Oxygen Consumption Rate Research Articles

Study on the Parameters of Collaborative Fire Prevention by Plugging Air Leakage with Isolation Wall and Injecting Nitrogen in the Goaf of Re-Mining Working Face

ABSTRACT This study focuses on preventing coal spontaneous combustion in re-mining working face, using Yunhe Coal Mine as a case study. The investigation of spontaneous combustion characteristics in both new and re-mined coal samples revealed that the re-mined coal exhibits a higher oxygen consumption rate and greater heat release intensity compared to new mining coal. Through field observations and numerical simulations, the distribution range of oxidation zones in goaf within different zones of the re-mining working face was determined. Based on these findings, a collaborative fire prevention measure is proposed, involving plugging air leakage with isolation wall and injecting nitrogen into the goaf. The implementation of these fire prevention measures results in a reduction in the size of the oxidation zone, an increase in the size of the asphyxiation zone, and a decrease in the maximum temperature. To further enhance fire prevention efforts, it is recommended that distinct cooperative fire prevention parameters be established for both new mining zones and re-mining zones. These research findings provide a theoretical foundation for more efficient fire prevention measures in re-mining working face.

Influence of Mitochondrial NAD(P) + Transhydrogenase (NNT) on Hypothalamic Inflammation and Metabolic Dysfunction Induced by a High-Fat Diet in Mice.

The mitochondrial protein NAD(P)+ transhydrogenase (NNT) has been implicated in the metabolic derangements observed in obesity. Mice with the C57BL/6J genetic background bear a spontaneous mutation in the Nnt gene and are known to exhibit increased susceptibility to diet-induced metabolic disorders. Most of the studies on NNT in the context of diet-induced obesity have compared C57BL/6J mice with other mouse strains, where differences in genetic background can serve as confounding factors. Moreover, these studies have predominantly employed a high-fat diet (HFD) consisting of approximately 60% of calories from fat, which may not accurately mimic real-world fat-rich diets. In this study, we sought to examine the role of NNT in diet-induced hypothalamic inflammation and metabolic syndrome by using a congenic mice model lacking NNT, along with a HFD providing approximately 45% of calories from fat. Our findings indicate that mice lacking NNT were more protected from HFD-induced weight gain but presented a worse performance on glucose tolerance test, albeit not in insulin tolerance test. Interestingly, the brown adipose tissue of HFD-fed Nnt +/+ mice presented a greater mass and a higher whole-tissue ex-vivo oxygen consumption rate. Also, HFD increased the expression of the inflammatory markers Il1β, Tlr4 and Iba1 in the hypothalamus of Nnt -/- mice. In conclusion, our study highlights the importance of NNT in the context of diet-induced obesity and metabolic syndrome, indicating its contribution to mitigate hypothalamic inflammation and suggesting its role in the brown adipose tissue increased mass.

Simulated ischaemia/reperfusion impairs trophoblast function through divergent oxidative stress- and MMP-9-dependent mechanisms.

Early-onset pre-eclampsia is believed to arise from defective placentation in the 1st trimester, leading to placental ischaemia/reperfusion (I/R) and oxidative stress. However, our current understanding of the effects of I/R and oxidative stress on trophoblast function is ambiguous in part due to studies exposing trophoblasts to hypoxia instead of I/R, and which report conflicting results. Here we present a model of simulated ischaemia/reperfusion (SI/R) to recapitulate the pathophysiological events of early-onset PE, by exposing 1st trimester cytotrophoblast HTR-8/SVneo cells to a simulated ischaemia buffer followed by reperfusion. We examined different ischaemia and reperfusion times and observed that 1h ischaemia and 24h reperfusion induced an increase in reactive oxygen species (ROS) production (p < 0.0001) and oxygen consumption rate (p < 0.01). SI/R-exposed trophoblast cells exhibited deficits in migration, proliferation and invasion (p < 0.01). While the deficits in migration and proliferation were rescued by antioxidants, suggesting a ROS-dependent mechanism, the loss of invasion was not affected by antioxidants, which suggests a divergent ROS-independent pathway. In line with this, we observed a decrease in MMP-9, the key regulatory enzyme necessary for trophoblast invasion (p < 0.01), which was similarly unaffected by antioxidants, and pharmacological inhibition of MMP-9 replicated the phenotype of deficient invasion (p < 0.01). Collectively, these data demonstrate that I/R impairs trophoblast migration and proliferation via a ROS-dependent mechanism, and invasion via a ROS-independent loss of MMP-9, disambiguating the role of oxidative stress and providing insights into the response of trophoblasts to I/R in the context of early-onset PE.

Analysis of Physiological Oxygen Concentrations in Different Abdominal Fat Layers by Body Mass Index.

Physiological oxygen concentration in adipose tissue is closely linked to metabolic disorders such as chronic inflammation and insulin resistance. However, the nature of the variation in the oxygen levels of adipose tissue with body mass index (BMI) and depths of abdominal fat remain unclear. Therefore, this study aimed to elucidate the patterns of oxygen concentration in adipose tissue layers according to BMI. In this study, patients undergoing abdominal fat removal surgery were divided into the normal-weight (NW) or overweight-obese (OW) groups based on their BMI. Oxygen concentrations in abdominal superficial (sSAT) and deep subcutaneous adipose tissue (dSAT) were measured. The oxygen consumption rate, mean cell area, and capillary density in both tissue layers were compared between the two groups. Furthermore, the interaction between these three variables, BMI, and adipose tissue oxygen concentration, was analyzed using linear regression. A total of 42 patients were recruited in this study and we observed that oxygen concentration in the sSAT was significantly lower than in the dSAT, irrespective of BMI. In terms of the oxygen concentration in the dSAT, OW's was significantly lower than that of NW's. Linear regression analysis revealed a significant correlation between dSAT oxygen concentration and BMI, mean adipocyte area, and vascular density. Individuals who are obese have significantly lower oxygen levels in the deep abdominal adipose tissue, and this is influenced by BMI, adipocyte area, and capillary density. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

VLDL induces EZH2/PRC2 complex-mediated cellular senescence in metabolic syndrome to enhance cardiotoxicity

Abstract Introduction In metabolic syndrome, very-low-density lipoprotein (VLDL) carries cardiotoxic lipids that cannot be completely modified by lipid-lowering medications. VLDL isolated from patients with metabolic syndrome (ms-VLDL) induces cardiac remodeling compared with that isolated from non-metabolic syndrome subjects (n-VLDL). Purpose This study focused on identifying dysregulated molecular pathways of ms-VLDL-associated with senescence. Methods RNA-sequencing, accompanied with IPA and KEGG pathway analysis were used to identify differentially expressed genes (DEGs) in cardiomyocytes after two different VLDL incubations, and the identified DEGs were subjected to functional annotation, including enriched molecular pathway and gene ontology analyses. A Seahorse XFe96 Analyzer was used to determine the mitochondrial biosynthesis oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Molecules involved in the mitochondrial pathway were validated using Western blotting, qPCR, and immunofluorescence. Results Compared to the n-VLDL group, the ms-VLDL group had a larger number of significant DEGs involved in several critical biological processes and molecular pathways, such as cardiomyocyte injury (ms-VLDL vs. n-VLDL for significant DEGs numbers, 2,642 vs. 1,725), senescence (259 vs. 184), and mitochondrial dysfunction (137 vs. 68). In terms of mitochondrial biosynthetic function, ms-VLDL induced 8.5 folds OCR reduction compared to n-VLDL, along with intra-mitochondrial calcium overload and excessive ROS. The essential genes involved in these pathways were shown to be differentially regulated, and our analysis identified the Ezh2/PRC2 complex, which is strongly linked to ms-VLDL-induced cardiomyocyte senescence and lipotoxicity. Conclusion This study identified the crucial roles of epigenetic modification enzyme Ezh2/PRC2 complex in induction the senescence pathway, which represents a potential mechanism for ms-VLDL-induced adverse cardiac remodeling in metabolic syndrome. Further functional studies are required to validate their roles in the pathogenesis of lipotoxicity and the connection of cardiomyopahty.RNA-seq of VLDL treated cardiomyocyteSenescence induction of VLDL

The role of digital health intervention in improving physical activity in cardiac rehabilitation center: a randomised controlled trial

Abstract Background Physical activity plays a crucial role in cardiac rehabilitation for secondary prevention. Despite its importance, participation rates in cardiac rehabilitation programs remain low. Telemedicine, particularly telerehabilitation, presents a viable solution by offering remote access to cardiac rehabilitation services. This innovative approach has the potential to significantly enhance patient outcomes. Purpose This study aimed to assess the effectiveness of digital health intervention in improving physical activity in cardiac rehabilitation center. Methods A prospective randomised controlled trial was conducted, enrolling 80 eligible cardiac rehabilitation patients. Participants were 1:1 randomised into two groups: a 12-week center-based cardiac rehabilitation program (control group), and a 12-week center-based cardiac rehabilitation program combined with a digital health intervention (intervention group). This digital health intervention consists of smartphone, web, and tablet applications to monitor physical activity outside of rehabilitation sessions and motivate patients to engage in more physical activities. Results Of the initial 80 patients, 70 completed the study, and the results are presented in Table 1. In the intervention group, there was a statistically significant improvement in peak rate of oxygen consumption (VO2 peak) (p &amp;lt; 0.01) and peak power output (W peak) (p &amp;lt; 0.01), as measured by cardiopulmonary exercise testing between the end and the beginning of the study at the significance level of 0.05. Similar improvements were also observed in the control group (p = 0.0002 for VO2 peak and p &amp;lt; 0.01 for W peak). After 12 weeks of intervention, significant between-group differences were found: We observe a greater improvement in VO2 peak, on average 1.39 (95% CI: 0.23-2.54) ml/kg, and in W peak, on average, 12.29 (95% CI: 4.12-20.45), higher in the intervention group compared to the control group. Regarding physical activity, the intervention group showed a significant improvement in step count (P = 0.002), measured by an accelerometer, whereas no significant improvement was observed in the control group (P = 0.9714). There is a statistically significant difference in the change of step count between the intervention and control group at the significance level of 0.05. We observe a greater improvement, on average 14 788 steps (95% CI: 4 246 – 25 331), in the intervention group compared to the control group. Conclusion This study shows that a combination of a digital health intervention based telerehabilitation with a center-based cardiac rehabilitation is more effective in increasing patient’s exercise capacity and physical activity compared with a center-based cardiac rehabilitation.Table 1:results

Smooth muscle cell-specific deletion of S100A4 modifies smooth muscle cell fate and inflammation in murine atherosclerotic lesions

Abstract Background S100A4, a calcium-binding protein, is crucial in smooth muscle cell (SMC) phenotypic switch, yet its role in atherosclerotic plaque development and SMC plasticity remains unclear. Our previous experiments using an S100A4 neutralizing antibody approach in ApoE-/- atherosclerotic-prone mice showed reduced atherosclerotic burden but did not establish a direct link between the various S100A4-expressing cells and atherosclerosis. Methods/Results Herein, we show that aortic Oil RedO staining in ApoE-/-; S100A4-/- mice subjected to a 12-week high-cholesterol-diet (HCD) revealed reduced lesion areas compared to ApoE-/- mice (Figure 1, from 21.29% of the total aorta in ApoE-/-; S100A4+/+ mice to 13.27% in ApoE-/-; S100A4-/- mice), highlighting a pivotal role for S100A4 in atherosclerotic plaque development. We then used a lineage tracing ApoE-/- mouse model, in which we induced an SMC-specific deletion of S100A4 (SMC-S100A4Δ/Δ). After 12 weeks of HCD, SMC-S100A4Δ/Δ and control mice (SMC-S100A4wt/wt) were sacrificed, and aortas were processed for en face Oil Red O staining, immunohistochemistry, and single-cell RNA sequencing (scRNA-seq). SMC-specific deletion of S100A4 reduced the necrotic core area (from 29.75% of total plaque area in SMC-S100A4wt/wt to 18.23% in SMC-S100A4Δ/Δ mice) without affecting total atherosclerotic plaque size suggesting a more potent impact on plaque composition. ScRNA-seq analysis from SMC-S100A4Δ/Δ and SMC-S100A4wt/wt mice showed that the inflammatory macrophage-like SMC phenotype was highly suppressed in the plaque and associated with increased SMC repair phenotypes as well as a global reduction of myeloid inflammatory cells. SMCs also retained specific contractile SMC markers, namely Acta2 and Myh11 (fold change of 2.285 and 2.492, respectively) hinting towards a more stable fibrous cap. Immunofluorescence staining on aortic roots plaque (Figure 2) confirmed those results with an increase of SMCs (from 11.02% to 16.18%) as well as a-smooth muscle actin (a-SMA, Acta2)-positive SMCs (from 3.25% to 5.1%) in SMC-S100A4 Δ/Δ mice. Furthermore, the Gene Set Enrichment Analysis (GSEA) of scRNAseq data revealed that, in SMC-S100A4Δ/Δ mice, genes related to mitochondrial metabolism and oxidative respiration were highly downregulated in all SMC clusters. We investigated SMC mitochondrial fitness in vitro and showed that S100A4-/- SMCs have an increased basal oxygen consumption rate and an increased proton leak (fold change of 1.37 and 1.96 respectively) suggestive of differences in cellular metabolic adaptability. Conclusion Our research emphasizes the significant role of S100A4 in plaque development, demonstrating how SMC-derived S100A4 knockdown affects plaque evolution, reducing inflammation, and promoting stability likely through influencing SMC phenotypic switch through metabolic pathways.

A novel m.5906G > a variant in MT-CO1 causes MELAS/Leigh overlap syndrome.

The MELAS/Leigh overlap syndrome manifests with a blend of clinical and radiographic traits from both MELAS and LS. However, the association of MELAS/Leigh overlap syndrome with MT-CO1 gene variants has not been previously reported. In this study, we report a patient diagnosed with MELAS/Leigh overlap syndrome harboring the m.5906G > A variant in MT-CO1, with biochemical evidence supporting the pathogenicity of the variant. The variant m.5906G > A that led to a synonymous variant in the start codon of MT-CO1 was filtered as the candidate disease-causing variant of the patient. Patient-derived fibroblasts were used to generate a series of monoclonal cells carrying different m.5906G > A variant loads for further functional assays. The oxygen consumption rate, ATP production, mitochondrial membrane potential and lactate assay indicated an impairment of cellular bioenergetics due to the m.5906G > A variant. Blue native PAGE analysis revealed that the m.5906G > A variant caused a deficiency in the content of mitochondrial oxidative phosphorylation complexes. Furthermore, molecular biology assays performed for the pathogenesis, mtDNA copy number, mtDNA-encoded subunits, and recovery capacity of mtDNA were all deficient due to the m.5906G > A variant, which might be caused by mtDNA replication deficiency. Overall, our findings demonstrated the pathogenicity of m.5906G > A variant and proposed a potential pathogenic mechanism, thereby expanding the genetic spectrum of MELAS/Leigh overlap syndrome.

Enhanced ROS Production and Mitochondrial Metabolic Shifts in CD4+ T Cells of an Autoimmune Uveitis Model.

Equine recurrent uveitis (ERU) is a spontaneously occurring autoimmune disease and one of the leading causes of blindness in horses worldwide. Its similarities to autoimmune-mediated uveitis in humans make it a unique spontaneous animal model for this disease. Although many aspects of ERU pathogenesis have been elucidated, it remains not fully understood and requires further research. CD4+ T cells have been a particular focus of research. In a previous study, we showed metabolic alterations in CD4+ T cells from ERU cases, including an increased basal oxygen consumption rate (OCR) and elevated compensatory glycolysis. To further investigate the underlying reasons for and consequences of these metabolic changes, we quantified reactive oxygen species (ROS) production in CD4+ T cells from ERU cases and compared it to healthy controls, revealing significantly higher ROS production in ERU-affected horses. Additionally, we aimed to define mitochondrial fuel oxidation of glucose, glutamine, and long-chain fatty acids (LCFAs) and identified significant differences between CD4+ T cells from ERU cases and controls. CD4+ T cells from ERU cases showed a lower dependency on mitochondrial glucose oxidation and greater metabolic flexibility for the mitochondrial oxidation of glucose and LCFAs, indicating an enhanced ability to switch to alternative fuels when necessary.

Validation of metaxin-2 deficient C. elegans as a model for MandibuloAcral Dysplasia associated to mtx-2 (MADaM) syndrome

MandibuloAcral Dysplasia associated to MTX2 gene (MADaM) is a recently described progeroid syndrome (accelerated aging disease) whose clinical manifestations include skin abnormalities, growth retardation, and cardiovascular diseases. We previously proposed that mtx-2-deficient C. elegans could be used as a model for MADaM and to support this, we present here our comprehensive phenotypic characterization of these worms using atomic force microscopy (AFM), transcriptomic, and oxygen consumption rate analyses. AFM analysis showed that young mtx-2-less worms had a significantly rougher, less elastic cuticle which becomes significantly rougher and less elastic as they age, and abnormal mitochondrial morphology. mtx-2 C. elegans displayed slightly delayed development, decreased pharyngeal pumping, significantly reduced mitochondrial respiratory capacities, and transcriptomic analysis identified perturbations in the aging, TOR, and WNT-signaling pathways. The phenotypic characteristics of mtx-2 worms shown here are analogous to many of the human clinical presentations of MADaM and we believe this validates their use as a model which will allow us to uncover the molecular details of the disease and develop new therapeutics and treatments.

MiR-124 coordinates metabolic regulators acting at early stages of human neurogenesis

Metabolic dysregulation of neurons is associated with diverse human brain disorders. Metabolic reprogramming occurs during neuronal differentiation, but it is not fully understood which molecules regulate metabolic changes at the early stages of neurogenesis. In this study, we report that miR-124 is a driver of metabolic change at the initiating stage of human neurogenesis. Proteome analysis has shown the oxidative phosphorylation pathway to be the most significantly altered among the differentially expressed proteins (DEPs) in the immature neurons after the knockdown of miR-124. In agreement with these proteomics results, miR-124-depleted neurons display mitochondrial dysfunctions, such as decreased mitochondrial membrane potential and cellular respiration. Moreover, morphological analyses of mitochondria in early differentiated neurons after miR-124 knockdown result in smaller and less mature shapes. Lastly, we show the potential of identified DEPs as novel metabolic regulators in early neuronal development by validating the effects of GSTK1 on cellular respiration. GSTK1, which is upregulated most significantly in miR-124 knockdown neurons, reduces the oxygen consumption rate of neural cells. Collectively, our data highlight the roles of miR-124 in coordinating metabolic maturation at the early stages of neurogenesis and provide insights into potential metabolic regulators associated with human brain disorders characterized by metabolic dysfunctions.

Unbiased complexome profiling and global proteomics analysis reveals mitochondrial impairment and potential changes at the intercalated disk in presymptomatic R14Δ/+ mice hearts.

Phospholamban (PLN) is a sarco-endoplasmic reticulum (SER) membrane protein that regulates cardiac contraction/relaxation by reversibly inhibiting the SERCA2a Ca2+-reuptake pump. The R14Δ-PLN mutation causes severe cardiomyopathy that is resistant to conventional treatment. Protein complexes and higher-order supercomplexes such as intercalated disk components and Ca+2-cycling domains underlie many critical cardiac functions, a subset of which may be disrupted by R14Δ-PLN. Complexome profiling (CP) is a proteomics workflow for systematic analysis of high molecular weight (MW) protein complexes and supercomplexes. We hypothesize that R14Δ-PLN may alter a subset of these assemblies, and apply CP workflows to explore these changes in presymptomatic R14Δ/+ mice hearts. Ventricular tissues from presymptomatic 28wk-old WT and R14Δ/+ mice were homogenized under non-denaturing conditions, fractionated by size-exclusion chromatography (SEC) with a linear MW-range exceeding 5 MDa, and subjected to quantitative data-independent acquisition mass spectrometry (DIA-MS) analysis. Unfortunately, current workflows for the systematic analysis of CP data proved ill-suited for use in cardiac samples. Most rely upon curated protein complex databases to provide ground-truth for analysis; however, these are derived primarily from cancerous or immortalized cell lines and, consequently, cell-type specific complexes (including cardiac-specific machinery potentially affected in R14Δ-PLN hearts) are poorly covered. We thus developed PERCOM: a novel CP data-analysis strategy that does not rely upon these databases and can, furthermore, be implemented on widely available spreadsheet software. Applying PERCOM to our CP dataset resulted in the identification of 296 proteins with disrupted elution profiles. Hits were significantly enriched for mitochondrial and intercalated disk (ICD) supercomplex components. Changes to mitochondrial supercomplexes were associated with reduced expression of mitochondrial proteins and maximal oxygen consumption rate. The observed alterations to mitochondrial and ICD supercomplexes were replicated in a second cohort of "juvenile" 9wk-old mice. These early-stage changes to key cardiac machinery may contribute to R14Δ-PLN pathogenesis.

Synergistic inhibition effect and mechanism of an inhibitor for entire process inhibition of coal spontaneous combustion

Traditional coal spontaneous combustion (CSC) inhibitors, while effective, have limitations such as frequent application or short-term efficacy. To this end, we developed a slow-release and water-soluble synergistic inhibitor (SWSI) to achieve long-term CSC inhibition. The SWSI was formulated by integrating synergistic antioxidants (SA) composed of ascorbic acid (AsA) and Fe-superoxide dismutase (Fe-SOD) dissolved in a super absorbent polymer (SAP) encapsulated within hydrogel microcapsules. The effectiveness of SWSI was evaluated through simultaneous thermal analysis and in-situ free radical tests. The formulation optimization demonstrated that AsA and Fe-SOD had the maximum synergistic inhibition effect at a 1:1 molar ratio. The optimal SA: SAP ratio of 3:1 achieved the lowest oxygen consumption rate and highest inhibition rate. The encapsulation formulation, consisting of 3% SA, 6% PAM, 1% CaCl2, and 0.5% citric acid, generated the highest swelling ratio. Simultaneous thermal analysis and in-situ free radical tests indicated that SWSI greatly increased feature temperatures and the apparent activation energy, lowered reaction heat, and substantially reduced free radical concentration in the full oxidation process. The newly developed SWSI offers a significant advancement in long-term CSC prevention by integrating physical and chemical inhibition, which provides sustained and effective inhibition throughout the entire oxidation process.

Spatheliachromen mitigates methylglyoxal-induced myotube atrophy by activating Nrf2, inhibiting ubiquitin-mediated protein degradation, and restoring mitochondrial function

BackgroundMethylglyoxal (MGO) is a potent precursor of glycative stress that leads to oxidative stress and muscle atrophy in diabetes. Spatheliachromen (FPATM-20), derived from Ficus pumila var. awkeotsang, exhibited potential antioxidant activity. PurposeThis study aimed to evaluate the potential impact and underlying mechanisms of FPATM-20 on MGO-induced myotube atrophy and mitochondrial dysfunction in mouse skeletal C2C12 myotubes. MethodsAtrophic and antioxidant factors were evaluated using immunofluorescence, enzyme-linked immunosorbent assay, and western blotting. Mitochondrial function was assessed using the ATP assay and Seahorse Cell Mito Stress Test. The glycogen content was determined using periodic acid-Schiff staining. Molecular docking was performed to determine the interaction between FPATM-20 and Keap1. ResultsIn myotubes treated with MGO, FPATM-20 activated the Nrf2 pathway, reduced ROS levels, enhanced antioxidant defense, and increased glycogen content. FPATM-20 improved myotube viability and size, upregulated myosin heavy chain (MyHC) expression, modulated ubiquitin-proteasome molecules (nuclear FoxO3a, atrogin-1, MuRF-1, and p62/SQSTM1), and inhibited apoptosis (Bax/Bcl-2 ratio and cleaved caspase 3). Moreover, FPATM-20 restored mitochondrial function, including mitochondrial membrane potential, mitochondrial oxygen consumption rate, and mitochondrial biogenesis pathway (nuclear PGC-1α/TFAM/FNDC5). The inhibition of Nrf2 with ML385 reversed the effects of FPATM-20 on MGO. Furthermore, molecular docking confirmed the binding of FPATM-20 to Keap1, a suppressor of Nrf2, showing the crucial role of Nrf2 in protective effects. ConclusionsFPATM-20 protects myotubes from MGO toxicity by activating the Nrf2 antioxidant defense, reducing protein degradation and apoptosis, and enhancing mitochondrial function. Thus, FPATM-20 may be a novel agent for preventing skeletal muscle atrophy.

Extremely Low-Frequency Electromagnetic Field (ELF-EMF) Increases Mitochondrial Electron Transport Chain Activities and Ameliorates Depressive Behaviors in Mice.

Compromised mitochondrial electron transport chain (ETC) activities are associated with depression in humans and rodents. However, the effects of the enhancement of mitochondrial ETC activities on depression remain elusive. We recently reported that an extremely low-frequency electromagnetic field (ELF-EMF) of as low as 10 μT induced hormetic activation of mitochondrial ETC complexes in human/mouse cultured cells and mouse livers. Chronic social defeat stress (CSDS) for 10 consecutive days caused behavioral defects mimicking depression in mice, and using an ELF-EMF for two to six weeks ameliorated them. CSDS variably decreased the mitochondrial ETC proteins in the prefrontal cortex (PFC) in 10 days, which were increased by an ELF-EMF in six weeks. CSDS had no effect on the mitochondrial oxygen consumption rate in the PFC in 10 days, but using an ELF-EMF for six weeks enhanced it. CSDS inactivated SOD2 by enhancing its acetylation and increased lipid peroxidation in the PFC. In contrast, the ELF-EMF activated the Sirt3-FoxO3a-SOD2 pathway and suppressed lipid peroxidation. Furthermore, CSDS increased markers for mitophagy, which was suppressed by the ELF-EMF in six weeks. The ELF-EMF exerted beneficial hormetic effects on mitochondrial energy production, mitochondrial antioxidation, and mitochondrial dynamics in a mouse model of depression. We envisage that an ELF-EMF is a promising therapeutic option for depression.

Physiological Challenges and Adaptations in Competitive Freediving

Competitive freediving is associated with extreme physiologic challenges due to the effects of apnea, submersion in water, and increased ambient pressure. There has nevertheless been a continued progression of world records across freediving disciplines in recent years, with breath-hold times exceeding 10 minutes, and reaching diving depths beyond 200 meters of seawater. The main physiological determinants of breath-hold endurance are the available oxygen stores, i.e., intrapulmonary gas volume, inspired gas concentration, and rate of oxygen consumption. Other factors such as psychological and inherent factors contribute to the individual tolerance to an increasing respiratory stimulus with prolonged breath-hold duration. A freediving athlete must be able to tolerate apnea to stay underwater long enough to reach great distance or depth and resurface safely. Elite freedivers exhibit somewhat remarkable physiological adaptations such as a more pronounced diving-response and hypercapnia tolerance compared to non-divers, as well as metabolic and cerebrovascular adaptations. To reach great depths, elite freedivers employ a breathing technique called glossophyryngeal insufflation (GI) that is enlarging the ratio of total lung capacity to residual volume, thus, mitigating risk of lung squeeze and increasing intrapulmonary gas volume, and thereby enhancing available oxygen stores. Pulmonary anatomy and physiology could not be accounted to restrict the breath-hold diving depths achieved by competitive athletes. However, the acutely increased intrapulmonary pressure during GI is transmitted to the pulmonary vasculature, thereby eliciting a right ventricular pressure overload, and left ventricular dysfunction that may augment hypotension and syncope during glossopharyngeal insufflation. Due to extreme diffusion gradients between alveolar pN2 and N2 pressures in the body tissues at great depth, N2 will be forced into blood and body tissues during descent, elevating risk of N2 narcosis and decompression illness during deep dives. Breath-hold training and preparation have been shown to enhance breath-hold performance. This review highlights recent data on the profound cardiovascular, respiratory, and gas exchange effects that are observed in competitive freedivers, and discusses possible adaptations and risks for humans.

N6-methyladenosine (m6A) reader HNRNPA2B1 accelerates the cervical cancer cells aerobic glycolysis.

N6-methyladenosine (m6A) modification is, a more common epigenetic modification, mainly found in mRNA. More and more researches have shown the important functions of m6A on human cancers. This study seeks to explore the role of hnRNPA2B1 and m6A-dependent mechanism in cervical cancer. Elevated hnRNPA2B1 indicated the poor prognosis of cervical cancer patients. Enforced hnRNPA2B1 reduced the apoptosis, and accelerated the proliferation and migration of cervical cancer cells in vitro. Besides, hnRNPA2B1 promoted the aerobic glycolysis of cervical cancer cells, including the lactate secretion, glucose uptake, ATP production, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). LDHA was found as the downstream target of hnRNPA2B1 by m6A site. Moreover, hnRNPA2B1 enhanced the mRNA stability of LDHA through m6A-dependent manner. LDHA inhibitor (FX-11) could reverse the effect of hnRNPA2B1. Taken together, the data revealed that hnRNPA2B1 promoted the proliferation, migration and aerobic glycolysis of cervical cancer cells by m6A/LDHA-dependent manner. These findings might bring a new idea for cervical cancer treatment.

Excess Potassium Promotes Autophagy to Maintain the Immunosuppressive Capacity of Myeloid-Derived Suppressor Cells Independent of Arginase 1.

Potassium ions (K+) are critical electrolytes that regulate multiple functions in immune cells. Recent studies have shown that the elevated concentration of extracellular potassium in the tumor interstitial fluid limits T cell effector function and suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). The effect of excess potassium on the biology of myeloid-derived suppressor cells (MDSCs), another important immune cell component of the tumor microenvironment (TME), is unknown. Here, we present data showing that increased concentrations of potassium chloride (KCl), as the source of K+ ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3β. Simultaneously, excess potassium ions significantly decrease the expression of arginase I (Arg I) and inducible nitric oxide synthase (iNOS) without reducing the ability of MDSCs to suppress T cell proliferation. Further investigation reveals that excess K+ ions decrease the expression of the transcription factor C/EBP-β and alter the expression of phosphorylated kinases. While excess K+ ions downregulated the expression levels of phospho-AMPKα (pAMPKα), it increased the levels of pAKT and pERK. Additionally, potassium increased mitochondrial respiration as measured by the oxygen consumption rate (OCR). Interestingly, all these alterations induced by K+ ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K+ ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs' immunosuppressive function by mechanisms independent of Arg I and iNOS. Overall, our in vitro and ex vivo findings offer valuable insights into the adaptations of MDSCs within the K+ ion-rich TME, which has important implications for MDSCs-targeted therapies.

Performance of Small-Scale Hermetic Storage Systems Under Periodic Access

This study characterizes the grain management performance of a novel integrated grain drying and storage system (iGDSS) adapted from 208 L drums to combat postharvest loss in developing countries through providing in situ mechanized drying and hermetic storage. The six-month storage trials of 14% moisture content maize compared different access mechanisms and two levels of pest pressure: 0 and 10 maize weevils/kg grain. This experiment allowed comparisons of differential oxygen consumption rates in small-scale hermetic systems with and without storage pests, which has not been widely reported in the literature. The iGDSS system was found to maintain grain quality parameters in dry grains with and without storage pests. After six months of storage, the results demonstrated no statistically significant difference in the moisture content, test weight, germination, proportion of broken and damaged kernels, and presence of colony-forming units between inoculated and non-inoculated systems. The iGDSS was also found to maintain oxygen intrusion rates of 0.10–0.13% O2/day, below recommended thresholds of 0.15% required to maintain benefits of modified atmosphere storage. These results indicate that the iGDSS can provide safe and reliable grain storage to smallholder farmers in developing countries, and that the drying functions of iGDSS can promote outcomes in hermetic storage.

SPAG4 enhances mitochondrial respiration and aerobic glycolysis in colorectal cancer cells by activating the PI3K/Akt signaling pathway.

Aerobic glycolysis plays a pivotal role in the progression of tumors. Previously, a glycolysis-associated prognostic model in CRC was constructed and the glycolysis-related gene SPAG4 was discovered to be upregulated in CRC and was correlated with adverse prognosis. To date, however, no study has elucidated the specific role of SPAG4 in the development of CRC. In our study, CRC cells were transfected with si-SPAG4 or OE-SPAG4 to evaluate the influence of SPAG4 silencing or overexpression on CRC cell malignant behaviors. CRC cell proliferation and metastasis were detected via CCK-8, colony formation, and Transwell assays. The oxygen consumption rate and extracellular acidification rate of CRC cells were determined by using an XF24 extracellular flux analyzer. The expression of SPAG4, key mitochondrial markers (NDUFA1, SDHB, ATP5A, and PGC-1α), key enzymes involved in glycolysis (GLUT1, HK2, LDHA, PKM2, and PFK1), and PI3K/Akt pathway-molecules and downstream transcription factor HIF-1α was assessed by RT-qPCR and western blot analysis. SPAG4 expression in CRC and normal tissue samples was tested through immunohistochemical staining. Finally, SPAG4-overexpressed CRC cells were treated with LY294002 to validate the inhibition of PI3K/Akt pathway on CRC cell malignant phenotypes. Our results showed that SPAG4 was upregulated in CRC cells and tissues, and high expression SPAG4 predicted shorter overall survival time. SPAG4 knockdown inhibited while SPAG4 overexpression enhanced CRC cell proliferation, migration, invasion, mitochondrial respiration, and aerobic glycolysis. Overexpressing SPAG4 elevated p-PI3K, p-Akt, p-mTOR, and HIF-1α protein levels, which were restored after LY294002 treatment. Furthermore, LY294002 abolished the promotion of SPAG4 overexpression on CRC malignant phenotypes. Collectively, SPAG4 plays an oncogenic role in CRC by promoting mitochondrial respiration and aerobic glycolysis through activating the PI3K/Akt signaling. These findings suggest that inhibition of SPAG4-mediated glucose metabolism may represent a potential strategy for the clinical treatment of CRC.