Noncoding RNA protects blood vessel walls
Investigators at Brigham & Women’s Hospital have identified a long noncoding RNA (lncRNA) that protected blood vessels from DNA damage, and so staved off atherosclerosis independently of effects on either the lipid composition of the vessel wall or inflammation, which are major direct contributors to atherosclerosis. The team profiled lncRNAs in LDL cholesterol receptor knockout mice that were fed a high-fat diet, and demonstrated that SNHG12 was highly expressed in cells of the vessel walls, that its expression decreased as atherosclerosis progressed, and that SNHG12 knockdown accelerated disease progression. Mechanistically, SNHG12 loss reduced the DNA damage response, sending cells into senescence. Treatment with the anti-DNA damage agent nicotinamide riboside (NR) reversed the effects of SNHG12 knockdown, and the authors concluded that “these findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.” Their work appeared in the Feb. 19, 2020, issue of Science Translational Medicine.
PD-1 blockade interferes with opioid analgesia
Opioid painkillers are a pillar of treatment in oncology, and immunotherapies, in particular PD-1 checkpoint blockers, are becoming another such pillar. Now, scientists at Duke University have demonstrated in both mice and primates that PD-1 checkpoint blockers can inhibit the analgesic effects of opioids. Previous work had shown that PD-1 is also expressed on neurons, including those of the dorsal root ganglion, and that PD-1 activation had analgesic effects. The authors demonstrated that PD-1 knockout mice derived less pain relief from opioids than their wild-type cousins, and were more susceptible to opioid-induced hyperalgesia, a paradoxical pain syndrome that can result from taking opiate drugs. In both mice and primates, an intrathecal injection of Opdivo (nivolumab, Bristol-Myers Squibb Co.) reduced the analgesic effects of opioids. The authors concluded that “anti-PD-1 immunotherapy may interfere with opioid analgesia in patients with cancer” by disrupting the interaction between PD-1 and mu opioid receptors. “In addition, PD-L1 might be used to treat clinical pain and enhance opioid analgesia in noncancer patients.” They reported their results in the Feb. 19, 2020, issue of Science Translational Medicine.
T-cell population is biomarker for beta cell function
Researchers at the University of Napoli Federico II have identified a peripheral T-cell population that was a potential biomarker for immune self-tolerance in type 1 diabetes. The regulatory T cells in question express the surface markers CD3 and CD56, and the researchers had previously demonstrated that the levels of CD3/CD56-expressing cells at the time of a type 1 diabetes (T1D) diagnosis predicted residual beta cell function one year later. In follow-up work, they demonstrated that three separate cohorts of newly diagnosed T1D patients had low levels of CD3/CD56-expressing cells. Mechanistically, the cells prevented CD8 “killer” T cells from attacking pancreatic beta cells by lowering their intracellular levels of reactive oxygen species. The authors concluded that the cells “constitute a regulatory cell population that controls CD8+ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D,” the authors wrote. They reported their results in the Feb. 17, 2020, online issue of Nature Immunology.
Glutaminase 1 is NASH target
Investigators at the Center for Cooperative Research in Biosciences have identified the enzyme glutaminase 1 as a potential target for the treatment of nonalcoholic steatohepatitis (NASH), a metabolic disease of the liver that is a major risk factor for fibrosis and cirrhosis. NASH is characterized by multiple changes to metabolism, and one of the processes that goes awry is the synthesis and secretion of very low-density lipoprotein (VLDL). In their experiments, the authors linked defective secretion of VLDL to hyperactive glutaminase 1. By catalyzing the formation of glutamate from glutamine, glutaminase 1 affected the synthesis of phospholipids that are necessary for the export of VLDL. Inhibiting glutaminase 1 restored VLDL export and reduced oxidative stress and fat accumulation in the liver. The team published its findings in the Feb. 18, 2020, issue of Cell Metabolism.
Oligodendrocyte-neural connections not just about myelin
Scientists at Technical University Munich have used a combination of sequencing and imaging to demonstrate that the precursors of oligodendrocytes, best known as the cells that make the myelin sheath, could be divided into functional subgroups. Previous work had established that there are subtypes of oligodendrocyte precursor cells (OPCs) running different gene expression programs, but whether individual cells could switch between those programs was not clear. In their experiments, the team showed that OPCs could form two subgroups. One type of cell showed high levels of calcium signaling, and rarely differentiated into myelin-forming cells even when it came into contact with axons, which triggers the formation of myelin. However, such OPCs did form extensive synaptic connections with neurons. The team’s results showed that “a significant proportion of OPCs are not directly involved in generating new myelin,” and that the cells forming the most extensive connections with neurons were not the ones forming myelin, leaving the function of the connections unresolved for now. The authors wrote that “this question remains to be addressed in future studies.” Their work appeared in the Feb. 17, 2020, issue of Nature Neuroscience.
Sharper look yields new potential kinase target in ovarian cancer
Researchers at Fox Chase Cancer Center have identified a so-far-untargeted kinase that was repeatedly seen as part of a “kinase signature” in high-grade serous ovarian cancer. Ovarian cancer is among the deadliest tumors, and targeted options exist only for the minority of patients with BRCA mutations, prompting the authors to search for untargeted kinases via enrichment strategies. They identified a “signature consisting of established HGSOC driver kinases, as well as several kinases previously unexplored” in ovarian cancer. One of those kinases was MRCKA, also known as CDC42BPA, which was overexpressed in about a quarter of ovarian cancer samples the team looked at. They showed that loss-of-function of the kinase, as well as inhibition with BDP9066 “decreased cell proliferation and spheroid formation and induced apoptosis” in cell culture. Their results appeared in the Feb. 18, 2020, issue of Science Signaling.
Structural insights could enable specific activation of GPCRs
Researchers have used modeling to gain new insights into how different ligands affected the structure of the angiotensin II receptor, and used those insights to design ligands that could selectively activate different downstream pathways. The angiotensin II receptor is one of the G protein-coupled receptors (GPCRs), which are collectively the target of roughly a third of currently marketed drugs. However, GPCRs are also coupled to beta-arrestins, and many drugs exert desired effects through one downstream signaling pathway and side effects through the other. A Stanford-led team used molecular modeling to understand the structural features necessary to activate each signaling pathway, while a companion paper by researchers from Duke University and Harvard Medical School used structural studies to gain insights into how the receptor confirmation was affected by each kind of ligand. The papers appeared back to back in the Feb. 21, 2020, issue of Science.
Autophagy activation may prevent metastasis
Investigators at the University of California, San Francisco have demonstrated autophagy’s potential utility to prevent metastasis. Autophagy is a cellular recycling mechanism that helps cells rid themselves of dysfunctional protein. Inhibiting autophagy can push cancer cells over the edge to apoptosis, and is being tested in clinical trials as a cancer strategy. However, much like angiogenesis, autophagy plays multiple roles at different stages, prompting the team to look at its role in metastasis. In cell culture and mouse models of breast cancer, they demonstrated that suppressing autophagy led to the emergence of aggressive cells that were more likely to metastasize. In particular, this was due to the accumulation of the protein NBR1. The authors wrote that “based on these results, we propose that autophagy induction should be further evaluated as a potential therapeutic strategy for the prevention of metastasis. On the whole, as future pharmacological compounds that specifically induce or inhibit autophagy are developed for cancer treatment, their long-term effects on metastasis remain an important consideration.” They reported their results in the Feb. 20, 2020, issue of Developmental Cell.
AI finds structurally unique antibiotics
Researchers at the Massachusetts Institute of Technology have used artificial intelligence to identify a compound with broad-spectrum bactericidal activity that was structurally dissimilar from clinically used classes of antibiotics. New antibiotics are becoming an increasingly urgent public health need. Of the challenges to developing successful new antibiotics, identifying lead compounds is a problem at the level of scientific discovery, as compounds discovered via natural product discovery tend to be similar to already-discovered antibiotics. In their work, the authors trained a neural network to recognize chemical compounds that were able to inhibit the growth of Escherichia coli bacteria, and then used the neural net to virtually screen a library of more than 100 million compounds. That resulted in the discovery of a compound the team named halicin, which was structurally dissimilar to existing clinical antibiotics. By affecting the pH gradient across the bacterial membrane, halicin had broad-spectrum antibacterial activity. The authors also identified two additional structurally unique molecules with broad-spectrum antibacterial activity. “This work highlights the significant impact that machine learning can have on early antibiotic discovery efforts by simultaneously increasing the accuracy rate of lead compound identification and decreasing the cost of screening efforts,” the authors wrote. Their study was published in the Feb. 20, 2020, issue of Cell.