PFOS facilitates liver inflammation and steatosis: An involvement of NLRP3 inflammasome-mediated hepatocyte pyroptosis.

Perfluorooctane sulfonate (PFOS) is a fluorinated organic pollutant with substantial accumulation in mammalian liver tissues. However, the impact of chronic PFOS exposure on liver disease progression and the underlying molecular mechanisms remain elusive. Herein, we for the first time revealed that micromolar range of PFOS exposure initiates the activation of NLR pyrin domain containing 3 (NLRP3) inflammasome to drive hepatocyte pyroptosis. We showed that 5 mg/kg/day PFOS exposure may exacerbated liver inflammation and steatosis in high-fat diet (HFD)-fed mice with concurrently elevated expression of NLRP3 and caspase-1. PFOS exposure resulted in viability impairment and LDH release in BRL-3A rat liver cells. 25-100 µM concentrations of PFOS exposure activated the NLRP3 inflammasome, leading to consequent GSDMD cleavage, IL-1ß release and the initiation of pyroptosis in a dose-dependent manner, whereas treatment with 10 µM NLRP3 inhibitor MCC950 abrogated this effect. Moreover, pretreatment of 5 mM ROS scavenger N-acetyl-L-cysteine (NAC) ameliorated PFOS-induced NLRP3 inflammasome activation and pyroptosis. Collectively, our data highlight a pivotal role of pyroptotic death in PFOS-mediated liver inflammation and metabolic disorder.

Perfluorooctane sulfonate aggravates CCl4-induced hepatic fibrosis via HMGB1/TLR4/Smad signaling.

Perfluorooctane sulfonate (PFOS) is a widespread environmental pollutant and may cause a variety of adverse health effects. The hepatotoxicity of PFOS has attracted particular attention, given the fact that the liver has one of the highest PFOS accumulations among human tissues. In this study, we revealed that subchronic PFOS exposure may exacerbate carbon tetrachloride (CCl4 )-induced liver fibrosis in animal models. Administration with 1 mg/kg PFOS every other day for 56 days dramatically enhanced CCl4 -mediated liver injury and hepatic stellate cell (HSC) activation. Furthermore, PFOS exposure may promote the activation of high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) signaling pathway through inducing the secretion of HMGB1 from hepatocytes. PFOS exposure induced the translocation of HMGB1 from the nucleus into the cytoplasm of hepatocytes and cultured BRL-3A cells at a starting concentration of 50 µM. This process is accompanied with concurrent flux of calcium, suggesting a link between calcium signaling and HMGB1 release following PFOS exposure. Finally, we showed that PFOS-exposed conditional medium (PFOS-CM) of hepatocytes may induce the translocation of Smad2/3 in HSCs in a TLR4-dependent manner. Taken together, subchronic PFOS exposure might play a pro-fibrotic role via a HMGB1/TLR4-dependent Smad signaling in HSCs. Our findings for the first time uncovered an involvement of PFOS exposure in liver fibrosis via HMGB1/TLR4/Smad signaling.

Nrf2 Signaling Elicits a Neuroprotective Role Against PFOS-mediated Oxidative Damage and Apoptosis.

Perfluorooctanesulfonate (PFOS) may cause neurotoxicity through the initiation of oxidative stress. In the current study, we investigated the role of anti-oxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in PFOS-induced neurotoxicity. We found that human neuroblastoma SH-SY5Y cells exhibited significant apoptotic cell death following PFOS exposure, and this process was accompanied with apparent accumulation of reactive oxidative species (ROS). In addition, we revealed that PFOS exposure caused marked activation of Nrf2 pathway and the expression of Nrf2 transcription target heme oxygenase-1. We further found that pre-treatment with ROS scavenger N-acetyl-L-cysteine (NAC) dramatically ameliorated PFOS-induced ROS production and Nrf2 signaling. In keeping with these findings, western blot and Cell Counter Kit-8 analyses revealed that pre-incubation with NAC suppressed PFOS-induced expression of pro-apoptotic proteins and impairment of neuronal viability. Moreover, antagonizing Nrf2 pathway with Nrf2 inhibitor brusatol resulted in increased ROS production and enhanced PFOS-induced expression of apoptosis related proteins. Finally, we showed that PFOS exposure altered mitochondrial transmembrane potential and disrupted normal mitochondrial morphology in SH-SY5Y cells. Whereas treatment with NAC ameliorated PFOS-induced mitochondrial disorders, co-incubation with brusatol augmented PFOS-induced mitochondrial deficits, consequently contributing to neuronal apoptosis. These results manifest that Nrf2 pathway plays a protective role in PFOS-induced neurotoxicity, providing new insights into the prevention and treatment of PFOS-related toxicities.

Nicotine triggers islet ß cell senescence to facilitate the progression of type 2 diabetes.

Cigarette smoking is a well-recognized risk factor for type 2 diabetes (T2DM), and may result in islet ß cell damage and impaired insulin secretion. However, the underlying mechanisms remain largely elusive. In the present study, we demonstrated that nicotine induced premature senescence of pancreatic ß cells in vitro and in vivo. The senescence-associated ß-galactosidase (SA-ß-Gal) assay showed that nicotine exposure induced apparent senescence phenotype of ß-TC-6 cells at an initiating dose of 100 µM and starting from 12 h. In addition, 100 and 500 µM of nicotine exposure altered the expression of senescence marker proteins, such as p16, p19 and p21. Furthermore, we uncovered that the levels of intracellular Ca2+ and reactive oxygen species (ROS) were significantly elevated in ß-TC-6 cells following exposure to 100 and 500 µM nicotine, while calcium channel blocker can reverse this effect. Furthermore, the senescence-inducing phenotype was confirmed in rat insulinoma INS-1 cells at a similar dose range, whereas blockade of nAChRs, calcium and ROS led to apparent impairment of senescence. Finally, we found that administration with 100 and 200 µg/mL nicotine in drinking water for 28 days significantly exacerbated aberrant glucose homeostasis in a mouse model of fat-induced T2DM. Of great intrigue, pancreatic ß cells exhibited significantly enhanced senescence following nicotine administration. Taken together, this study suggests that premature senescence plays a pivotal role in nicotine-triggered ß cell destruction and glucose intolerance, providing a theoretical basis for targeted prevention and treatment of smoking-induced T2DM.

ROS-mediated JNK pathway critically contributes to PFOS-triggered apoptosis in SH-SY5Y cells.

Recent studies have indicated that perfluorooctane sulfonate (PFOS) and its derivatives can lead to neurotoxicity. In the present study, we showed that PFOS may trigger neuronal apoptosis through a c-Jun N-terminal kinase (JNK)-related mechanism. We revealed that c-Jun N-terminal kinase (JNK) was robustly activated in PFOS-exposed neuronal cells. The doses of PFOS that initiates JNK activation coincides with that inducing neuronal apoptosis, as confirmed by western blot and Annexin V-PE/7-AAD analyses. In addition, we found that reactive oxidative species (ROS) accumulation plays a casual role in PFOS-initiated JNK activation, as treatment with ROS scavenger N-acetyl-l-cysteine (NAC) abrogated PFOS-induced mitochondrial and nuclear translocation of phosphorylated JNK (p-JNK). In keeping with this notion, the expression of JNK downstream pro-apoptotic target Bim was increased following PFOS exposure in JNK- and ROS-dependent manners. Finally, Annexin V-PE/7-AAD analysis uncovered that treatment with NAC or SP600125 could significantly impair PFOS-induced neuronal apoptosis. These findings implicate that JNK signaling is critically involved in PFOS-induced neuronal death by virtue of mitochondrial translocation and the transcription of pro-apoptotic genes.

Ring roads and urban biodiversity: distribution of butterflies in urban parks in Beijing city and correlations with other indicator species.

The capital of China, Beijing, has a history of more than 800 years of urbanization, representing a unique site for studies of urban ecology. Urbanization can severely impact butterfly communities, yet there have been no reports of the species richness and distribution of butterflies in urban parks in Beijing. Here, we conducted the first butterfly survey in ten urban parks in Beijing and estimated butterfly species richness. Subsequently, we examined the distribution pattern of butterfly species and analyzed correlations between butterfly species richness with park variables (age, area and distance to city center), and richness of other bioindicator groups (birds and plants). We collected 587 individual butterflies belonging to 31 species from five families; 74% of the species were considered cosmopolitan. The highest butterfly species richness and abundance was recorded at parks located at the edge of city and species richness was significantly positively correlated with distance from city center (p < 0.05). No significant correlations were detected between the species richness and park age, park area and other bioindicator groups (p > 0.05). Our study provides the first data of butterfly species in urban Beijing, and serves as a baseline for further surveys and conservation efforts.

Perfluorooctane sulfonate mediates secretion of IL-1ß through PI3K/AKT NF-кB pathway in astrocytes.

Perfluorooctane sulfonate (PFOS) is a persistent and bioaccumulative compound that has been widely used in various fields of life and industrial productions, because of its special chemical and physical properties. Numerous studies have indicated significant neurotoxic effect of PFOS, especially on neurons and microglia. However, the influence of PFOS on astrocyte physiology remains unclear. In this study, we showed that PFOS triggered reactive astrocytosis in time- and dose-dependent manners. The low-doses of PFOS increased the cell number and the expression of glial fibrillary acidic protein (GFAP), a well-known hallmark of reactive astrocytes, in C6 astrocyte cells. ELISA and RT-PCR analysis showed that PFOS promoted the expression and secretion of Interleukin-1 beta (IL-1ß) in dose- and time-dependent manners. Furthermore, PFOS exposure could induce the phosphorylation and degradation of IκBα, and the translocation of NF-κB p65 from the cytoplasm to the nucleus in C6 glioma cell line. Thus, the NF-кB signaling pathway can be activated after PFOS exposure. In addition, pretreatment with AKT inhibitor LY294002 could obviously attenuate PFOS-induced NF-κB activation and IL-1ß secretion. Taken together, these results indicated that PFOS could facilitate reactive astrocytosis and the secretion of pro-inflammatory cytokines through AKT-dependent NF-κB signaling pathway.