Liver-derived protein helps lung, kidney repair

Investigators at the Mount Sinai School of Medicine have identified a role for apolipoprotein M (ApoM) in the repair of injuries to the lungs and kidneys. One change in aging bodies is that internal organs lose the ability to repair themselves, and switch to fibrotic scarring to deal with wear and tear instead. The authors showed that sphingosine-1-phosphate (S1P) mediated “an inter-organ communication network responsible for reparative responses in the lung and kidney,” and that to do so, it needed the assistance of liver-produced ApoM, a high-density lipoprotein. Plasma transfer or recombinant ApoM could prevent fibrosis of the lung or kidney in aged mice after injury. The authors concluded that “these data reveal an integrative organ adaptation that involves circulating S1P chaperone [ApoM]…, which signals via endothelial S1PR1 to spur regeneration over fibrosis.” Their work appeared in the June 18, 2020, online issue of Developmental Cell.

Multiracial study gives new diabetes insights

Researchers from multiple consortia, including the VA Million Veteran Program, the Human Pancreas Analysis Program and the Regeneron Genetics Center, have conducted a meta-analysis of risk studies for type 2 diabetes (T2D) in multi-ancestry cohorts, and they identified both generally valid and ancestry-specific risk genes. As with much of medical research, most genomewide association studies on T2D and associated cardiovascular risk have been conducted on European ancestry populations, with Asian ancestry a distant second. As a result, such studies are unable to explain the known disparities in prevalence, severity and co-morbidities that exist in populations of different ancestries. In their work, the authors looked at individuals with European, African American, Hispanic, South Asian and East Asian ancestry, linking risk loci for T2D to outcome data for both macrovascular outcomes, including heart attack and stroke, and microvascular diseases such as chronic kidney disease and neuropathy. “This study complements prior genetic studies of T2D through the use of large-scale clinical data in conjunction with polygenic scores and evaluation of context specificity for genetic effects on T2D vascular sequelae, and by describing the regulatory circuits that influence T2D risk,” the authors wrote. “These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.” They published their results in the June 15, 2020, online issue of Nature Genetics.

The molecular structure of the cancer drug cisplatin causes it to concentrate in tiny non-membrane bound organelles called condensates held together by the protein MED1. By altering other drugs to concentrate in specific condensates, drug developers may be able to improve targeting efficacy in future. Credit: Isaac Klein, Whitehead Institute

New way to target drugs, independently of drug target

Scientists at the Whitehead Institute for Biomedical Research have gained new insights into intracellular drug behavior. The team showed that drugs containing a specific chemical structure, an aromatic ring, tended to concentrate in membraneless organelles called condensates. Condensates form around specific seed proteins, and the authors showed that both cisplatin and mitoxantrones, chemotherapies with different targets, concentrated in condensates independently of the presence of their targets. The team also showed that the size of condensates affected drug concentrations within them, and that this phenomenon contributed to tamoxifen resistance in vitro, as large condensates contained drug concentrations that were too low for the drug to effectively inhibit its target. The team suggested “that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.” They reported their results in the June 19, 2020, issue of Science.

Microbiome-produced metabolites improve gut health

Investigators at The Scripps Research Institute have identified microbiome-produced metabolites that were able to remodel the gut microbiome composition of mice on a high-fat diet to resemble that of animals on a low-fat diet. Microbiome composition exerts many effects on physiology and health, and efforts to harness it have included probiotics and prebiotics, as well as the identification of individual microbial metabolites that are responsible for the microbiome’s health effects. The authors screened for microbiome metabolites that affected the composition of the microbiome itself, with the rationale that altering the microbiome composition as a whole could have more broadly beneficial effects than individual metabolites. The team first showed that cyclic d,l-α-peptides remodeled the microbiome of mice on a high-fat diet toward the low-fat-diet microbiome state. Oral treatment with cyclic d,l-α-peptides “reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells,” the authors wrote. “Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.” Their work appeared in the June 15, 2020, online issue of Nature Biotechnology.

Universal flu vaccine more challenging than anticipated

Scientists at The Scripps Research Institute have undertaken a detailed study of broadly neutralizing antibodies (bnAbs) to the stem of the influenza virus hemagglutinin (HA) protein, and they found that flu strains of subtype H3 had a higher potential to develop resistance than H1 subtype strains. Flu strains are classified by their hemagglutinin (H) and neuraminidase (N), two surface proteins that the virus uses to enter host cells. Several broadly neutralizing antibodies to the stem region of hemagglutinin have been discovered, raising hopes for a universal flu vaccine. However, when the authors undertook a detailed study of the stem regions of the hemagglutinin of the 1968 Hong Kong pandemic strain, looking at the in vitro fitness of 147 of 152 possible single mutants and 6,234 of 10,108 possible double mutants across the eight amino acids that are critical for recognition by two separate bnAbs, they showed that several substitutions for isoleucine-145 decreased bnAb binding to the virus, but this was not true to the same extent for H1 hemagglutinin forms. The authors also showed that strong resistance mutations occurred, albeit at low levels, in circulating H3N2 strains, where they did not reduce in vitro viral fitness or in vivo pathogenicity. The authors concluded that “this study highlights a potential challenge for development of a truly universal influenza vaccine.” Their study appeared in the June 19, 2020, issue of Science.

The bow ties that bind

Scientists at the University of Copenhagen have mapped the complete network of protein-protein interactions within dendritic cells, and identified nearly 300 proteins, which they termed “knot” proteins, that linked protein complexes into bow-tie motifs. No protein is an island, either, and protein complexes greatly influence the ways their individual members function. However, understanding protein complexes becomes difficult as the complexes themselves increase in size. The team developed a new method to visualize nearly 300,000 protein-protein interactions of about 8,600 proteins, and used it to discover knot proteins. “Collectively, the bow-tie motifs are a pervasive and previously unnoted topological trend in cellular interactomes. As such, these results provide fundamental knowledge on how intracellular protein connectivity is organized and operates.” They reported their findings in the June 16, 2020, issue of Cell Reports.

FOXO1 regulates HIV latency

Researchers at the University of California at San Francisco have discovered new roles for the transcription factor FOXO1 in HIV latency. FOXO1 regulates the activity and quiescence of CD4 T cells, and nondividing or latent CD4 T cells are a major reservoir of HIV in chronic infections, which is in turn a major barrier to HIV cure. The researchers said that because of FOXO1’s role in CD4 T-cell latency, it would also promote, directly or indirectly, the establishment and maintenance of the HIV reservoir. They demonstrated that inhibiting FOXO1 in resting T cells reactivated HIV via changes in autophagy. The authors concluded that “our studies uncover a link of FOXO1, ER stress and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.” They reported their results in the June 16, 2020, online issue of Nature Microbiology.

Patient genetic variants linked to wound microbiomes

Microbiomes are found in wounds as much as anywhere else on the body, and they influence whether wounds heal or become chronic. Now, researchers at Texas Tech University have shown that gene variants in two host genes, TLN2 and ZNF521, correlated with both the overall number of bacteria in the wounds, and with the abundance of several pathogenic species, including Pseudomonas aeruginosa and Staphylococcus epidermidis. TLN2 variants affected focal adhesion binding domains, likely influencing bacterial adhesion and/or migration, though the specific cell type where TLN2 variation was important remained unclear. The team also showed that having high levels of P. aeruginosa correlated with low levels of overall bacterial variation in wounds, and that such wounds healed more slowly. “The prospect that patient genetics shape chronic wound microbiome composition highlights a new opportunity to identify biomarkers” for the risk of persistence, the authors wrote. “Given that wound persistence is associated with development of multiple drug-resistant pathogens, such models could identify cases where aggressive targeted therapy is warranted at onset.” Their study appeared in the June 18, 2020, online issue of PLoS Pathogens.

New COPD target

Researchers at Justus-Liebig University have identified NADPH oxidase organizer 1 (NOXO1) as a driver of emphysema and tobacco smoke-induced pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). Important COPD pathophysiological events include an inflammatory-cell influx and increased oxidative stress, with increased numbers of apoptotic cells. Structural remodeling of the pulmonary vasculature has also been proposed as contributing to, or even driving, the development of pulmonary emphysema. Most COPD patients exhibit alterations of the pulmonary vasculature, with the most severe COPD cases showing an abnormally high mean pulmonary arterial pressure, leading ultimately to PH. The team showed that NOXO1 was up-regulated in two models of lung emphysema and in human COPD. Noxo1-knockout mice were protected against tobacco smoke-induced pulmonary hypertension and emphysema. The authors concluded that “NOXO1 may have potential as a therapeutic target in emphysema.” They published their work in the June 8, 2020, edition of Nature Metabolism.

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