutyrate dose-dependently increased myotube mitochondrial biogenesis and function. • 4-Phenylbutyrate rescued myotube mitochondrial function during insulin resistance. • Low-levels of 4-Phenylbutyrate increased extracellular BCAA accumulation during insulin resistance. [ABSTRACT FROM AUTHOR]

In the present study, we examined the mitochondrial hydrogen peroxide (mH2O2) generating capacity of α-ketoglutarate dehydrogenase (KGDH) and compared it to components of the electron transport chain using liver mitochondria isolated from male and female C57BL6N mice. We show for the first time there are some sex dimorphisms in the production of mH2O2 by electron transport chain complexes I and III when mitochondria are fueled with different substrates. However, in our investigations into these sex effects, we made the unexpected and compelling discovery that 1) KGDH serves as a major mH2O2 supplier in male and female liver mitochondria and 2) KGDH can form mH2O2 when liver mitochondria are energized with fatty acids but only when malate is used to prime the Krebs cycle. Surprisingly, 2-keto-3-methylvaleric acid (KMV), a site-specific inhibitor for KGDH, nearly abolished mH2O2 generation in both male and female liver mitochondria oxidizing palmitoyl-carnitine. KMV inhibited mH2O2 production in liver mitochondria from male and female mice oxidizing myristoyl-, octanoyl-, or butyryl-carnitine as well. S1QEL 1.1 (S1) and S3QEL 2 (S3), compounds that inhibit reactive oxygen species generation by complexes I and III, respectively, without interfering with OxPhos and respiration, had a negligible effect on the rate of mH2O2 production when pyruvate or acyl-carnitines were used as fuels. However, inclusion of KMV in reaction mixtures containing S1 and/or S3 almost abolished mH2O2 generation. Together, our findings suggest KGDH is the main mH2O2 generator in liver mitochondria, even when fatty acids are used as fuel. [ABSTRACT FROM AUTHOR]

What are the effects of different types of exercise treatments on oxygen consumption, quality of life and mortality in people with coronary heart disease? Systematic review with network meta-analysis of randomised controlled trials. Adults with coronary heart disease. Exercise interventions including aerobic (continuous or high-intensity interval) training, resistance training, respiratory muscle exercises, water-based exercises, yoga, Tai chi, Qigong exercises and a combination of different types of exercise. Oxygen consumption, quality of life and mortality. This review included 178 randomised controlled trials with 19,143 participants. Several exercise interventions improved peak oxygen consumption (mL/kg/min): high-intensity interval training (MD 4.5, 95% CI 3.7 to 5.4); combined water-based exercises and moderate-intensity continuous training (MD 3.7, 95% CI 1.3 to 6.0); combined aerobic and resistance exercise (MD 3.4, 95% CI 2.5 to 4.3); water-based exercises (MD 3.4, 95% CI 0.6 to 6.2); combined respiratory muscle training and aerobic exercise (MD 3.2, 95% CI 0.6 to 5.8); Tai chi (MD 3.0, 95% CI 1.0 to 5.0); moderate-intensity continuous training (MD 3.0, 95% CI 2.3 to 3.6); high-intensity continuous training (MD 2.7, 95% CI 1.6 to 3.8); and resistance training (MD 2.2, 95% CI 0.6 to 3.7). Quality of life was improved by yoga (SMD 1.5, 95% CI 0.5 to 2.4), combined aerobic and resistance exercise (SMD 1.2, 95% CI 0.6 to 1.7), moderate-intensity continuous training (SMD 1.1, 95% CI 0.6 to 1.6) and high-intensity interval training (SMD 0.9, 95% CI 0.1 to 1.6). All-cause mortality was reduced by continuous aerobic exercise (RR 0.67, 95% CI 0.53 to 0.86) and combined aerobic and resistance exercise (RR 0.58, 95% CI 0.36 to 0.94). Continuous aerobic exercise also reduced cardiovascular mortality (RR 0.56, 95% CI 0.42 to 0.74). People with coronary heart disease may use a range of exercise modalities to improve oxygen consumption, quality of life and mortality. PROSPERO CRD42022344545. [ABSTRACT FROM AUTHOR]

Oxygen consumption (VO 2), carbon dioxide generation (VCO 2), and respiratory quotient (RQ), which is the ratio of VO 2 to VCO 2 , are critical indicators of human metabolism. To seek a link between the patient's metabolism and pathophysiology of critical illness, we investigated the correlation of these values with mortality in critical care patients. This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Age 18 years or older healthy volunteers and patients who underwent mechanical ventilation were enrolled. A high-fidelity automation device, which accuracy is equivalent to the gold standard Douglas Bag technique, was used to measure VO 2 , VCO 2 , and RQ at a wide range of fraction of inspired oxygen (F I O 2). We included a total of 21 subjects including 8 post-cardiothoracic surgery patients, 7 intensive care patients, 3 patients from the emergency room, and 3 healthy volunteers. This study included 10 critical care patients, whose metabolic measurements were performed in the ER and ICU, and 6 died. VO 2 , VCO 2 , and RQ of survivors were 282 +/− 95 mL/min, 202 +/− 81 mL/min, and 0.70 +/− 0.10, and those of non-survivors were 240 +/− 87 mL/min, 140 +/− 66 mL/min, and 0.57 +/− 0.08 (p = 0.34, p = 0.10, and p < 0.01), respectively. The difference of RQ was statistically significant (p < 0.01) and it remained significant when the subjects with F I O 2 < 0.5 were excluded (p < 0.05). Low RQ correlated with high mortality, which may potentially indicate a decompensation of the oxygen metabolism in critically ill patients. [ABSTRACT FROM AUTHOR]

Skeletal muscle is a heterogeneous tissue composed of different types of muscle fibers, demonstrating substantial plasticity. Physiological or pathological stimuli can induce transitions in muscle fiber types. However, the precise regulatory mechanisms behind these transitions remains unclear. This paper reviews the classification and characteristics of muscle fibers, along with the classical mechanisms of muscle fiber type transitions. Additionally, the role of exercise-induced muscle fiber type transitions in disease intervention is reviewed. Epigenetic pathways mediate cellular adaptations and thus represent potential targets for regulating muscle fiber type transitions. This paper focuses on the mechanisms by which epigenetic modifications couple mitochondrial function and contraction characteristics. Reactive Oxygen Species (ROS) are critical signaling regulators for the health-promoting effects of exercise. Finally, we discuss the role of exercise-induced ROS in regulating epigenetic modifications and the transition of muscle fiber types. [Display omitted] • Contractile property couples to metabolic capacity in muscle fiber type transition. • Epigenetic machinery couples muscle contractile property to mitochondrial function. • Exercise modulates epigenetic machinery through the ROS/AMPK pathway. [ABSTRACT FROM AUTHOR]

The monitoring of acidosis and hypoxia is crucial because both factors promote cancer progression and impact the efficacy of anti-cancer treatments. A phosphonated tetrathiatriarylmethyl (pTAM) has been previously described to monitor both parameters simultaneously, but the sensitivity to tackle subtle changes in oxygenation was limited. Here, we describe an innovative approach combining the pTAM radical and lithium phthalocyanine (LiPc) crystals to provide sensitive simultaneous measurements of extracellular pH (pH e) and pO 2. Both parameters can be measured simultaneously as both EPR spectra do not overlap, with a gain in sensitivity to pO 2 variations by a factor of 10. This procedure was applied to characterize the impact of carbogen breathing in a breast cancer 4T1 model as a proof-of-concept. No significant change in pH e and pO 2 was observed using pTAM alone, while LiPc detected a significant increase in tumor oxygenation. Interestingly, we observed that pTAM systematically overestimated the pO 2 compared to LiPc. In addition, we analyzed the impact of an inhibitor (UK-5099) of the mitochondrial pyruvate carrier (MPC) on the tumor microenvironment. In vitro , the exposure of 4T1 cells to UK-5099 for 24 h induced a decrease in pH e and oxygen consumption rate (OCR). In vivo , a significant decrease in tumor pH e was observed in UK-5099-treated mice, while there was no change for mice treated with the vehicle. Despite the change observed in OCR, no significant change in tumor oxygenation was observed after the UK-5099 treatment. This approach is promising for assessing in vivo the effect of treatments targeting tumor metabolism. [Display omitted] • Acidosis and hypoxia are detrimental factors in cancer progression. • Innovative EPR procedure to measure extracellular pH and pO 2 simultaneously. • Using both LiPc with pTAM allows a gain in sensitivity to oxygen variations by a factor of 10. • Proof-of-concept studies using carbogen breathing and MPC inhibition. [ABSTRACT FROM AUTHOR]

Slowing down or stopping the natural process of cataractogenesis is certainly a challenge for those who today propose an option other than surgery. Addressing the same problem in different ways constitutes a new approach to solving what is today the number one cause of reversible blindness worldwide. The technological revolution, as well as the advances in the biological sciences, allows us to conceive mechanisms never thought of before to stop the process that, as a common pathway, constitutes opacification of the crystalline lens. A new dawn for cataracts is coming through molecular, newly-discovered mechanisms. Cataractogenesis and molecular pathways have reactive free oxygen species as a common pathway. Surgical removal is today's gold standard, but perhaps not for much longer. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection (HFpEF) and diabetes mellitus (DM) commonly co-exist. However, it is unclear if DM modifies the haemodynamic and cardiometabolic phenotype in patients with HFpEF. We aimed to interrogate the haemodynamic and cardiometabolic effects of DM in HFpEF. We compared the haemodynamic and metabolic profiles of non-DM patients and patients with DM–HFpEF at rest and during exercise using right heart catheterisation and mixed venous blood gas analysis. Of 181 patients with HFpEF, 37 (20%) had DM. Patients with DM displayed a more adverse exercise haemodynamic response vs HFpEF alone (mean pulmonary arterial pressure: 47 mmHg [interquartile range {IQR} 42–55] vs 42 [38–47], p<0.001; workload indexed pulmonary capillary wedge pressure indexed: 0.80 mmHg/W [0.44–1.23] vs 0.57 [0.43–1.01], p=0.047). HFpEF–DM patients had a lower mixed venous oxygen saturation at rest (70% [IQR 66 – 73] vs 72 [69–75], p=0.003) and were unable to enhance O 2 extraction to the same extent (Δ-28% [-33 to -15] vs -29 [-36 to -21], p=0.029), this occurred at a 22% lower median workload. Resting mixed venous lactate levels were higher in those with DM (1.5 mmol/L [IQR 1.1–1.9] vs 1 [0.9–1.3], p<0.001), and during exercise indexed to workload (0.09 mmol/L/W [0.06–0.13] vs 0.08 [0.05–0.11], p=0.018). Concurrent diabetes and HFpEF was associated with greater metabolic responses at rest, with enhanced wedge driven pulmonary hypertension and relative lactataemia during exercise without appropriate augmentation of oxygen consumption. [ABSTRACT FROM AUTHOR]

Postprandial metabolism is a relevant indicator of overall metabolic health, which can be influenced by a single bout of exercise before food consumption. The present study examined the effects of an acute, fasted, low-intensity exercise on postprandial metabolism and appetite sensations. We hypothesized that exercise would induce an increase in postprandial fat oxidation, associated with better satiety responses. Twenty-two healthy adults (16 females) attended the laboratory twice separated by a minimum of 3 days to perform 2 conditions: (1) a control condition and (2) an exercise condition (EX) with a 30-minute low-intensity walking exercise performed before the breakfast (500-kcal fixed meal). Subjective appetite sensations were assessed before and up to 60 minutes after the meal in regular intervals. Energy expenditure and substrate oxidation were measured until 2 hours after the meal. Energy expenditure and carbohydrate oxidation were higher in the EX condition (condition effect: P <.01). There was no effect of exercise on appetite sensations and overall fat oxidation, but a higher increase in relative and absolute fat oxidation was observed from 15- to 45-minutes postmeal in EX compared with control (time × condition interaction effect: P <.05). In the EX condition only, postprandial satiety was associated positively with postprandial fat oxidation and negatively with carbohydrate oxidation. To conclude, a fasted low-intensity exercise induced an enhancement of postprandial metabolic flexibility through the modulation of fat oxidation. Substrate oxidation appeared to be related to satiety only after exercise, suggesting a specific regulation of appetite induced by exercise. This study explored the effects of low-intensity exercise in a fasted state on postprandial satiety and energy metabolism, compared to a control condition. The exercise impacted significantly the postprandial energy expenditure and substrate oxidation, and although it did not modify the appetite sensations, significant correlations between satiety and substrate oxidation were observed after exercise, but not after the control condition. ↗: increase , →: associated with, CHO: carbohydrate. [Display omitted] [ABSTRACT FROM AUTHOR]

BHLHE40 is a basic helix-loop-helix transcription factor that is involved in multiple cell activities including differentiation, cell cycle, and epithelial-to-mesenchymal transition. While there is growing evidence to support the functions of BHLHE40 in energy metabolism, little is known about the mechanism. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed pyruvate dehydrogenase (PDH) activity and enhanced lactated dehydrogenase (LDH) activity were observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKa Thr172 and enhanced phosphorylation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) Ser293 and lactate dehydrogenase A (LDHA) Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKa phosphorylation by directly suppressing the transcription of an AMPKa-specific phosphatase, PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylatedAMPKa correlatedwith the prognosis of endometrial cancer patients. Because AMPK is a central regulator of energy metabolism in cancer cells, targeting the BHLHE40-PPM1F-AMPK axis may represent a strategy to control cancer development. [ABSTRACT FROM AUTHOR]