Ursolic acid impairs cellular lipid homeostasis and lysosomal membrane integrity in breast carcinoma cells

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cells11244079/s1, Figure S1: UA kills MCF7 cells partly through apoptosis; Figure S2: UA causes LC3 puncta formation in MCF7 and HCT15 cells; Figure S3: UA causes LMP prior to MOMP and alters lysosomal localization in HeLa cells; Figure S4: Additional lipidomics data; Table S1: List of resources; Table S2: Internal lipid and drug standards; Table S3: Precursor ion, fragment ion, and neutral loss for lipid identification; Table S4: All experiments.Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms. In this report, we identify lysosomes as the essential targets of the anti-cancer activity of ursolic acid. The treatment of MCF7 breast cancer cells with ursolic acid elevates lysosomal pH, alters the cellular lipid profile, and causes lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol. Lysosomal membrane permeabilization precedes the essential hallmarks of apoptosis placing it as an initial event in the cascade of effects induced by ursolic acid. The disruption of the lysosomal function impairs the autophagic pathway and likely partakes in the mechanism by which ursolic acid kills cancer cells. Furthermore, we find that combining treatment with ursolic acid and cationic amphiphilic drugs can significantly enhance the degree of lysosomal membrane permeabilization and cell death in breast cancer cells.This work was supported by grants from the Danish National Research Foundation (DNRF125), European Research Council (AdG340751), Danish Cancer Society (R167-A11061) and, Novo Nordisk Foundation (NNF19OC0054296), to M.J., K.M. was supported by the Independent Research Fund Denmark (6108–00542B) and Novo Nordisk Foundation (NNF17OC0029432).info:eu-repo/semantics/publishedVersio

Contribution of Pollinator-Mediated Crops to Nutrients in the Human Food Supply

The contribution of nutrients from animal pollinated world crops has not previously been evaluated as a biophysical measure for the value of pollination services. This study evaluates the nutritional composition of animal-pollinated world crops. We calculated pollinator dependent and independent proportions of different nutrients of world crops, employing FAO data for crop production, USDA data for nutritional composition, and pollinator dependency data according to Klein et al. (2007). Crop plants that depend fully or partially on animal pollinators contain more than 90% of vitamin C, the whole quantity of Lycopene and almost the full quantity of the antioxidants β-cryptoxanthin and β-tocopherol, the majority of the lipid, vitamin A and related carotenoids, calcium and fluoride, and a large portion of folic acid. Ongoing pollinator decline may thus exacerbate current difficulties of providing a nutritionally adequate diet for the global human population

Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10−8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (Pcombined = 1.2×10−12), rs864537 near CD247 (Pcombined = 2.2×10−11), rs2298428 near UBE2L3 (Pcombined = 2.5×10−10), and rs11203203 near UBASH3A (Pcombined = 1.1×10−8). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10−8 (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases

To be financed or not : the role of patents for venture capital financing

This paper investigates how patent applications and grants held by new ventures improve their ability to attract venture capital (VC) financing. We argue that investors are faced with considerable uncertainty and therefore rely on patents as signals when trying to assess the prospects of potential portfolio companies. For a sample of VC-seeking German and British biotechnology companies we have identified all patents filed at the European Patent Office (EPO). Applying hazard rate analysis, we find that in the presence of patent applications, VC financing occurs earlier. Our results also show that VCs pay attention to patent quality, financing those ventures faster which later turn out to have high-quality patents. Patent oppositions increase the likelihood of receiving VC, but ultimate grant decisions do not spur VC financing, presumably because they are anticipated. Our empirical results and interviews with VCs suggest that the process of patenting generates signals which help to overcome the liabilities of newness faced by new ventures

Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (“concordant”) direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive (“discordant”) relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms—early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways—that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.Peer reviewe

Cognitive and Socio-Emotional Deficits in Platelet-Derived Growth Factor Receptor-β Gene Knockout Mice

Platelet-derived growth factor (PDGF) is a potent mitogen. Extensive in vivo studies of PDGF and its receptor (PDGFR) genes have reported that PDGF plays an important role in embryogenesis and development of the central nervous system (CNS). Furthermore, PDGF and the β subunit of the PDGF receptor (PDGFR-β) have been reported to be associated with schizophrenia and autism. However, no study has reported on the effects of PDGF deletion on mice behavior. Here we generated novel mutant mice (PDGFR-β KO) in which PDGFR-β was conditionally deleted in CNS neurons using the Cre/loxP system. Mice without the Cre transgene but with floxed PDGFR-β were used as controls. Both groups of mice reached adulthood without any apparent anatomical defects. These mice were further examined by conducting several behavioral tests for spatial memory, social interaction, conditioning, prepulse inhibition, and forced swimming. The test results indicated that the PDGFR-β KO mice show deficits in all of these areas. Furthermore, an immunohistochemical study of the PDGFR-β KO mice brain indicated that the number of parvalbumin (calcium-binding protein)-positive (i.e., putatively γ-aminobutyric acid-ergic) neurons was low in the amygdala, hippocampus, and medial prefrontal cortex. Neurophysiological studies indicated that sensory-evoked gamma oscillation was low in the PDGFR-β KO mice, consistent with the observed reduction in the number of parvalbumin-positive neurons. These results suggest that PDGFR-β plays an important role in cognitive and socioemotional functions, and that deficits in this receptor may partly underlie the cognitive and socioemotional deficits observed in schizophrenic and autistic patients