Prostaglandin E2 Stimulates the Expansion of Regulatory Hematopoietic Stem and Progenitor Cells in Type 1 Diabetes

Hematopoietic stem and progenitor cells (HSPCs) are multipotent stem cells that have been harnessed as a curative therapy for patients with hematological malignancies. Notably, the discovery that HSPCs are endowed with immunoregulatory properties suggests that HSPC-based therapeutic approaches may be used to treat autoimmune diseases. Indeed, infusion with HSPCs has shown promising results in the treatment of type 1 diabetes (T1D) and remains the only “experimental therapy” that has achieved a satisfactory rate of remission (nearly 60%) in T1D. Patients with newly diagnosed T1D have been successfully reverted to normoglycemia by administration of autologous HSPCs in association with a non-myeloablative immunosuppressive regimen. However, this approach is hampered by a high incidence of adverse effects linked to immunosuppression. Herein, we report that while the use of autologous HSPCs is capable of improving C-peptide production in patients with T1D, ex vivo modulation of HSPCs with prostaglandins (PGs) increases their immunoregulatory properties by upregulating expression of the immune checkpoint-signaling molecule PD-L1. Surprisingly, CXCR4 was upregulated as well, which could enhance HSPC trafficking toward the inflamed pancreatic zone. When tested in murine and human in vitro autoimmune assays, PG-modulated HSPCs were shown to abrogate the autoreactive T cell response. The use of PG-modulated HSPCs may thus provide an attractive and novel treatment of autoimmune diabetes

Impact of rapid urbanization on the surface water's quality: a long-term environmental and physicochemical investigation of Tajan river, Iran (2007-2017)

Sustainable development of our society requires protection and monitoring of aquatic environments, as they are the pivotal water resources and niche for wildlife animals. In this research, physicochemical parameters of Tajan river's water were determined and compared with standards to assess the rural and human activity impact on water quality. First, monitoring and analyzing the water quality of the river were performed for 11 years (from 2007 to 2017). Based on calculated water quality index (WQI) values, Tajan river's water quality falls into four categories: good water with WQI less than 30 at upstream and middle of the river, poor water, and very poor to even unsuitable water (WQI ranges from 86 to 134) at the more urbanized locations. The high values of WQI are due to an elevated concentration of sulfate, nitrate, total dissolved solids (TDS), and chloride substances. The source of contaminations, according to the geochemistry of the area and having more than 90% growth rate in the population near to the most polluted location, is probably anthropogenic activities. Then, the long-term experimental data set has been utilized for developing a statistical model to be used for prediction of water quality with a few chemical analyses, generating a rapid and low-cost water quality evaluation for this river. The model was developed based on the stepwise multiple linear regression (MLR) approach and confirmed the experimental observation data of the most defective elements on WQI were respectively SO4, NO3, TDS, Cl, pH, and EC. This study presents a long-term evaluation of changes in surface water quality at a region with a recent rapid urban and civil development providing a suitable case to understand better human-water relations

Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy

Cardiovascular disorders are one of the leading causes of mortality and morbidity worldwide. Recent advances showed a promising role of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a critical player in regulating plasma LDL levels and lipid metabolism

Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy

Cardiovascular disorders are one of the leading causes of mortality and morbidity worldwide. Recent advances showed a promising role of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a critical player in regulating plasma LDL levels and lipid metabolism

The Association of Proprotein Convertase Subtilisin/Kexin Type 9 to Plasma Low-Density Lipoproteins: An Evaluation of Different Methods

Background: Proprotein convertase subtilisin/kexin type-9 (PCSK9) is key regulator of low-density lipoprotein (LDL) metabolism. A significant proportion of PCSK9 is believed to be associated with LDL in plasma as it circulates, although this finding is still a matter of debate. The purpose of this study was to establish an experimental method to investigate the presence of such an interaction in the bloodstream. Methods: We compared a number of well-established methods for lipoprotein (LP) isolation to clarify whether PCSK9 associates differently to circulating lipoproteins, such as KBr gradient ultracentrifugation, physical precipitation of ApoB-LPs, fast protein liquid chromatography (FPLC) and iodixanol gradient ultracentrifugation. Results: Our data show heterogeneity in PCSK9 association to lipoproteins according to the method used. Two methods, iodixanol ultracentrifugation and column chromatography, which did not involve precipitation or high salt concentration, consistently showed an interaction of PCSK9 with a subfraction of LDL that appeared to be more buoyant and have a lower size than average LDL. The percent of PCSK9 association ranged from 2 to 30% and did not appear to correlate to plasma or LDL cholesterol levels. Conclusions: The association of PCSK9 to LDL appeared to be sensitive to high salt concentrations. FPLC and iodixanol gradient ultracentrifugation appeared to be the most suitable methods for the study of this association

Additional file 1 of Enhanced molecular release from elderly bone samples using collagenase I: insights into fatty acid metabolism alterations

Additional file 1: Fig. S1. The SANIST AI-QC pipeline. Fig. S2. Fellowchart presentation of metabolite extraction in different experimental groups. Internal controls were added before the addition of first solvent for each group. Fig. S3. Data validation examples with locally constructed library in NIST software platform. The query molecules are in red, and the best match found in the library is in blue. Table S1. Functional Enrichment analysis for the modified metabolic pathways according to the identified metabolites according to similarity with HDMB. Table S2. Enrichment analysis for the pool of identified molecules’ chemical types. Table S3. Statistical comparison of cortical and trabecular bone metabolites extracted with different methods

Copper, Nickel, and Zinc Cyclam–Amino Acid and Cyclam–Peptide Complexes May Be Synthesized with “Click” Chemistry and Are Noncytotoxic

We describe the synthesis of cyclam metal complexes derivatized with amino acids or a tripeptide using a copper(I)-catalyzed Huisgen “click” reaction. The linker triazole formed during the synthesis plays an active coordinating role in the complexes. The reaction conditions do not racemize the amino acid stereocenters. However, a methylene group adjacent to the triazole is susceptible to H/D exchange under ambient conditions, an observation which has potentially important implications for structures involving stereocenters adjacent to triazoles in click-derived structures. The successful incorporation of several amino acids is described, including reactive tryptophan and cysteine side chains. All complexes are formed rapidly upon introduction of the relevant metal salt, including synthetically convenient cases where trifluoroacetate salts of cyclam derivatives are used directly in the metalation. None of the metal complexes displayed any cytotoxicity to mammalian cells, suggesting that the attachment of such complexes to amino acids and peptides does not induce toxicity, further supporting their potential suitability for labeling/imaging studies. One Cu­(II)–cyclam–triazole–cysteine disulfide complex displayed moderate activity against MCF-10A breast nontumorigenic epithelial cells