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PM2.5-related neurological and mental diseases, such as cognitive impairment and stroke, tend to cause disability. Six-week-old male C57BL/6 mice were divided into 6 groups and exposed to concentrated PM2.5 or filtered air for 2, 4, and 6 months, respectively. The neurobehavioral changes of mice were tested. The weight of the whole brain and olfactory bulbs were recorded at the end of exposure, and the brain structure was observed by hematoxylin and eosin (HE) staining. Serum indicators, mRNA, and protein expressions were detected. The spatial learning memory ability was impaired, and the mice were more anxious after PM2.5 exposure. Relative brain weight decreased with age, and PM2.5 exposure exceeded the decrease of relative brain weight. Interestingly, superoxide dismutase (SOD) and albumin decreased in the PM2.5-exposed groups although neuronal morphology and other serum indicators did not show significant difference between PM and FA groups. Moreover, PM2.5 induced the increase of plasminogen at 2 months but recovered at 4 months and then increased at 6 months again. The results from protein expression and transcriptomic test demonstrated that PI3K/AKT/FoxO1 pathway might be activated after 6-month PM2.5 exposure in mice. Indicators albumin, the percentage of albumin over IgG (A/G value), and plasminogen were the main serous changes in mice after early-stage (2 months) and long-term (6 months) PM2.5 exposure. In addition, early-stage injury induced by PM2.5 might recover at later time point and display significant injury again with the exposure time. PM2.5 exposure-induced brain injury might be associated with the activation of PI3K/AKT/FoxO1 pathway.

AIMS To explore the role of nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in ambient fine particulate matter (PM2.5)-related metabolic disorders. METHODS In this study, the C57BL/6 and db/db mice were exposed to concentrated PM2.5 or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) for 12 weeks. Indices of lipid metabolism, glucose metabolism, insulin sensitivity, and protein expression of NLRP3 inflammasome in visceral adipose tissue (VAT) were measured, respectively. RESULTS The results showed that PM2.5 exposure increased circulatory insulin, triglycerides (TG), and total cholesterol (TC), and decreased high-density lipoprotein (HDL) in both C57BL/6 and db/db mice. The levels of NLRP3-related circulatory inflammatory cytokines including both interleukin (IL)-18 and IL-1β in serum were increased in the PM2.5-exposed mice and accompanied by the elevation in fasting blood glucose and insulin. The results also showed that exposure to PM2.5 promoted the activation of NLRP3, pro-caspase-1, caspase-1, and apoptosis-associated speck-like protein containing CARD (ASC), simultaneously accompanied by the increase of IL-18 and IL-1β expression in VAT, but the statistically significant difference only found in the db/db mice, not in C57BL/6 mice. CONCLUSION The activation of NLRP3 inflammasome might be not the main mechanism of PM2.5-related metabolic disorders in wide type mice but it partly mediated the exacerbation of metabolic disorders in diabetic model mice.

Epidemiological evidences have indicated that fine particulate matter (PM2.5 ) exposure is associated with the occurrence and development of hypertension. The present study aims to explore the effects of parental PM2.5 exposure on blood pressure in offspring and elucidate the potential mechanism. The parental male and female C57BL/6 mice were exposed to concentrated PM2.5 or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) for 16 weeks. At week 12, the mice were assigned to breed offspring. The male offspring mice were further exposed to PM2.5 or FA as above method. During the parental exposure, the average PM2.5 concentration was 133.7 ± 53.32 μg/m3 in PM chamber, whereas the average concentration in FA chamber was 9.4 ± 0.23 μg/m3 . Similarly, during the offspring exposure, the average concentration in PM and FA chamber were 100.76 ± 26.97 μg/m3 and 9.15 ± 0.15 μg/m3 , respectively. The PM2.5 -exposed offspring mice displayed the elevation of blood pressure, the increase of angiotensin II (Ang II), the decrease of angiotensin converting enzyme 2 (ACE2) and Ang (1-7) in serum when compared with the FA-exposed offspring mice. The similar results displayed in the proteins expression of ACE2, AT1R, and Ang (1-7) in vessel and kidney. More importantly, parental PM exposure further induced the increase in serous Ang II and the protein expression of AT1R in vessel, but decrease in ACE2 and Ang (1-7). The serous Ang II was positively associated with splenic T helper type 17 (Th17) cell population and serous IL (interleukin)-17A, but negatively associated with T regular (Treg) cell population and serous IL-10. The results suggested that parental air pollution exposure might induce the elevation of offspring blood pressure via mediate Th17- and Treg-related immune microenvironment.

While it is known that air borne particulate matter (PM2.5) may pass through the pulmonary circulation of blood at the alveolar level between lung and heart and cross the air-blood barrier, the mechanism and effects are not completely clear. In this study the imaging method fluorescence lifetime imaging microscopy (FLIM) is adopted for visualization with high spatial resolution and quantification of PM particles in mouse lung and heart tissues. The results showed that the median numbers of particles in lung of mice exposed to particulate matter of diameter less than 2.5 µm (PM2.5) was about 2.0 times more than that in the filtered air (FA)-treated mice, and about 1.3 times more in heart of PM2.5-treated mice than in FA-treated mice. Interestingly, PM2.5 particles were more abundant in heart than lung, likely due to how PM particles are cleared by phagocytosis and transport via circulation from lungs. It is proposed that the powerful flow of blood through the heart may contribute to invasion of PM2.5 particles into heart muscles. The histopathological evaluations revealed that exposure of PM2.5 to lungs dilated air spaces and showed signs of inflammation. Moreover, heart tissues showed inflammation and amyloid deposition. The component analysis of concentrated airborne PM2.5 particles suggested traffic exhausts and industrial emissions as predominant sources. Our results strongly suggest association of PM2.5 exposure to chronic lung and heart tissue injuries. The current study supports the contention that industrial air pollution is one of the causative factors for rising levels of chronic pulmonary and cardiac diseases.

Both the epidemiological and animal experimental studies have reported the association between PM2.5 and respiratory, cardiovascular, and metabolic diseases. However, the study linking PM2.5 and hepatic injury is few, and the relative mechanism has not been fully elucidated. Thirty-two 6-week-old male C57BL/6 mice were exposed to filtered air (FA) or concentrated PM2.5 for 12 weeks using Shanghai Meteorological and Environmental Animal Exposure System (“Shanghai-METAS”), respectively. At week 11, the mice began to be treated with intraperitoneal injection of normal 0.9% saline or AMPK activator (AICAR). The mRNA levels of IL-6 and TNF-α, and protein expressions of AMPK, GLUT4, NF-κB, p38MAPK, ERK, and JNK in the liver and UCP-1 in brown adipose tissue (BAT) were measured. Meanwhile, histopathological examination both in the liver and BAT was performed to evaluate the histopathological changes. PM2.5 exposure induced steatosis, hepatocyte ballooning, lobular and portal inflammation in the liver, and the brown adipocyte swelling in BAT. The results found that PM mice displayed higher IL-6, TNF-α, NF-κB, and JNK expression and lower AMPK, GLUT4, and UCP-1 when compared with FA mice. The AICAR injection upregulated the expressions of GLUT4 in the liver of PM-AIC mice when compared with the PM mice. However, there were no significant effects of AICAR on histopathological condition. The current study showed that ambient PM2.5 exposure might induce the hepatic injury along with the lipid metabolism disorder in BAT. AMPK activation can ameliorate most of the harmful effects and might become the potential target for treating PM2.5-induced hepatic injury.

Skin, as the major organ of a human body, is constantly exposed to PM2.5 stimulation, which may exert specific toxic influences on the physiology of skin. This study aims to investigate the effect of PM2.5 on the formation of inflammasomes in skin cells and to explore the potential mechanism linking PM2.5 and skin inflammation. Changes in mRNA and protein levels of inflammasome-related genes were detected by real-time PCR and western blot in human immortalized epidermal cells (HaCaT) treated with PM2.5 at multiple concentrations for 24 hours. The expression of NLRP1 was increased significantly both in mRNA and protein levels after PM2.5 exposure while the elevated secretory protein level of IL-1β in cell culture was detected by ELISA, which is one of the main downstream factors of NLRP1. In addition, the upregulation of NLRP1 and IL-1β could be reversed by NF-κB inhibitor indicating that PM2.5 may promote NLRP1 expression through activating NF-κB pathway. Furthermore, high ROS level was also found in cells treated with PM2.5 and inhibition of ROS could also reverse NK-κB production stimulated by PM2.5 that means ROS is involved in this skin inflammation process.

Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM2.5 and cold stress contribute to the development of asthma. However, the combined effects of these two risking factors are unknown. In this study, we investigated the combined effects of PM2.5 exposure and cold stress (PMCS) on asthma, as well as the underlying mechanisms by using a murine model. After different exposures, the immune-pathological changes and redox states in groups were evaluated. Besides, the balance of TH1/TH2 cells and the acetylation levels of H3K9 and H3K14 in IL-4 gene promotor were detected. Our results showed that, compared with other exposures, PMCS led to an increased inflammation and redox levels in mice. It also significantly increased the percentage of TH2 T cells, which was correlated with hyperacetylation of H3K9 and H3K14 in IL-4 gene promoter in CD4+T cells. Furthermore, a significantly increased P300 and decreased HDAC1 were detected in CD4 + T cells in PMCS group. In conclusion, our findings demonstrated that PMCS exacerbated asthma in mice by increasing H3K9 and H3K14 acetylation in IL-4 gene promoter in CD4 + T cells, and P300 and HDAC1 might contribute to their combined effects.

Air pollution causes a great disease burden worldwide. Recent evidences suggested that PM

To explore the role of nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in ambient fine particulate matter (PMIn this study, the C57BL/6 and db/db mice were exposed to concentrated PMThe results showed that PMThe activation of NLRP3 inflammasome might be not the main mechanism of PM

Epidemiological and experimental studies have indicated that ambient fine particulate matter (PM2.5) exposure is associated with the occurrence and development of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). However, the mechanism is not clear yet, and there are few studies to explore the possible prevention measure. In this study, C57BL/6 and db/db mice were exposed to concentrated PM2.5 or filtered air using Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) for 12 weeks. From week 11, some of the mice were assigned to receive a subcutaneous injection of AMPK activator (AICAR). Lipid metabolism, glucose tolerance, insulin sensitivity and energy homeostasis were measured. Meanwhile, the respiratory, systemic and visceral fat inflammatory response was detected. The results showed that PM2.5 exposure induced the impairments of glucose tolerance, insulin resistance, lipid metabolism disorders and disturbances of energy metabolism in both C57BL/6 and db/db mice. These impairments might be consistent with the increased respiratory, circulating and visceral adipose tissue (VAT) inflammatory response, which was characterized by the release of IL-6 and TNF-α in lung, serum and VAT. More importantly, AICAR administration led to the significant enhancement of energy metabolism, elevation of AMPK as well as the decreased IL-6 and TNF-α in VAT of PM2.5-exposed mice, which suggesting that AMPK activation might attenuate the inflammatory responses in VAT via the inhibition of MAPKs and NFκB. The study indicated that exposure to ambient PM2.5 under the concentration which is often seen in some developing countries could induce the occurrence of metabolic disorders in normal healthy mice and exacerbate metabolic disorders in diabetic mice. The adverse impacts of PM2.5 on insulin sensitivity, energy homeostasis, lipid metabolism and inflammatory response were associated with AMPK inhibition. AMPK activation might inhibit PM2.5-induced metabolic disorders via inhibition of inflammatory cytokines release. These findings suggested that AMPK activation is a potential therapy to prevent some of the metabolic disorders attributable to air pollution exposure.

PM

Photodynamic therapy (PDT) is a promising cancer treatment that can be implemented using various agents. The conventional photosensitizer Al (III) phthalocyanine chloride tetrasulfonic acid (Pc) has limitations of selectivity in tumor targeting, low affinity to cancer cells, and low two-photon absorption. This study presents a novel photosensitizer FA-TiO2-Pc, which has the TiO2 nanoparticle conjugated with a tumor targeting agent of folic acid (FA), and Pc. FA-TiO2-Pc possessed high targeted photodynamic therapeutic activity and excellent biocompatibility. This promising photosensitizer showed high therapeutic drug efficiency in vitro at a low concentration dose and short incubation time under one-photon excitation (OPE). In vivo, when treated with a low dose of FA-TiO2-Pc and low light irradiation, the tumor growth was depressed in mice bearing HeLa xenograft tumors with minimal side effects. In addition, the two-photon absorption of FA-TiO2-Pc was also enhanced compared to Pc, proving that FA-TiO2-Pc system has a great potential to be used for the therapy of the folate receptor positive cancer cells in both OPE-PDT and two-photon excitation (TPE)-PDT agents. © 2020 Elsevier B.V. Fig. 1B and C was modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License. (https://creativecommons.org/licenses/by/3.0/).

Epidemiological evidences have indicated that fine particulate matter (PM

Background Fine particulate matter (PM 2.5 )-induced neurological and mental diseases, such as cognitive impairment and stroke, tend to cause disability. In this study, we plan to find the appropriate biological indicators reflecting the early effects of PM 2.5 exposure and explore the toxicity of inhaling PM 2.5 along with its pathological mechanism on nervous system. Methods Male C57BL/6 mice were divided into 6 groups and exposed to concentrated PM 2.5 or filtered air for 2, 4 and 6 months, respectively. Their performances of ethology were tested by Morris water maze, elevated plus maze and buried food pellet test. Weight of whole brain and olfactory bulbs were recorded when the mice were sacrificed and the brain structure was observed by HE staining. ROS, SOD, IL-6, TNF-α, IL-1β, BDNF, β-hydroxybutyric, IgG, albumin, fibrinogen and plasminogen were tested. The mRNA expressions of the cortex were detected by RNA sequencing and real-time PCR, and the corresponding proteins were detected by Western blot. Results The spatial learning memory ability were impaired and the mice performed anxiously after PM 2.5 exposure. Relative brain weight decreased along with age and PM 2.5 inhaled exposure exceeded the process. But neuronal morphology, inflammatory cytokines, ROS, β-hydroxybutyric, BDNF, IgG and fibrinogen did not change. Intriguingly, SOD and albumin decreased, while plasminogen increased after PM 2.5 exposure. PI3K-AKT-FoxO1 pathway was activated after 6-month PM 2.5 exposure. Conclusion Albumin, A/G value and plasminogen are main serum indicators of early-stage (2 month) PM 2.5 exposure, and long-term (6 month) PM 2.5 exposure induced brain injury potentially through the activation of PI3K/AKT/FoxO1 pathway.

Background Exposure to ambient fine particulate matter (PM2.5) is associated with various adverse health outcomes. Although several mechanisms have been proposed including oxidative stress and inflammatory responses, the exact mechanism is still unknown. Few studies have investigated the mechanism linking PM2.5 and blood pressure (BP). In this study, we measured urinary metabolites and BP -related renin-angiotensin-aldosterone system (RAAS) to investigate the associations between ambient PM2.5 exposure and BP in healthy C57BL/6 mice. Methods The C57BL/6 mice were exposed to ambient concentrated PM2.5 or filtered air (FA) for 16 weeks. Systolic BP and diastolic BP were measured by noninvasive BP system. The urine metabolites were quantified using the untargeted metabolomics approach. The expression of RAAS -related proteins angiotensin-converting enzyme (ACE)2, angiotensin (Ang) II, Ang (1–7) and aldosterone (ALD) were measured using Western blot and ELISA kits. Results The metabolomics analysis demonstrated that PM2.5 exposure induced significant changes of some metabolites in urine, including stress hormones, amino acids, fatty acids, and lipids. Furthermore, there was an elevation of BP, increase of serous Ang II and ALD, along with the decrease of ACE2 and Ang (1–7) in kidney in the PM2.5-exposed mice compared with FA-exposed mice. Conclusions The results demonstrated that PM2.5 exposure-induced BP elevation might be associated with RAAS activation. Meanwhile, PM2.5 exposure-induced changes of stress hormone and lipid metabolism might mediate the activation of RAAS. The results suggested that the systemic stress hormone and lipid metabolism was associated with the development of hypertension.

Skin, as the major organ of a human body, is constantly exposed to PM2.5 stimulation, which may exert specific toxic influences on the physiology of skin. This study aims to investigate the effect of PM2.5 on the formation of inflammasomes in skin cells and to explore the potential mechanism linking PM2.5 and skin inflammation. Changes in mRNA and protein levels of inflammasome-related genes were detected by real-time PCR and western blot in human immortalized epidermal cells (HaCaT) treated with PM2.5 at multiple concentrations for 24 hours. The expression of NLRP1 was increased significantly both in mRNA and protein levels after PM2.5 exposure while the elevated secretory protein level of IL-1β in cell culture was detected by ELISA, which is one of the main downstream factors of NLRP1. In addition, the upregulation of NLRP1 and IL-1β could be reversed by NF-κB inhibitor indicating that PM2.5 may promote NLRP1 expression through activating NF-κB pathway. Furthermore, high ROS level was also found in cells treated with PM2.5 and inhibition of ROS could also reverse NK-κB production stimulated by PM2.5 that means ROS is involved in this skin inflammation process.

Both cold stress and ambient fine particle particulate matter (PM

Previous studies have indicated that the main air pollutant fine particulate matter (≤2.5 μm; PM2.5) exposure is associated with the development of atherosclerosis. Although the mechanism is not fully illustrated, the inflammatory responses play an important role. The present study aimed to explore whether PM2.5-exacerbated atherosclerosis was mediated by the cooperation of cluster of differentiation 36 (CD36) and nucleotide-binding oligomerization domain-like receptor protein (NLRP3) inflammasome in apolipoprotein E-/- (ApoE-/-) mice. Thirty-two ApoE-/- mice were randomly divided into two groups. One group was fed with high fat chow (HFC) for 10 weeks to establish atherosclerotic model, and the other was fed with normal chow (NC). From week 11, the mice were exposed to concentrated PM2.5 (PM) or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. In both NC and HFC groups, PM2.5 exposure induced the formation of atherosclerosis plaque. Similarly, PM mice appeared higher lipid content in the aortic root than that in the FA mice. Compared with the FA mice, PM mice appeared a decrease in high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 along with an increase in apolipoprotein B, low density lipoprotein-cholesterol (LDL-C) and oxidized low-density lipoprotein (ox-LDL). Moreover, PM2.5 exposure induced increase of CD36 in serum and aorta. In both NC and HFC groups, NLRP3 inflammasome activation-related indicators were activated or increased in the aorta of the PM mice when compared with the FA mice. The cooperation of CD36 and NLRP3 inflammasome activation may be the potential mechanisms linkixposed to concentrated PM2.5 (PM) or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. In both NC and HFC groups, PM2.5 exposure induced the formation of atherosclerosis plaque. Similarly, PM mice appeared higher lipid content in the aortic root than that in the FA mice. Compared with the FA mice, PM mice appeared a decrease in high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 along with an increase in apolipoprotein B, low density lipoprotein-cholesterol (LDL-C) and oxidized low-density lipoprotein (ox-LDL). Moreover, PM2.5 exposure induced increase of CD36 in serum and aorta. In both NC and HFC groups, NLRP3 inflammasome activation-related indicators were activated or increased in the aorta of the PM mice when compared with the FA mice. The cooperation of CD36 and NLRP3 inflammasome activation may be the potential mechanisms linking air pollution and HFC-induced atherosclerosis even in the mice with NC intake.

Substantial epidemiological and experimental studies have shown that ambient fine particulate matter (PM2.5) exposure can lead to myocardial damage in human and animal through the mechanism of inflammation and oxidative stress. The purpose of the current study was to investigate whether selenium yeast (SeY) supplementation could prevent cardiovascular injury caused by PM2.5 in rats. Fifty-six Sprague-Dawley rats were randomly divided into seven groups: saline control group; solvent control group, low-, middle-, and high-dose Se pretreatment groups, PM2.5 exposure group, and high-dose Se control group. The rats were pretreated with different concentration of dietary SeY for 28 days, then were exposed to PM2.5 by intratracheal instillation every other day, a total of three times. The levels of inflammatory markers (tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), soluble intercellular adhesion molecule-1 (sICAM-1), and oxidative responses-related indicators total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) were measured in blood and myocardium of the left ventricle. The results showed that although PM2.5 caused a decrease of T-AOC, T-AOD, and GSH-Px and increase of MDA and sICM-1, pretreatment with SeY induced a dose-dependent increase in these anti-oxidative indicators and a decrease in oxidative indicators. In addition, the levels of TNF-α and IL-1β in Se pretreatment groups were significantly lower than that in PM2.5 exposure group. The results indicated that Se supplementation could effectively prevent cardiovascular inflammation and oxidative stress induced by PM2.5. The results also indicated that the nutritional supplementation might be an effective way to protecting people’s health from air pollution.

Lots of epidemiological and experimental studies have found that ambient fine particulate matter (PM2.5) exposure is associated with the development of cardiopulmonary diseases, obesity and diabetes. This study focused on the effects of cumulative PM2.5 exposure on pulmonary and systemic inflammation and insulin resistance. Thirty-two 6-week-old male Balb/c mice were randomly divided into four groups (FA, PM, WEEK and DAY groups) and were continuously or intermittently exposed to concentrated PM2.5 or filtered air (FA) for four weeks using Shanghai Meteorological and Environmental Animal Exposure System ("Shanghai-METAS"). The levels of IL-6 and TNF-α in serum, bronchoalveolar lavage fluid (BALF), lung tissues and white adipose tissue (WAT) were measured. Meanwhile, the expression of NF-κB and phosphor-NF-κB in lung tissue was detected by Western blot. Glucose tolerance and insulin resistance were also determined at the end of exposure. The results found that the mice in PM group displayed moderate inflammatory cell infiltration in lung, whereas the mice in WEEK and DAY groups displayed slight inflammatory cell infiltration in lung. Compared with the mice in FA group, the mRNA expressions of IL-6 and TNF-α in lung tissue and WAT significantly increased in the mice of PM group. Importantly, IL-6 and TNF-α mRNA expressions in PM group were higher than those in WEEK and DAY groups. The protein expression of phospho-NF-κB in lung tissue showed that PM group showed the activation of NF-κB, which was higher than that in the WEEK and DAY groups. Meanwhile, the mice in PM group showed more severe glucose tolerance and insulin resistance than that in the WEEK and DAY groups. The results suggested that the reduction of PM2.5 cumulative exposure may alleviate pulmonary and adipose inflammation, insulin resistance and glucose tolerance impairment. The results provided a clue that the interruption of ambient PM2.5 exposures by systems such as indoor air purification could be of benefit to people's health.

Inflammation and oxidative stress are important risk factors in PM2.5-induced injury. The current study attempted to study the role of caspase recruitment domain (CARD) 9 in ambient PM2.5-induced pulmonary injury in mice. The CARD9-/- and C57BL/6 mice were exposed to 3.6, 7.8 and 15.6mg/kgbw of PM2.5 or saline by intratracheal instillation. After the last PM2.5 exposure, the spleen, bronchoalveolar lavage fluid (BALF) and pulmonary tissue were collected and examined. The results showed that PM2.5 exposure induced inflammatory cell infiltration and alveolar septal thickening in the lung. Regulatory T (Treg) cells in spleen of CARD9-/- mice were significantly higher than that in the C57BL/6 mice, whereas the T helper cells 17 (Th17) were lower. The levels of interleukin (IL)-6 and IL-17A in BALF of the CARD9-/- mice were significantly lower than that in the C57BL/6 mice. The mRNA expression of IL-17A, IL-6 and RORγt in the lung of the CARD9-/- mice is significantly lower than that in the C57BL/6 mice, whereas the mRNA levels of Foxp3 in CARD9-/- mice were significantly higher than that in the C57BL/6 mice at the same dose of PM2.5. The protein expression of nuclear factor κB (NF-κB) is higher in the C57BL/6 mice than that in the CARD9-/- mice. This study indicates that ambient PM2.5-induced pulmonary injury is associated with the immune and inflammatory response. CARD9-mediated Th17/Treg differentiation probably played an important role in PM2.5-induced pulmonary damage.

Objective This study aims to observe whether the combined treatment with vitamin E (vit E) and omega-3 polyunsaturated fatty acids (Ω-3 FA) could prevent the fine particulate matter (PM2.5)-induced cardiovascular injury through alleviating inflammation and oxidative stress. At the same time, the appropriate combination dosage of vit E and Ω-3 FA was explored to find an optimized protective dose to protect the injury induced by PM2.5. Methods: The SD rats were pretreated with different concentration of vit E and Ω-3 FA separately or jointly. Then the rats were exposed to ambient PM2.5 by intratracheal instillation for three times. The expression of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) in serum and supernatant of cardiac tissue were detected by ELISA kits. The levels of malondialdehyde (MDA), superoxide Dismutase (SOD) and glutathione-peroxidase (GSH-Px) in myocardium and the level of MDA in serum were measured. Meanwhile, the cardiac injury was evaluated by histopathological examination. Results: Compared with the severe injury of rats in PM2.5 exposure group, the rats in vit E or Ω-3 FA-pretreated groups had a slighter injury in heart. Meanwhile, pretreatment with vit E or Ω-3 FA induced a significantly alleviation of the inflammatory cytokines (TNF-α, IL-1β, IL-6) and the elevation of the anti-oxidative activity especially in the rats pretreated with combined vit E and Ω-3 FA. In addition, the combined protecting effects of vit E and Ω-3 FA showed a dose-dependent manner. Conclusion: Supplementation with vit E and Ω-3 FA could protect the PM2.5-induced injury, and the combination of vit E and Ω-3 FA might produce more effective effects than the separate nutrient did.

Ambient fine particulate matter (PMThe normal healthy C57BL/6 mice were exposed to concentrated ambient PMThere were 2213 metabolites identified in total and 163 of them were significantly different between FA- and PM-exposed mice. The KEGG pathway analysis suggested that there were nine perturbed metabolic pathways related to amino acid metabolism. The amino acid metabolism what mainly impacted by PMThe current study provided a critical information on evaluating the systemic toxicity of PM

Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM

Parental exposure to ambient fine particulate matter (PM2.5) has been associated with some of adverse health outcomes in offspring. The association between parental PM2.5 exposure and the development of metabolic syndrome (MetS) in offspring, and the effects of parental PM2.5 exposure on the susceptibility of offspring mice to PM2.5, has not been evaluated. The C57BL/6 parental mice (male and female mice) were exposed to filtered air (FA) or concentrated PM2.5 (PM) using Shanghai-METAS for a total of 16 weeks. At week 12 during the exposure, we allowed the parental male and female mice to breed offspring mice. The male offspring mice were divided into 4 groups and exposed to PM and FA again. The results showed that whether the parental mice were exposed to PM2.5 or not, the offspring mice exposure to PM2.5 appeared the elevation of blood pressure, insulin resistance, impairment of glucose tolerance, and dyslipidemia when compared to the offspring mice exposure to FA. More importantly, no matter what the offspring mice were exposed to, parental PM exposure overwhelmingly impacted the fasting blood insulin, homeostasis model assessment-insulin resistance, serous low-density lipoprotein cholesterol, and total cholesterol, splenic T helper cell 17 (Th17) and Treg cells, serous interleukin (IL)-17A, IL-6, and IL-10 in offspring mice. The results suggested that the parental exposure to air pollution might induce the development of MetS in offspring and might enhance the susceptibility of offspring to environmental hazards. The effects of parental PM exposure on offspring might be related to the changes of immune microenvironment.

The study was conducted to explore the mechanisms linking traffic-related air pollution and cardio-metabolic risk. The participants included 371 men and women aged from 45 to 75 in an urban residential area in Shanghai, China. The participants were divided into four categories (≤50, 51–100, 101–200 and >200 m) according to the residential distance to major road. Additionally, the personal fine particulate matter (PM2.5) was measured from 8:00 am to 6:00 pm to assess the PM2.5 exposure in general residents. Then, the continuous subclinical measurements and biological effects related to cardio-metabolic disorders were detected. The generalized linear regression analysis was applied for estimating the adjusted hazards ratio for cardio-metabolic disorders relative to traffic-related air pollution. The average personal PM2.5 is 111.1 μg/m3 in the participants living within 50 m to major road, which is significantly higher than the personal PM2.5 (68.2 μg/m3) in the participants living more than 200 m away from the major road. The participants living within 50 m to major road compared with those living more than 200 m away have 1.15 times higher of heart rate (HR), 1.95 times higher of fasting insulin, 1.30 times higher of homeostasis model assessment of insulin resistance (HOMA-IR), 1.56 times higher of low-density lipoprotein cholesterol (LDL-C), 8.39 times higher of interleukin 6 (IL-6), 4.30 times higher of augmentation index (AI), 1.60 times higher of systolic blood pressure (SBP) and 1.91 times higher of diastolic blood pressure (DBP). Contrary to the increase in above biological effects, there were 1.06 times lower of low frequency (LF), 1.05 times lower of high frequency (HF), 2.54 times lower of IL-10, 4.61 times lower of nitric oxide (NO), 1.19 times lower of superoxide dismutase (SOD) and 1.85 times lower of total antioxidant capacity (T-AOC). There was no clear exposure–response relationship can be observed in the fasting glucose, LF/HF, cholesterol and high-density lipoprotein (HDL). Long-term exposure to traffic-related air pollution may contribute to the development or exacerbation of cardio-metabolic disorders. The mechanisms linking air pollution and cardio-metabolic disorders may be associated with the increased systemic inflammation and oxidative stress, reduced insulin sensitivity and elevated arterial stiffness and blood pressure.

This paper constructs a two-stage monopolistic competition model that explains the large number of zeros and missing bilateral FDI flows, as well as positive bilateral FDI flows we observe in the data. A Heckman two-step selection procedure is used to empirically estimate the model by employing data for 101 countries from 1995 to 2002. I show that certain characteristics previously considered important to determine FDI flows in traditional OLS estimations may only matter for multinationals selecting into FDI relationships, and in some cases, they may even negatively affect FDI flows.

Background Ambient fine particulate matter (PM2.5) exposure has been linked with various adverse health outcomes. However, the urine metabolomics changes impacted by PM2.5 have not been well elucidated. Methods The normal healthy C57BL/6 mice were exposed to concentrated ambient PM2.5 (PM) or filtered air (FA) for four weeks using “Shanghai-METAS”. The urinary metabolome was quantified using liquid/gas chromatography coupled with mass spectrometry. Results There were 2213 metabolites identified in total and 163 of them were significantly different between FA- and PM-exposed mice. The KEGG pathway analysis suggested that there were nine perturbed metabolic pathways related to amino acid metabolism. The amino acid metabolism what mainly impacted by PM2.5 were beta-alanine, arginine, proline, alanine, aspartate, glutamate, phenylalanine, glycine, serine, threonine and tyrosine metabolism. Meanwhile, nineteen differential metabolites related to lipid metabolism and seven differential metabolites related to glucose homeostasis were different between FA and PM mice. Furthermore, the glucose and its metabolites were significantly increased in the PM mice compared with the FA mice. Conclusion The current study provided a critical information on evaluating the systemic toxicity of PM2.5. The results demonstrated that there were significant alterations in urine metabolome by short-term exposure to PM, including amino acid metabolism, lipid metabolism and glucose metabolism. The metabolomics approach might be an effective tool to evaluate the potential mechanism of PM2.5 in inducing adverse health outcomes.

Lots of epidemiological and experimental studies have found that ambient fine particulate matter (PM

Epidemiological evidences have indicated that fine particulate matter (PM2.5) is associated with the increased risk of cardiovascular morbidity and mortality. Although several mechanisms linking PM2.5 and inflammatory responses have been widely implicated, the detailed mechanisms involving the occurrence of inflammation in PM2.5-induced adverse effects are lacking. This study aims to investigate whether PM2.5 exposure-induced cardiovascular injury is associated with NLRP3 inflammasome activation in apolipoprotein E-/- (Apo E-/-) mice. Thirty-two Apo E-/- mice were randomly divided into four groups. The mice were fed with normal chow (NC) or high-fat chow (HFC) for 10 weeks, respectively. From week 11, the mice were exposed to concentrated PM2.5 (PM) or filter air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. The cardiac function and myocardial injury were evaluated by echocardiography and histopathological examination. Meanwhile, the expression of NLRP3-related signaling pathway in myocardium was detected. Compared with the FA mice, the PM mice showed the underlying cardiac dysfunction and injury in both NC and HFC groups. Mononuclear macrophages (CD11c+) were significant higher in bone marrow of the PM mice than that in the FA mice, whilst CD206+ macrophages were lower. Accordingly, PM2.5 exposure induced the increase of circulating inflammatory cytokine TNF-α and decrease of anti-inflammatory cytokine IL-10. PM2.5 exposure was also associated with the activation of NLRP3 inflammasome, which characterized by elevated protein expression of NLRP3, ASC, caspase-1, IL-1β and IL-18 in myocardium. All these results demonstrated PM2.5-related cardiac injury is mediated by macrophages polarization and NLRP3 inflammasome activation.

To observe whether vitamin E( Ve) and ω-3 polyunsaturated fatty acids( ω-3 FA) could prevent the fine particulate matter( PM_(2. 5))-induced cardiovascular injury and explore the potential mechanism.The SD rats were assigned randomly to 8 groups, those were control group, PM_(2. 5)group, Ve treatment groups( 3, 10, 30 mg/( kg·d)) and ω-3 FA treatment groups( 10, 30 and 90 mg/( kg·d)). The rats were pretreated with different concentration of Ve and ω-3 FA separately for 14 days, then were exposed to ambient PM_(2. 5) by intratracheal instillation( 10 mg/kg BW). All the rats were sacrificed after the last PM_(2. 5) exposure, then the arterial blood, lungs and cardiac tissues were collected. The expressions of tumor necrosis factor-α( TNF-α), interleukin-1β( IL-1β), interleukin-6( IL-6) in serum, bronchoalveolar lavage fluid and supernatant of cardiac tissue were detected by ELISA kits. The levels of malondialdehyde( MDA), superoxide dismutase( SOD) and glutathione-peroxidase( GSH-Px) in serum and myocardium were also measured.Compared with the severe injury of rats in PM_(2. 5) exposure group, the rats in Ve or ω-3 FA groups had a slighter injury in lung and cardiac tissue with the increase of Ve and ω-3 FA. Similarly, the levels of IL-1β, IL-6 in bronchoalveolar lavage fluid had a decreasing trend with the increase of Ve and ω-3 FA compared with the PM_(2. 5) exposure groups. Meanwhile, the expressions of TNF-α in Ve and ω-3 FA high dose groups were significantly reduced when compared with the PM_(2. 5) exposure group( P0. 05). In addition, the MDA levels in serum were markedly decreased and the activities of SOD were significantly increased compared with the PM_(2. 5)exposure group( P0. 05 or P0. 01) whereas the SOD activities were elevated only in the ω-3 FA high dose groups( P0. 05). Meanwhile, the levels of IL-6 and TNF-α in serum had an obvious decrease compared with the PM_(2. 5) exposure group( P0. 01). Similarly, compared with the PM_(2. 5)exposure group, the expressions of MDA were markedly decreased and the activities of SOD and GSH-Px in myocardium were significantly increased( P0. 05 or P0. 01) in the Ve treatment group. In addition, the activities of GSH-Px was found higher only in the ω-3 FA high treatment group compared with the PM_(2. 5)exposure group( P0. 05). Meanwhile, the levels of IL-1β and TNF-α in cardiac tissue had an obvious decrease trend with the increase of Ve and ω-3 FA.PM_(2. 5) exposure may increase inflammatory response and oxidative stress, supplementation with Ve and ω-3 FA could prevent the PM_(2. 5)-induced inflammatory reaction and oxidative stress damage by increasing the activities of SOD and GSH-Px.

The current study was conducted to observe the effects of fine particles( PM_(2. 5)) on energy metabolism and inflammation. The potential mechanism linking PM_(2. 5)and type 2 diabetes was explored.C57 BL /6 mice were randomly assigned to 2 groups. The mice in exposure group were intratracheal instilled of 15 mg / kg BW PM_(2. 5). The mice in control were instilled with saline. The instillation were conducted three times per week for 18 weeks. Insulin resistance test( ITT) and introperitoneal glucose tolerance test( IPGTT) were determined after the last exposure. The mRNA expression of IL-6, IL-17 A, MAPK, NF-κB and TNF-α were analyzed in liver and white adipose tissue.The body weight of mice in PM_(2. 5)group [( 24. 976 ± 0. 571) g] showed significant decrease compared to that in control mice [( 28. 452 ± 1. 520) g]( P0. 05). Blood glucose significantly increased in exposure group. The mice in exposure group showed insulin resistance and glucose tolerance impairment. The expression of IL-6 mRNAexpression in liver( 0. 373 ± 0. 185) and in white adipose tissue( 0. 364 ± 0. 089)increased along with the increase of TNF-α mRNA expression( 0. 008 ± 0. 002) in white adipose tissue.The PM_(2. 5)exposure may be associated with the development of diabetes. The potential mechanism could be the impaired glucose tolerance, elevated insulin resistance and the increase of inflammatory response.

To evaluate if selenium yeast could inhibit the rat lung injury induced by ambient fine particulate matter( PM_(2. 5) ).Fifty-six male SpragueDawley rats were randomly allocated in seven groups( n = 8 each). Saline control group, the rats were exposed to 0. 9% saline by instillation. PM_(2. 5) exposure group, rats were exposed to PM_(2. 5) by intra-tracheal instillation every other day for three times with the accumulated dose of 40 mg/kg. Selenium yeast treatment groups, three groups of rat were exposed to PM_(2. 5) . Then the rats were given low, middle and high dose of selenium yeast, and the doses were 8. 75, 17. 5 and 35 mg/kg, respectively. High dose selenium yeast control group, rats were given high dose of selenium yeast only. Solvent control group, therats were given 1% carboxymethyl cellulose. Saline and PM_(2. 5) were given in the first week. In the second week, selenium yeast and solvent were given by gavage. The rats were sacrificed 24 hours after the last gavage. The bronchoalveolar lavage fluid( BALF)was collected to count the neutrophils numbers and analyze the markers related to inflammation, oxidative stress and cell damage. The lung lobe that was not been lavaged was processed for light microscopic examination.The proportions of neutrophils in BALF and the pathologic scores of lung in PM_(2. 5) - exposed groups were significantly higher than control( P0. 05). Selenium yeast treatment caused decrease in tumor necrosis factor-α( TNF-α), interleukin-1β( IL-1β), lactate dehydrogenase( LDH), total protein( TP), alkaline phosphatase( AKP) and malondialdehyde( MDA) compared with the only PM_(2. 5) exposure group. Meanwhile, the dose-dependent increase in totalsuperoxide dismutase( T-SOD) and glutathione peroxidase( GSH-Px) activities were observed. There were no significant differences among the groups of saline control group, high dose selenium yeast control group and solvent control group.Selenium yeast treatment may protect against acute injury induced by PM_(2. 5) in rat lung.

Substantial epidemiological and experimental studies have shown that ambient fine particulate matter (PM

Inflammation and metabolic disorder are common pathophysiological conditions, which play a vital role in the development of obesity and type 2 diabetes. The purpose of this study was to explore the effects of caspase recruitment domain (CARD) 9 in the high fat diet (HFD)‐treated mice and attempt to find a molecular therapeutic target for obesity development and treatment. Sixteen male CARD9−/− and corresponding male WT mice were fed with normal diet or high fat diet, respectively, for 12 weeks. Glucose tolerance, insulin resistance, oxygen consumption and heat production of the mice were detected. The CARD9/MAPK pathway‐related gene and protein were determined in insulin‐responsive organs using Western blotting and quantitative PCR. The results showed that HFD‐induced insulin resistance and impairment of glucose tolerance were more severe in WT mice than that in the CARD9−/− mice. CARD9 absence significantly modified O2 consumption, CO 2 production and heat production. CARD9−/− mice displayed the lower expression of p38 MAPK, JNK and ERK when compared to the WT mice in both HFD‐ and ND‐treated groups. HFD induced the increase of p38 MAPK, JNK and ERK in WT mice but not in the CARD9−/− mice. The results indicated that CARD9 absence could be a vital protective factor in diet‐induced obesity via the CARD9/MAPK pathway, which may provide new insights into the development of gene knockout to improving diet‐induced obesity and metabolism disorder.

The current study was conducted to observe the effects of fine particulate matter (PM2.5) on human keratinocyte cell line (HaCaT) cells. The potential mechanism linking PM2.5 and skin was explored. HaCaT cells were cultured and then accessed in plate with PM2.5. Cell viability was tested by Cell Counting Kit-8. The mRNA and protein expression of Filaggrin, Loricrin, Involucrin, and Repetin were analyzed. The levels of Granulocyte-macrophage Colony Stimulating Factor, Thymic Stromal Lymphopoietin, Tumor Necrosis Factor-α, Interleukin-1α, and Interleukin-8 were detected in the supernatant of the HaCaT cell with enzyme-linked immunosorbent assay kits. Cell viability decreased with the increase in PM2.5. Compared with the control group, the protein expression of Filaggrin, Repetin, Involucrin, and Loricrin showed different expression patterns in PM2.5 treatment groups. The level of Tumor Necrosis Factor-α, Thymic Stromal Lymphopoietin, Interleukin-1α, and Interleukin-8 significantly increased in the cells treated with PM2.5. Ambient PM2.5 may increase the risk of eczema and other skin diseases. The relative mechanism may be associated with the impairment of the skin barrier and the elevation of inflammatory responses.

Air pollution has been accepted as an important contributor to asthma development and exacerbation. However, the evidence is limited in China. In this study, we investigated the acute effect of air pollution on asthma hospitalization in Shanghai, China. We applied over-dispersed generalized additive model adjusted for weather conditions, day of the week, long-term and seasonal trends. An interquartile range increase in the moving average concentrations of PM10, SO2, NO2 and BC on the concurrent day and previous day corresponded to 1.82%, 6.41%, 8.26% and 6.62% increase of asthmatic hospitalization, respectively. The effects of SO2 and NO2 were robust after adjustment for PM10. The associations appeared to be more evident in the cool season than in the warm season. Our results contribute to the limited data in the scientific literature on acute effects of air pollution on asthma in high exposure settings, which are typical in developing countries.

Background: Exposure to particulate matter ≤ 2.5 μm in diameter (PM2.5) increases blood pressure (BP) in humans and animal models. Abnormal activation of the sympathetic nervous system may have a role in the acute BP response to PM2.5 exposure. The mechanisms responsible for sympathetic nervous system activation and its role in chronic sustenance of hypertension in response to PM2.5 exposure are currently unknown. Objectives: We investigated whether central nervous system inflammation may be implicated in chronic PM2.5 exposure-induced increases in BP and sympathetic nervous system activation. Methods: C57BL/6J mice were exposed to concentrated ambient PM2.5 (CAPs) for 6 months, and we analyzed BP using radioactive telemetric transmitters. We assessed sympathetic tone by measuring low-frequency BP variability (LF-BPV) and urinary norepinephrine excretion. We also tested the effects of acute pharmacologic inhibitors of the sympathetic nervous system and parasympathetic nervous system. Results: Long-term CAPs exposure significantly increased basal BP, paralleled by increases in LF-BPV and urinary norepinephrine excretion. The increased basal BP was attenuated by the centrally acting α2a agonist guanfacine, suggesting a role of increased sympathetic tone in CAPs exposure–induced hypertension. The increase in sympathetic tone was accompanied by an inflammatory response in the arcuate nucleus of the hypothalamus, evidenced by increased expression of pro-inflammatory genes and inhibitor kappaB kinase (IKK)/nuclear factor–kappaB (NF-κB) pathway activation. Conclusion: Long-term CAPs exposure increases BP through sympathetic nervous system activation, which may involve hypothalamic inflammation. Citation: Ying Z, Xu X, Bai Y, Zhong J, Chen M, Liang Y, Zhao J, Liu D, Morishita M, Sun Q, Spino C, Brook RD, Harkema JR, Rajagopalan S. 2014. Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation. Environ Health Perspect 122:79–86; http://dx.doi.org/10.1289/ehp.1307151