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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. 

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.