No abstract

The widely recognized neuroprotective effect of iron chelators is contributed by their ability to prevent reactive oxygen species (ROS) generation via the Fenton reaction, which sequesters redox-active Fe. An additional neuroprotective mechanism of iron-chelating compounds is to regulate the transcriptional activator hypoxia-inducible factor 1α (HIF-1α). In the present study, we observed that intranasal administration of deferoxamine decreased beta-amyloid (Aβ) deposition and rescued synapse loss in the brain of Aβ precursor protein and presenilin-1 (APP/PS1) double transgenic mice. We found that deferoxamine (DFO) up-regulated HIF-1α mRNA expression and its protein level, and further induced the proteins that are encoded from HIF-1-adaptive genes, including transferrin receptor (TFR), divalent metal transporter 1 (DMT1), and brain-derived neurotrophic factor (BDNF). The effects of DFO on the induction and stabilization of HIF-1α were further confirmed in vitro. This was accompanied by a decrease of Fe in the CA3 region of the hippocampus. Western blotting studies revealed that DFO differentially enhanced the phosphorylation of mitogen-activated protein kinase (MAPK)/P38 kinase in vitro and in vivo. The results suggest that the DFO may up-regulate several HIF-1-dependent neuroprotective-adaptive genes in AD via activating P38/HIF-1α pathway, which may serve as important therapeutic targets to the disease.

Pathogens and hosts require rapid modulation of virulence and defense mechanisms at the infection axis, but monitoring such modulations is challenging. In studying the human fungal pathogen Cryptococcus neoformans , mouse and rabbit infection models are often employed to shed light on the disease mechanisms but that may not be clinically relevant. In this study, we developed an animal infection model using the non-human primate cynomolgus monkey Macaca fascicularis . In addition, we systematically profiled and compared transcriptional responses between the infected mice and the cynomolgus monkey, using simultaneous or dual RNA next-generation sequencing. We demonstrated that there are shared but distinct transcriptional profiles between the two models following C . neoformans infection. Specifically, genes involved in immune and inflammatory responses are all upregulated. Osteoclastogenesis and insulin signaling are also significantly co-regulated in both models and disrupting an osteoclastogenesis-associated gene (OC-STAMP) or the insulin-signaling process significantly altered the host tolerance to C . neoformans . Moreover, C . neoformans was shown to activate metal sequestration, dampen the sugar metabolism, and control cell morphology during infection. Taking together, we described the development of a non-human primate model of cryptococcosis that allowed us to perform an in-depth analysis and comparison of transcriptome profiles during infections of two animal models and conceptually identify host genes important in disease responses. This study provides new insights in understanding fungal pathogenesis mechanisms that potentially facilitate the identification of novel drug targets for the treatment of cryptococcal infection.

No abstract

Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity. Here, we compare the acetylomes of baker’s yeast and the three deadliest human fungal pathogens, Cryptococcus neoformans , Candida albicans , and Aspergillus fumigatus . Using mass spectrometry enriched for acetylated peptides together with public data from Saccharomyces cerevisiae , we show that fungal acetylomes are characterized by dramatic evolutionary dynamics and limited conservation in core biological processes. Notably, the levels of protein acetylation in pathogenic fungi correlate with their pathogenicity. Using gene knockouts and pathogenicity assays in mice, we identify deacetylases with critical roles in virulence and protein translation elongation. Finally, through mutational analysis of deactylation motifs we find evidence of positive selection at specific acetylation motifs in fungal pathogens. These results shed new light on the pathogenicity regulation mechanisms underlying the evolution of fungal acetylomes.

Human chromosome 20q12-13.1 has been linked to type 2 diabetes mellitus (T2DM) in multiple studies. We screened a 5.795Mb region for diabetes-related susceptibility genes in a Caucasian cohort of 310 controls and 300 cases with T2DM and end stage renal disease (ESRD), testing 390 SNPs for association with T2DM-ESRD. The most significant SNPs were found in the perigenic regions, HNF4A (hepatocyte nuclear factor 4-alpha), SLC12A5 (potassium-chloride cotransporter member 5), CDH22 (cadherin-like 22), ELMO2 (engulfment and cell motility 2), SLC13A3 (sodium-dependent dicarboxylate transporter member 3), and PREX1 (phosphatidylinositol 3,4,5-triphosphate-dependent RAC exchanger 1). Haplotype analysis found 6 haplotype blocks globally associated with disease (p<0.05). We replicated the PREX1 SNP association in an independent case control T2DM population, and inferred replication of CDH22, ELMO2, SLC13A3, SLC12A5, and PREX1 using in silico perigenic analysis of two T2DM genome wide association study (GWAS) data sets. We found substantial heterogeneity between study results.

Tauopathies refer to a group of neurodegenerative disorders caused by the accumulation of insoluble hyperphosphorylated Tau protein in the brain. The inhibition and interruption of Tau aggregation are considered important strategies to ameliorate the neurodegenerative process. Previous work has shown that hexapeptide 306VQIVYK311 (PHF6) located in the repeat domain 3 of Tau protein drives Tau aggregation and itself forms a β-sheet structure similar to those of Tau-oligomers and neurofibrillary tangles (NFTs). In this study, a mirror image phage display technology was used to screen protease-resistant and low-immunogenic d-enantiomeric peptides for their capacity to inhibit Tau aggregation. Following the preparation of d-enantiomeric PHF6 fibrils and M13 phage peptide library biopanning, 7 sets of high specificity peptides were obtained. Through ELISA and competition inhibition assays, we chose a highly specific peptide p-NH with the sequence N-I-T-M-N-S-R-R-R-R-N-H. The molecular docking results showed that p-NH interacted with PHF6 fibrils mainly through van der Waals forces and hydrogen bonding and could inhibit PHF6 aggregation in a d-configuration and concentration-dependent manner. In vitro, p-NH prohibited the formation of PHF6 fibrils and was able to enter into mouse neuroblastoma N2a cells (N2a cells) to inhibit Tau hyperphosphorylation and aggregation. Intranasal administration of p-NH reduced NFTs and improved the cognitive ability of TauP301S transgenic mice. These findings represent a straightforward methodology to find therapeutic peptides with potential applications in tauopathies.

PZn screen from phage display technique and PZn loaded nanoparticles inhibiting Aβ aggregation and neurotoxicity in vitro and in vivo.