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Francisco Pan-Montojo Oleg Anichtchik Yanina Dening Lilla Knels Stefan Pursche Roland Jung Sandra Jackson Gabriele Gille Maria Grazia Spillantini Heinz Reichmann Richard H. W. Funk 《PloS one》2010,5(1)
In patients with Parkinson''s disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system. 相似文献
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Pasquale Ferranti Sergio Lilla Lina Chianese Francesco Addeo 《The protein journal》1999,18(5):595-602
Multiple forms of αs1-casein were identified in the four major ruminant species by structural characterization of the protein fraction. While αs1-casein phenotypes were constituted by a mixture of at least seven molecular forms in ovine and caprine species, there were only two forms in bovine and water buffalo species. In ovine and caprine forms the main component corresponded to the 199-residue-long form, and the deleted proteins differed from the complete one by the absence of peptides 141–148, 110–117, or Gln78, or a combination of such deletions. The deleted segments corresponded to the sequence regions encoded by exons 13 and 16, and by the first triplet of exon 11 (CAG), suggesting that the occurrence of the short protein forms is due to alternative skipping, as previously demonstrated for some caprine and ovine phenotypes. The alternative deletion of Gln78 in αs1-casein, the only form common to the milk of all the species examined and located in a sequence region joining the polar phosphorylation cluster and the hydrophobic C-terminal domain of the protein, may play a functional role in the stabilization of the milk micelle structure. 相似文献
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Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS 总被引:2,自引:0,他引:2
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Manuel de Lera Ruiz Junying Zheng Michael Y. Berlin Kevin D. McCormick Robert G. Aslanian Robert West Joyce Hwa Jean Lachowicz Margaret van Heek 《Bioorganic & medicinal chemistry letters》2013,23(21):6004-6009
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test. 相似文献
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Martina Wendel Anna Petzold Roland Koslowski Michael Kasper Antje Augstein Lilla Knels Jörg-Uwe Bleyl Thea Koch 《Histochemistry and cell biology》2000,122(5):507-517
Pulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ETB receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ETA and ETB receptor mRNA, and ETA receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ETA nor ETB receptor mRNA which were also not induced by bleomycin. We conclude that, while ETB receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ETA receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement. 相似文献
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