Zinc oxide nanoparticles induce acute lung injury via oxidative stress-mediated mitochondrial damage and NLRP3 inflammasome activation: In vitro and in vivo studies.

The widespread application of zinc oxide nanoparticles (ZnO-NPs) brings convenience to our lives while also renders threats to public health and ecological environment. The lung has been recognized as a primary target of ZnO-NPs, however, the detrimental effects and mechanism of ZnO-NPs on the respiratory system have not been thoroughly characterized so far. To investigate the effect of ZnO-NPs on acute lung injury (ALI), Sprague Dawley rats were intratracheally instilled with ZnO-NPs suspension at doses of 1, 2, and 4 mg/kg/day for 3 consecutive days. Our study revealed that ZnO-NPs induced ALI in rats characterized by increased airway resistance, excessive inflammatory response and lung histological damage. In addition, we identified several molecular biomarkers related to the potential mechanism of ZnO-NP-induced ALI, including oxidative stress, mitochondrial damage, and NLRP3 inflammasome activation. The results of in vitro experiments showed that the viability of A549 cells decreased with the increase in ZnO-NPs concentration. Meanwhile, it was also found that ZnO-NP treatment induced the production of ROS, the decrease in mitochondrial membrane potential and activation of NLRP3 inflammasome in A549 cells. Furthermore, to explore the underlying molecular mechanisms of ZnO-NP-induced ALI, N-acetyl-L-cysteine (a ROS scavenger), Cyclosporin A (an inhibitor for mitochondrial depolarization) and Glibenclamide (an inhibitor for NLRP3 inflammasome activity) were used to pre-treat A549 cells before ZnO-NPs stimulation in the in vitro experiments, respectively. The results from this study suggested that ZnO-NP-induced ROS production triggered the accumulation of damaged mitochondria and assembly of NLRP3 inflammatory complex, leading to maturation and release of IL-1ß. Moreover, ZnO-NP-induced NLRP3 inflammasome activation was partly mediated by mitochondrial damage. Taken together, our study suggested that ZnO-NPs induced ALI through oxidative stress-mediated mitochondrial damage and NLRP3 inflammasome activation and provided insight into the mechanisms of ZnO-NPs-induced ALI.

The Association between Circulating 25-Hydroxyvitamin D and Carotid Intima-Media Thickness Is Mediated by Gut Microbiota and Fecal and Serum Metabolites in Adults.

SCOPE: Vitamin D is vital to cardiovascular health. This study examines the association between plasma 25-hydroxyvitamin D (25[OH]D) and the progression of carotid intima-media thickness (cIMT) and identifies the potential mediating biomarkers of gut microbiota and metabolites in adults. METHODS AND RESULTS: This 9-year prospective study includes 2975 subjects with plasma 25(OH)D at baseline and determined cIMT every 3 years. Higher circulating 25(OH)D is associated with decreased odds of higher (≥median) 9-year cIMT changes at the common carotid artery (hΔCCA-cIMT) (p-trend < 0.001). Multivariable-adjusted OR (95%CI) of hΔCCA-cIMT for tertiles 2 and 3 (vs. 1) of 25(OH)D is 0.87 (0.73-1.04) and 0.68 (0.57-0.82). Gut microbiome and metabolome analysis identify 18 biomarkers significantly associated with both 25(OH)D and hΔCCA-cIMT, including three microbial genera, seven fecal metabolites, eight serum metabolites, and pathway of synthesis and degradation of ketone bodies. Mediation/path analyses show the scores generated from the overlapped differential gut microbiota, fecal and serum metabolites, and serum acetoacetic acid alone could mediate the beneficial association between 25(OH)D and hΔCCA-cIMT by 10.8%, 23.1%, 59.2%, and 62.0% (all p < 0.05), respectively. CONCLUSIONS: These findings show a beneficial association between plasma 25(OH)D and the CCA-cIMT progression. The identified multi-omics biomarkers provide novel mechanistic insights for the epidemiological association.

Combined exposure of heat stress and ozone enhanced cognitive impairment via neuroinflammation and blood brain barrier disruption in male rats.

BACKGROUND: Heat stress (HS) exposure has been linked to cognitive dysfunction. In reality, high temperature does not occur alone in environment, and ozone (O3) and heatwaves usually co-exist in atmospheric environment. However, whether O3 exposure exacerbates HS-induced cognitive impairment and the potential underlying mechanisms have not been explored experimentally. The aim of this study was to determine the co-effects and mechanisms of HS and O3 on the cognitive dysfunction. METHODS: 48 Sprague Dawley male rats were randomly divided into 4 groups: control, HS, O3 and HS plus O3 (HO3) groups. Rats in HS and HO3 group were exposed to 40 °C every morning from 9:00 to 12:00 for 15 consecutive days. While rats in O3 and HO3 groups were exposed to 0.7 ppm O3 the same day from 14:00 to 17:00 for 15 days. Cognitive performance was examined with Morris water maze test. Neurodegeneration, glial activation, neuroinflammation, blood brain barrier (BBB) disruption and apoptosis were evaluated by Western blot, Elisa, immunohistochemistry and immunofluorescence staining. RESULTS: HS induced cognitive decline and neuronal damage in rats. Further studies showed that exposure of rats to HS could also induce glial activation, neuroinflammation and neuronal apoptosis in hippocampus, and decrease in the expressions of ZO-1, claudin-5 and occluding, indicative of BBB disruption. Impressively, the neuronal effects induced by HS, as depicted above, could be worsened by co-exposure to O3 in rats. CONCLUSIONS: Co-exposure to O3 promotes HS-induced cognitive impairment in rats possibly through glial-mediated neuroinflammation and BBB disruption.

Work-Related Stress and Occurrence of Cardiovascular Disease: A 13-Year Prospective Study.

OBJECTIVE: The aim of the study is to investigate the influence of work-related psychological and physical stresses on risk of cardiovascular disease (CVD). METHODS: A total of 5651 CVD-free participants older than 50 years from the Survey of Health, Ageing and Retirement in Europe were followed up for 13 years to detect incident CVD. Work-related stress was assessed using job strain and job reward questionnaire. Cox regression model was used to estimate the association. RESULTS: High physical demands (hazard ratio [HR], 1.30) and low reward (HR, 1.19) compared with their counterparts, as well as active physical jobs (HR, 1.41) and high physical strain (HR, 1.45) in comparison with low physical strain were associated with higher risk of incident CVD after adjusting for confounders. However, combining physically stressful jobs with low reward did not further increase the CVD risk. CONCLUSIONS: Avoiding physically stressful jobs or providing appropriate reward may reduce the occurrence of CVD.

The gut microbiota-bile acid axis links the positive association between chronic insomnia and cardiometabolic diseases.

Evidence from human cohorts indicates that chronic insomnia is associated with higher risk of cardiometabolic diseases (CMD), yet whether gut microbiota plays a role is unclear. Here, in a longitudinal cohort (n = 1809), we find that the gut microbiota-bile acid axis may link the positive association between chronic insomnia and CMD. Ruminococcaceae UCG-002 and Ruminococcaceae UCG-003 are the main genera mediating the positive association between chronic insomnia and CMD. These results are also observed in an independent cross-sectional cohort (n = 6122). The inverse associations between those gut microbial biomarkers and CMD are mediated by certain bile acids (isolithocholic acid, muro cholic acid and nor cholic acid). Habitual tea consumption is prospectively associated with the identified gut microbiota and bile acids in an opposite direction compared with chronic insomnia. Our work suggests that microbiota-bile acid axis may be a potential intervention target for reducing the impact of chronic insomnia on cardiometabolic health.

Human Gut Antibiotic Resistome and Progression of Diabetes.

The antibiotic resistance crisis underlies globally increasing failures in treating deadly bacterial infections, largely due to the selection of antibiotic resistance genes (ARG) collection, known as the resistome, in human gut microbiota. So far, little is known about the relationship between gut antibiotic resistome and host metabolic disorders such as type 2 diabetes (T2D). Here, metagenomic landscape of gut antibiotic resistome is profiled in a large multiomics human cohort (n = 1210). There is a significant overall shift in gut antibiotic resistome structure among healthy, prediabetes, and T2D groups. It is found that larger ARG diversity is associated with a higher risk of T2D. The novel diabetes ARG score is positively associated with glycemic traits. Longitudinal validation analysis confirms that the ARG score is associated with T2D progression, characterized by the change of insulin resistance. Collectively, the data describe the profiles of gut antibiotic resistome and support its close relationship with T2D progression.

Working life job strain status and cognitive aging in Europe: A 12-year follow-up study.

BACKGROUND: To examine the association of job strain with cognitive ability and the influence of life-course job strain on later life cognitive decline. METHODS: Data were derived from six waves of the Survey of Health, Aging, and Retirement in Europe. The study sample consists of 13349 participants aged 50 to 98 years at wave 2 and has been followed up for 12-years. Job strain status across working life was assessed using a short demand-control job strain model containing two core dimensions: job demands and job control collected in wave 3. Cognitive abilities concerning episodic memory was assessed by immediate recall and delayed recall tests, executive function was evaluated by verbal fluency test collected in all waves (waves 2-7) except wave 3. Mixed-effects model was used to estimate working life job strain and its cumulative effect on cognitive decline. RESULTS: Both passive and high strain jobs were associated with lower levels of cognitive ability (episodic memory and verbal fluency) in comparison with active job. Long exposure to active- or low strain-job was associated with higher cognitive ability whereas long exposure to passive job or moderate duration of high strain job was associated with lower cognitive ability. The rate of memory decline was positively related to moderate duration of passive job and negatively related to long-term exposure to low strain job. LIMITATIONS: Information on working conditions was based on self-reported recollections. CONCLUSIONS: Working life variation in job strain status and their duration may explain individual differences in cognitive ability in later life.

Impact of effort reward imbalance at work on suicidal ideation in ten European countries: The role of depressive symptoms.

BACKGROUND: Evidence of the association between effort reward imbalance (ERI) and suicidal ideation is sparse. This study examined the influence of ERI at work on suicidal ideation and the mediating effect of depressive symptoms. METHODS: There were 4963 workers aged 50+ without suicidal ideation at baseline in the Survey of Health, Aging and Retirement in Europe, these workers were followed-up for 8-years to detect incident suicidal ideation. ERI was measured by a short ERI questionnaire. Suicidal ideation was evaluated by one item derived from the 12-item Europe-depression scale, and depressive symptoms were assessed by the remaining 11 items in the scale. Cox models were employed to explore the relationship adjusting for potential confounders. Mediation analysis was used to test the mediating effect of depressive symptoms. RESULTS: A significantly higher incidence of suicidal ideation was related with high effort (HR = 1.51) and low reward (HR = 1.42), respectively. A high effort-low reward imbalance was associated with even higher risk of suicidal ideation (HR = 1.96) as compared to low effort-high reward combination. The association was varied by gender, region, education and household income. Depressive symptoms mediated a modest proportion (natural indirect effect 14.4%) of the total association between ERI and suicidal ideation. LIMITATION: Suicidal ideation definition based on self-administered questionnaires which could lead to false negatives. And some unmeasured confounders might have biased the results. CONCLUSIONS: Efforts in promoting balanced effort-reward at work may reduce suicidal ideation among working population aged 50+. Avoiding depressive symptoms may further enhance such efforts.