Akt Inhibition as Preconditioning Treatment to Protect Kidney Cells against Anoxia

Lesions issued from the ischemia/reperfusion (I/R) stress are a major challenge in human pathophysiology. Of human organs, the kidney is highly sensitive to I/R because of its high oxygen demand and poor regenerative capacity. Previous studies have shown that targeting the hypusination pathway of eIF5A through GC7 greatly improves ischemic tolerance and can be applied successfully to kidney transplants. The protection process correlates with a metabolic shift from oxidative phosphorylation to glycolysis. Because the protein kinase B Akt is involved in ischemic protective mechanisms and glucose metabolism, we looked for a link between the effects of GC7 and Akt in proximal kidney cells exposed to anoxia or the mitotoxic myxothiazol. We found that GC7 treatment resulted in impaired Akt phosphorylation at the Ser473 and Thr308 sites, so the effects of direct Akt inhibition as a preconditioning protocol on ischemic tolerance were investigated. We evidenced that Akt inhibitors provide huge protection for kidney cells against ischemia and myxothiazol. The pro-survival effect of Akt inhibitors, which is reversible, implied a decrease in mitochondrial ROS production but was not related to metabolic changes or an antioxidant defense increase. Therefore, the inhibition of Akt can be considered as a preconditioning treatment against ischemia.

The opto-respiratory compromise: Balancing oxygen supply and light transmittance in the retina

The light-absorbing retina has an exceptionally high oxygen demand, which imposes two conflicting needs: high rates of blood perfusion and an unobstructed light path devoid of blood vessels. This review discusses mechanisms and physiological tradeoffs underlying retinal oxygen supply in vertebrates and examines how these physiological systems supported the evolution of vision.

Metabolic Signaling in a Theoretical Model of the Human Retinal Microcirculation

Impaired blood flow and oxygenation contribute to many ocular pathologies, including glaucoma. Here, a mathematical model is presented that combines an image-based heterogeneous representation of retinal arterioles with a compartmental description of capillaries and venules. The arteriolar model of the human retina is extrapolated from a previous mouse model based on confocal microscopy images. Every terminal arteriole is connected in series to compartments for capillaries and venules, yielding a hybrid model for predicting blood flow and oxygenation throughout the retinal microcirculation. A metabolic wall signal is calculated in each vessel according to blood and tissue oxygen levels. As expected, a higher average metabolic signal is generated in pathways with a lower average oxygen level. The model also predicts a wide range of metabolic signals dependent on oxygen levels and specific network location. For example, for high oxygen demand, a threefold range in metabolic signal is predicted despite nearly identical PO2 levels. This whole-network approach, including a spatially nonuniform structure, is needed to describe the metabolic status of the retina. This model provides the geometric and hemodynamic framework necessary to predict ocular blood flow regulation and will ultimately facilitate early detection and treatment of ischemic and metabolic disorders of the eye.

Ammonium and organic carbon co-removal under feammox-coupled-with-heterotrophy condition as an efficient approach for nitrogen treatment

Nitrification is the rate limiting step in the nitrogen removal processes since nitrifiers have high oxygen demand, but poorly compete with aerobic heterotrophs. In a laboratory-scaled system, we investigated a process of ammonium oxidation under ferric-iron reducing condition (feammox) in the presence of organic carbon using influents with high NH4+ and COD contents, and ferrihydrite as the only electron acceptor. Batch incubations testing influents with different NH4+ and COD concentrations revealed that the [COD]/[NH4+] ratio of 1.4 and the influent redox potential ranging from − 20 to + 20 mV led to the highest removal efficiencies, i.e. 98.3% for NH4+ and 58.8% for COD. N2 was detected as the only product of NH4+ conversion, whereas NO2− and NO3− were not detected. While operating continuously with influent having a [COD]/[NH4+] ratio of 1.4, the system efficiently removed NH4+ (> 91%) and COD (> 54%) within 6 day retention time. Fluorescence in situ hybridization analyses using Cy3-labeled 16S rRNA oligonucleotide probes revealed that gamma-proteobacteria dominated in the microbial community attaching to the matrix bed of the system. The iron-reduction dependent NH4+ and COD co-removal with a thorough conversion of NH4+ to N2 demonstrated in this study would be a novel approach for nitrogen treatment.

The chromatin remodelling factor Chd7 protects auditory neurons and sensory hair cells from stress-induced degeneration

Neurons and sensory cells are particularly vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission1-4. The mechanisms that protect them from stress-induced death and degeneration remain elusive. Here we show that embryonic deletion of the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons or hair cells leads to sensorineural hearing loss due to postnatal degeneration of both cell types. Mechanistically, we demonstrate that CHD7 controls the expression of major stress pathway components. In its absence, hair cells are hypersensitive, dying rapidly after brief exposure to stress inducers, suggesting that sound at the onset of hearing triggers their degeneration. In humans, CHD7 haploinsufficiency causes CHARGE syndrome, a disorder affecting multiple organs including the ear5,6. Our findings suggest that CHD7 mutations cause developmentally silent phenotypes that predispose cells to postnatal degeneration due to a failure of protective mechanisms.

The murburn precepts for photoreception

Murburn concept is a redox mechanistic scheme involving interactive equilibriums of discretized or organized proteins/substrates molecules, unbound ions and radicals (or reactive species); which may afford selective/specific electron transfers, particularly at phospholipid interfaces. Earlier, we have applied murburn concept to provide parsimonious explanations (grounded in thermodynamics and kinetics) for various physiological/bioenergetic routines like xenobiotic metabolism, unusual dose responses, aerobic respiration, thermogenesis, homeostasis, trans-membrane potential, oxygenic photosynthesis, etc. While proposing the murburn model for photophosphorylation, we had projected that the murburn mechanism could also be relevant for photoreception physiology. Herein, we expand on this aspect and present the basic scheme and evidence in support for the murburn model of photoreception, with retinal/opsin as the salient photon-impingement response-transducing element. In alignment with our earlier murburn schemes, we propose that diffusible reactive oxygen species (DROS, as exemplified by superoxide, which is currently deemed a toxic product of all-trans retinal and NADPH oxidase interactions) is produced in rod/cone cells upon photoactivation and it plays a crucial role in the visual cycle. This is supported by the fact that layers of photoreceptive neural cells precede the rod/cone cells (with respect to the presentation to oncoming light ray/photon), there exists high oxygen demand in retina, copious ROS are detected in functional retina, NAD(P)H/reductase is involved in the cycle, events occur at sub-micrometer dimensioned phospholipid disks stacked to stabilize DROS and minimize free protons (quite like the thylakoids that harbor carotenoids in chloroplasts and cyanobacteria), etc. In the new scheme, photo-electric activation leads to charge separation and hyperpolarization. This electro-chemical signaling serves is the front-runner to a trigger for action potential relay along a neuron and the superoxide mediated phosphorylation of GDP bound to transducin serves as the initiator of signal transduction cascade. The newly proposed scheme allows a facile electrical connectivity of the retina-photoreceptors with the brain via the optic nerve, and is anatomically correlated with the structure and resolution or retina, and is kinetically viable.

Hypoferremia predicts hospitalization and oxygen demand in COVID-19 patients

ABSTRACTBackgroundIron metabolism might play a crucial role in cytokine release syndrome in COVID-19 patients. Therefore we assessed iron metabolism markers in COVID-19 patients for their ability to predict disease severity.MethodsCOVID-19 patients referred to the Heidelberg University Hospital were retrospectively analyzed. Patients were divided into outpatients (cohort A, n=204), inpatients (cohort B, n=81), and outpatients later admitted to hospital because of health deterioration (cohort C, n=23).ResultsIron metabolism parameters were severely altered in patients of cohort B and C compared to cohort A. In multivariate regression analysis including age, gender, CRP and iron-related parameters only serum iron and ferritin were significantly associated with hospitalization. ROC analysis revealed an AUC for serum iron of 0.894 and an iron concentration <6µmol/l as the best cutoff-point predicting hospitalization with a sensitivity of 94.7% and a specificity of 67.9%. When stratifying inpatients in a low- and high oxygen demand group serum iron levels differed significantly between these two groups and showed a high negative correlation with the inflammatory parameters IL-6, procalcitonin, and CRP. Unexpectedly, serum iron levels poorly correlate with hepcidin.ConclusionWe conclude that measurement of serum iron can help predicting the severity of COVID-19. The differences in serum iron availability observed between the low and high oxygen demand group suggest that disturbed iron metabolism likely plays a causal role in the pathophysiology leading to lung injury.KEY POINTSIron metabolism parameters are severely altered in COVID-19 patients.Measurement of serum iron can help predicting the severity of COVID-19.

Exercise and myocardial injury in hypertrophic cardiomyopathy

ObjectiveTroponin and high signal intensity on T2-weighted (HighT2) cardiovascular magnetic resonance imaging (CMRi) are both markers of myocardial injury in hypertrophic cardiomyopathy (HCM). The interplay between exercise and disease development remains uncertain in HCM. We sought to assess the occurrence of postexercise troponin rises and its determinants.MethodsMulticentre project on patients with HCM and mutation carriers without hypertrophy (controls). Participants performed a symptom limited bicycle test with hs-cTnT assessment pre-exercise and 6 hours postexercise. Pre-exercise CMRi was performed in patients with HCM to assess measures of hypertrophy and myocardial injury. Depending on baseline troponin (< or >13 ng/L), a rise was defined as a >50% or >20% increase, respectively.ResultsTroponin rises occurred in 18% (23/127) of patients with HCM and 4% (2/53) in mutation carriers (p=0.01). Comparing patients with HCM with and without a postexercise troponin rise, maximum heart rates (157±19 vs 143±23, p=0.004) and maximal wall thickness (20 mm vs 17 mm, p=0.023) were higher in the former, as was the presence of late gadolinium enhancement (85% vs 57%, p=0.02). HighT2 was seen in 65% (13/20) and 19% (15/79), respectively (p<0.001). HighT2 was the only independent predictor of troponin rise (adjusted odds ratio 7.9; 95% CI 2.7 to 23.3; p<0.001).ConclusionsPostexercise troponin rises were seen in about 20% of patients with HCM, almost five times more frequent than in mutation carriers. HighT2 on CMRi may identify a group of particularly vulnerable patients, supporting the concept that HighT2 reflects an active disease state, prone to additional injury after a short episode of high oxygen demand.

The Water Footprint of Wool Scouring

Raw wool contains high percentage by weight of natural contaminants. It is usually treated by a scouring process in the first stage of textile processing. Wool scouring process consumes large quantities of fresh water and produces concentrated effluent with very high oxygen demand, aggravating the water resource shortage and environmental impacts. Water footprint (WF) is a multidimensional indicator that shows water consumption volumes by source and polluted volumes by type of pollution. This study discusses the environmental impacts assessment of wool scouring process based on the WF theory. Through cases study, it was found that chemical oxygen demand (CODCr) was the most critical pollutant associated with the largest pollutant-specific original grey WF (WFori, grey), while NH3-N was the most critical pollutant associated with the largest pollutant-specific residuary grey WF (WFres, grey). The average WFori, greyof wool scouring process was 51878 m3/d, approximately 291 times of blue WF (WFblue). After treatment of the scouring effluent through floatation reflux-biological contact oxidizing technology, the WFori, greyreduced to 558 m3/d. Refluxing and regulating, oil removal were two important processes that contributed largely to effluent treatment as they reduced WFori, greyby 28537 m3/d and 23171 m3/d, respectively.