Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by the loss of nigral dopaminergic neurons leading to impaired striatal dopamine signaling, α-synuclein- (α-syn-) rich inclusions, and neuroinflammation. Degenerating neurons are surrounded by activated microglia with increased secretion of interleukin-1ß (IL-1ß), driven largely by the NLRP3 inflammasome. A critical role for microglial NLRP3 inflammasome activation in the progression of both dopaminergic neurodegeneration and α-syn pathology has been demonstrated in parkinsonism mouse models. Fibrillar α-syn activates this inflammasome in mouse and human macrophages, and we have shown previously that the same holds true for primary human microglia. Dopamine blocks microglial NLRP3 inflammasome activation in the MPTP model, but its effects in this framework, highly relevant to PD, remain unexplored in primary human microglia and in other in vivo parkinsonism models. METHODS: Biochemical techniques including quantification of IL-1ß secretion and confocal microscopy were employed to gain insight into dopamine signaling-mediated inhibition of the NLRP3 inflammasome mechanism in primary human microglia and the SYN120 transgenic mouse model. Dopamine and related metabolites were applied to human microglia together with various inflammasome activating stimuli. The involvement of the receptors through which these catecholamines were predicted to act were assessed with agonists in both species. RESULTS: We show in primary human microglia that dopamine, L-DOPA, and high extracellular K+, but not norepinephrine and epinephrine, block canonical, non-canonical, and α-syn-mediated NLRP3 inflammasome-driven IL-1ß secretion. This suggests that dopamine acts as an inflammasome inhibitor in human microglia. Accordingly, we provide evidence that dopamine exerts its inhibitory effect through dopamine receptor D1 and D2 (DRD1 and DRD2) signaling. We also show that aged mice transgenic for human C-terminally truncated (1-120) α-syn (SYN120 tg mice) display increased NLRP3 inflammasome activation in comparison to WT mice that is diminished upon DRD1 agonism. CONCLUSIONS: Dopamine inhibits canonical, non-canonical, and α-syn-mediated activation of the NLRP3 inflammasome in primary human microglia, as does high extracellular K+. We suggest that dopamine serves as an endogenous repressor of the K+ efflux-dependent microglial NLRP3 inflammasome activation that contributes to dopaminergic neurodegeneration in PD, and that this reciprocation may account for the specific vulnerability of these neurons to disease pathology.

Pea peels as a value-added food ingredient for snack crackers and dry soup.

The food industry produces large quantities of waste, which is available in bulk at zero cost. This study aimed to investigate a new method to maximize the protein intake from pea peels and its further utilization as a value-added food ingredient to produce healthy snack crackers and dry soup. Dehydrated green curd of pea peel (DGCPp) with high protein content (35%) was prepared and incorporated into snack cracker and instant soup powder. Wheat flour was substituted with DGCPp to prepare crackers at three substitution levels (5, 10, and 15%) compared to the cracker control sample (100% wheat flour). Increasing the level of this substitution improved the nutritional value of crackers, with highest protein content was in DGCPp crackers (15%). Crackers also had higher contents of mineral and essential amino acids. The physicochemical and sensorial properties of soup samples were significantly influenced by the addition of DGCPp. Higher rehydration value and mineral content (Ca, Mg, Fe, and Zn) were observed in DGCPp soup samples compared to the control sample. Soup samples of all proportions were more acceptable by all the panelists compared with the control sample. With these findings, it can be concluded that DGCPp can be utilized in a variety of food products (such as crackers and soups) with higher nutritive values.

Cytotoxic effects of persistent organic pollutants on the freshwater snail (Lanistes carinatus) in Kafr El-Zayat, Egypt.

Effects of industrial and municipal wastewaters on the freshwater snail, Lanistes carinatus, were evaluated. Concentrations of some chemicals in some effluents were greater than permissible limits promulgated internationally by various jurisdictions. Pesticides and polychlorinated biphenyls (PCBs) observed in tissues of snails collected during summer were greater than those measured in snails collected during winter. Catalase activities observed during autumn were greater than those observed during other seasons. Activities of catalase were greater at all sites near sources of contamination than in snails from the reference site (S6). Lactate dehydrogenase activity was also greater at all sites relative to the location designated as the reference (S6), at which activities did not exceed 8.10 U/L. Patterns of genomic DNA in snails, as determined by use of OPA-02 primer, were significantly different among sites. Location S1 (Belshay village) exhibited 11 bands, followed by S2 (El-Demer zone) and S5 (Rosetta branch) which exhibited 6 bands. In contrast, all sites exhibited greater numbers of bands when the OPA-08 primer was used. Thus, DNA fingerprinting, lactate dehydrogenase, and catalase offer useful biomarkers in ecotoxicology and risk assessment programs.

Histological and ultrastructural studies of oogenesis in the sea-urchin Paracentrotus lividus.

Changes in the fine structure of growing female germ cells of Paracentrotus lividus and the sequence of their stages were examined by the light and the electron microscope. The investigation showed that, in the previtellogenic stage, the cytoplasm contained numerous vacuoles and few yolk granules. In the vitellogenic stage, the number of yolk granules increased and, as the oocytes attained maturity, the cytoplasms became packed with yolk. The structure of the nutritive phagocytes is also described and their relationship to the developing oocytes is discussed.