Increase In Oxygen Consumption Research Articles

343 The relationship between pulmonary arterial pressure phenotypes and oxygen consumption in beef cattle

Abstract The objective of this study was to determine if a phenotypic relationship between pulmonary arterial pressure (PAP) and oxygen consumption exists in beef cattle. Pulmonary arterial pressure is used as an indicator of pulmonary hypertension in cattle which is indicative of the susceptibility to both high-altitude disease and feedlot heart failure of an individual. Cattle with greater PAP are typically hypoxic and have initiated expression of compensatory mechanisms their cardio-pulmonary systems employ to combat this alveolar hypoxia. In turn, this causes an increase in PAP and, ultimately, right-sided heart failure. If hypoxic individuals consume more oxygen as a compensation mechanism, oxygen consumption as a trait could be used as an indicator of the prediction of PAP and feedlot heart failure and would be especially useful for cattle in deep phenotyping systems. Data used in the study included cattle with PAP measures on a total of 132 individuals. The data consisted of both steers (n = 99) and heifers (n = 33) from a ranch located in southern Wyoming at an elevation of approximately 2,195 m. After weaning on the ranch, cattle were transported to Colorado State University’s Agriculture Research, Development and Education Center located in Fort Collins, CO (elevation: 1,558 m). Oxygen consumption was measured using a Greenfeed system (C-Lock, Rapid City, South Dakota). To determine if a relationship exists between oxygen consumption and PAP, a simple linear regression model was used to regress PAP on average daily oxygen consumption. Effects included in the model were sex and phenotypic PAP. Average daily oxygen consumption was measured in kilograms per day and averaged 6.6 ± 1.66 kg with a range of 2.3 to 10.45 kg. Pulmonary arterial pressure averaged 42.6 ± 7.96 mm Hg and ranged from 33 to 81 mm Hg. In this data, sex did not account for a significant amount of variability in phenotypic PAP (P > 0.05). Oxygen consumption did account for a significant amount of variability in PAP (P < 0.05), and it was found that with every 1 kg increase of oxygen consumption, PAP is estimated to increase 1.02 mm Hg. These results indicate that a statistical relationship between oxygen consumption and PAP exists. Although these findings suggest that greater oxygen consumption leads to greater PAP, further research is required to fully comprehend the relationship between beef cattle PAP and oxygen consumption.

ING5 inhibits aerobic glycolysis of lung cancer cells by promoting TIE1-mediated phosphorylation of pyruvate dehydrogenase kinase 1 at Y163.

Aerobic glycolysis is critical for tumor growth and metastasis. Previously, we have found that the overexpression of the inhibitor of growth 5 (ING5) inhibits lung cancer aggressiveness and epithelial-mesenchymal transition (EMT). However, whether ING5 regulates lung cancer metabolism reprogramming remains unknown. Here, by quantitative proteomics, we showed that ING5 differentially regulates protein phosphorylation and identified a new site (Y163) of the key glycolytic enzyme PDK1 whose phosphorylation was upregulated 13.847-fold. By clinical study, decreased p-PDK1Y163 was observed in lung cancer tissues and correlated with poor survival. p-PDK1Y163 represents the negative regulatory mechanism of PDK1 by causing PDHA1 dephosphorylation and activation, leading to switching from glycolysis to oxidative phosphorylation, with increasing oxygen consumption and decreasing lactate production. These effects could be impaired by PDK1Y163F mutation, which also impaired the inhibitory effects of ING5 on cancer cell EMT and invasiveness. Mouse xenograft models confirmed the indispensable role of p-PDK1Y163 in ING5-inhibited tumor growth and metastasis. By siRNA screening, ING5-upregulated TIE1 was identified as the upstream tyrosine protein kinase targeting PDK1Y163. TIE1 knockdown induced the dephosphorylation of PDK1Y163 and increased the migration and invasion of lung cancer cells. Collectively, ING5 overexpression-upregulated TIE1 phosphorylates PDK1Y163, which is critical for the inhibition of aerobic glycolysis and invasiveness of lung cancer cells.

Differential roles for the oxygen sensing enzymes PHD1 and PHD3 in the regulation of neutrophil metabolism and function.

Neutrophils are essential in the early innate immune response to pathogens. Harnessing their antimicrobial powers, without driving excessive and damaging inflammatory responses, represents an attractive therapeutic possibility. The neutrophil population is increasingly recognised to be more diverse and malleable than was previously appreciated. Hypoxic signalling pathways are known to regulate important neutrophil behaviours and, as such, are potential therapeutic targets for regulating neutrophil antimicrobial and inflammatory responses. We used a combination of in vivo and ex vivo models, utilising neutrophil and myeloid specific PHD1 or PHD3 deficient mouse lines to investigate the roles of oxygen sensing prolyl hydroxylase enzymes in the regulation of neutrophilic inflammation and immunity. Mass spectrometry and Seahorse metabolic flux assays were used to analyse the role of metabolic shifts in driving the downstream phenotypes. We found that PHD1 deficiency drives alterations in neutrophil metabolism and recruitment, in an oxygen dependent fashion. Despite this, PHD1 deficiency did not significantly alter ex vivo neutrophil phenotypes or in vivo outcomes in mouse models of inflammation. Conversely, PHD3 deficiency was found to enhance neutrophil antibacterial properties without excessive inflammatory responses. This was not linked to changes in the abundance of core metabolites but was associated with increased oxygen consumption and increased mitochondrial reactive oxygen species (mROS) production. PHD3 deficiency drives a favourable neutrophil phenotype in infection and, as such, is an important potential therapeutic target.

Impact of run-of-river damming on increasing phytoplankton biomass and species shift in a large Amazonian river

Run-of-river (ROR) dams, often perceived as having minimal environmental impact, can induce significant hydrodynamic changes that alter aquatic ecosystems. We investigated the impacts of an ROR dam on the Madeira River, the largest Amazon tributary, focusing on phytoplankton communities, their ecological implications, and related environmental factors. Our study examined changes in biomass and environmental factors (using General Linear Mixed Models - GLMM), species composition (using PERMANOVA) before and after damming, in both the main channel and tributaries (N = 549 samples). We also identified indicator species associated with different damming phases and regions through an indicator value analysis. The results showed that, following dam construction, the phytoplankton community changed in both the main channel and tributaries, with a shift from lotic diatoms to lentic phytoflagellates. This transition was likely facilitated by altered hydrodynamics and possibly influenced by the decomposition of flooded vegetation in the dam's influence zone. The decomposition of this vegetation could explain both the observed increase in oxygen consumption and the subsequent rise in phytoflagellate biomass after damming. However, despite the overall increase in phytoplankton biomass, the values remained within oligotrophic to mesotrophic conditions, consistent with the low nutrient concentrations recorded. However, we caution that the dam-created hydrodynamic conditions are optimal for phytoplankton growth, potentially exacerbating nutrient-related issues in the future. We recommend proactive management strategies to prevent nutrient enrichment from activities such as agriculture and livestock in isolated Amazon areas affected by dams, thereby mitigating potential degradation of water quality linked to increased phytoplankton biomass.

Flavopiridol inhibits adipogenesis and improves metabolic homeostasis by ameliorating adipose tissue inflammation in a diet-induced obesity model

Repositioning of FDA approved/clinical phase drugs has recently opened a new opportunity for rapid approval of drugs, as it shortens the overall process of drug discovery and development. In previous studies, we predicted the possibility of better activity profiles of flavopiridol, the FDA approved orphan drug with better fit value 2.79 using a common feature pharmacophore model for anti-adipogenic compounds (CFMPA). The present study aimed to investigate the effect of flavopiridol on adipocyte differentiation and to determine the underlying mechanism. Flavopiridol inhibited adipocyte differentiation in different cell models like 3T3-L1, C3H10T1/2, and hMSCs at 150 nM. Flavopiridol was around 135 times more potent than its parent molecule rohitukine. The effect was mediated through down-regulation of key transcription factors of adipogenesis i.e. Peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and their downstream targets, including adipocyte protein −2 (aP2) and fatty acid synthase (FAS). Further, results revealed that flavopiridol arrested the cell cycle in G1/S phase during mitotic clonal expansion by suppressing cell cycle regulatory proteins i.e. Cyclins and CDKs. Flavopiridol inhibited insulin-stimulated signalling in the early phase of adipocyte differentiation by downregulation of AKT/mTOR pathway. In addition, flavopiridol improved mitochondrial function in terms of increased oxygen consumption rate (OCR) in mature adipocytes. In the mouse model of diet-induced obesity, flavopiridol attenuated obesity-associated adipose tissue inflammation and improved serum lipid profile, glucose tolerance as well as insulin sensitivity. In conclusion, the FDA approved drug flavopiridol could be placed as a potential drug candidate for the treatment of cancer and obesity comorbid patients.

Spectrum of Non-Obstructive Coronary Artery Disease and Its Relationship with Atrial Fibrillation.

This article aims to analyze the relationship between non-obstructive coronary artery disease (NOCAD) and atrial fibrillation (AF), exploring the underlying pathophysiological mechanisms and implications for clinical management. NOCAD and AF are prevalent cardiovascular conditions that often coexist, yet their interrelation is not well understood. NOCAD can lead to ischemic necrosis of cardiomyocytes and their replacement with fibrous tissue, sustaining focal ectopic activity in atrial myocardium. Atrial fibrillation, on the other hand, the most common sustained cardiac arrhythmia, is able to accelerate atherosclerosis and increase oxygen consumption in the myocardium, creating a mismatch between supply and demand, and thus promoting the development or worsening of coronary ischemia. Therefore, NOCAD and AF seem to be a complex interplay with one begets another.

Acute hypoxic conditions preceding endotoxin administration result in an increased proinflammatory cytokine response in healthy men.

Tissues often experience hypoxia at sites of inflammation due to malperfusion, massive immune cell recruitment, and increased oxygen consumption. Organisms adapt to these hypoxic conditions through the transcriptional activation of various genes. In fact, there is significant crosstalk between the transcriptional responses to hypoxia and inflammatory processes. This interaction, named inflammatory hypoxia, plays a crucial role in various diseases including malignancies, chronic inflammatory lung diseases, and sepsis. To further elucidate the crosstalk between hypoxia and inflammation in vivo and assess its potential for innovative therapies, our study aimed at investigating the impact of acute hypoxic conditions on inflammation-induced immune responses. To this end, we exposed healthy human subjects to hypoxia either before (hypoxia priming) or after a single intravenous (i.v.) injection of 0.4 ng/kg LPS. Our data show that hypoxia exposure prior to LPS injection (hypoxia priming) amplified the proinflammatory response. This was reflected by an increase in body temperature, plasma noradrenaline levels, and the production of proinflammatory cytokines (i.e., IL-6 and TNF-α), compared with LPS control conditions. These effects were not observed when participants were exposed to hypoxia after LPS administration, demonstrating that the interaction between hypoxia and inflammation highly depends on the timing of both stimuli. Our findings suggest that acute hypoxia (i.e., hypoxia priming) modulates transient inflammation, leading to an enhanced proinflammatory response in healthy human subjects. This highlights the need for further investigations to understand the pathology of various hypoxia-inducible factor (HIF)-associated inflammatory diseases and to develop suitable, innovative therapies.NEW & NOTEWORTHY To our knowledge, this is the first in vivo study investigating the effects of hypoxia preceding (hypoxia priming) or following LPS administration on the endotoxin-induced inflammatory response in healthy human subjects. The data show that hypoxia priming amplified the proinflammatory response, reflected by an increased body temperature, increased plasma noradrenaline levels, and higher production of proinflammatory cytokines (i.e., IL-6 and TNF-α) compared with LPS control conditions.

Multiplex genome editing eliminates the Warburg Effect without impacting growth rate in mammalian cells.

The Warburg effect is ubiquitous in proliferative mammalian cells, including cancer cells, but poses challenges for biopharmaceutical production, as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production via knockout have failed in mammalian bioprocessing since lactate dehydrogenase has proven essential. However, here we eliminated the Warburg effect in Chinese hamster ovary (CHO) and HEK293 cells by simultaneously knocking out lactate dehydrogenase and regulators involved in a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA. In contrast to long-standing assumptions about the role of aerobic glycolysis, Warburg-null cells maintain wildtype growth rate while producing negligible lactate. Further characterization of Warburg-null CHO cells showed a compensatory increase in oxygen consumption, a near total reliance on oxidative metabolism, and higher cell densities in fed-batch cell culture. These cells remained amenable for production of diverse biotherapeutic proteins, reaching industrially relevant titers and maintaining product glycosylation. Thus, the ability to eliminate the Warburg effect is an important development for biotherapeutic production and provides a tool for investigating a near-universal metabolic phenomenon.

Effect of a new resistance training method on the metaboreflex in cardiac rehabilitation patients: a randomized controlled trial.

Patients with cardiac disease exhibit exaggerated sympathoexcitation, pressor, and ventilatory responses to muscle metaboreflex activation (MMA). However, the effects of cardiac rehabilitation (CR) and especially resistance training (RT) modalities on MMA are not well known. This study investigated how CR impacts MMA in such patients, specifically examining the effects of two different resistance training (RT) protocols following 12weeks of CR. In addition to endurance exercises, 32 patients were randomized into either a 3/7 RT modality (comprising 5 sets of 3-7 repetitions) or a control (CTRL) modality (involving 3 sets of 9 repetitions), with distinct inter-set rest intervals (15s for 3/7 and 60s for CTRL). MMA, gauged by blood pressure (BP) and ventilatory (Ve) responses during a handgrip exercise at 40% effort and subsequent post-exercise circulatory occlusion, demonstrated CR's significant impact. Systolic BP, initially at + 28 ± 23% pre-CR, improved to + 11 ± 15% post-CR (P = .011 time effect; P = .131 group effect). Diastolic BP showed a similar trend, from + 27 ± 23% to + 13 ± 15% (P = .099 time effect; P = .087 group effect). Ve, initially at + 60 ± 39%, reduced to + 14 ± 19% post-CR (P < .001 time effect; P = .142 group effect). Critical parameters-maximal oxygen consumption, lean mass, hand grip, and quadriceps strength-exhibited parallel increases in both 3/7 and CTRL groups (P < .05 time effect; P > .3 group effect). Ultimately, CR demonstrated comparable improvements in MMA across both RT modalities, indicating its positive influence on cardiovascular responses and physical performance in individuals with cardiac conditions.

Rare earth elements and warming: Implications for adult mussel health and sperm quality

The present study aimed to investigate the effects of europium (Eu) exposure (10 μg/L), warming (a 4 °C increase), and their combination on Mytilus galloprovincialis. Biochemical and histopathological changes in adult mussels were evaluated after a 28-day exposure period. Additionally, biochemical and physiological alterations in sperm were measured following a 30-min exposure period. The overall responses to each treatment were assessed using the Integrated Biological Response index version 2 (IBRv2). In adult mussels, warming elevated metabolism and activated glutathione S-transferases (GSTs), leading to redox imbalance and cellular damage. Europium exposure alone slightly enhanced metabolism and GSTs activity, resulting in cellular damage and histopathological injuries in digestive tubules. The combined exposure to Eu and warming was the most detrimental treatment for adults, as indicated by the highest IBRv2 value. This treatment slightly increased metabolism and uniquely elevated the activity of antioxidant enzymes, as well as GSTs and carboxylesterases. Despite these responses, they were inadequate to prevent redox imbalance, cellular damage, and histopathological injuries in digestive tubules and gills. Regarding sperm, warming reduced reactive oxygen species (ROS) production but raised lipid peroxidation levels. Sperm exposed to this treatment also increased their oxygen consumption and exhibited reduced velocity. The IBRv2 indicated that Eu was the most harmful treatment for sperm, significantly increasing ROS production and notably decreasing sperm velocity. When combined with warming, Eu elevated superoxide anion (O2-) production, lowered sperm velocity, and increased oxygen consumption. This study underscores the importance of investigating the effects of rare earth elements and their interaction with climate change-related factors.

Mitochondria-containing extracellular vesicles from mouse vs. human brain endothelial cells for ischemic stroke therapy

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.

Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.

The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.

Effects of Endurance Training on Antioxidant and Hormonal Status in Peripheral Blood of Young Healthy Men.

(1) Background: Physical activity may cause an imbalance in the major functions of the human body. This study aimed to investigate the effects of endurance running training on the parameters of the antioxidant defense system (SOD, CAT, GPx, GR, GSH), LPO (malondialdehyde, MDA), and stress hormones (A, NA) in young healthy, previously untrained men. (2) Methods: The training program was as follows: 8 weeks of running, three times per week; the duration of a single session was 30-70 min, the intensity was twice a week in the so-called extensive endurance zone, and once a week in the anaerobic threshold zone. Blood samples were collected from the subjects, before and after the running program. (3) Results: The training program resulted in a significant increase in maximal oxygen consumption (p < 0.001). The activities of SOD, GPx, and GR also increased significantly (p < 0.05, p < 0.01, and p < 0.05, respectively), while CAT activity and GSH and MDA concentrations remained unchanged. The concentration of A decreased (p < 0.05), while the NA concentration increased significantly (p < 0.05). SOD, GPx, GR, and NA positively correlated with VO2max (p < 0.05, p < 0.001, p < 0.01, p < 0.05, respectively), while a negative correlation was detected between A and VO2max (p < 0.05). (4) Conclusions: These results indicate that there is no persistent oxidative stress in response to the applied 8-week running program, probably due to exercise-induced protective alterations in the antioxidant defense system. Furthermore, adaptations occurred at the hormonal level, making the organism more ready for a new challenge.

Nuclear factor erythroid 2-related factor 2 activation in streptozotocin-induced diabetic rats normalize renal hemodynamics and oxygen consumption.

Diabetic kidney disease is a major contributor to end stage renal disease. A change in kidney oxygen homeostasis leading to decreased tissue oxygen tension is an important factor initiating alterations in kidney function in diabetes. However, the mechanism contributing to changed oxygen homeostasis is still unclear. Hyperglycemia-induced production of reactive oxygen species and an altered response to them have previously been demonstrated. In the present study, chronic treatment with DL-sulforaphane to induce nuclear factor erythroid 2-related factor 2 (Nrf2) expression, a master transcriptional regulator binding to antioxidant response elements inducing increased protection against reactive oxygen species, is studied. Sprague-Dawley rats were made diabetic using streptozotocin and either left untreated or received daily subcutaneous injections of DL-sulforaphane for 4 weeks. Age-matched non-diabetic rats served as controls. After 4 weeks of treatment, rats were anesthetized using thiobutabarbital, and kidney functions were studied in terms of glomerular filtration rate (GFR), renal blood flow (RBF), sodium transport, kidney oxygen consumption, and kidney oxygen tension. Mitochondria was isolated from kidney cortical tissue and investigated using high-resolution respirometry. GFR was increased in diabetics but not RBF resulting in increased filtration fraction in diabetics. DL-sulforaphane treatment did not affect RBF and GFR in controls but decreased the same parameters in diabetics. Increased GFR resulted in increased sodium transport and oxygen consumption, hence decreased efficiency in diabetics compared to controls. Increased oxygen consumption in diabetics resulted in decreased cortical tissue oxygen tension. DL-sulforaphane treatment decreased oxygen consumption in diabetics, whereas transport efficiency was not significantly affected. DL-sulforaphane treatment increased cortical pO2 in diabetics. DL-sulforaphane treatment affects renal hemodynamics, improving cortical oxygen tension but not mitochondrial efficiency.

Chemogenetic Excitation of Ventromedial Hypothalamic Steroidogenic Factor 1 (SF1) Neurons Increases Muscle Thermogenesis in Mice.

Allostatic adaptations to a perceived threat are crucial for survival and may tap into mechanisms serving the homeostatic control of energy balance. We previously established that exposure to predator odor (PO) in rats significantly increases skeletal muscle thermogenesis and energy expenditure (EE). Evidence highlights steroidogenic factor 1 (SF1) cells within the central and dorsomedial ventromedial hypothalamus (c/dmVMH) as a modulator of both energy homeostasis and defensive behavior. However, the brain mechanism driving elevated EE and muscle thermogenesis during PO exposure has yet to be elucidated. To assess the ability of SF1 neurons of the c/dmVMH to induce muscle thermogenesis, we used the combined technology of chemogenetics, transgenic mice, temperature transponders, and indirect calorimetry. Here, we evaluate EE and muscle thermogenesis in SF1-Cre mice exposed to PO (ferret odor) compared to transgenic and viral controls. We detected significant increases in muscle temperature, EE, and oxygen consumption following the chemogenetic stimulation of SF1 cells. However, there were no detectable changes in muscle temperature in response to PO in either the presence or absence of chemogenetic stimulation. While the specific role of the VMH SF1 cells in PO-induced thermogenesis remains uncertain, these data establish a supporting role for SF1 neurons in the induction of muscle thermogenesis and EE similar to what is seen after predator threats.

Optimized Partial Freezing Protocol Enables 10-Day Storage of Rat Livers.

Preserving organs at subzero temperatures with halted metabolic activity holds the potential to prolong preservation and expand the donor organ pool for transplant. Our group recently introduced partial freezing, a novel approach in high-subzero storage at -15°C, enabling 5 days storage of rodent livers through precise control over ice nucleation and unfrozen fraction. However, increased vascular resistance and tissue edema suggested a need for improvements to extend viable preservation. Here, we describe an optimized partial freezing protocol with key optimizations including increased concentration of propylene glycol to reduce ice recrystallization and maintained osmotic balance through an increase in bovine serum albumin, all while minimizing sheer stress during cryoprotectant unloading with an acclimation period. These approaches ensured the viability during preservation and recovery processes, promoting liver function and ensuring optimal preservation. This was evidenced by increased oxygen consumption, decreased vascular resistance and edema. Ultimately, we show that using the optimized protocol, livers can be stored for 10 days with comparable vascular resistance and lactate levels to 5 days, outperforming the viability of time-matched cold stored livers as the current gold standard. This study represents a significant advancement in expanding organ availability through prolonged preservation and thereby revolutionizing transplant medicine.

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F Mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer's disease (AD). The APP NL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APP NL-F/NL-F mice. Thus, four month old male and female APP NL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg Dasatinib + 50 mg/kg Quercetin, or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + Quercetin treatment in female APP NL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-β (Aβ) 42 and senescence associated-β-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APP NL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

Mice Lacking Mrs2 Magnesium Transporter are Hypophagic and Thin When Maintained on a High-Fat Diet.

Genes regulating body fat are shared with high fidelity by mice and humans, indicating that mouse knockout (KO) phenotyping might identify valuable antiobesity drug targets. Male Mrs2 magnesium transporter (Mrs2) KO mice were recently reported as thin when fed a high-fat diet (HFD). They also exhibited increased energy expenditure (EE)/body weight and had beiged adipocytes that, along with isolated hepatocytes, demonstrated increased oxygen consumption, suggesting that increased EE drove the thin phenotype. Here we provide our data on these and additional assays in Mrs2 KO mice. We generated Mrs2 KO mice by homologous recombination. HFD-fed male and female Mrs2 KO mice had significantly less body fat, measured by quantitative magnetic resonance, than wild-type (WT) littermates. HFD-fed Mrs2 KO mice did not demonstrate increased EE by indirect calorimetry and could not maintain body temperature at 4 °C, consistent with their decreased brown adipose tissue stores but despite increased beige white adipose tissue. Instead, when provided a choice between HFD and low-fat diet (LFD), Mrs2 KO mice showed a significant 15% decrease in total energy intake resulting from significantly lower HFD intake that offset numerically increased LFD intake. Food restriction studies performed using WT mice suggested that this decrease in energy intake could explain the loss of body fat. Oral glucose tolerance test studies revealed significantly improved insulin sensitivity in Mrs2 KO mice. We conclude that HFD-fed Mrs2 KO mice are thin with improved insulin sensitivity, and that this favorable metabolic phenotype is driven by hypophagia. Further evaluation is warranted to determine the suitability of MRS2 as a drug target for antiobesity therapeutics.

Mouse vascularized adipose spheroids: an organotypic model for thermogenic adipocytes.

Adipose tissues, particularly beige and brown adipose tissue, play crucial roles in energy metabolism. Brown adipose tissues' thermogenic capacity and the appearance of beige cells within white adipose tissue have spurred interest in their metabolic impact and therapeutic potential. Brown and beige fat cells, activated by environmental factors like cold exposure or by pharmacology, share metabolic mechanisms that drive non-shivering thermogenesis. Understanding these two cell types requires advanced, yet broadly applicable in vitro models that reflect the complex microenvironment and vasculature of adipose tissues. Here we present mouse vascularized adipose spheroids of the stromal vascular microenvironment from inguinal white adipose tissue, a tissue with 'beiging' capacity in mice and humans. We show that adding a scaffold improves vascular sprouting, enhances spheroid growth, and upregulates adipogenic markers, thus reflecting increased adipocyte maturity. Transcriptional profiling via RNA sequencing revealed distinct metabolic pathways upregulated in our vascularized adipose spheroids, with increased expression of genes involved in glucose metabolism, lipid metabolism, and thermogenesis. Functional assessment demonstrated increased oxygen consumption in vascularized adipose spheroids compared to classical 2D cultures, which was enhanced by β-adrenergic receptor stimulation correlating with elevated β-adrenergic receptor expression. Moreover, stimulation with the naturally occurring adipokine, FGF21, induced Ucp1 mRNA expression in the vascularized adipose spheroids. In conclusion, vascularized inguinal white adipose tissue spheroids provide a physiologically relevant platform to study how the stromal vascular microenvironment shapes adipocyte responses and influence activated thermogenesis in beige adipocytes.

Study on combustion characteristics of glass fiber/phenolic resin composites

In order to study the combustion characteristics of glass fiber/phenolic resin composites, a conical calorimeter was used to explore the combustion characteristics of glass fiber/phenolic resin composites in an aircraft frame under different thermal radiation intensities, and the fire hazard of the materials was evaluated by evaluation index, and the limiting oxygen index at different temperatures was explored by combining the high temperature oxygen index meter. The test results show that when the ambient temperature increases from 20 °C to 220 °C, the limiting oxygen index first increases from 86.6 % to 93.7 %, and then decreases to 84.4 %. The oxygen consumption and CO2 release increase with the increase of thermal radiation intensity during combustion, and the release of CO decreases with the increase of thermal radiation. The heat release rate curve of the test material has only 1 enhancement peak. The heat radiation intensity increased from 50 kW/m2 to 70 kW/m2, and the peak heat release rate of the test material combustion increased from 64.7 kW/m2 to 100.7 kW/m2. The rate of mass loss of materials accelerates with the increase of thermal radiation intensity; As the intensity of thermal radiation increases, the fire hazard of the material increases.