1. Urine metabolites associated with cardiovascular effects from exposure of size-fractioned particulate matter in a subway environment: A randomized crossover study
Furong Deng, Xuan Yang, Wenlou Zhang, Xu Jia, Jingyi Zhang, Dayu Hu, Yannan Zhang, Zhiwei Sun, Mengtian Chu, Junchao Duan Environ Int . 2019 Sep;130:104920. doi: 10.1016/j.envint.2019.104920.
Background:Ambient particulate matter (PM) is closely associated with morbidity and mortality from cardiovascular disease. Urine metabolites can be used as a non-invasive means to explore biological mechanisms for such associations, yet has not been performed in relation to different sizes of PM. In this randomized crossover study, we used metabolomics approach to explore the urine biomarkers linked with cardiovascular effects after PM exposure in a subway environment.Methods and results:Thirty-nine subjects were exposed to PM for 4 h in subway system, with either a respirator intervention phase (RIP) with facemask and no intervention phase (NIP) in random order with a 2-week washout period. Electrocardiogram (ECG) parameters and ambulatory blood pressure (BP) were monitored during the whole riding period and urine samples were collected for metabolomics analysis. After exposure to PM for 4 h in subway system, 4 urine metabolites in male and 7 urine metabolites in female were screened out by UPLC/Q-TOF MS/MS-based metabolomics approach. Cardiovascular parameters (HRV and HR) predominantly decreased in response to all size-fractions of PM and were more sensitive in response to different size-fractioned PM in males than females. Besides LF/HF, most of the HRV indices decrease induced by the increase of all size-fractioned PM while PM1.0was found as the most influential one on indicators of cardiovascular effects and urine metabolites both genders. Prolyl-arginine and 8-OHdG were found to have opposing role regards to HRV and HR in male.Conclusion:Our data indicated that short-term exposure to PM in a subway environment may increase the risk of cardiovascular disease as well as affect urine metabolites in a size dependent manner (besides PM0.5), and male were more prone to trigger the cardiovascular events than female after exposure to PM; whereas wearing facemask could effectively reduce the adverse effects caused by PM.
2. A new non-natural arginine-like amino acid derivative with a sulfamoyl group in the side-chain
Rosaria De Marco, Carlo Siciliano, Angelo Liguori, Francesca Perri, Maria L Di Gioia, Antonella Leggio, Maria C Viscomi Amino Acids . 2010 Mar;38(3):691-700. doi: 10.1007/s00726-009-0267-2.
Sulfamoylation of the L-ornithine methyl ester side-chain generates a non-natural arginine isostere which can be coupled with N-Fmoc-L-proline to synthesize analogues which maintain the structural characteristics of the biologically important Pro-Arg dipeptide sequence. As a probe of its biological importance, the sulfamoylated amino acid derivative was also incorporated as P1 residue in tripeptide structures matching the C-terminal subsequence of fibrinogen. The reported results demonstrate that the functionalization of L-ornithine side-chain with a neutral sulfamoyl group can generate an arginine bioisostere which can be used for the synthesis of prototypes of a new class of human thrombin inhibitors.
3. Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity
Lillian M Daughrity, John D Fryer, Jeannie Chew, Dennis W Dickson, Martin Kampmann, Aishe Kurti, Aliesha D O'Raw, Sarah R Pickles, Rosa Rademakers, Mei Yue, Michael E Ward, Mariam A Gachechiladze, Yari Carlomagno, Christopher D Link, Tania F Gendron, Yanwei Wu, Yong-Jie Zhang, James Shorter, Yuping Song, Leonard Petrucelli, Connor Ludwig, Wen-Lang Lin, Alexander McCampbell, Lin Guo, Karen Jansen-West, Michael DeTure, Monica Castanedes-Casey, Abhishek Datta, Giovanna Antognetti, Ruilin Tian, Jimei Tong, Jonathan W Andersen, Björn Oskarsson, Patrick K Gonzales, Mercedes Prudencio Science . 2019 Feb 15;363(6428):eaav2606. doi: 10.1126/science.aav2606.
How hexanucleotide GGGGCC (G4C2) repeat expansions inC9orf72cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G4C2repeats. The expression of green fluorescent protein-conjugated (PR)50(a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis ofC9orf72-associated FTD and ALS.
