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Journal of Nanobiotechnology Jun 2024Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human...
BACKGROUND
Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms.
METHODS
A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated β-gal (SA-β-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed.
RESULTS
Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the mA demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition.
CONCLUSION
H-Exs secreted circBRCA1 regulated by mA modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI.
Topics: Female; Granulosa Cells; Oxidative Stress; MicroRNAs; Animals; Exosomes; Rats; RNA, Circular; Humans; Primary Ovarian Insufficiency; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Forkhead Box Protein O1; Rats, Sprague-Dawley; Mesenchymal Stem Cells; Adult
PubMed: 38918838
DOI: 10.1186/s12951-024-02583-5 -
Journal of Nanobiotechnology Jun 2024Breast cancer ranks second as the most common malignancy globally, after lung cancer. Among the various subtypes of breast cancer, HER2 positive breast cancer (HER2...
INTRODUCTION
Breast cancer ranks second as the most common malignancy globally, after lung cancer. Among the various subtypes of breast cancer, HER2 positive breast cancer (HER2 BC)poses a particularly challenging prognosis due to its heightened invasiveness and metastatic potential. The objective of this study was to construct a composite piezoelectric nanoparticle based on poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) for imaging and treatment of HER2 BC.
METHOD
By reshaping the crystal structure of P(VDF-TrFE) piezoelectric nanoparticles, improving hydrophilicity, and incorporating imaging capabilities, we developed piezoelectric composite nanoparticles (PGd@tNBs) that integrate imaging and therapeutic functions. The in vitro characterization encompassed the assessment of piezoelectric properties, hydrophilicity, imaging performance, and therapeutic efficacy of these particles. The targeting and therapeutic effectiveness of PGd@tNBs particles were further validated in the SK-BR3 cell line and subsequently confirmed in HER2-positive tumor-bearing mice.
RESULTS
The nanoparticle demonstrated excellent biocompatibility and impressive multimodal imaging performance. Magnetic resonance imaging (MRI) observations revealed significant accumulation of PGd@tNBs particles in the HER2 positive tumor, exhibiting superior contrast-enhanced ultrasound performance compared to traditional ultrasound contrast agents, and small animal in vivo imaging showed that PGd@tNBs particles were primarily excreted through respiration and urinary metabolism. Piezoforce Microscopy characterization highlighted the outstanding piezoelectric properties of PGd@tNBs particles. Upon targeted binding to HER2-BC, ultrasound stimulation influenced the cell membrane potential, leading to reversible electroporation. This, in turn, affected the balance of calcium ions inside and outside the cells and the mitochondrial membrane potential. Following ingestion by cells, PGd@tNBs, when exposed to ultrasound, triggered the generation of reactive oxygen species (ROS), resulting in the consumption of glutathione and superoxide dismutase and achieving sonodynamic therapy. Notably, repeated ultrasound stimulation, post PGd@tNBs particles binding and entry into cells, increased ROS production and elevated the apoptosis rate by approximately 45%.
CONCLUSION
In conclusion, the PGd@tNBs particles developed exhibit outstanding imaging and therapeutic efficacy, holding potential for precise diagnosis and personalized treatment of HER2 BC.
Topics: Animals; Female; Breast Neoplasms; Humans; Mice; Cell Line, Tumor; Receptor, ErbB-2; Nanoparticles; Magnetic Resonance Imaging; Ultrasonic Therapy; Mice, Nude; Mice, Inbred BALB C; Contrast Media; Apoptosis
PubMed: 38918812
DOI: 10.1186/s12951-024-02639-6 -
Cell Biochemistry and Biophysics Jun 2024Toll-like receptors 3 (TLR3) are innate immune receptors expressed on a wide range of cell types, including glial cells. Inflammatory responses altered by hyperglycemia...
Toll-like receptors 3 (TLR3) are innate immune receptors expressed on a wide range of cell types, including glial cells. Inflammatory responses altered by hyperglycemia highlight the need to explore the molecular underpinnings of these changes in cellular models. Therefore, here we estimated TLR3-mediated response of astrocytes cultured at normal (NG, 5 mM) and high (HG, 22.5 mM) glucose concentrations for 48 h before stimulation with polyinosinic:polycytidylic acid Poly(I:C) (PIC) for 6 h. Seahorse Extracellular Flux Analyzer (Seahorse XFp) was used to estimate the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Although adaptation to HG affected ECAR and OCR, the stimulation of cells with PIC had no effect on ECAR. PIC reduced maximal OCR, but this effect disappeared upon adaptation to HG. PIC-stimulated release of cytokines IL-1β, IL-10 was reduced, and that of IL-6 and iNOS was increased in the HG model. Adaptation to HG reduced PIC-stimulated synthesis of COX-derived oxylipins measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Adaptation to HG did not alter PIC-stimulated p38 activity, ERK mitogen-activated protein kinase, STAT3 and ROS production. Metformin exhibited anti-inflammatory activity, reducing PIC-stimulated synthesis of cytokines and oxylipins. Cell adaptation to high glucose concentration altered the sensitivity of astrocytes to TLR3 receptor activation, and the hypoglycemic drug metformin may exert anti-inflammatory effects under these conditions.
PubMed: 38918312
DOI: 10.1007/s12013-024-01380-z -
European Journal of Applied Physiology Jun 2024To measure oxygen demand, uptake, and deficits in competitive cross-country skiers during outdoor roller skiing at different competition durations, ranging from the...
PURPOSE
To measure oxygen demand, uptake, and deficits in competitive cross-country skiers during outdoor roller skiing at different competition durations, ranging from the endurance domain to the sprint domain.
METHODS
Ten competitive cross-country skiers (6 males; O 78 ± 3 and 4 females; O 62 ± 3 mL∙kg∙min) raced time trials consisting of 1, 2, and 4 laps in a 1.6 km racecourse in a randomized order with 35 min recovery in-between. Oxygen uptake was measured using a wearable metabolic system while oxygen demand was estimated from kinematic data (GPS and IMU) and an athlete-specific model of skiing economy. Skiing economy and O was established on a separate test day using six submaximal constant-load trials at different speeds and inclines, and one maximal-effort trial on a roller-skiing treadmill.
RESULTS
Average oxygen demand was 112 ± 8%, 103 ± 7% and 98 ± 7% of O during the 1 (3:37 ± 0:20 m:ss), 2 (7:36 ± 0:38 m:ss) and 4 (15:43 ± 1:26 m:ss) lap time trials, respectively, and appeared to follow an inverse relationship with time-trial duration. Average oxygen uptake was unaffected by race length (86 ± 5%, 86 ± 5%, and 86 ± 7% of O, respectively). Accumulated oxygen deficit at the end of each time trial was 85 ± 13, 106 ± 32 and 158 ± 62 mL∙kg, while oxygen deficits per work bout was 23 ± 3, 18 ± 3 and 16 ± 3 mL∙kg for the 1, 2, and 4-lap time trials, respectively.
CONCLUSION
Elite cross-country skiers adjust their pacing strategies from attaining relatively small oxygen deficits per work bout in the endurance domain, to larger deficits in the sprint domain. This indicates a shift in strategy from prioritizing stable work-economy and rate-of-recovery in the endurance domain, to maximizing power output in the sprint domain.
PubMed: 38918220
DOI: 10.1007/s00421-024-05531-1 -
Reproduction (Cambridge, England) Jun 2024L-Carnitine (LC) is known to play key roles in lipid metabolism and antioxidative activity, implicating enhanced cryotolerance of bovine blastocysts. However,...
L-Carnitine (LC) is known to play key roles in lipid metabolism and antioxidative activity, implicating enhanced cryotolerance of bovine blastocysts. However, sustainability of LC supplementation during culture period on preimplantation development beyond the blastocyst stage has not been investigated so far. Therefore, all embryos were cultured under fatty acid free conditions, one group with LC (LC-Embryos) and the control group without LC (Control) supplementation. Transfer to recipients was conducted on day 6. Elongation-stage embryos were recovered on day 14; metrics of embryo recollection, developmental rates to early elongation-stage as well as mean embryo length did not differ between the groups. Gene expression analysis via NGS revealed 341 genes to be differentially regulated between elongation-stage embryos derived from LC supplementation compared to controls. These played mainly a role in molecular functions and biological processes like oxidoreductase activity, ATP dependent activity, cellular stress and respiration. Pathways like oxidative phosphorylation and thermogenesis, ECM receptor signaling, PI3K-Akt and focal adhesion were affected by differentially regulated genes. Moreover, all DEGs located on the mitochondria were significantly downregulated in the LC-Embryos, being in line with lower mitochondrial copy number and mtDNA integrity compared to the control group. Finally, we uncovered alterations of the bioenergetic profile on day 7 as a consequence of LC supplementation for the first time, revealing significantly higher oxygen consumption rates, ATP linked respiration and spare capacity for LC-embryos. Conclusively, we uncovered direct effects of LC supplementation during the culture period on the bioenergetic profile going along with sustainable effects on mtDNA copy numbers and transcriptome profile of bovine day 14 embryos.
PubMed: 38917030
DOI: 10.1530/REP-24-0004 -
The Journal of Cell Biology Sep 2024Context-dependent physiological remodeling of the extracellular matrix (ECM) is essential for development and organ homeostasis. On the other hand, consumption of...
Context-dependent physiological remodeling of the extracellular matrix (ECM) is essential for development and organ homeostasis. On the other hand, consumption of high-caloric diet leverages ECM remodeling to create pathological conditions that impede the functionality of different organs, including the heart. However, the mechanistic basis of high caloric diet-induced ECM remodeling has yet to be elucidated. Employing in vivo molecular genetic analyses in Drosophila, we demonstrate that high dietary sugar triggers ROS-independent activation of JNK signaling to promote fatty acid oxidation (FAO) in the pericardial cells (nephrocytes). An elevated level of FAO, in turn, induces histone acetylation-dependent transcriptional upregulation of the cytokine Unpaired 3 (Upd3). Release of pericardial Upd3 augments fat body-specific expression of the cardiac ECM protein Pericardin, leading to progressive cardiac fibrosis. Importantly, this pathway is quite distinct from the ROS-Ask1-JNK/p38 axis that regulates Upd3 expression under normal physiological conditions. Our results unravel an unknown physiological role of FAO in cytokine-dependent ECM remodeling, bearing implications in diabetic fibrosis.
Topics: Animals; Extracellular Matrix; Fatty Acids; Oxidation-Reduction; Drosophila Proteins; Myocardium; Cytokines; Drosophila melanogaster; MAP Kinase Signaling System; Reactive Oxygen Species; Transcription Factors; Fibrosis; Pericardium
PubMed: 38916917
DOI: 10.1083/jcb.202306087 -
Die Anaesthesiologie Jun 2024In recent years, reports of health problems associated with nitrous oxide consumption have significantly increased. In Germany, nitrous oxide (NO) is easily available in... (Review)
Review
In recent years, reports of health problems associated with nitrous oxide consumption have significantly increased. In Germany, nitrous oxide (NO) is easily available in cartridges without legal restrictions. The main reason for its popularity in the party scene are the euphoric, psychedelic effects of the gas. In addition to severe and sometimes irreversible health problems associated with long-term use of nitrous oxide, e.g., anemia and nerve damage, life-threatening or fatal consequences of acute nitrous oxide consumption can also occur: accidents under the influence of nitrous oxide, pneumothorax, pneumopericardium and shock due to an explosive increase in airway pressure when inhaled directly from the cartridge. But the most common cause of severe complications is asphyxia as the gas is usually inhaled pure from large balloons and without oxygen. The resulting hypoxia during use may be perpetuated by the diffusion hypoxia that occurs during the reoxygenation period. Nitrous oxide as a cause in accidental or intoxication events is usually not detectable but can only be identified as a trigger based on the patient's history or the circumstances. Acute medical treatment is symptomatic.
PubMed: 38916748
DOI: 10.1007/s00101-024-01427-z -
Journal of Sports Sciences May 2024We assessed the accuracy and inter-sessional reliability of traditional (manual) compared to automatic (AutoHR) heart rate (HR) clamping methods during submaximal...
We assessed the accuracy and inter-sessional reliability of traditional (manual) compared to automatic (AutoHR) heart rate (HR) clamping methods during submaximal intensity continuous cycling. On separate occasions, thirteen males cycled at an HR corresponding to 80% of the ventilatory threshold for 18 min. Cycling power output was adjusted using either manual or AutoHR methods, encompassing three trials per method. For the manual method, cycling power output was adjusted every 30 s by 0, 5 or 10 W at the experimenter's discretion. Conversely, AutoHR automatically adjusted power output based on the difference between target and actual HR. Participants' HR was measured at 1 Hz. Root-mean square error (RMSE) and intraclass correlation coefficients (ICC) were calculated from the difference between measured and target HR to represent accuracy and reliability of each method. The RMSE for the manual method (3.2 ± 2.6 bpm) was significantly higher compared to AutoHR (2.8 ± 2.3 bpm) ( < 0.01, = 0.13); inter-day ICC were 0.92 and 0.89 for manual adjustment and AutoHR, respectively. Automatic methods to clamp HR are more accurate than manual approaches during submaximal intensity continuous cycling and can be easily implemented for uniform HR control in individual and group training sessions at minimal cost.
Topics: Humans; Male; Heart Rate; Bicycling; Reproducibility of Results; Young Adult; Adult; Ergometry; Exercise Test; Oxygen Consumption
PubMed: 38916194
DOI: 10.1080/02640414.2024.2369353 -
The Journal of Sports Medicine and... Jul 2024Oxygen uptake efficiency slope (OUES) is an objective physiological measure that can be obtained from a standard graded exercise test. However, there is conflicting...
BACKGROUND
Oxygen uptake efficiency slope (OUES) is an objective physiological measure that can be obtained from a standard graded exercise test. However, there is conflicting evidence regarding sex differences in OUES values in children. Therefore, this study investigated potential sex differences in absolute, ratio-scaled, and allometrically scaled OUES in 8.0- to 12.0-year-old children.
METHODS
Retrospective and prospective data of 18 boys and 22 girls were utilized. All participants had undergone familiarization before performing a maximal cycle ergometer test to determine OUES. These values were also ratio-scaled and allometrically scaled to mass and body surface area (BSA). Group differences were tested via independent sample t-tests (or Mann-Whitney U if not normally distributed).
RESULTS
Absolute OUES values (VO
2 mL∙min/log10 VE L∙min) were significantly higher in boys compared to girls (1860.8±359.3 vs. 1514.3±212.6). When scaled to mass (VO2 mL∙kg∙min/log10 VE L∙kg∙min), OUES was no longer significantly different between groups, but when scaled to BSA (VO2 mL∙m∙min/log10 VE L∙m∙min), OUES was significantly higher in the boys than the girls (1414.4±204.2 vs. 1268.9±134.6). When allometry was applied for mass (OUES/mass) boys had significantly higher value than girls (350.8±46.7 vs. 305.0±31.5).CONCLUSIONS
The present study demonstrated that boys had greater OUES values scaled to BSA and allometrically scaled to body mass. These findings provide further evidence of sex differences with OUES values in preadolescent children and implies the need for sex-specific reference values prior to using OUES for the assessment of cardiorespiratory pathology in children.
Topics: Humans; Male; Child; Female; Exercise Test; Oxygen Consumption; Sex Factors; Retrospective Studies; Prospective Studies; Body Surface Area
PubMed: 38916085
DOI: 10.23736/S0022-4707.24.15597-1 -
The Journal of Sports Medicine and... Jul 2024An athlete's career inevitably goes through periods of forced physical exercise interruption like a knee injury. Advanced echocardiographic methods and cardiopulmonary...
BACKGROUND
An athlete's career inevitably goes through periods of forced physical exercise interruption like a knee injury. Advanced echocardiographic methods and cardiopulmonary exercise testing (CPET) are essential in evaluating athletes in the period elapsing after the injury. However, the feasibility of a maximal pre-surgery CPET and the capacity of resting advanced echocardiographic techniques to predict cardiorespiratory capacity still need to be clarified.
METHODS
We evaluated 28 non-professional athletes aged 18-52, involved in prevalently aerobic or alternate aerobic/anaerobic sports activities, affected by a knee pathology with indications for surgical treatment. The evaluation was performed at rest by trans-thoracic echocardiography, including global longitudinal strain (GLS) and myocardial work (MW) assessment, and during exercise by CPET.
RESULTS
The percent-predicted peak oxygen consumption (peak VO
2 %) was 82.8±13.7%, the mean respiratory exchange ratio was 1.16±0.08, and the mean ventilation/carbon dioxide (VE /VCO2 ) slope was 24.23±3.36. Peak VO2 % negatively correlated with GLS (r=-0.518, P=0.003) and global wasted work (GWW) (r =-0.441, P=0.015) and positively correlated with global work efficiency (GWE) (r=0.455, P=0.012). Finally, we found that the VE /VCO2 slope during exercise was negatively correlated with GWE (r=-0.585, P=0.001) and positively correlated with GWW (r=0.499, P=0.005).CONCLUSIONS
A maximal CPET can be obtained in deconditioned athletes because of a knee injury, allowing a comprehensive functional pre-surgery evaluation. In these patients, peak VO
2 is reduced due to decreased physical activity after injury; however, a lower cardiopulmonary efficiency may be a concause of the injury itself. In addition, we demonstrated that the MW indexes obtained at rest could predict exercise capacity and ventilatory efficiency as evaluated by CPET.Topics: Humans; Exercise Test; Adult; Oxygen Consumption; Male; Knee Injuries; Young Adult; Female; Middle Aged; Echocardiography; Adolescent; Cardiorespiratory Fitness; Athletes
PubMed: 38916084
DOI: 10.23736/S0022-4707.24.15496-5