Tissue Oxygen Consumption Research Articles

Hypoxia signaling in the adipose tissue.

Obesity per se is rapidly emerging all over the planet and further accounts for many other life-threatening conditions, such as diabetes, cardiovascular diseases, and cancers. Decreased oxygen supply or increased relative oxygen consumption in the adipose tissue results in adipose tissue hypoxia, which is a hallmark of obesity. This review aims to provide an up-to-date overview of the hypoxia signaling in the adipose tissue. First, we summarize literature evidence to demonstrate that hypoxia is regularly observed during adipose tissue remodeling in human and rodent models of obesity. Next, we discuss how hypoxia-inducible factors (HIFs) are regulated and how adipose tissues behave in response to hypoxia. Then, the differential roles of adipose HIF-1α and HIF-2α in adipose tissue biology and obesity pathology are highlighted. Finally, the review emphasizes the importance of modulating adipose hypoxia as a therapeutic avenue to assist adipose tissues in functionally adapting to hypoxic conditions, ultimately promoting adipose health and improving outcomes due to obesity.

Rate of body weight gain during early gestation in F0 beef heifers has effects that extend multigenerationally to the F2 fetuses.

Our aim was to investigate the effects of maternal (F0) body weight (BW) gain during the first 84 d of gestation on body composition, ovarian reserve, and hormonal and metabolic parameters of breeding-age F1 heifers, as well as the body weight and morphometry of F2 fetuses. The study also evaluated the effect of maternal body weight gain (F0) on the mRNA relative abundance of the small intestine of both F1 heifers and F2 fetuses. Crossbred Angus heifers (F0; n = 100) were managed to gain 0.20kg/d (low gain [LG], n = 50) or 0.75kg/d (moderate gain [MG], n = 50) for the first 84 d of gestation. Subsequently, F0 dams were managed on a common forage-based diet for the rest of gestation until the weaning of the F1 offspring. At 15 months of age a subset of F1 heifers was randomly selected for the current experiment (n = 8 LG and n = 8 MG). Heifers were bred via artificial insemination (AI; d 0), then harvested on d 84 of gestation. On d -10, 42, and 84, BW was recorded, and blood was collected and analyzed for concentrations of glucose, non-esterified fatty acids, progesterone, insulin, and insulin-like growth factor-1. Weight of F1 carcasses, organs, gravid uteri, and F2 fetuses and organs were recorded at harvest. Visible follicles were counted on F1 ovaries at harvest, and histology was used to count microscopic follicles. Liver and jejunal samples from F1 heifers were collected to measure tissue oxygen consumption and jejunal samples from F1 heifers and F2 fetuses were collected for mRNA relative abundance analysis. Body weight of F1 heifers from MG dams tended to be 12kg greater (P = 0.06) than for F1 heifers from LG dams. Concentrations of glucose were greater (P = 0.03) in F1 heifers from the MG group, with no differences in other blood metabolites or follicular populations (P ≥ 0.16). Interestingly, mammary glands were heavier (P = 0.05) and placentas and body depth tended to be heavier and greater, respectively (P ≤ 0.10), for F2 fetuses from F0 LG heifers. Oxygen consumption in the liver and jejunum, as well as mRNA relative abundance in the jejunum of F1 heifers, were not affected by F0 rate of gain (P ≥ 0.16). However, the NDUFC1, SDHA, UQCR1, and PPARG genes were upregulated (P ≤ 0.05) in the jejunum of F2 fetuses from the LG group. In conclusion, BW gain of F0 heifers during early gestation exerts subtle effects on pre-breeding BW and blood metabolites in F1 offspring, with impacts present in F2 placenta, mammary gland, and intestine.

Kv beta complex facilitates exercise-induced augmentation of myocardial perfusion and cardiac growth.

The oxygen sensitivity of voltage-gated potassium (Kv) channels regulates cardiovascular physiology. Members of the Kv1 family interact with intracellular Kvβ proteins, which exhibit aldo-keto reductase (AKR) activity and confer redox sensitivity to Kv channel gating. The Kvβ proteins contribute to vasoregulation by controlling outward K+ currents in smooth muscle upon changes in tissue oxygen consumption and demand. Considering exercise as a primary physiological stimulus of heightened oxygen demand, the current study tested the role of Kvβ proteins in exercise performance, exercise-induced adaptations in myocardial perfusion, and physiological cardiac growth. Our findings reveal that genetic ablation of Kvβ2 proteins diminishes baseline exercise capacity in mice and attenuates the enhancement in exercise performance observed after long-term training. Moreover, we demonstrate that Kvβ2 proteins are critical for exercise-mediated enhancement in myocardial perfusion during cardiac stress as well as adaptive changes in cardiac structure. Our results underscore the importance of Kvβ proteins in metabolic vasoregulation, highlighting their role in modulating both exercise capacity and cardiovascular benefits associated with training. Furthermore, our study sheds light on a novel molecular target for enhancing exercise performance and improving the health benefits associated with exercise training in patients with limited capacity for physical activity.

Assessment of Autoregulation of the Cerebral Circulation during Acute Lung Injury in a Neonatal Porcine Model.

In neonates with acute lung injury (ALI), targeting lower oxygenation saturations is suggested to limit oxygen toxicity while maintaining vital organ function. Although thresholds for cerebral autoregulation are studied for the management of premature infants, the impact of hypoxia on hemodynamics, tissue oxygen consumption and extraction is not well understood in term infants with ALI. We examined hemodynamics, cerebral autoregulation and fractional oxygen extraction, as measured by near-infrared spectroscopy (NIRS) and blood gases, in a neonatal porcine oleic acid injury model of moderate ALI. We hypothesized that in ALI animals, cerebral oxygen extraction would be increased to a greater degree than kidney or gut oxygen extraction as indicative of the brain's adaptive efforts to increase cerebral oxygen extraction at the expense of splanchnic end organs. Fifteen anesthetized, ventilated 5-day-old neonatal piglets were divided into moderate lung injury by treatment with oleic acid or control (sham injection). The degree of lung injury was quantified at baseline and after establishment of ALI by blood gases, ventilation parameters and calculated oxygenation deficit, hemodynamic indices by echocardiography and lung injury score by ultrasound. PaCO2 was maintained constant during ventilation. Cerebral, renal and gut oxygenation was determined by NIRS during stepwise decreases in inspired oxygen from 50% to 21%, correlated with PaO2 and PvO2; changes in fractional oxygen extraction (ΔFOE) were calculated from NIRS and from regional blood gas samples. The proportion of cerebral autoregulation impairment attributable to blood pressure, and to hypoxemia, was calculated from autoregulation nomograms. ALI manifested as hypoxemia with increasing intrapulmonary shunt fraction, decreased lung compliance and increased resistance, and marked increase in lung ultrasound score. Brain, gut and renal NIRS, obtained from probes placed over the anterior skull, central abdomen and flank, respectively, correlated with concurrent SVC (brain) or IVC (gut, renal) PvO2 and SvO2. Cerebral autoregulation was impaired after ALI as a function of blood pressure at all FiO2 steps, but predominantly by hypoxemia at FiO2 < 40%. Cerebral ΔFOE was higher in ALI animals at all FiO2 steps. We conclude that in an animal model of neonatal ALI, cerebrovascular blood flow regulation is primarily dependent on oxygenation. There is not a defined oxygenation threshold below which cerebral autoregulation is impaired in ALI. Cerebral oxygen extraction is enhanced in ALI, reflecting compensation for exhausted cerebral autoregulation due to the degree of hypoxemia and/or hypotension, thereby protecting against tissue hypoxia.

THE INFLUENCE OF BIOCOMPATIBILITY OF THE EXTRACORPOREAL OXYGENATOR CIRCUIT ON THE DEGREE OF HEMOLYSIS AND OPTIMIZATION OF OXYGEN STATUS IN MINIMALLY INVASIVE CORONARY ARTERY BYPASS GRAFTING

Introduction. A distinctive feature of cardiopulmonary bypass in minimally invasive coronary artery bypass grafting (CABG) is the significantly longer perfusion time, involving active blood drainage from the vein to the cardiotomy reservoir, which carries the risk of hemolysis development. In this context, mechanical hemolysis disrupts the gas transport function of the blood.&#x0D; The aim of the research. Reducing hemolysis and optimizing oxygen status of patients during minimally invasive coronary artery bypass grafting surgeries.&#x0D; Materials and methods. The study included 60 patients, who underwent minimally invasive coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) under moderate hypothermia. The patients were divided into two groups of 30 individuals each. To improve the biocompatibility of the oxygenator, the circuit in Group 1 (Gr1) was treated with an adaptive composition, while in Group 2 (Gr2), the oxygenator circuit remained untreated. The following parameters were examined: hemoglobin (Hb), hematocrit (Ht), red blood cell count (RBC), oxygen delivery index (DO2I), oxygen consumption index (VO2I), oxygen extraction ratio (O2ER%), oxygen extraction index (O2EI%), venous (SpvO2), and arterial (SpaO2) oxygen saturation, oxygen tension in arterial (PaO2) and venous blood (PvO2), acid-base status of the blood (pH, pCO2,HCO3ˉ, BE), and the degree of hemolysis.&#x0D; Results. Before initiation of cardiopulmonary bypass (CPB), an insignificant increase in O2IE% was observed in Gr1 (26.07±1.57) and Gr2 (27.11±0.81); p=0.875, indicating an increase in tissue oxygen consumption. At the hypothermic stage CPB, both Gr1 and Gr2 demonstrated a statistically significant decrease in Hb, Ht, and RBC levels (p&lt;0.05) due to hemodilution, accompanied by a decrease in IDO2, IVO2, O2IE%, and O2ER% in both groups due to hypothermia. After rewarming, O2ER% in Gr1 (22.91±2.68) and Gr2 (24.59±2.02); p=0.191, and O2EI% in Gr1 (22.92±2.44) and Gr2 (24.61±2.01); p=0.215, were in the normal range. After weaning off cardiopulmonary bypassin Gr2, O2EI% was 27.34±1.97, indicating an increase in oxygen consumption and oxygen extraction. Upon separation from CPB, Gr2 showed a tendency to mild compensated metabolic acidosis, mainly due to HCO3ˉ 21.9±0.3. During the rewarming stage, the hemolysis value was 0.36±0.09in Gr1 and 0.45±0.17 in Gr2 (p&lt;0.001). After CPB, hemolysis was 0.41±0.15 in Gr1 and 0.61±0.22 in Gr2 (p&lt;0.001).&#x0D; Conclusions. Improving the biocompatibility of the extracorporeal oxygenatorcircuit makes it possible to reduce hemolysis and optimise the patient's oxygen status after cardiopulmonary bypass in minimally invasive coronary artery bypass grafting.

Non-invasive blood glucose estimation method based on the phase delay between oxy- and deoxyhemoglobin using visible and near-infrared spectroscopy.

Many researchers have attempted to estimate blood glucose levels (BGLs) noninvasively using near-infrared (NIR) spectroscopy. However, the optical absorption change induced by blood glucose is weak in the NIR region and often masked by interference from other components such as water and hemoglobin. Instead of using direct optical absorption by glucose, this study proposes an index calculated from oxy- and deoxyhemoglobin signals that shows a good correlation with BGLs while using conventional visible and NIR spectroscopy. The metabolic index, which is based on tissue oxygen consumption, was derived through analytical methods and further verified and reproduced in a series of glucose challenge experiments. Blood glucose estimation units were prototyped by utilizing commercially available smart devices. Our experimental results showed that the phase delay between the oxy- and deoxyhemoglobin signals in near-infrared spectroscopy correlates with BGL measured by a conventional continuous glucose monitor. The proposed method was also confirmed to work well with visible spectroscopy systems based on smartphone cameras. The proposed method also demonstrated excellent repeatability in results from a total of 19 oral challenge tests. This study demonstrated the feasibility of non-invasive glucose monitoring using existing photoplethysmography sensors for pulse oximeters and smartwatches. Evaluating the proposed method in diabetic or unhealthy individuals may serve to further increase its practicality.

Spatially resolved quantification of oxygen consumption rate in ex vivo lymph node slices.

Cellular metabolism has been closely linked to activation state in cells of the immune system, and the oxygen consumption rate (OCR) in particular serves as a valuable metric for assessing metabolic activity. Several oxygen sensing assays have been reported for cells in standard culture conditions. However, none have provided a spatially resolved, optical measurement of local oxygen consumption in intact tissue samples, making it challenging to understand regional dynamics of consumption. Therefore, here we established a system to monitor the rates of oxygen consumption in ex vivo tissue slices, using murine lymphoid tissue as a case study. By integrating an optical oxygen sensor into a sealed perfusion chamber and incorporating appropriate correction for photobleaching of the sensor and of tissue autofluorescence, we were able to visualize and quantify rates of oxygen consumption in tissue. This method revealed for the first time that the rate of oxygen consumption in naïve lymphoid tissue was higher in the T cell region compared to the B cell and cortical regions. To validate the method, we measured OCR in the T cell regions of naïve lymph node slices using the optical assay and estimated the consumption rate per cell. The predictions from the optical assay were similar to reported values and were not significantly different from those of the Seahorse metabolic assay, a gold standard method for measuring OCR in cell suspensions. Finally, we used this method to quantify the rate of onset of tissue hypoxia for lymph node slices cultured in a sealed chamber and showed that continuous perfusion was sufficient to maintain oxygenation. In summary, this work establishes a method to monitor oxygen consumption with regional resolution in intact tissue explants, suitable for future use to compare tissue culture conditions and responses to stimulation.

Adipose Tissue Hypoxia in Obesity: Clinical Reappraisal of Hypoxia Hypothesis.

Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thereby, compared to lean subjects, obese individuals have almost half lower capillary density and more than half lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 alpha (HIF-1α) activity also requires phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR)-mediated signaling. Especially HIF-1α is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia contributes to several biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation, and insulin resistance (IR). Pathogenesis of obesity-related comorbidities is attributed to intermittent hypoxia (IH), which is mostly observed in visceral obesity. Proinflammatory phenotype of the adipose tissue is a crucial link between IH and the development of IR. Inhibition of adaptive unfolded protein response (UPR) in hypoxia increases β cell death. Moreover, deletion of HIF-1α worsens β cell function. Oxidative stress, as well as the release of proinflammatory cytokines/adipokines in obesity, is proportional to the severity of IH. Reactive oxygen species (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal; however, mitochondrial ROS production is required for hypoxic HIF-1α protein stabilization. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible for the dysregulated adipocytokines production in obesity. Hypoxia both inhibits adipocyte differentiation from preadipocytes and macrophage migration from the hypoxic adipose tissue. Upon reaching a hypertrophic threshold beyond the adipocyte fat loading capacity, excess extracellular matrix (ECM) components are deposited, causing fibrosis. HIF-1α initiates the whole pathological process of fibrosis and inflammation in the obese adipose tissue. In addition to stressed adipocytes, hypoxia contributes to immune cell migration and activation which further aggravates adipose tissue fibrosis. Therefore, targeting HIF-1α might be an efficient way to suppress hypoxia-induced pathological changes in the ECM. The fibrosis score of adipose tissue correlates negatively with the body mass index and metabolic parameters. Inducers of browning/beiging adipocytes and adipokines, as well as modulations of matrix remodeling enzyme inhibitors, and associated gene regulators, are potential pharmacological targets for treating obesity.

MATHEMATICAL INVESTIGATION OF OXYGEN TRANSPORT IN INTACT MUSCLES VIS-A-VIS TISSUE METABOLISM

The human muscle tissue is an active cite with varied aerobic consumption. The supply of oxygen to the muscle cells is governed by the demand for oxygen that varies across different metabolic states of the body tissues. Most of the models designed to simulate oxygen flow in the body are based on the assumption of constant rate of oxygen consumption in muscle tissues. This generates a picture contrary to the physiological ambience where the rates vary in response to level of activity in which muscles are involved. In this context, we have taken recourse to a comparative analysis of zero-order, first-order and Michaelis-Menten oxygen consumption rate inside the muscle tissue. The model is based on the reaction-diffusion equation, and the exact solution is obtained and compared with the numerical solution using MATLAB and both are in good agreement.

Mathematical modeling of cerebral oxygen transport from capillaries to tissue

A non-linear model of oxygen transport from a capillary to tissue is considered. The model takes into account the convection of oxygen in the blood, its diffusion transfer through the capillary wall, and the diffusion and consumption of oxygen in tissue. In the current work, a boundary value problem for the oxygen transport model is studied. The existence theorem is proved and a numerical algorithm is constructed and implemented. The numerical experiments studying the effect of low hematocrit and reduced blood flow rate on cerebral hypoxia in preterm infants are conducted.

An Approach for Estimating Oxygen Consumption in Tissues Based on TOLD MRI Signal

An Approach for Estimating Oxygen Consumption in Tissues Based on TOLD MRI Signal

Central venous-to-arterial CO2 difference as a biomarker of outcome in children who underwent surgery for congenital heart disease.

In congenital heart surgery, low cardiac output syndrome (LCOS) is a major cause of morbidity in the immediate post-operative period. A decrease in cardiac output leads to an increase in tissue oxygen consumption. Several biomarkers such as venous oxygen saturation (SvO2), arteriovenous oxygen difference (DavO2), and lactate can assess tissue perfusion in the presence of LCOS. Recently, central venous to arterial CO2 difference (ΔCO2) has been proposed as a biomarker of tissue ischemia that could be used as a predictor of death in neonatal patients. This study aimed to analyze the relationship between ΔCO2 and immediate post-operative outcomes in pediatric patients undergoing congenital heart surgery and its correlation with DavO2, SvO2, and lactate. We conducted a longitudinal study of patients aged 0-18 years who underwent congenital heart surgery with or without cardiopulmonary bypass at the Instituto Nacional de Pediatría, from March 2019 to March 2021. Eighty-two patients were included; the median age was 17 months. About 59% had a ΔCO2 ≥ 6 mmHg. Patients with ΔCO2 ≥ 6 mmHg had a vasoactive-inotropic score > 5 (p < 0.001), DavO2 > 5 mL/dL (p = 0.048), and lactate > 2 mmol/L (p = 0.027), as well as a longer hospital stay (p = 0.043). Patients with ΔCO2 > 6 mmHg and vasoactive-inotropic score ≥ 10 were 12.6 times more likely to die. ΔCO2 is a good marker of tissue hypoperfusion and outcome in the post-operative period of congenital heart surgery.

Tissue oxygen partial pressure as a viability metric for ex vivo brain tissue slices

BackgroundDespite the prevalent use of the ex vivo brain slice preparation in neurophysiology research, a reliable method for judging tissue viability ― and thus suitability of a slice for inclusion in an experiment ― is lacking. The utility of indirect electrophysiological measures of tissue health is model-specific and needs to be used cautiously. In this study, we verify a more direct test of slice viability, based on tissue oxygen consumption rate. New methodWe hypothesised that the minimum intra-slice partial pressure of oxygen (pO2min) would correlate with tissue oxygen consumption rate, providing an accessible method for reliably assessing tissue viability status. Using mouse brain cortex slices, we measured tissue oxygen consumption rate using a Fick’s law diffusion–consumption model applied to full intra-tissue pO2 profiles and compared this to pO2min and 2,3,5-triphenol tetrazolium chloride (TTC) viability staining. ResultsTissue pO2min correlated strongly with oxygen consumption rate in both neurophysiological active and quiescent tissue (in “no-magnesium” and “normal” artificial cerebrospinal fluid, respectively) (R2 =49.7% and 42.1%, respectively). Both correlated with TTC viability stain. Oxygen consumption rate was positively related to the frequency of seizure-like event activity in no-magnesium artificial cerebrospinal fluid (R2 = 44.8%). Comparison with existing methodsWhile measurement of tissue oxygen levels and oxygen consumption is not new, intra-tissue pO2min is a novel approach to assess brain slice viability. ConclusionThe results confirm that tissue oxygen minimum pO2min is a robust metric for estimating tissue viability status — the lower the pO2min, the healthier the tissue.

Altered tissue oxygenation in patients with post COVID-19 syndrome.

Post COVID-19 syndrome (PCS) is a complex condition with partly substantial impact on patients' social and professional life and overall life quality. Currently, the underlying cause(s) of PCS are unknown. Since PCS-specific symptoms could be associated with systemic alterations in tissue oxygen supply, we aimed to investigate changes in tissue oxygenation in patients with PCS. A case-control study including 30 PCS patients (66.6 % males, 48.6 ± 11.2 years, mean time after (first) acute infection: 324 days), 16 cardiologic patients (CVD) (65.5 % males, 56.7 ± 6.3 years) and 11 young healthy controls (55 % males, 28.5 ± 7.4 years) was conducted. Near infrared spectroscopy (NIRS) was used to assess changes in tissue oxygenation during an arterial occlusion protocol on the non-dominant forearm (brachioradialis, 760/850 nm, 5 Hz). The protocol included 10-min rest, a 2-min baseline measurement followed by a 3-min ischemic period (upper-arm cuff, 50 mmHg above resting systolic blood pressure) and a 3-min reoxygenation period. PCS patients were grouped by presence of arterial hypertension and elevated BMI to assess the impact of risk factors. No differences in mean tissue oxygenation in the pre-occlusion phase existed between groups (p ≥ 0.566). During ischemia, comparisons of linear regressions slopes revealed slower oxygen desaturation for PCS patients (-0.064 %/s) compared to CVD patients (-0.08 %/s) and healthy subjects (-0.145 %/s) (p < 0.001). After cuff release, slowest speed for reoxygenation was detected in PCS patients at 0.84 %/s compared to CVD patients (1.04 %/s) and healthy controls (CG: 2.07 %/s) (p < 0.001). The differences between PCS patients and CVD patients during ischemia remained significant also after correction for risk factors. Analyses of complications during acute infection, persistence of PCS symptoms (time after acute infection), or PCS severity (number of lead symptoms) as confounding factors did not reveal a significant effect. This study provides evidence that the rate of tissue oxygen consumption is persistently altered in PCS and that PCS patients show an even slower decline in tissue oxygenation during occlusion than CVD patients. Our observations may at least partly explain PCS-specific symptoms such as physical impairment and fatigue.

High-Resolution Respirometry to Assess Mitochondrial Function in Human Spermatozoa.

Semen quality is often studied by routine semen analysis, which is descriptive and often inconclusive. Male infertility is associated with altered sperm mitochondrial activity, so the measurement of sperm mitochondrial function is an indicator of sperm quality. High-resolution respirometry is a method of measuring the oxygen consumption of cells or tissues in a closed-chamber system. This technique can be implemented to measure respiration in human sperm and provides information about the quality and integrity of the sperm mitochondria. High-resolution respirometry allows the cells to move freely, which is an a priori advantage in the case of sperm. This technique can be applied with intact or permeabilized spermatozoa and allows for the study of intact sperm mitochondrial function and the activity of individual respiratory chain complexes. The high-resolution oxygraph instrument uses sensors to measure the oxygen concentration coupled with sensitive software to calculate the oxygen consumption. The data are used to calculate respiratory indices based on the oxygen consumption ratios. Consequently, the indices are the proportions of two oxygen consumption rates and are internally normalized to the cell number or protein mass. The respiratory indices are an indicator of sperm mitochondrial function and dysfunction.

Smart Nanosystem-Mediated Inhibition of Mitochondrial Respiration for Enhanced Phototherapy-Induced Antitumor Immunity.

Here, based on oxygen-dependent photodynamic therapy (PDT) and oxygen-consumed oxidative phosphorylation of cancer tissues, we designed and developed a nanosystem (named CyI&Met-Liposome, LCM) to co-encapsulate the photosensitizer CyI and mitochondrial respiration inhibitor metformin (Met) as a PDT enhancer. We synthesized nanoliposomes encapsulating Met and CyI with excellent photodynamic/photothermal and anti-tumor immune properties using a thin film dispersion method. Confocal microscopy and flow cytometry were used to assess the cellular uptake, PDT, photothermal therapy (PTT) and immunogenicity of nanosystem in vitro. Finally, two tumor models in mice were constructed to investigate the tumor suppression and immunity in vivo. The resulting nanosystem relieved hypoxia in tumor tissues, enhanced PDT efficiency, and amplified antitumor immunity induced by phototherapy. As a photosensitizer, CyI effectively killed the tumor by generating toxic singlet reactive oxygen species (ROS), while the addition of Met reduced oxygen consumption in tumor tissues, thereby evoking an immune response via oxygen-boosted PDT. Both in vitro and in vivo results illustrated that LCM effectively restricted the respiration of tumor cells to reduce tumor hypoxia, thus providing continuous oxygen for enhanced CyI-mediated PDT. Furthermore, T cells were recruited and activated at high levels, providing a promising platform to eliminate the primary tumors and synchronously realize effective inhibition of distant tumors.

Determination of Krogh Coefficient for Oxygen Consumption Measurement from Thin Slices of Rodent Cortical Tissue Using a Fick's Law Model of Diffusion.

To investigate the impact of experimental interventions on living biological tissue, ex vivo rodent brain slices are often used as a more controllable alternative to a live animal model. However, for meaningful results, the biological sample must be known to be healthy and viable. One of the gold-standard approaches to identifying tissue viability status is to measure the rate of tissue oxygen consumption under specific controlled conditions. Here, we work with thin (400 μm) slices of mouse cortical brain tissue which are sustained by a steady flow of oxygenated artificial cerebralspinal fluid (aCSF) at room temperature. To quantify tissue oxygen consumption (Q), we measure oxygen partial pressure (pO2) as a function of probe depth. The curvature of the obtained parabolic (or parabola-like) pO2 profiles can be used to extract Q, providing one knows the Krogh coefficient Kt, for the tissue. The oxygen trends are well described by a Fick's law diffusion-consumption model developed by Ivanova and Simeonov, and expressed in terms of ratio (Q/K), being the rate of oxygen consumption in tissue divided by the Krogh coefficient (oxygen diffusivity × oxygen solubility) for tissue. If the fluid immediately adjacent to the tissue can be assumed to be stationary (i.e., nonflowing), one may invoke conservation of oxygen flux K·(∂P/∂x) across the interface to deduce (Kt/Kf), the ratio of Krogh coefficients for tissue and fluid. Using published interpolation formulas for the effect of salt content and temperature on oxygen diffusivity and solubility for pure water, we estimate Kf, the Krogh coefficient for aCSF, and hence deduce the Kt coefficient for tissue. We distinguish experimental uncertainty from natural biological variability by using pairs of repeated profiles at the same tissue location. We report a dimensionless Krogh ratio (Kt/Kf)=0.562±0.088 (mean ± SD), corresponding to a Krogh coefficient Kt=(1.29±0.21)×10-14 mol/(m·s·Pa) for mouse cortical tissue at room temperature, but acknowledge the experimental limitation of being unable to verify that the fluid boundary layer is truly stationary. We compare our results with those reported in the literature, and comment on the challenges and ambiguities caused by the extensive use of 'biologically convenient' non-SI units for tissue Krogh coefficient.

Early vasopressin infusion improves oxygenation in infants with congenital diaphragmatic hernia.

Congenital Diaphragmatic Hernia (CDH) is a complex disease including a diaphragmatic defect, lung hypoplasia, and pulmonary hypertension. Despite its increasing use in neonates, the literature on the use of vasopressin in neonates is limited. The aim of this work is to analyze the changes in clinical and hemodynamic variables in a cohort of CDH infants treated with vasopressin. Among CDH infants managed at the Neonatal Intensive Care Unit (NICU) of our hospital from May 2014 to January 2019, all infants who were treated with vasopressin, because of systemic hypotension and pulmonary hypertension, were enrolled in this retrospective study. The primary outcome was the change in oxygenation index (OI) after the start of the infusion of vasopressin. The secondary outcomes were the changes in cerebral andsplanchnic fractional tissue oxygen extraction (FTOEc and FTOEs) at near-infrared spectroscopy, to understand the balance between oxygen supply and tissue oxygen consumption after the start of vasopressin infusion. We also reported as secondary outcomes the changes in ratio of arterial oxygen partial pressure (PaO2) to fraction of inspired oxygen (FiO2), heart rate, mean arterial pressure, serum pH, and serum sodium. We included 27 patients with isolated CDH who received vasopressin administration. OI dramatically dropped when vasopressin infusion started, with a significant reduction according to ANOVA for repeated measures (p = 0.003). A global significant improvement in FTOEc and FTOEs was detected (p = 0.009 and p = 0.004, respectively) as a significant reduction in heart rate (p = 0.019). A global significant improvement in PaO2/FiO2 ratio was observed (p < 0.001) and also at all time points: at 6 h since infusion (p = 0.015), 12 h (p = 0.009), and 24 h (p = 0.006), respectively. A significant reduction in sodium levels was observed as expected side effect (p = 0.012). No significant changes were observed in the remaining outcomes. Our data suggest that starting early vasopressin infusion in CDH infants with pulmonary hypertension could improve oxygenation index and near-infrared spectroscopy after 12 and 24 h of infusion. These pilot data represent a background for planning future larger randomized trials to evaluate the efficacy and safety of vasopressin for the CDH population.

Role of glutamate in thymic energy metabolism

Objective. To analyze the energetic role of glutamate in thymocytes and tissues of the thymus at different stages of its age-related involution.Materials and methods. The studies were performed on white male rats. The state of energy metabolism was determined by the rate of oxygen consumption by thymus tissues and thymocytes using a polarographic method.Results. It was found that in the thymus tissues of 4, 5 and 6-month-old rats the rate of oxygen consumption is constant and does not significantly change in response to glutamate administration. Thymocytes - the immunocompetent thymus cells of 3- and 8-month-old animals, despite similar levels of oxygen consumption on endogenous substrates, respond differently to glutamate action. In thymocytes of 3-month-old animals, the action of glutamate has a more pronounced stimulating effect on bioenergetic processes compared to 8-month-old animals. There is a reason to believe that the decrease in the efficiency of glutamate action as the animals grow older is caused by the processes of age-related involution of the thymusConclusion. Glutamate stimulates aerobic respiration in the thymocytes of 3- and 8-month-old animals, with a greater stimulating effect in the thymocytes of younger animals. At the same time, glutamate does not cause significant changes in the rate of oxygen consumption in the thymus tissues of 4-, 5-, and 6-month-old animals.

Inhibiting amyloid beta (1-42) peptide-induced mitochondrial dysfunction prevents the degradation of synaptic proteins in the entorhinal cortex.

Increasing evidence suggests that mitochondrial dysfunction and aberrant release of mitochondrial reactive oxygen species (ROS) play crucial roles in early synaptic perturbations and neuropathology that drive memory deficits in Alzheimer’s disease (AD). We recently showed that solubilized human amyloid beta peptide 1–42 (hAβ1–42) causes rapid alterations at glutamatergic synapses in the entorhinal cortex (EC) through the activation of both GluN2A- and GluN2B-containing NMDA receptors. However, whether disruption of mitochondrial dynamics and increased ROS contributes to mechanisms mediating hAβ1–42-induced synaptic perturbations in the EC is unknown. Here we assessed the impact of hAβ1–42 on mitochondrial respiratory functions, and the expression of key mitochondrial and synaptic proteins in the EC. Measurements of mitochondrial respiratory function in wild-type EC slices exposed to 1 μM hAβ1–42 revealed marked reductions in tissue oxygen consumption and energy production efficiency relative to control. hAβ1–42 also markedly reduced the immunoexpression of both mitochondrial superoxide dismutase (SOD2) and mitochondrial-cytochrome c protein but had no significant impact on cytosolic-cytochrome c expression, voltage-dependent anion channel protein (a marker for mitochondrial density/integrity), and the immunoexpression of protein markers for all five mitochondrial complexes. The rapid impairments in mitochondrial functions induced by hAβ1–42 were accompanied by reductions in the presynaptic marker synaptophysin, postsynaptic density protein (PSD95), and the vesicular acetylcholine transporter, with no significant changes in the degradative enzyme acetylcholinesterase. We then assessed whether reducing hAβ1–42-induced increases in ROS could prevent dysregulation of entorhinal synaptic proteins, and found that synaptic impairments induced by hAβ1–42 were prevented by the mitochondria-targeted antioxidant drug mitoquinone mesylate, and by the SOD and catalase mimetic EUK134. These findings indicate that hAβ1–2 can rapidly disrupt mitochondrial functions and increase ROS in the entorhinal, and that this may contribute to synaptic dysfunctions that may promote early AD-related neuropathology.