Differential pulmonary toxicity and autoantibody formation in genetically distinct mouse strains following combined exposure to silica and diesel exhaust particles.

BACKGROUND: Inhalation of airborne particulate matter, such as silica and diesel exhaust particles, poses serious long-term respiratory and systemic health risks. Silica exposure can lead to silicosis and systemic autoimmune diseases, while DEP exposure is linked to asthma and cancer. Combined exposure to silica and DEP, common in mining, may have more severe effects. This study investigates the separate and combined effects of occupational-level silica and ambient-level DEP on lung injury, inflammation, and autoantibody formation in two genetically distinct mouse strains, thereby aiming at understanding the interplay between genetic susceptibility, particulate exposure, and disease outcomes. Silica and diesel exhaust particles were administered to mice via oropharyngeal aspiration. Assessments of lung injury and host response included in vivo lung micro-computed tomography, lung function tests, bronchoalveolar lavage fluid analysis including inflammatory cytokines and antinuclear antibodies, and histopathology with particle colocalization. RESULTS: The findings highlight the distinct effects of silica and diesel exhaust particles (DEP) on lung injury, inflammation, and autoantibody formation in C57BL/6J and NOD/ShiLtJ mice. Silica exposure elicited a well-established inflammatory response marked by inflammatory infiltrates, release of cytokines, and chemokines, alongside mild fibrosis, indicated by collagen deposition in the lungs of both C57BL/6J and NOD/ShilLtJ mice. Notably, these strains exhibited divergent responses in terms of respiratory function and lung volumes, as assessed through micro-computed tomography. Additionally, silica exposure induced airway hyperreactivity and elevated antinuclear antibody levels in bronchoalveolar lavage fluid, particularly prominent in NOD/ShiLtJ mice. Moreover, antinuclear antibodies correlated with extent of lung inflammation in NOD/ShiLTJ mice. Lung tissue analysis revealed DEP loaded macrophages and co-localization of silica and DEP particles. However, aside from contributing to airway hyperreactivity specifically in NOD/ShiLtJ mice, the ambient-level DEP did not significantly amplify the effects induced by silica. There was no evidence of synergistic or additive interaction between these specific doses of silica and DEP in inducing lung damage or inflammation in either of the mouse strains. CONCLUSION: Mouse strain variations exerted a substantial influence on the development of silica induced lung alterations. Furthermore, the additional impact of ambient-level DEP on these silica-induced effects was minimal.

Differential Pulmonary Toxicity and Autoantibody Formation in Genetically Distinct Mouse Strains Following Combined Exposure to Silica and Diesel Exhaust Particles.

Background: Inhalation of airborne particulate matter, such as silica and diesel exhaust particles, poses serious long-term respiratory health risks. Silica exposure can lead to silicosis and systemic autoimmune diseases, while DEP exposure is linked to asthma and cancer. Combined exposure to silica and DEP, common in mining, may have more severe effects. This study investigates the separate and combined effects of silica and DEP on lung injury, inflammation, and autoantibody formation in two genetically distinct mouse strains, thereby aiming at understanding the interplay between genetic susceptibility, particulate exposure, and disease outcomes. Silica and diesel exhaust particles were administered to mice via oropharyngeal aspiration. Assessments of lung injury and host response included in vivo lung micro-computed tomography, lung function tests, bronchoalveolar lavage fluid analysis including inflammatory cytokines and antinuclear antibodies, and histopathology with particle colocalization. Results: Silica exposure elicited a well-established inflammatory response marked by inflammatory infiltrates, release of cytokines, and chemokines, alongside limited fibrosis, indicated by collagen deposition in the lungs of both C57BL/6J and NOD/ShilLtJ mice. Notably, these strains exhibited divergent responses in terms of respiratory function and lung volumes, as assessed through micro-computed tomography. Additionally, silica exposure induced airway hyperreactivity and elevated antinuclear antibody levels in bronchoalveolar lavage fluid, particularly prominent in NOD/ShiLtJ mice. Lung tissue analysis revealed DEP loaded macrophages and co-localization of silica and DEP particles. Conclusion: Mouse strain variations exerted a substantial influence on the development of silica induced lung alterations. Furthermore, the additional impact of diesel exhaust particles on these silica-induced effects was minimal.

A cluster randomised controlled trial of a secondary school intervention to reduce intake of sugar-sweetened beverages: Mid-intervention impact of switchURsip environmental strategies.

ISSUE ADDRESSED: Secondary schools provide an opportune setting for interventions addressing excessive sugar-sweetened beverage (SSB) intake in adolescence. This trial aimed to assess the impact of school environmental strategies, delivered as part of a broader intervention, among Year 7-9 students' SSB consumption. METHODS: Between March and July 2018, we conducted a cluster randomised controlled trial with 862 students attending six secondary schools (3 intervention and 3 control) in New South Wales. The intervention targeted SSB availability, placement, promotion and pricing, and increased availability and promotion of water. Control schools followed their usual programmes. Primary outcomes included mean daily SSB consumption (millilitres) and mean daily percentage energy from SSB (kilojoules). Sub-group analysis explored primary outcomes for gender, school year level and frequency of canteen use. RESULTS: Of the 2265 eligible students, 1092 (50.2%) provided active parental consent and 940 (86.0%) participated in baseline data collection. No significant differences were observed between groups at follow-up for mean daily SSBs consumed (-10.17 mL, CI: -24.78; 45.12, P = 0.57) or mean daily percentage energy from SSBs (-0.20%, CI: -0.87; 0.47, P = .56). Significant effects were observed among girls in intervention compared to girls in control schools for mean daily SSB consumption (-52.02 mL, CI 99.8; 94.14, P = .03) and mean daily percentage of energy from SSBs (-0.90%, CI: -1.82; 0.02, P = .05). CONCLUSIONS: At 3-month mid-intervention evaluation, the intervention failed to impact on mean daily consumption and mean percentage energy from SSBs, overall. However, an intervention effect was observed in girls. The limited overall effect is likely due to inadequate intervention dose related to the short duration, limiting opportunities for schools to fully implement the environmental strategies. SO WHAT?: A longer intervention duration with additional implementation support to allow adequate time to embed the strategies within the school is recommended. Implementation support strategies would ensure staff are supported throughout the process.

Inhibition of Fatty Acid Synthesis Aggravates Brain Injury, Reduces Blood-Brain Barrier Integrity and Impairs Neurological Recovery in a Murine Stroke Model.

Inhibition of fatty acid synthesis (FAS) stimulates tumor cell death and reduces angiogenesis. When SH-SY5Y cells or primary neurons are exposed to hypoxia only, inhibition of FAS yields significantly enhanced cell injury. The pathophysiology of stroke, however, is not only restricted to hypoxia but also includes reoxygenation injury. Hence, an oxygen-glucose-deprivation (OGD) model with subsequent reoxygenation in both SH-SY5Y cells and primary neurons as well as a murine stroke model were used herein in order to study the role of FAS inhibition and its underlying mechanisms. SH-SY5Y cells and cortical neurons exposed to 10 h of OGD and 24 h of reoxygenation displayed prominent cell death when treated with the Acetyl-CoA carboxylase inhibitor TOFA or the fatty acid synthase inhibitor cerulenin. Such FAS inhibition reduced the reduction potential of these cells, as indicated by increased NADH2 +/NAD+ ratios under both in vitro and in vivo stroke conditions. As observed in the OGD model, FAS inhibition also resulted in increased cell death in the stroke model. Stroke mice treated with cerulenin did not only display increased brain injury but also showed reduced neurological recovery during the observation period of 4 weeks. Interestingly, cerulenin treatment enhanced endothelial cell leakage, reduced transcellular electrical resistance (TER) of the endothelium and contributed to poststroke blood-brain barrier (BBB) breakdown. The latter was a consequence of the activated NF-κB pathway, stimulating MMP-9 and ABCB1 transporter activity on the luminal side of the endothelium. In conclusion, FAS inhibition aggravated poststroke brain injury as consequence of BBB breakdown and NF-κB-dependent inflammation.

Lithium modulates miR-1906 levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation.

Lithium is neuroprotective in preclinical stroke models. In addition to that, poststroke neuroregeneration is stimulated upon transplantation of mesenchymal stem cells (MSCs). Preconditioning of MSCs with lithium further enhances the neuroregenerative potential of MSCs, which act by secreting extracellular vesicles (EVs). The present work analyzed whether MSC preconditioning with lithium modifies EV secretion patterns, enhancing the therapeutic potential of such derived EVs (Li-EVs) in comparison with EVs enriched from native MSCs. Indeed, Li-EVs significantly enhanced the resistance of cultured astrocytes, microglia, and neurons against hypoxic injury when compared with controls and to native EV-treated cells. Using a stroke mouse model, intravenous delivery of Li-EVs increased neurological recovery and neuroregeneration for as long as 3 months in comparison with controls and EV-treated mice, albeit the latter also showed significantly better behavioral test performance compared with controls. Preconditioning of MSCs with lithium also changed the secretion patterns for such EVs, modifying the contents of various miRNAs within these vesicles. As such, Li-EVs displayed significantly increased levels of miR-1906, which has been shown to be a new regulator of toll-like receptor 4 (TLR4) signaling. Li-EVs reduced posthypoxic and postischemic TLR4 abundance, resulting in an inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, decreased proteasomal activity, and declined both inducible NO synthase and cyclooxygenase-2 expression, all of which culminated in reduced levels of poststroke cerebral inflammation. Conclusively, the present study demonstrates, for the first time, an enhanced therapeutic potential of Li-EVs compared with native EVs, interfering with a novel signaling pathway that yields both acute neuroprotection and enhanced neurological recovery.

Increased telomere length and mtDNA copy number induced by multi-walled carbon nanotube exposure in the workplace.

Carbon nanotubes (CNTs) except MWCNT-7 have been classified as Group 3 ["Not classifiable as to its carcinogenicity to humans"] by the IARC. Despite considerable mechanistic evidence in vitro/in vivo, the classification highlights a general lack of data, especially among humans. In our previous study, we reported epigenetic changes in the MWCNT exposed workers. Here, we evaluated whether MWCNT can also cause alterations in aging related features including relative telomere length (TL) and/or mitochondrial copy number (mtDNAcn). Relative TL and mtDNAcn were measured on extracted DNA from peripheral blood from MWCNT exposed workers (N = 24) and non-exposed controls (N = 43) using a qPCR method. A higher mtDNAcn and longer TL were observed in MWCNT exposed workers when compared to controls. Independent of age, sex, smoking behavior, alcohol consumption and BMI, MWCNT-exposure was associated with an 18.30 % increase in blood TL (95 % CI: 7.15-30.62 %; p = 0.001) and 35.21 % increase in mtDNAcn (95 % CI: 19.12-53.46 %). Our results suggest that exposure to MWCNT can induce an increase in the mtDNAcn and TL; however, the mechanistic basis or consequence of such change requires further experimental studies.

Distinct autophagy-apoptosis related pathways activated by Multi-walled (NM 400) and Single-walled carbon nanotubes (NIST-SRM2483) in human bronchial epithelial (16HBE14o-) cells.

Given the recent development in the field of particle and fibre toxicology, parallels have been drawn between Carbon nanotubes (CNTs) and asbestos. It is now established that both multi-walled (MWCNTs) and single-walled (SWCNTs) carbon nanotubes might contribute to pulmonary disease. Although multiple mechanisms might be involved in CNT induced pathogenesis, systematic understanding of the relationship between different CNT exposure (MWCNT vs SWCNT) and autophagy/ apoptosis/ necrosis, in human lung epithelial cells remains limited. In this study, we demonstrate that exposure to MWCNT (NM-400), but not SWCNT (NIST-SRM2483), leads to an autophagic response after acute exposure (24 h). MWCNT exposure was characterized by an increase in anti-apoptotic BCL2, downregulation of executor Caspase-3/7 and increase in expression of genes from the autophagy machinery. For SWCNT exposure however, we observed an overexpression of executor Caspase-3/7 and upregulation of pro-apoptotic BAX; enrichment for processes like cornification, apoptotic process, cell differentiation from proteomic analysis. These results clearly indicate a major difference in the pathways initiated by the CNTs, in vitro. While the present study design provides mechanistic understanding after an acute exposure for the tested CNTs, we believe that the information obtained here would have relevance in better understanding of CNT toxicity and pathogenesis in general.

A randomised controlled trial of an intervention to increase the implementation of a healthy canteen policy in Australian primary schools: study protocol.

BACKGROUND: The implementation of healthy school canteen policies has been recommended as a strategy to help prevent unhealthy eating and excessive weight gain. Internationally, research suggests that schools often fail to implement practices consistent with healthy school canteen policies. Without a population wide implementation, the potential benefits of these policies will not be realised. The aim of this trial is to assess the effectiveness of an implementation intervention in increasing school canteen practices consistent with a healthy canteen policy of the New South Wales (NSW), Australia, government known as the 'Fresh Tastes @ School NSW Healthy School Canteen Strategy'. METHODS/DESIGN: The parallel randomised trial will be conducted in 70 primary schools located in the Hunter region of New South Wales, Australia. Schools will be eligible to participate if they are not currently meeting key components of the healthy canteen policy. Schools will be randomly allocated after baseline data collection in a 1:1 ratio to either an intervention or control group using a computerised random number function in Microsoft Excel. Thirty-five schools will be selected to receive a multi-component intervention including implementation support from research staff, staff training, resources, recognition and incentives, consensus and leadership strategies, follow-up support and implementation feedback. The 35 schools allocated to the control group will not receive any intervention support as part of the research trial. The primary outcome measures will be i) the proportion of schools with a canteen menu that does not contain foods or beverages restricted from regular sale ('red' and 'banned' items) and ii) the proportion of schools where healthy canteen items ('green' items) represent the majority (>50%) of products listed on the menu. Outcome data will be collected via a comprehensive menu audit, conducted by dietitians blind to group allocation. Intervention effectiveness will be assessed using logistic regression models adjusting for baseline values. DISCUSSION: The proposed trial will represent a novel contribution to the literature, being the first randomised trial internationally to examine the effectiveness of an intervention to facilitate implementation of a healthy canteen policy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000311752.

Inhibiting TGF-beta signaling restores immune surveillance in the SMA-560 glioma model.

Transforming growth factor-beta (TGF-beta) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-beta activity in gliomas is to disrupt the signaling cascade at the level of the TGF-beta receptor I (TGF-betaRI) kinase, thus abrogating TGF-beta-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-betaRI kinase inhibitor, was evaluated for its therapeutic potential in cell culture and in an in vivo glioma model. The syngeneic, orthotopic glioma model SMA-560 was used to evaluate the efficacy of SX-007. Cells were implanted into the striatum of VM/Dk mice. Dosing began three days after implantation and continued until the end of the study. Efficacy was established by assessing survival benefit. SX-007 dosed at 20 mg/kg p.o. once daily (q.d.) modulated TGF-beta signaling in the tumor and improved the median survival. Strikingly, approximately 25% of the treated animals were disease-free at the end of the study. Increasing the dose to 40 mg/kg q.d. or 20 mg/kg twice daily did not further improve efficacy. The data suggest that SX-007 can exert a therapeutic effect by reducing TGF-beta-mediated invasion and reversing immune suppression. SX-007 modulates the TGF-beta signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF-beta-mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-betaRI inhibitor may be useful in the treatment of glioblastoma.