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Aim: To identify the physiological role of the acid‐base sensing enzyme, soluble adenylyl cyclase (sAC), in red blood cells (RBC) of the model teleost fish, rainbow trout. Methods: We used: (i) super‐resolution microscopy to determine the subcellular location of sAC protein; (ii) live‐cell imaging of RBC intracellular pH (pHi) with specific sAC inhibition (KH7 or LRE1) to determine its role in cellular acid‐base regulation; (iii) spectrophotometric measurements of haemoglobin–oxygen (Hb‐O2) binding in steady‐state conditions; and (iv) during simulated arterial‐venous transit, to determine the role of sAC in systemic O2 transport. Results: Distinct pools of sAC protein were detected in the RBC cytoplasm, at the plasma membrane and within the nucleus. Inhibition of sAC decreased the setpoint for RBC pHi regulation by ~0.25 pH units compared to controls, and slowed the rates of RBC pHi recovery after an acid‐base disturbance. RBC pHi recovery was entirely through the anion exchanger (AE) that was in part regulated by HCO3−‐dependent sAC signaling. Inhibition of sAC decreased Hb‐O2 affinity during a respiratory acidosis compared to controls and reduced the cooperativity of O2 binding. During in vitro simulations of arterial‐venous transit, sAC inhibition decreased the amount of O2 that is unloaded by ~11%. Conclusion: sAC represents a novel acid‐base sensor in the RBCs of rainbow trout, where it participates in the modulation of RBC pHi and blood O2 transport though the regulation of AE activity. If substantiated in other species, these findings may have broad implications for our understanding of cardiovascular physiology in vertebrates. [ABSTRACT FROM AUTHOR]

Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. High Alt Med Biol. 25:174–185, 2024.—Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system in vivo remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O2 affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO2%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO2% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In ex vivo experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (−0.72 ± 0.062 vs.−0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94β-His146β in nitrosyl -Hb(NO-Hb), NO-HbβCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues. [ABSTRACT FROM AUTHOR]

Introduction: Elite breath-hold divers (BHD) enduring apneas of more than 5 min are characterized by tolerance to arterial blood oxygen levels of 4.3 kPa and low oxygen-consumption in their hearts and skeletal muscles, similar to adult seals. Adult seals possess an adaptive higher hemoglobin-concentration and Bohr effect than pups, and when sedated, adult seals demonstrate a blood shift from the spleen towards the brain, lungs, and heart during apnea. We hypothesized these observations to be similar in human BHD. Therefore, we measured hemoglobin- and 2,3-biphosphoglycerate-concentrations in BHD (n = 11) and matched controls (n = 11) at rest, while myocardial mass, spleen and lower extremity volumes were assessed at rest and during apnea in BHD. Methods and results: After 4 min of apnea, left ventricular myocardial mass (LVMM) determined by 15O-H2O-PET/CT (n = 6) and cardiac MRI (n = 6), was unaltered compared to rest. During maximum apnea (-6 min), lower extremity volume assessed by DXA-scan revealed a -268 mL decrease, and spleen volume, assessed by ultrasonography, decreased -102 mL. Compared to age, BMI and VO2max matched controls (n = 11), BHD had similar spleen sizes and 2,3- biphosphoglycerate-concentrations, but higher total hemoglobinconcentrations. Conclusion: Our results indicate: 1) Apnea training in BHD may increase hemoglobin concentration as an oxygen conserving adaptation similar to adult diving mammals. 2) The blood shift during dry apnea in BHD is 162% more from the lower extremities than from the spleen. 3) In contrast to the previous theory of the blood shift demonstrated in sedated adult seals, blood shift is not towards the heart during dry apnea in humans. [ABSTRACT FROM AUTHOR]

Osteoarthritis is considered one of the leading causes of chronic disability and is a significant problem on human health and the economy. Chronic pain is the dominant symptom that prompts patients to seek medical attention. Pain mechanisms in osteoarthritis remained unknown for a long time. However, it is known that chronic inflammation of the joint can be a key factor in the occurrence and exacerbation of pain or changes in the perception of pain. Pharmacological therapy is often based on the use of steroidal and non-steroidal anti-inflammatory drugs, but their long-term use or large doses can cause side effects. That is why the development of new methods of treatment of inflammatory processes is the object of active research, as they can affect various mechanisms. In this context, carboxytherapy is an interesting alternative or addition to existing treatment regimens aimed at reducing pain in patients with osteoarthritis. This method involves the administration of medical carbon dioxide (CO2) to improve blood supply to tissues, which can contribute to humoral, biochemical and tissue mechanisms. Studying the effects of carboxytherapy in animal models of inflammation is important for understanding its potential benefits and mechanisms of action. Objective. Study of anti-inflammatory properties of carboxytherapy both in monotherapy and in its combined use. Methods. Carboxytherapy is the injection of carbon dioxide in monotherapy and when used in combination on the formalin model of inflammation in animals. Results. The obtained research results prove the anti-inflammatory properties of carbon dioxide on the model offormalin inflammation in animals. Conclusions. The combined use of carboxytherapy enhanced the effect of conventional drugs on the formalin model of inflammation in animals. The establishment of an anti-inflammatory effect of carboxytherapy indicates the therapeutic value of CO2, while emphasizing the need for further in-depth studies to explore its mechanisms and confirm the efficacy for clinical use. [ABSTRACT FROM AUTHOR]

IntroductionElite breath-hold divers (BHD) enduring apneas of more than 5 min are characterized by tolerance to arterial blood oxygen levels of 4.3 kPa and low oxygen-consumption in their hearts and skeletal muscles, similar to adult seals. Adult seals possess an adaptive higher hemoglobin-concentration and Bohr effect than pups, and when sedated, adult seals demonstrate a blood shift from the spleen towards the brain, lungs, and heart during apnea. We hypothesized these observations to be similar in human BHD. Therefore, we measured hemoglobin- and 2,3-biphosphoglycerate-concentrations in BHD (n = 11) and matched controls (n = 11) at rest, while myocardial mass, spleen and lower extremity volumes were assessed at rest and during apnea in BHD.Methods and resultsAfter 4 min of apnea, left ventricular myocardial mass (LVMM) determined by 15O-H2O-PET/CT (n = 6) and cardiac MRI (n = 6), was unaltered compared to rest. During maximum apnea (∼6 min), lower extremity volume assessed by DXA-scan revealed a ∼268 mL decrease, and spleen volume, assessed by ultrasonography, decreased ∼102 mL. Compared to age, BMI and VO2max matched controls (n = 11), BHD had similar spleen sizes and 2,3- biphosphoglycerate-concentrations, but higher total hemoglobin-concentrations.ConclusionOur results indicate: 1) Apnea training in BHD may increase hemoglobin concentration as an oxygen conserving adaptation similar to adult diving mammals. 2) The blood shift during dry apnea in BHD is 162% more from the lower extremities than from the spleen. 3) In contrast to the previous theory of the blood shift demonstrated in sedated adult seals, blood shift is not towards the heart during dry apnea in humans.

White seabass (Atractoscion nobilis) increasingly experience periods of low oxygen (O2; hypoxia) and high carbon dioxide (CO2, hypercapnia) due to climate change and eutrophication of the coastal waters of California. Hemoglobin (Hb) is the principal O2 carrier in the blood and in many teleost fishes Hb-O2 binding is compromised at low pH; however, the red blood cells (RBC) of some species regulate intracellular pH with adrenergically stimulated sodium-proton-exchangers (β-NHEs). We hypothesized that RBC β-NHEs in white seabass are an important mechanism that can protect the blood O2-carrying capacity during hypoxia and hypercapnia. We determined the O2-binding characteristics of white seabass blood, the cellular and subcellular response of RBCs to adrenergic stimulation, and quantified the protective effect of β-NHE activity on Hb-O2 saturation. White seabass had typical teleost Hb characteristics, with a moderate O2 affinity (Po2 at half-saturation; P50 2.9 kPa) that was highly pH-sensitive (Bohr coefficient -0.92; Root effect 52%). Novel findings from super-resolution microscopy revealed β-NHE protein in vesicle-like structures and its translocation into the membrane after adrenergic stimulation. Microscopy data were corroborated by molecular and phylogenetic results and a functional characterization of β-NHE activity. The activation of RBC β-NHEs increased Hb-O2 saturation by ∼8% in normoxic hypercapnia and by up to ∼20% in hypoxic normocapnia. Our results provide novel insight into the cellular mechanism of adrenergic RBC stimulation within an ecologically relevant context. β-NHE activity in white seabass has great potential to protect arterial O2 transport during hypoxia and hypercapnia but is less effective during combinations of these stressors.

Acute altitude hypoxia represents the cause of multiple adverse consequences. Current treatments are limited by side effects. Recent studies have shown the protective effects of resveratrol (RSV), but the mechanism remains unknown. To address this, the effects of RSV on the structure and function of hemoglobin of adult (HbA) were preliminarily analyzed using surface plasmon resonance (SPR) and oxygen dissociation assays (ODA). Molecular docking was conducted to specifically analyze the binding regions between RSV and HbA. The thermal stability was characterized to further validate the authenticity and effect of binding. Changes in the oxygen supply efficiency of HbA and rat RBCs incubated with RSV were detected ex vivo. The effect of RSV on the anti-hypoxic capacity under acute hypoxic conditions in vivo was evaluated. We found that RSV binds to the heme region of HbA following a concentration gradient and affects the structural stability and rate of oxygen release of HbA. RSV enhances the oxygen supply efficiency of HbA and rat RBCs ex vivo. RSV prolongs the tolerance times of mice suffering from acute asphyxia. By enhancing the oxygen supply efficiency, it alleviates the detrimental effects of acute severe hypoxia. In conclusion, RSV binds to HbA and regulates its conformation, which enhances oxygen supply efficiency and improves adaption to acute severe hypoxia. [ABSTRACT FROM AUTHOR]

Understanding how animals living in highland adapt to extreme conditions is critical to evolutionary biology. In contrast to birds and mammals, little information was available on the adaptation mechanisms for O2 transport in high-altitude ectothermic vertebrates. Here we report for the first time on hematological parameters, amino acid sequences of α and β chains of hemoglobin (Hb), O2 affinity of purified hemoglobins (Hbs) and their sensitivities to anion allosteric effector (H+, Cl−, ATP) and temperature in the high-altitude (2,292 m) black-spotted frogs (Pelophylax nigromaculatus) from the Qinghai-Tibet plateau (QTP) compared with the low-altitude (135 m) population. Our results showed that high-altitude black-spotted frogs exhibit significantly increased relative lung mass, hematocrit, and hemoglobin concentration, but significantly decreased body mass and erythrocyte volume, which could improve the blood O2 carrying capability. Compared with the low-altitude population, the purified Hbs of high-altitude black-spotted frogs possessed significantly higher intrinsic Hb-O2 affinity, similar low anion allosteric effector sensitivities, Bohr effects and temperature sensitivities. The elevated Hb-O2 affinity of highland frogs could maximize the O2 extraction from the lungs. Molecular dynamics simulations showed that the Gln123Glu substitution on α2 chain in highland frogs could form a hydrogen bond with 127Lys on α2 chain, resulting in the elimination of a hydrogen bond between 127Lys on α2 chain and 141Arg on α1 chain. This could weaken the interaction between two semirigid dimers (α1β1 and α2β2) and then lead to the high intrinsic Hb-O2 affinity in high-altitude black-spotted frogs.

The functional properties of hemoglobin have been studied in some representatives of the populations of roach Rutilus rutilus L., ide Leuciscus idus L., and bream Abramis brama (L.). The presence of several groups of fish with different functional properties of hemoglobin are found for the first time in the studied populations. Two such groups are found in the roach population, two in the ide population, and four in the bream population, indicating a heterogeneity of the studied populations of fish by the functional properties of hemoglobin. [ABSTRACT FROM AUTHOR]

Rowing performance may be enhanced by attenuated metabolic acidosis following bicarbonate (BIC) supplementation. This study evaluated the dose of BIC needed to eliminate the decrease in plasma pH during maximal ergometer rowing and assessed the consequence for change in plasma volume. Six oarsmen performed "2,000-m" maximal ergometer rowing trials with BIC (1 M; 100–325 ml) and control (CON; the same volume of isotonic saline). During CON, pH decreased from 7.42 ± 0.01 to 7.17 ± 0.04 (mean and SD; p < 0.05), while during BIC, pH was maintained until the sixth minute where it dropped to 7.32 ± 0.08 and was thus higher than during CON (p < 0.05). The buffering effect of BIC on metabolic acidosis was dose dependent and 300–325 mmol required to maintain plasma pH. Compared to CON, BIC increased plasma sodium by 4 mmol/L, bicarbonate was maintained, and lactate increased to 25 ± 7 vs. 18 ± 3 mmol/L (p < 0.05). Plasma volume was estimated to decrease by 24 ± 4% in CON, while with BIC the estimate was by only 7 ± 6% (p < 0.05) and yet BIC had no significant effect on performance [median 6 min 27 s (range 6 min 09 s to 6 min 57 s) vs. 6 min 33 s (6 min 14 s to 6 min 55 s)]. Bicarbonate administration attenuates acidosis during maximal rowing in a dose-dependent manner and the reduction in plasma volume is attenuated with little consequence for performance. [ABSTRACT FROM AUTHOR]

Acute altitude hypoxia represents the cause of multiple adverse consequences. Current treatments are limited by side effects. Recent studies have shown the protective effects of resveratrol (RSV), but the mechanism remains unknown. To address this, the effects of RSV on the structure and function of hemoglobin of adult (HbA) were preliminarily analyzed using surface plasmon resonance (SPR) and oxygen dissociation assays (ODA). Molecular docking was conducted to specifically analyze the binding regions between RSV and HbA. The thermal stability was characterized to further validate the authenticity and effect of binding. Changes in the oxygen supply efficiency of HbA and rat RBCs incubated with RSV were detected ex vivo. The effect of RSV on the anti-hypoxic capacity under acute hypoxic conditions in vivo was evaluated. We found that RSV binds to the heme region of HbA following a concentration gradient and affects the structural stability and rate of oxygen release of HbA. RSV enhances the oxygen supply efficiency of HbA and rat RBCs ex vivo. RSV prolongs the tolerance times of mice suffering from acute asphyxia. By enhancing the oxygen supply efficiency, it alleviates the detrimental effects of acute severe hypoxia. In conclusion, RSV binds to HbA and regulates its conformation, which enhances oxygen supply efficiency and improves adaption to acute severe hypoxia.

White seabass (Atractoscion nobilis) increasingly experience periods of low oxygen (O2; hypoxia) and high carbon dioxide (CO2, hypercapnia) due to climate change and eutrophication of the coastal waters of California. Hemoglobin (Hb) is the principal O2 carrier in the blood and in many teleost fishes Hb-O2 binding is compromised at low pH; however, the red blood cells (RBC) of some species regulate intracellular pH with adrenergically stimulated sodium-proton-exchangers (b-NHEs). We hypothesized that RBC β-NHEs in white seabass are an important mechanism that can protect the blood O2-carrying capacity during hypoxia and hypercapnia. We determined the O2-binding characteristics of white seabass blood, the cellular and subcellular response of RBCs to adrenergic stimulation, and quantified the protective effect of b-NHE activity on Hb-O2 saturation. White seabass had typical teleost Hb characteristics, with a moderate O2 affinity (PO2 at half-saturation; P50 2.9 kPa) that was highly pH-sensitive (Bohr coefficient -0.92; Root effect 52%). Novel findings from super-resolution microscopy revealed b-NHE protein in vesiclelike structures and its translocation into the membrane after adrenergic stimulation. Microscopy data were corroborated by molecular and phylogenetic results and a functional characterization of β-NHE activity. The activation of RBC b-NHEs increased Hb-O2 saturation by ~8% in normoxic hypercapnia and by up to ~20% in hypoxic normocapnia. Our results provide novel insight into the cellular mechanism of adrenergic RBC stimulation within an ecologically relevant context. β-NHE activity in white seabass has great potential to protect arterial O2 transport during hypoxia and hypercapnia but is less effective during combinations of these stressors. [ABSTRACT FROM AUTHOR]

The Asiatic toad (Bufo gargarizans) belonging to the family of Bufonidae (Anura: Amphibia) is successfully residing on the Qinghai–Tibetan Plateau (QTP). To investigate whether the oxygen delivery undergoes adaptive adjustments to high-altitude environments in Asian toads inhabiting the QTP (Zoige County, 3446 m), choosing low-altitude populations (Chengdu City, 500 m) as control, we measured hematological traits, O2 affinities of whole blood, Hb-O2 affinities of purified Hbs, their sensitivities to temperature, and allosteric effectors (H+, Cl− and ATP). Our results showed that high-altitude Asiatic toads possessed significantly increased hemoglobin concentration, hematocrit, and red blood cell count, but significantly decreased erythrocyte volume compared with low-altitude toads. The whole blood and purified Hbs of high-altitude Asiatic toads both exhibited significantly higher O2 affinities compared with low-altitude toads. Substantially increased intrinsic Hb-O2 affinities of high-altitude Asiatic toads Hbs are likely to be the main reason for its elevated Hb-O2 affinities given the anionic cofactor sensitivities of high- and low-altitude toads were similar. The Hbs of high-altitude toads were also characterized by distinctly strong Bohr effects at the low temperature and low-temperature sensitivities. The adaptive adjustments of hematological traits could enhance the blood–O2 carrying capacity of high-altitude Asiatic toads. The increased Hb-O2 affinities could safeguard the pulmonary O2 uploading under hypoxia. The strong Bohr effects at the low temperature could help the release of O2 in metabolic tissues and cold limbs, while low-temperature sensitivity could minimize the effect of temperature fluctuation on the Hb–O2 affinity. [ABSTRACT FROM AUTHOR]

The evolution of hemoglobin function in the transition from water‐ to air‐breathing has been highly debated but remains unresolved. Here, we characterized the hemoglobin function in five closely related water‐ and air‐breathing catfishes. We identify distinct directions of hemoglobin evolution in the clades that evolved air‐breathing, and we show strong selection on hemoglobin function within the catfishes. These findings show that the lack of a general direction in hemoglobin function in the transition from water‐ to air‐breathing may have resulted from divergent selection on hemoglobin function in independent clades of air‐breathing fishes. Research highlights: 1.We show that the evolution of air‐breathing resulted in distinct changes in hemoglobin function.2.This illustrates that the adaptations to air‐breathing cannot be generalized across independent groups of air‐breathing fishes. [ABSTRACT FROM AUTHOR]

The efficiency of pulmonary gas exchange has long been assessed using the alveolar-arterial difference in PO2, the A-aDO2, a construct developed by Richard Riley ~70years ago. However, this measurement is invasive (requiring an arterial blood sample), time consuming, expensive, uncomfortable for the patients, and as such not ideal for serial measurements. Recent advances in the technology now provide for portable and rapidly responding measurement of the PO2 and PCO2 in expired gas, which combined with the well-established measurement of arterial oxygen saturation via pulse oximetry (SpO2) make practical a non-invasive surrogate measurement of the A-aDO2, the oxygen deficit. The oxygen deficit is the difference between the end-tidal PO2 and the calculated arterial PO2 derived from the SpO2 and taking into account the PCO2, also measured from end-tidal gas. The oxygen deficit shares the underlying basis of the measurement of gas exchange efficiency that the A-aDO2 uses, and thus the two measurements are well-correlated (r 2~0.72). Studies have shown that the new approach is sensitive and can detect the age-related decline in gas exchange efficiency associated with healthy aging. In patients with lung disease the oxygen deficit is greatly elevated compared to normal subjects. The portable and non-invasive nature of the approach suggests potential uses in first responders, in military applications, and in underserved areas. Further, the completely non-invasive and rapid nature of the measurement makes it ideally suited to serial measurements of acutely ill patients including those with COVID-19, allowing patients to be closely monitored if required. [ABSTRACT FROM AUTHOR]

The efficiency of pulmonary gas exchange has long been assessed using the alveolar-arterial difference in PO2, the A-aDO2, a construct developed by Richard Riley ~70years ago. However, this measurement is invasive (requiring an arterial blood sample), time consuming, expensive, uncomfortable for the patients, and as such not ideal for serial measurements. Recent advances in the technology now provide for portable and rapidly responding measurement of the PO2 and PCO2 in expired gas, which combined with the well-established measurement of arterial oxygen saturation via pulse oximetry (SpO2) make practical a non-invasive surrogate measurement of the A-aDO2, the oxygen deficit. The oxygen deficit is the difference between the end-tidal PO2 and the calculated arterial PO2 derived from the SpO2 and taking into account the PCO2, also measured from end-tidal gas. The oxygen deficit shares the underlying basis of the measurement of gas exchange efficiency that the A-aDO2 uses, and thus the two measurements are well-correlated (r2~0.72). Studies have shown that the new approach is sensitive and can detect the age-related decline in gas exchange efficiency associated with healthy aging. In patients with lung disease the oxygen deficit is greatly elevated compared to normal subjects. The portable and non-invasive nature of the approach suggests potential uses in first responders, in military applications, and in underserved areas. Further, the completely non-invasive and rapid nature of the measurement makes it ideally suited to serial measurements of acutely ill patients including those with COVID-19, allowing patients to be closely monitored if required.

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Dive capacities of air-breathing vertebrates are dictated by onboard O2 stores, suggesting that physiologic specialization of diving birds such as penguins may have involved adaptive changes in convective O2 transport. It has been hypothesized that increased hemoglobin (Hb)-O2 affinity improves pulmonary O2 extraction and enhances the capacity for breath-hold diving. To investigate evolved changes in Hb function associated with the aquatic specialization of penguins, we integrated comparative measurements of whole-blood and purified native Hb with protein engineering experiments based on site-directed mutagenesis. We reconstructed and resurrected ancestral Hb representing the common ancestor of penguins and the more ancient ancestor shared by penguins and their closest nondiving relatives (order Procellariiformes, which includes albatrosses, shearwaters, petrels, and storm petrels). These two ancestors bracket the phylogenetic interval in which penguin-specific changes in Hb function would have evolved. The experiments revealed that penguins evolved a derived increase in Hb-O2 affinity and a greatly augmented Bohr effect (i.e., reduced Hb-O2 affinity at low pH). Although an increased Hb-O2 affinity reduces the gradient for O2 diffusion from systemic capillaries to metabolizing cells, this can be compensated by a concomitant enhancement of the Bohr effect, thereby promoting O2 unloading in acidified tissues. We suggest that the evolved increase in Hb-O2 affinity in combination with the augmented Bohr effect maximizes both O2 extraction from the lungs and O2 unloading from the blood, allowing penguins to fully utilize their onboard O2 stores and maximize underwater foraging time. [ABSTRACT FROM AUTHOR]

Nonantibiotic approaches must be developed to kill pathogenic bacteria and ensure that clinicians have a means to treat wounds that are infected by multidrug-resistant bacteria. This study prepared matchstick-like Ag 2 S-ZnS heteronanostructures (HNSs). Their hydrophobic surfactants were then replaced with hydrophilic poly(ethylene glycol) (PEG) and thioglycolic acid (TGA) through the ligand exchange method, and this was followed by ascorbic acid (AA) conjugation with TGA through esterification, yielding well-dispersed PEGylated Ag 2 S-ZnS@TGA-AA HNSs. The ZnS component of the HNSs has innate semiconductivity, enabling the generation of electron-hole pairs upon irradiation with a light of wavelength 320 nm. These separate charges can react with oxygen and water around the HNSs to produce reactive oxygen species. Moreover, some holes can oxidize the surface-grafted AA to produce protons, decreasing the local pH and resulting in the corrosion of Ag 2 S, which releases silver ions. In evaluation tests, the PEGylated Ag 2 S-ZnS@TGA-AA had synergistic antibacterial ability and inhibited Gram-negative Escherichia coli and Gram-positive methicillin-resistant Staphylococcus aureus (MRSA). Additionally, MRSA-infected wounds treated with a single dose of PEGylated Ag 2 S-ZnS@TGA-AA HNSs under light exposure healed significantly more quickly than those not treated, a result attributable to the HNSs' excellent antibacterial and Bohr effects.

Bohr, Hasselbalch and Krogh demonstrated a group of sigmoid curves under various carbon dioxide contents in 1904. Hill fitted these curves in 1910 with Hill equation without the physical meanings of Hill coefficient and dissociation constant. In 1965, Monod-Wyman-Changeux model (MWC) popularized the word “allostery” with 81 words of symmetry to define an orthosteric nature of cooperativity in a single and symmetric sigmoid curve. Paradoxically the MWC model didn’t quantify the homotropic Hill coefficient and confusingly described the symmetry of sigmoid shapes with three allosteric variables. A heterotropic Bohr equation, by clarifying the biophysical symmetry in allostery, suggests the solution of allosteric coefficients with only one Bohr variable. We reveal that the mathematical need of a fictional monomer by MWC model justify a symmetric logistic curve with a parabolic kernel of dissociation constant to model the 1904 sigmoid curves. The logistic-derived Bohr equation and its half-saturated P50 equation successfully used the embedded P50 values in the 1904 sigmoidal curves to quantify their hyperbolic conformational shifts and Hill coefficients (n) pending for a century. Both are the logarithmic functions of carbon dioxide. This truly quantitative Bohr equation digitizes the allosteric regulation of the orthosteric affinity by precisely cloning the original group of dissociation/association curves published in 1904. The Bohr equation honestly suggests that nature should have chosen the allosteric Bohr effects to modify hemoglobin to cope with the swift dynamic of gas exchange. The discovery of the Bohr function in Bohr equation challenges the feasibility of the orthosteric cooperativity of hemoglobin.

COVID-19 has specific characteristics that distinguish this disease from many other infections. We suggest that the pathogenesis of severe forms of COVID-19 can be associated with acidosis. This review article discusses several mechanisms potentially linking the damaging effects of COVID-19 with acidosis and shows the existence of a vicious cycle between the development of hypoxia and acidosis in COVID-19 patients. At the early stages of the disease, inflammation, difficulty in gas exchange in the lungs and thrombosis collectively contribute to the onset of acidosis. In accordance with the Verigo-Bohr effect, a decrease in blood pH leads to a decrease in oxygen saturation, which contributes to the exacerbation of acidosis and results in a deterioration of the patient’s condition. A decrease in pH can also cause conformational changes in the S-protein of the virus and thus lead to a decrease in the affinity and avidity of protective antibodies. Hypoxia and acidosis lead to dysregulation of the immune system and multidirectional pro- and anti-inflammatory reactions, resulting in the development of a “cytokine storm”. In this review, we highlight the potential importance of supporting normal blood pH as an approach to COVID-19 therapy.

A hallmark of non-rapid eye movement (REM) sleep is the decreased brain activity as measured by global reductions in cerebral blood flow, oxygen metabolism, and glucose metabolism. It is unknown whether the blood oxygen level dependent (BOLD) signal undergoes similar changes. Here we show that, in contrast to the decreases in blood flow and metabolism, the mean global BOLD signal increases with sleep depth in a regionally non-uniform manner throughout gray matter. We relate our findings to the circulatory and metabolic processes influencing the BOLD signal and conclude that because oxygen consumption decreases proportionately more than blood flow in sleep, the resulting decrease in paramagnetic deoxyhemoglobin accounts for the increase in mean global BOLD signal. [ABSTRACT FROM AUTHOR]

A successful spawning migration in salmon depends on their athletic ability, and thus on efficient cardiovascular oxygen (O2) transport. Most teleost fishes have highly pH-sensitive haemoglobins (Hb) that can release large amounts of O2 when the blood is acidified at the tissues. We hypothesized that plasma-accessible carbonic anhydrase (paCA; the enzyme that catalyses proton production from CO2) is required to acidify the blood at the tissues and promote tissue O2 extraction. Previous studies have reported an elevated tissue O2 extraction in hypoxia-acclimated teleosts that may also be facilitated by paCA. Thus, to create experimental contrasts in tissue O2 extraction, Atlantic salmon were acclimated to normoxia or hypoxia (40% air saturation for more than six weeks), and the role of paCA in enhancing tissue O2 extraction was tested by inhibiting paCA at rest and during submaximal exercise. Our results show that: (i) in both acclimation groups, the inhibition of paCA increased cardiac output by one-third, indicating a role of paCA in promoting tissue O2 extraction during exercise, recovery and at rest; (ii) the recruitment of paCA was plastic and increased following hypoxic acclimation; and (iii) maximal exercise performance in salmon, and thus a successful spawning migration, may not be possible without paCA. [ABSTRACT FROM AUTHOR]

The affinity of hemoglobin (Hb) for oxygen (O2) is an important factor influencing the transport of this gas especially in hypoxia and in different diseases such as anemia or cystic fibrosis. By the affinity measurement, the determination of the Hb: O2 dissociation curve is used. The presented method to establish the Hb: O2 oxygen dissociation curve (CDO) simplifies the protocols normally used, since it eliminates the requirement of specific equipment to equilibrate blood with oxygen at fixed levels of oxygen pressure (PO2). By using mathematical equations, it is possible to establish the saturation change of hemoglobin (SO2) at increasing oxygen partial pressure. Similarly, the method determines typical aspects of the Hb: O2 binding as the pH dependence (Bohr coefficient) and the association type of protein with its ligand by the Hill diagram. By this simplification, the method is applicable in laboratory practices in human and animal population, as well as in the investigation of different experimental conditions. [ABSTRACT FROM AUTHOR]

The effect of external hypoxia on the functional properties of hemoglobin in crucian carp Carassius carassius and bream Abramis brama has been studied. The study revealed that the affinity of hemoglobin to oxygen and Bohr effect values increase under influence of external hypoxia. [ABSTRACT FROM AUTHOR]

Accumulating evidence is highlighting the importance of a system of enhanced hemoglobin-oxygen (Hb-O2) unloading for cardiovascular O2 transport in teleosts. Adrenergically stimulated sodium-proton exchangers (β-NHE) create H+ gradients across the red blood cell (RBC) membrane that are short-circuited in the presence of plasma-accessible carbonic anhydrase (paCA) at the tissues; the result is a large arterial-venous pH shift that greatly enhances O2 unloading from pH-sensitive Hb. However, RBC intracellular pH (pHi) must recover during venous transit (31–90 s) to enable O2 loading at the gills. The halftimes (t1/2) and magnitudes of RBC β-adrenergic stimulation, short-circuiting with paCA and recovery of RBC pHi, were assessed in vitro, on rainbow trout whole blood, and using changes in closed-system partial pressure of O2 as a sensitive indicator for changes in RBC pHi. In addition, the recovery rate of RBC pHi was assessed in a continuous-flow apparatus that more closely mimics RBC transit through the circulation. Results indicate that: 1) the t1/2 of β-NHE short-circuiting is likely within the residence time of blood in the capillaries, 2) the t1/2 of RBC pHi recovery is 17 s and within the time of RBC venous transit, and 3) after short-circuiting, RBCs reestablish the initial H+ gradient across the membrane and can potentially undergo repeated cycles of short-circuiting and recovery. Thus, teleosts have evolved a system that greatly enhances O2 unloading from pH-sensitive Hb at the tissues, while protecting O2 loading at the gills; the resulting increase in O2 transport per unit of blood flow may enable the tremendous athletic ability of salmonids. [ABSTRACT FROM AUTHOR]

ABSTRACT: The acceleration of nerve regeneration remains a clinical challenge. We previously demonstrated that transcutaneous CO2 application using a novel hydrogel increases the oxygen concentration in local tissue via an “artificial Bohr effect” with the potential to prevent muscle atrophy. In this study, we investigated the effect of transcutaneous CO2 administration on limb function after peripheral nerve injury in a rat sciatic nerve injury model. In total, 73 Sprague–Dawley rats were divided into a sham group, a control group (crush injury to sciatic nerve and no treatment) or a CO2 group (crush injury with transcutaneous CO2 application). CO2 was administered percutaneously for 20 min five times per week. Scores for the sciatic function index and pinprick test were significantly higher in the CO2 group than control group. The muscle wet weight ratios of the tibialis anterior and soleus muscles were higher in the CO2 group than control group. Electrophysiological examination showed that the CO2 group had higher compound motor action potential amplitudes and shorter distal motor latency than the control group. Histological examination of the soleus muscle sections at postoperative week 2 showed shorter fiber diameter in the control group than in the CO2 group. The mRNA expression of Atrogin‐1 and MuRF‐1 was lower, mRNA expression of VEGF and myogenin and MyoD was higher in CO2 group at postoperative week 2 compared to the control group. Clinical significance: Transcutaneous CO2 application has the therapeutic potential to accelerate the recovery of muscle atrophy in peripheral nerve injury. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1653–1658, 2018. [ABSTRACT FROM AUTHOR]

Background: Oxygenation of the skin has been shown to improve cell growth and cell biosynthesis, which can subsequently improve the skin's appearance.1,2 However, the majority of skin oxygenation techniques are invasive.3,4 A noninvasive skin oxygenation treatment, also known as a carboxytherapy facial, with TriPollar® radiofrequency device has emerged called OxyGeneo™, which is provided by the geneO+™ skin care platform (Pollogen Ltd., Tel Aviv, Israel). Objective: This study addresses the clinical effectiveness of the aforementioned noninvasive skin oxygenation treatment on skin texture, fine lines/wrinkles, and skin pigmentation over an eight-week time period. Methods and materials: Ten patients with fine lines, wrinkles, hyperpigmentation, and rough skin texture received six weekly treatments over a two-month period. Five patients received NeoRevive™ and five received NeoBright™ topical infusions, with the selection made according to each individual's skin conditions and type. These patients were evaluated using the VISIA complexion analysis system (Canfield Scientific, Inc., Parsippany, New Jersey) and patient and evaluator assessments and satisfaction surveys. Results: Each individual measurement varied by patient, but the change in value of each category that was assessed prior to treatment and post-treatment indicated an improvement. All patients in the study stated an improvement in overall skin appearance, skin texture, brightness, and shininess. Nine out of the 10 patients reported that their skin was softer and had a more youthful appearance after the treatments, and seven out of the 10 patients saw a minor improvement in fine lines and wrinkles. Lastly, five out of the 10 patients noticed an improvement in skin pigmentation. Conclusion: The results indicated the combination of the three-in-one OxyGeneo treatment of exfoliation, infusion and oxygenation using TriPolar radiofrequency prompted an improvement in skin texture and tone. This is an optimal procedure that can be implemented in patients looking for noninvasive, safe, and effective rejuvenation treatments with no associated downtime post-procedure. [ABSTRACT FROM AUTHOR]

Inhabiting deep and sealed subterranean burrows, mole rats exhibit a remarkable suite of specializations, including eusociality (living in colonies with single breeding queens), extraordinary longevity, cancer immunity and poikilothermy, and extreme tolerance of hypoxia and hypercapnia. With little information available on adjustments in haemoglobin (Hb) function that may mitigate the impact of exogenous and endogenous constraints on the uptake and internal transport of O2, we measured haematological characteristics, as well as Hb-O2 binding affinity and sensitivity to pH (Bohr effect), CO2, temperature and 2,3-diphosphoglycerate (DPG, the major allosteric modulator of Hb-O2 affinity in red blood cells) in four social and two solitary species of African mole rats (family Bathyergidae) originating from different biomes and soil types across Central and Southern Africa. We found no consistent patterns in haematocrit (Hct) and blood and red cell DPG and Hb concentrations or in intrinsic Hb-O2 affinity and its sensitivity to pHand DPGthat correlate with burrowing, sociality and soil type. However, the results reveal low specific (pH independent) effects of CO2 on Hb-O2 affinity compared with humans that predictably safeguard pulmonary loading under hypoxic and hypercapnic burrow conditions. The O2 binding characteristics are discussed in relation to available information on the primary structure of Hbs from adult and developmental stages of mammals subjected to hypoxia and hypercapnia and the molecular mechanisms underlying functional variation in rodent Hbs. [ABSTRACT FROM AUTHOR]

The effect of the prelethal state on functional properties of hemoglobin has been studied in the goldfish Carassius auratus. A considerable decrease in hemoglobin affinity for oxygen and the Bohr effect values and the change in the shape of the curve of oxygen equilibrium have been detected. Such state may be compared to the effect of strong short-term stress. [ABSTRACT FROM AUTHOR]

Teleosts comprise 95% of fish species, almost one-half of all vertebrate species, and represent one of the most successful adaptive radiation events among vertebrates. This is thought to be in part because of their unique oxygen (O2) transport system. In salmonids, recent in vitro and in vivo studies indicate that hemoglobin-oxygen (Hb-O2) unloading to tissues may be doubled or even tripled under some conditions without changes in perfusion. This is accomplished through the short circuiting of red blood cell (RBC) pH regulation, resulting in a large arterial-venous pH difference within the RBC and induced reduction in Hb-O2 affinity. This system has three prerequisites: 1) highly pH-sensitive hemoglobin, 2) rapid RBC pH regulation, and 3) a heterogeneous distribution of plasma-accessible CA in the cardiovascular system (presence in the tissues and absence at the gills). Although data are limited, these attributes may be general characteristics of teleosts. Although this system is not likely operational to the same degree in other vertebrates, some of these prerequisites do exist, and the generation and elimination of pH disequilibrium states at the RBC will likely enhance Hb-O2 unloading to some degree. In human disease states, there are conditions that may partly satisfy those for enhanced Hb-O2 unloading, tentatively an avenue for future work that may improve treatment efficacy. [ABSTRACT FROM AUTHOR]

Oxygen uptake ([Formula: see text]o2) measured at the mouth, which is equal to the cardiac output (CO) times the arterial-venous oxygen content difference [C(a-v)O2], increases more than 10- to 20-fold in normal subjects during exercise. To achieve this substantial increase in oxygen uptake [[Formula: see text]o2 = CO × C(a-v)O2] both CO and the arterial-venous difference must simultaneously increase. Although this occurs in normal subjects, patients with heart failure cannot achieve significant increases in cardiac output and must rely primarily on changes in the arterial-venous difference to increase [Formula: see text]o2 during exercise. Inadequate oxygen delivery to the tissue during exercise in heart failure results in tissue anaerobiosis, lactic acid accumulation, and reduction in exercise tolerance. H+ is an important regulatory and feedback mechanism to facilitate additional oxygen delivery to the tissue (Bohr effect) and further aerobic production of ATP when tissue anaerobic metabolism increases the production of lactate (anaerobic threshold). This H+ production in the muscle capillary promotes the continued unloading of oxygen (oxyhemoglobin desaturation) while maintaining the muscle capillary Po2 (Fick principle) at a sufficient level to facilitate aerobic metabolism and overcome the diffusion barriers from capillary to mitochondria ("critical capillary Po2," 15-20 mm Hg). This mechanism is especially important during exercise in heart failure where cardiac output increase is severely constrained. Several compensatory mechanisms facilitate peripheral oxygen delivery during exercise in both normal persons and patients with heart failure. [ABSTRACT FROM AUTHOR]

Atlantic cod are a commercially important species believed to be threatened by warming seas near their southern, equatorward upper thermal edge of distribution. Limitations to circulatory O2 transport, in particular cardiac output, and the geographic distribution of functionally different haemoglobin (Hb) genotypes have separately been suggested to play a role in setting thermal tolerance in this species. The present study assessed the thermal sensitivity of O2 binding in Atlantic cod red blood cells with different Hb genotypes near their upper thermal distribution limit and modelled its consequences for the arterio-venous O2 saturation difference, Sa-vO2, another major determinant of circulatory O2 supply rate. The results showed statistically indistinguishable red blood cell O2 binding between the three HbI genotypes in wild-caught Atlantic cod fromthe Irish Sea (53°N). Red blood cells had an unusually low O2 affinity, with reduced or even reversed thermal sensitivity between pH 7.4 and 7.9, and 5.0 and 20.0°C. This was paired with strongly pH-dependent affinity and cooperativity of red blood cell O2 binding (Bohr and Root effects). Modelling of Sa-vO2 at physiological pH, temperature and O2 partial pressures revealed a substantial capacity for increases in Sa-vO2 to meet rising tissue O2 demands at 5.0 and 12.5°C, but not at 20°C. Furthermore, there was no evidence for an increase of maximal Sa-vO2 with temperature. It is suggested that Atlantic cod at such high temperatures may solely depend on increases in cardiac output and blood O2 capacity, or thermal acclimatisation of metabolic rate, for matching circulatory O2 supply to tissue demand. [ABSTRACT FROM AUTHOR]

The kinetics of the reaction of 5,5'-dithiobis(2-nitrobenzoate) with guinea pig oxy- and carbonmonoxyhaemoglobin are biphasic. The two phases differ in rate by two orders of magnitude. For the fast phase, quantitative analysis of the pH dependence of the apparent second order rate constant, kapp, shows that it has all the characteristics associated with the reaction of CysF9(93)β, a sulphydryl group that is invariant in all mammalian haemoglobins. The slow kinetic phase is assigned to CysH3(125)β. Quantitative analysis of the pH dependence of kapp for this phase at 50 mM ionic strength gave an unusually low pKa of 6.0 for this sulphydryl group. Published data on guinea pig haemoglobin show that it has a much-enhanced acid Bohr effect compared to human haemoglobin. This indicates that CysH3(125)β functions as an acid Bohr group in guinea pig haemoglobin. Comparison with human haemoglobin indicates that this cysteine reduces the alkaline Bohr effect of guinea pig haemoglobin between pH 7 and 6, and enhances its acid Bohr effect below pH 6. From kinetic data collected at high salt concentration, and in the presence of inositol hexakisphosphate, it is shown that the pKa of the sulphydryl increases to ca 9 and 7.7, respectively. Under these conditions, CysH3(125)β ceases to be an acid Bohr group.DOI: http://dx.doi.org/10.4314/bcse.v27i1.11