Exosomes deliver sepsis treatment

Investigators at Ilias Biologics Inc. and the Korea Advanced Institute of Science have reported that treating sepsis with exosomes loaded with super-repressor lkΒ to prevent the pro-inflammatory transcription factor NFkB from moving into the nucleus and setting off gene expression changes driving uncontrolled inflammation helped mice with sepsis live longer and recover from organ damage. The treatment significantly lowered pro-inflammatory markers but not an anti-inflammatory cytokine, suggesting it could be applied during the early phase of sepsis, before the immune system is suppressed. “Exosomes are a promising vehicle for intracellular delivery of srIkB and constitute a new option for sepsis therapy,” the authors wrote. “Our data demonstrate that Exo-srIkB acts as an inhibitor of NFkB and can directly counteract the overwhelming inflammatory response, thus ameliorating the proinflammatory cytokine storm and subsequent organ damage.” They reported their results in the April 8, 2020, issue of Science Advances.

Dopamine has epigenetic role in addiction

Dopamine is well known as a neurotransmitter involved in reward seeking, which gives it a role in addiction as well. Now researchers at the Mount Sinai School of Medicine and the University at Buffalo have identified a role for dopamine in addiction that was independent of its neurotransmitter activity. They showed that dopamine could be added to DNA in neurons of the ventral tegmental areas as an epigenetic tag, and the dopaminylation of a specific glutamine residue played “a critical role in cocaine-induced transcriptional plasticity in the midbrain.” By reducing such dopaminylation, the authors “reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior” in addicted rats undergoing withdrawal. The authors concluded, “These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity” in the midbrain. They reported their findings in the April 10, 2020, issue of Science.

Rejuvenating inflammation’s end

Inflammation is one of the processes whose control declines with aging, leaving older individuals, on the average, equally able to mount an inflammatory response but less able to end that response when compared to younger folks. Researchers at University College London have identified the pathway from the surface receptor TIM-4, which enables engulfment of apoptotic cells by macrophages, to p38 MAP kinase signaling. “Administering an orally active p38 inhibitor to elderly individuals rescued TIM-4 expression, cleared apoptotic bodies and restored a macrophage resolution phenotype. Thus, inhibiting p38 in elderly individuals rejuvenated their resolution response to be more similar to that of younger people. This is the first resolution defect identified in humans that has been successfully reversed, thereby highlighting the tractability of targeting pro-resolution biology to treat diseases driven by chronic inflammation,” the authors wrote. Their work appeared in the April 6, 2020, online issue of Nature Immunology.

Gut repair with an iron will

Investigators at Cornell University and INSERM have identified a new mechanism for iron regulation. Iron deficiency and iron excess are both toxic, and iron levels are tightly regulated in the blood as well as in individual cells. The team showed that iron levels are also controlled in the gut. Many gastrointestinal disorders induce bleeding, which leads to high iron levels in the gut. The team showed that when they were activated by microbes, antigen-presenting dendritic cells in the gut also produced hepcidin, which led to sequestration of iron by phagocytes, which facilitated intestinal repair. The phagocytes also influenced the gut microbiome, and fecal transplantation impaired mucosal healing. “Our results indicate that hepcidin mimetics could be a beneficial therapeutic strategy in the context of FMT or gastrointestinal diseases where mucosal healing is an emerging therapeutic goal,” the authors wrote. Their work appeared in the April 10, 2020, issue of Science.

Multiple drivers explained

A team at Japan’s National Cancer Center Research Institute has undertaken a details analysis of oncogenes with multiple driver mutations. While typically, only one driver mutation is observed in a given oncogene, there are exceptions, and the team looked at the comprehensive landscape of such exceptions. They found that multiple driver mutations did not co-occur at random, but were enriched in specific oncogenes and tended to be near each other when they did occur. In a pan-cancer analysis of nearly 61,000 samples, they identified 20 oncogenes that had multiple mutations at higher than expected frequencies. In 14 of those genes, multiple mutations occurred in multiple tumor types, while six of them were tumor-specific. “Together oncogenic [multiple mutations] are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations,” the authors wrote. They published their results in the April 9, 2020, issue of Nature.

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