Clotbuster's clot-busting may be beside the point

Researchers from Albert Einstein Medical College and the University of Pittsburgh Medical Center have identified brain protective functions of recombinant tissue plasminogen activator (tPA) beyond its main effect of breaking down blood clots, and a compound that could target the same functions without affecting clotting. The only FDA-approved ischemic stroke therapy, tPA has been underutilized because it can worsen hemorrhagic stroke. The team demonstrated that tPA also restored neuronal connections after damage through affecting EGFR signaling. "Functional restoration was independent of tPA's proteolytic activity – a mutant, protease-inactive form of tPA, tPA-S478A, was as effective as regular tPA," the authors wrote. "Results of our preclinical studies support the view that tPA-S478A has the therapeutic potential to enhance brain regeneration and functional restoration in stroke victims. Unlike regular tPA, tPA-S478A does not bear the risk of inducing intracerebral hemorrhage." They published their findings in the April 17, 2019, issue of the Proceedings of the National Academy of Sciences.

Signature matching for PARP inhibitors

Homologous recombination (HR) DNA repair defects, which sensitize cells to PARP inhibitors, can most famously result from BRCA deficiencies. But there are other mutations that lead to HR deficiencies as well, and in some cases, cells can have HR deficiencies without mutations in any of the genes known to cause such deficiencies. Researchers at Harvard Medical School have developed an algorithm that could detect the telltale signature of HR from targeted sequencing samples. Current analytic methods require whole genome or whole exome data to detect HR, but the Signature Multivariate Analysis (SigMA) computational method "detects the HR-deficiency signature even from low mutation counts, by using a likelihood-based measure combined with machine-learning techniques," the authors wrote. The team showed that HR-deficient cell lines identified were sensitive to PARP inhibitors, and ovarian cancer patients identified by the method responded better to platinum-based chemotherapy. The authors concluded that "our method substantially increases the number of patients that may be considered for treatments targeting HR deficiency." Their work appeared in the April 15, 2019, issue of Nature Genetics.

Why PD-1 isn't CTLA4

The checkpoint molecule PD-1 is expressed on T cells throughout their life, but PD-1 and PD-L1 targeting does not affect the activation of T cells, as CTLA4 checkpoint blockers do. Researchers at Tokushima University have demonstrated that during the activation phase of T cells, PD-L1 expressed on antigen-presenting cells (APCs) interacted with another surface molecule, CD80, that was also expressed by the APCs (called cis). The interaction between the two molecules prevented PD-L1 from interacting with PD-1 and inhibiting T-cell activity in early stages of T-cell activation. "Using knock-in mice where cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1," the authors wrote. "Targeted manipulation of cis-PD-L1/CD80 interactions might therefore lead to new therapeutic opportunities for the treatment of cancer, autoimmune diseases and chronic inflammation." The team reported its findings in the April 19, 2019, issue of Science.

Melanocortin receptor signaling can cut both ways in obesity

Researchers from the University of Cambridge have gained new insights into signaling of melanocortin 4 receptor (MC4R) and how it relates to body mass index (BMI). Loss of function of the MC4R, a G protein-coupled receptor (GPCR), causes obesity. However, by investigating MC4R sequence and function in UK Biobank samples of roughly half a million individuals, the researchers were able to identify more than 60 variants. Many of those variants predisposed their owners to increased BMI via GPCR-based signaling. But the team also showed that four of those variants caused gain-of-function signaling via a different pathway, the beta-arrestin pathway, and gain-of-function variants "were associated with significantly lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease," the authors wrote. "Harnessing beta-arrestin biased MC4R signaling may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases." They published their results in the April 18, 2019, issue of Cell.

'Protein intron' is basis for selective antibiotic

A team from the Institut Pasteur has engineered an antibacterial toxin that specifically killed antibiotic-resistant Vibrio cholerae bacteria in mixed populations of drug-resistant and drug-sensitive populations. The team designed plasmids that each contained two separate halves of a toxin combined with two separate halves of an "intein," the protein version of an intron. Inteins can be spliced out of proteins after translation. The plasmids were active only in the presence of transcription factors specific to drug-resistant V. cholerae. The team demonstrated that their plasmids were able to express the two halves of the toxin, which were joined and activated by the intein, to selectively kill V. cholerae in the microbiota of two of its natural hosts, zebrafish and crustacean larvae. "Targeted killing of pathogenic bacteria without harming beneficial members of host microbiota holds promise as a strategy to cure disease and limit both antimicrobial-related dysbiosis and development of antimicrobial resistance," the authors wrote. "Toxins split with inteins could form the basis of precision antimicrobials to target pathogens that are antibiotic resistant." Their work was published in the April 15, 2019, issue of Nature Biotechnology.

Glycosylation controls proteasome activity via sequence editing

Proteasome activity is an important general cellular housekeeping mechanism, and its dysfunction has been implicated in aging in general and in neurodegeneration and cancer in particular. Previous work has shown that the glycosylation status of a protein called SKN-1 was important for proteasome function in C. elegans. Now, researchers from Massachusetts General Hospital have shown that the glycosylation status was important because it served as a signal for amino acid editing. "Deglycosylation dependent protein sequence editing explains how ER-associated and cytosolic isoforms of SKN-1 perform distinct cytoprotective functions corresponding to those of mammalian Nrf1 and Nrf2," the authors concluded. "Our data support the hypothesis that boosting proteasome levels via Nrf1 can enhance proteostasis and may be a useful approach for treatment of neurodegenerative diseases." They reported their findings in the April 18, 2019, issue of Cell.

Parkinson's drug inhibits obesity gene

Researchers from the Chinese National Institute of Biological Sciences and the Beijing Institute of Genomics have identified the FDA-approved drug entacapone as an inhibitor of FTO protein. The fat mass and obesity gene, which codes for FTO, has been identified as involved with body mass through genome-wide association studies, and FTO protein appears to affect metabolism in multiple organs, including the brain, the liver and fat tissue. The researchers "used a structure-based virtual screening of U.S. Food and Drug Administration–approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice," by directly interacting with the transcription factor forkhead box protein O1 (FOXO1). The team reported their results in the April 17, 2019, issue of Science Translational Medicine.

Strengthening muscle cell production

Scientists at the Sanford Burnham Prebys Medical Discovery Institute have identified a signaling pathway that controlled the fate decisions of muscle stem cells. Stem cells can either self-renew to replenish the stem cell reservoir of their tissue, or differentiate into mature cells. As organisms age, cells become replenished less efficiently, and approximately 10% of the elderly have sarcopenia or muscle wasting. Wasting can be hastened by diseases such as cancer, and muscular dystrophies are a group of several dozen genetic diseases characterized by muscle wasting as a result of various mutations. In their work, the team identified the transcription factor Stat3 and its regulation of Fam3 as critical for the generation of new muscle cells from stem cells. "Fam3a is a Stat3-regulated secreted factor that promotes muscle stem cell oxidative metabolism and differentiation, and suggests that Fam3a is a potential tool to modulate cell fate choices," the authors wrote. They reported their findings in the April 17, 2019, issue of Nature Communications.

Opioids impervious to GLP-1 agonists

Analogues of glucagon-like peptide 1 (GLP-1) are diabetes medications, and previous studies have shown they could also reduce the reinforcing and rewarding effects of alcohol, cocaine, amphetamine and nicotine in rodents. Now, however, researchers from the University of Copenhagen have shown that they were ineffective in affecting the response to opioids. The team tested exendin-4, a GLP-1 agonist whose synthetic form exenatide is an FDA-approved diabetes medication, in rodent models of opioid addiction. "Ex4 did not attenuate the addiction-related behavioral effects of opioids, indicating that GLP-1 analogs would not be useful medications in the treatment of opioid addiction," the authors wrote. "This difference between opioids and other drug classes investigated to date may shed light on the mechanism of action of GLP-1 receptor treatment in the addictive effects of alcohol, central 65 stimulants, and nicotine." Their findings appeared in the April 8, 2019, issue of eneuro.

Targeting FATP2 tames myeloid suppressor cells

In tumor immune interactions, myeloid suppressor cells are among the bad guys – their activity suppresses immune responses, including those activated by checkpoint inhibition, and promotes tumor progression and metastasis. Scientists at The Wistar Institute have demonstrated that those activities were due to up-regulation of fatty acid transporter protein 2 (FATP2), which reprogrammed the cells through mechanisms that involved the uptake of arachidonic acid and the synthesis of prostaglandin E2. The "FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy," the authors wrote. Their work appeared in the April 18, 2019, issue of Nature.

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