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Recent findings from comparative and evolutionary physiologists reveal novel insights into the regulation of inflammation and immune function under conditions of chronic-sustained and intermittent hypoxia. Comparative approaches provide a valuable gateway for discovering essential principals of physiology and adaptive molecular strategies utilized in nature that protect against clinically relevant stressors, which can guide therapeutic developments in biomedical science. 

BackgroundDoxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI‐002) that can be easily self‐administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract. Methods and ResultsHBI‐002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI‐002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI‐002 had a 6.3‐fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase‐1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI‐002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI‐002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function. ConclusionsThese findings strongly support using HBI‐002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage. 

This is the first study to determine the red blood cell lifespan in a marine mammal species. High concentrations of carbon monoxide (CO) were found in the blood of bottlenose dolphins and in the blood and breath of belugas compared with healthy humans. Red blood cell turnover accounted for these high levels in bottlenose dolphins, but there may be alternative mechanisms of endogenous CO production that are contributing to the CO concentrations observed in belugas. 

Wound healing presents a unique challenge for patients with diabetes. Gas therapies have gained significant attention in the wound-healing community. Carbon monoxide (CO) is a small molecule that is well known for its immune-modulating properties when administered at sublethal concentrations. CO is currently in clinical trials for lung disease, sickle cell anemia, and organ transplantation. Here, we investigated the effects of CO in an in vitro wound-healing model and subsequently developed and tested CO gas-entrapping materials (CO-GEMs) for topical application on wounds to promote healing. In this study, we report the efficacy of CO-GEMs in treating full-thickness wounds and pressure ulcers in diabetic mouse models. Collectively, our findings demonstrate that these novel gas entrapping materials could serve as an alternative therapy to both protect the wound bed and promote healing and replace bulky hyperbaric chambers, standard gauze wound dressings, or expensive skin grafts. 

Marine mammals such as northern elephant seals (NES) routinely experience hypoxemia and ischemia-reperfusion events to many tissues during deep dives with no apparent adverse effects. Adaptations to diving include increased antioxidants and elevated oxygen storage capacity associated with high hemoprotein content in blood and muscle. The natural turnover of heme by heme oxygenase enzymes (encoded by HMOX1 and HMOX2 ) produces endogenous carbon monoxide (CO), which is present at high levels in NES blood and has been shown to have cytoprotective effects in laboratory systems exposed to hypoxia. To understand how pathways associated with endogenous CO production and signaling change across ontogeny in diving mammals, we measured muscle CO and baseline expression of 17 CO-related genes in skeletal muscle and whole blood of three age classes of NES. Muscle CO levels approached those of animals exposed to high exogenous CO, increased with age, and were significantly correlated with gene expression levels. Muscle expression of genes associated with CO production and antioxidant defenses ( HMOX1 , BVR , GPX3 , PRDX1 ) increased with age and was highest in adult females, while that of genes associated with protection from lipid peroxidation ( GPX4 , PRDX6 , PRDX1 , SIRT1 ) was highest in adult males. In contrast, muscle expression of mitochondrial biogenesis regulators ( PGC1A , ESRRA , ESRRG ) was highest in pups, while genes associated with inflammation ( HMOX2 , NRF2 , IL1B ) did not vary with age or sex. Blood expression of genes involved in regulation of inflammation ( IL1B , NRF2 , BVR , IL10 ) was highest in pups, while HMOX1 , HMOX2 and pro-inflammatory markers ( TLR4 , CCL4 , PRDX1 , TNFA ) did not vary with age. We propose that ontogenetic upregulation of baseline HMOX1 expression in skeletal muscle of NES may, in part, underlie increases in CO levels and expression of genes encoding antioxidant enzymes. HMOX2 , in turn, may play a role in regulating inflammation related to ischemia and reperfusion in muscle and circulating immune cells. Our data suggest putative ontogenetic mechanisms that may enable phocid pups to transition to a deep-diving lifestyle, including high baseline expression of genes associated with mitochondrial biogenesis and immune system activation during postnatal development and increased expression of genes associated with protection from lipid peroxidation in adulthood. 

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. 

The dive response, bradycardia (decreased heart rate) and peripheral vasoconstriction, is the key mechanism allowing breath-hold divers to perform long-duration dives while actively swimming and hunting prey. This response is variable and modulated by factors such as dive duration, depth, exercise and cognitive control. This study assesses the potential role of exercise and relative lung volume in the regulation of heart rate (fH) during dives of adult female California sea lions instrumented with ECG, depth, and 3-axis acceleration data loggers. A positive relationship between activity (minimum specific acceleration) and fH throughout dives suggested increased muscle perfusion associated with exercise. However, apart from late ascent, fH during dives was still less than or equal to resting heart rate (on land). In addition, the activity-fH relationship was weaker in long, deep dives consistent with prioritization of blood oxygen conservation over blood oxygen delivery to muscle in those dives. Pulmonary stretch receptor reflexes may also contribute to fH regulation as fH profiles generally paralleled changes in relative lung volume, especially in shallower dives and during early descent and late ascent of deeper dives. Overall, these findings support the concept that both exercise and pulmonary stretch receptor reflexes may influence the dive response in sea lions. 

COoking with gas Low concentrations of carbon monoxide (CO) have shown therapeutic benefit in preclinical models, but safe delivery of appropriate dose has been challenging to achieve. Here, inspired by molecular gastronomy, Byrne et al . designed gas-entrapping materials (GEMs) using components generally recognized as safe, including xanthan gum, methylcellulose, maltodextrin, and corn syrup. Solid, hydrogel, and foam GEMs containing CO could deliver different concentrations of the gas to healthy rodents and pigs through noninhaled routes. In rodent models of colitis, acetaminophen overdose, and radiation-induced proctitis, rectally administered foam GEMs reduced tissue injury and inflammation. Foam GEMs could help achieve safe therapeutic CO delivery.