TNF-α derived from arsenite-induced microglia activation mediated neuronal necroptosis.

Arsenic, an identified environmental toxicant, poses threats to the health of human beings through contaminated water and food. Recently, increasing reports focused on arsenic-induced nerve damage, however, the underlying mechanism remains elusive. Microglia are important immune cells in the nervous system, which produce a large number of inflammatory factors including TNF-α when activated. Recent reports indicated that TNF-α is involved in the process of necroptosis, a new type of programmed cell death discovered recently. Although there were evidences suggested that arsenic could induce both microglia activation and TNF-α production in the nervous system, the mechanism of arsenic-induced neurotoxicity due to microglia activation is rarely studied. In addition, the role of microglia-derived TNF-α in response to arsenic exposure in necroptosis has not been documented before. In this study, we found that arsenite induced microglial activation through p38 MAPK signaling pathway, leading to the production of TNF-α. Microglia-derived TNF-α further induced necroptosis in the neuronal cells. Our findings suggested that necroptosis induced by microglia-derived TNF-α upon arsenite exposure partially played a role in arsenic-induced cell death which underlie the fundamental event of arsenic-related neurotoxicity.

Trophodynamics of Emerging Brominated Flame Retardants in the Aquatic Food Web of Lake Taihu: Relationship with Organism Metabolism across Trophic Levels.

Despite the increasing use and discharge of novel brominated flame retardants, little information is available about their trophodynamics in the aquatic food web, and their subsequent relationships to compound metabolism. In this study, concentrations of 2,4,6-tribromophenyl allyl ether (ATE), 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH), tetrabromo- o-chlorotoluene (TBCT), pentabromobenzyl acrylate (PBBA), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), bis(2-ethylhexyl)-3,4,5,6-tetrabromo-phthalate (TBPH), and decabromodiphenyl ethane (DBDPE) were measured in 17 species, including plankton, invertebrates, and fish from Lake Taihu, South China. Trophodynamics of the compounds were assessed, and metabolic rates were measured in the liver microsomes of crucian (trophic level [TL]: 2.93), catfish (TL: 3.86), and yellow-head catfish (TL: 4.3). Significantly positive relationships were found between trophic levels and lipid-normalized concentrations of ATE, BTBPE, and TBPH; their trophic magnification factors (TMFs) were 2.85, 2.83, and 2.42, respectively. Consistently, the three chemicals were resistant to metabolism in all fish microsomes. No significant relationship was observed for ßTBECH ( p = 0.116), and DBDPE underwent trophic dilution in the food web (TMFs = 0.37, p = 0.021). Moreover, these two chemicals showed steady metabolism with incubation time in all fish microsomes. TBCT and PBBA exhibited significant trophic magnifications in the food web (TMF = 4.56, 2.01). Though different metabolic rates were observed for the two compounds among the tested fish species, TBCT and PBBA both showed metabolic resistance in high-trophic-level fish. These results indicated that metabolism of organisms at high trophic levels plays an important role in the assessment of trophic magnification potentials of these flame retardant chemicals.

Feeling better or not: Adjusting affective style moderates the association between sleep duration and positive affect on next day.

Affect is intertwined with sleep, yet how to adjust sleep duration to enhance affect remains unknown. Previous studies found that adjusting affective style, reflecting interindividual differences in emotion regulation, functions in processes where sleep modulates our affective state. Hence, this study examined whether and how it moderates the association between daily sleep duration and subsequent affect. An ambulatory assessment design was employed among 64 participants, wherein both within-person sleep duration and affect, and between-person affective styles were measured. Multilevel moderation analysis and simple-slope analysis were applied to test the moderation of adjusting affective style in the sleep-affect association. This study found that adjusting affective style significantly moderated the association between sleep duration and subsequent positive affect. Specifically, the association between sleep duration and subsequent positive affect was positive under higher adjusting affective style and negative under extremely lower adjusting affective style. However, such moderation was not observed in associations between subsequent negative affect and sleep duration. This study uncovers the relationship between sleep duration and subsequent affect, wherein the likelihood for individuals to reach more positive affective state by increasing sleeping duration might count on their ability of emotion regulation. Additionally, negative affect cannot be downregulated simply through long sleep duration.

Microglia-derived IL-1ß promoted neuronal apoptosis through ER stress-mediated signaling pathway PERK/eIF2α/ATF4/CHOP upon arsenic exposure.

Arsenic is the leading toxicant of hazardous environmental chemicals, which is linked with neurotoxicity including cognitive dysfunction, neurodevelopmental alterations and neurodegenerative disorders. It has been suggested that sustained pro-inflammatory response is one of the triggering factors of arsenic-induced neurotoxicity. Microglia, the immune cells in the central nervous system, response to physiological and pathological stress, and release a large array of pro-inflammatory cytokines if activated excessively. Several studies indicated that arsenic was capable of inducing microglia activation, however, the role of the subsequently released pro-inflammatory cytokines in arsenic-induced neurotoxicity remains to be elucidated. Our findings demonstrated that arsenic-induced cognitive dysfunction, microglia activation, up-regulation and release of IL-1ß and ER stress-mediated apoptosis could be attenuated by minocycline, a recognized inhibitor of microglia activation. In addition, the IL-1 receptor antagonist IL-1ra diminished arsenic-induced activation of ER stress-mediated apoptotic pathway PERK/eIF2α/ATF4/CHOP and neuronal apoptosis. Our findings provided evidences that arsenic-induced microglia activation also contributed to neuronal apoptosis through pro-inflammatory cytokine. Microglia-derived IL-1ß promoted hippocampal neuronal apoptosis through ER stress-mediated PERK/eIF2α/ATF4/CHOP apoptotic pathway. Neuronal apoptosis induced by prolonged activation of microglia was partially involved in the arsenic-induced cognitive dysfunction.

Calreticulin regulated intrinsic apoptosis through mitochondria-dependent and independent pathways mediated by ER stress in arsenite exposed HT-22 cells.

Arsenic is a naturally occurring environmental toxicant. Chronic exposure to arsenic is linked with neurological damage. Although the mechanisms remain to be elucidated, it is currently believed that neural cell apoptosis is one of the underlying mechanisms of arsenic-induced neurotoxicity. Calreticulin (CRT) is a quality control chaperone located in the lumen of the endoplasmic reticulum (ER), which participates in many signaling pathways including apoptosis. However, the role of CRT in apoptosis is controversial. Whether CRT plays a role in arsenite-induced apoptosis and the relationship between CRT and ER stress-mediated apoptosis have not been mentioned before. In this study, we found that CRT expression as well as the cell apoptosis levels increased in a dose dependent manner upon arsenite exposure in HT-22 cells, a mouse hippocampal neural cell line. In addition, arsenite exposure resulted in the up-regulation of ER stress indicator GRP78 and ER stress-related proteins including p-PERK, ATF4, CHOP, calpain2 and cleaved caspases-12, accompanied by the down-regulation of Bcl-2 and up-regulation of Bax and cleaved caspase-3. Silence of CRT remarkably alleviated arsenite-induced apoptosis and reversed the expression of the proteins above. Our findings confirmed the role of CRT in the induction of apoptosis upon arsenite exposure and suggested that CRT mediated the intrinsic apoptotic cell death including both mitochondria-dependent (PERK/ATF4/CHOP/Bcl-2) and independent (calpain2/caspases-12) pathways initiated by ER stress, which we believed to be a previously undocumented property of arsenite-induced apoptosis.