Author Correction: Generation of a selective senolytic platform using a micelle-encapsulated Sudan Black B conjugated analog
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Mitochondrial priming and response to BH3 mimetics in “one-two punch” senogenic-senolytic strategies
A one-two punch sequential regimen of senescence-inducing agents followed by senolytic drugs has emerged as a novel therapeutic strategy in cancer. Unfortunately, cancer cells undergoing therapy-induced senescence (TIS) vary widely in their sensitivity to senotherapeutics, and companion diagnostics to predict the response of TIS cancer cells to a specific senolytic drug are lacking. Here, we hypothesized that the ability of the BH3 profiling assay to functionally measure the mitochondrial priming state—the proximity to the apoptotic threshold—and the dependencies on pro-survival BCL-2 family proteins can be exploited to inform the sensitivity of TIS cancer cells to BH3-mimetics. Replicative, mitotic, oxidative, and genotoxic forms of TIS were induced in p16-null/p53-proficient, BAX-deficient, and BRCA1-mutant cancer cells using mechanistically distinct TIS-inducing cancer therapeutics, including palbociclib, alisertib, doxorubicin, bleomycin, and olaparib. When the overall state of mitochondrial priming and competence was determined using activator peptides, the expected increase in overall mitochondrial priming was an exception rather than a generalizable feature across TIS phenotypes. A higher level of overall priming paralleled a higher sensitivity of competent TIS cancer cells to BCL-2/BCL-xL- and BCL-xL-targeted inhibitors when comparing TIS phenotypes among themselves. Unexpectedly, however, TIS cancer cells remained equally or even less overally primed than their proliferative counterparts. When sensitizing peptides were used to map dependencies on anti-apoptotic BCL-2 family proteins, competent TIS cancer cells appeared to share a dependency on BCL-xL. Furthermore, regardless of senescence-inducing therapeutic, stable/transient senescence acquisition, or genetic context, all TIS phenotypes shared a variable but significant senolytic response to the BCL-xL-selective BH3 mimetic A1331852. These findings may help to rethink the traditional assumption of the primed apoptotic landscape of TIS cancer cells. BCL-xL is a conserved anti-apoptotic effector of the TIS BCL2/BH3 interactome that can be exploited to maximize the efficacy of “one-two punch” senogenic-senolytic strategies.
Chemical linkers switch triglycerol detergents from bacterial protein purification to mild antibiotic amplification
Non-ionic detergents enable the investigation of cell membranes, including biomolecule purification and drug delivery. The question of whether non-ionic detergents associated with satisfying protein yields following extraction and affinity purification of proteins from lysed E. coli membranes can amplify antibiotics on whole-cell E. coli remains to be addressed. We unlock the modular chemistry of linear triglycerol detergents to reveal that more polar, non-ionic detergents that form globular micelles work better in amplifying antimicrobial activities of antibiotics than in purifying the membrane proteins mechanosensitive channel and aquaporin Z. Less polar detergents that form worm-like micelles indicate poor performances in both applications. With chromatography we demonstrate how fine-tuning the polarity of chemical linkers between detergent headgroups and tails can switch the utility of detergents from protein purification to antibiotic amplification. We anticipate our findings to be a starting point for structure-property studies to better understand detergent designs in supramolecular chemistry and membrane research.
Anthropogenic organic aerosol in Europe produced mainly through second-generation oxidation
Exposure to anthropogenic atmospheric aerosol is a major health issue, causing several million deaths per year worldwide. The oxidation of aromatic hydrocarbons from traffic and wood combustion is an important anthropogenic source of low-volatility species in secondary organic aerosol, especially in heavily polluted environments. It is not yet established whether the formation of anthropogenic secondary organic aerosol involves mainly rapid autoxidation, slower sequential oxidation steps or a combination of the two. Here we reproduced a typical urban haze in the ‘Cosmics Leaving Outdoor Droplets’ chamber at the European Organization for Nuclear Research and observed the dynamics of aromatic oxidation products during secondary organic aerosol growth on a molecular level to determine mechanisms underlying their production and removal. We demonstrate that sequential oxidation is required for substantial secondary organic aerosol formation. Second-generation oxidation decreases the products’ saturation vapour pressure by several orders of magnitude and increases the aromatic secondary organic aerosol yields from a few percent to a few tens of percent at typical atmospheric concentrations. Through regional modelling, we show that more than 70% of the exposure to anthropogenic organic aerosol in Europe arises from second-generation oxidation.
Regulation of mammalian cellular metabolism by endogenous cyanide production
Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.
On-patient medical record and mRNA therapeutics using intradermal microneedles
Medical interventions often require timed series of doses, thus necessitating accurate medical record-keeping. In many global settings, these records are unreliable or unavailable at the point of care, leading to less effective treatments or disease prevention. Here we present an invisible-to-the-naked-eye on-patient medical record-keeping technology that accurately stores medical information in the patient skin as part of microneedles that are used for intradermal therapeutics. We optimize the microneedle design for both a reliable delivery of messenger RNA (mRNA) therapeutics and the near-infrared fluorescent microparticles that encode the on-patient medical record-keeping. Deep learning-based image processing enables encoding and decoding of the information with excellent temporal and spatial robustness. Long-term studies in a swine model demonstrate the safety, efficacy and reliability of this approach for the co-delivery of on-patient medical record-keeping and the mRNA vaccine encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This technology could help healthcare workers make informed decisions in circumstances where reliable record-keeping is unavailable, thus contributing to global healthcare equity.
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