Exploiting the Potential of Iridium(III) bis-Nitrone Complexes as Phosphorogenic Bifunctional Reagents for Phototheranostics.

Cross-linking strategies have found wide applications in chemical biology, enabling the labeling of biomolecules and monitoring of protein-protein interactions. Nitrone exhibits remarkable versatility and applicability in bioorthogonal labeling due to its high reactivity with strained alkynes via the strain-promoted alkyne-nitrone cycloaddition (SPANC) reaction. In this work, four cyclometalated iridium(III) polypyridine complexes functionalized with two nitrone units were designed as novel phosphorogenic bioorthogonal reagents for bioimaging and phototherapeutics. The complexes showed efficient emission quenching, which is attributed to an efficient nonradiative decay pathway via the low-lying T1/S0 minimum energy crossing point (MECP), as revealed by computational studies. However, the complexes displayed significant emission enhancement and lifetime extension upon reaction with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) derivatives. In particular, they showed a remarkably higher reaction rate toward a bis-cyclooctyne derivative (bis-BCN) compared with its monomeric counterpart (mono-BCN). Live-cell imaging and (photo)cytotoxicity studies revealed higher photocytotoxicity in bis-BCN-pretreated cells, which is ascribed to the enhanced singlet oxygen (1O2) photosensitization resulting from the elimination of the nitrone-associated quenching pathway. Importantly, the cross-linking properties and enhanced reactivity of the complexes make them highly promising candidates for the development of hydrogels and stapled/cyclized peptides, offering intriguing photophysical, photochemical, and biological properties. Notably, a nanosized hydrogel (2-gel) demonstrated potential as a drug delivery system, while a stapled peptide (2-bis-pDIKK) exhibited p53-Mdm2 inhibitory activity related to apoptosis and a cyclized peptide (2-bis-RGD) showed cancer selectivity.

Exploring alkali-treated corn cob for high-rate removal of NOX and SO2 from flue gas: Focus on carbon release capacity, removal performance, and comparison with conventional carbon sources.

This investigation explored the potential of utilizing alkali-treated corn cob (CC) as a solid carbon source to improve NOX and SO2 removal from flue gas. Leaching experiments unveiled a hierarchy of chemical oxygen demand release capacity: 0.03 mol/L alkali-treated CC > 0.02 mol/L > 0.01 mol/L > 0.005 mol/L > control. In NOX and SO2 removal experiments, as the inlet NOX concentration rose from 300 to 1000 mg/m3, the average NOX removal efficiency increased from 58.56 % to 80.00 %. Conversely, SO2 removal efficiency decreased from 99.96 % to 91.05 %, but swiftly rebounded to 98.56 % by day 18. The accumulation of N intermediates (NH4+, NO3-, NO2-) increased with escalating inlet NOX concentration, while the accumulation of S intermediates (SO42-, SO32-, S0) varied based on shifts in the population of functional bacteria. The elevation in inlet NOX concentration stimulated the growth of denitrifying bacteria, enhancing NOX removal efficiency. Concurrently, the population of nitrate-reducing sulfur-oxidizing bacteria and sulfate-reducing bacteria expanded, aiding in the accumulation of S0 and the removal of SO2. The comparison experiments on carbon sources confirmed the comparable NOX and SO2 removal efficiencies of alkali-treated CC and glucose, yet underscored differences in intermediates accumulation due to distinct genus structures.

Effect of Nitrosyl Iron Complex with 3,4-Dichlorothiophenolyls on the Level of Cyclic Nucleotide In Vitro.

The effect of a promising NO donor, a binuclear nitrosyl iron complex (NIC) with 3,4-dichlorothiophenolyls [Fe2(SC6H3Cl2)2(NO)4], on the adenylate cyclase and soluble guanylate cyclase enzymatic systems was studied. In in vitro experiments, this complex increased the concentration of important secondary messengers, such as cAMP and cGMP. An increase of their level by 2.4 and 4.5 times, respectively, was detected at NIC concentration of 0.1 mM. The ligand of the complex, 3,4-dichlorothiophenol, produced a less pronounced effect on adenylate cyclase. It was shown that the effect of this complex on the activity of soluble guanylate cyclase was comparable to the effect of anionic nitrosyl complex with thiosulfate ligands that exhibits vasodilating and cardioprotective properties.

Long-term ambient air pollution exposure and renal function and biomarkers of renal disease.

BACKGROUND: Despite accumulating evidence of an association between air pollution and renal disease, studies on the association between long-term exposure to air pollution and renal function are still contradictory. This study aimed to investigate this association in a large population with relatively low exposure and with improved estimation of renal function as well as renal injury biomarkers. METHODS: We performed a cross-sectional analysis in the middle-aged general population participating in the Swedish CardioPulmonary bioImaging Study (SCAPIS; n = 30 154). Individual 10-year exposure to total and locally emitted fine particulate matter (PM2.5), inhalable particulate matter (PM10), and nitrogen oxides (NOx) were modelled using high-resolution dispersion models. Linear regression models were used to estimate associations between exposures and estimated glomerular filtration rate (eGFR, combined creatinine and cystatin C) and serum levels of renal injury biomarkers (KIM-1, MCP-1, IL-6, IL-18, MMP-2, MMP-7, MMP-9, FGF-23, and uric acid), with consideration of potential confounders. RESULTS: Median long-term PM2.5 exposure was 6.2 µg/m3. Almost all participants had a normal renal function and median eGFR was 99.2 mL/min/1.73 m2. PM2.5 exposure was associated with 1.3% (95% CI 0.6, 2.0) higher eGFR per 2.03 µg/m3 (interquartile range, IQR). PM2.5 exposure was also associated with elevated serum matrix metalloproteinase 2 (MMP-2) concentration, with 7.2% (95% CI 1.9, 12.8) higher MMP-2 per 2.03 µg/m3. There was a tendency towards an association between PM10 and higher levels of uric acid, but no associations were found with the other biomarkers. Associations with other air pollutants were null or inconsistent. CONCLUSION: In this large general population sample at low exposure levels, we found a surprising association between PM2.5 exposure and a higher renal filtration. It seems unlikely that particle function would improve renal function. However, increased filtration is an early sign of renal injury and may be related to the relatively healthy population at comparatively low exposure levels. Furthermore, PM2.5 exposure was associated with higher serum concentrations of MMP-2, an early indicator of renal and cardiovascular pathology.

Catalytic Ozonation of Low Concentration Toluene over MnFeOx-USY Catalyst: Effects of Interactions between Catalytic Components and Introduction of Gas Phase NOx.

A series of Mn and Fe metal oxide catalysts loaded onto USY, as well as single metal oxides, were prepared and characterized. The effects of interactions between the catalytic components and the introduction of gas phase NO on the catalytic ozonation of toluene were investigated. Characterization showed that there existed strong interactions between MnOx, FeOx, and USY, which enhanced the content of oxygen vacancies and acid sites of the catalysts and thus boosted the generation of reactive oxygen species and the adsorption of toluene. The MnFeOx-USY catalyst with MnOx and FeOx dimetallic oxides exhibited the most excellent performance of catalytic ozonation of toluene. On the other hand, the presence of NOx in reaction gas mixtures significantly promoted both toluene conversion and mineralization, which was attributed to the formation of nitrate species on the catalysts surface and thus the increase of both acid sites and toluene oxidation sites. Meanwhile, the reaction mechanism between O3 and C7H8 was modified in which the strong interactions between MnOx, FeOx, and USY accelerated the reaction progress based on the L-H route. In addition, the formation of the surface nitrate species not only promoted reaction progress following the L-H route but also resulted in the occurrence of the reaction via the E-R route.

Mitigation of Fetal Radiation Injury from Mid-Gestation Total-body Irradiation by Maternal Administration of Mitochondrial-Targeted GS-Nitroxide JP4-039.

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal radiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal radiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)-nitroxide radiation mitigator JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total-body irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time-and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed a significant reduction of mitochondrial function in the fetal brain after 3 Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. One day after TBI (E14.5) maternal administration of JP4-039, which passes through the placenta, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. Treatment also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. JP4-039 administration following irradiation resulted in increased survival of pups. These findings indicate that JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure.

Nitroxide radical conjugated ovalbumin theranostic nanosystem for enhanced dendritic cell-based immunotherapy and T1 magnetic resonance imaging.

Melanoma, known for its aggressive metastatic nature, presents a formidable challenge in cancer treatment, where conventional therapies often fall short. This study introduces a pioneering approach utilizing metal-free nanosystem as tumor vaccines, spotlighting their potential in revolutionizing melanoma treatment. This work employed organic nitroxides, specifically 4-carboxy-TEMPO, in combination with chitosan (CS), to create a novel nanocomposite material - the CS-TEMPO-OVA nanovaccines. This composition not only improves biocompatibility and extends blood circulation time of TEMPO but also marks a significant departure from traditional gadolinium-based contrast agents in MRI technology, addressing safety concerns. CS-TEMPO-OVA nanovaccines demonstrate excellent biocompatibility at both the cellular and organoid level. They effectively stimulate bone marrow-derived dendritic cells (BMDCs), which in turn promote the maturation and activation of T cells. This ultimately leads to a strong production of essential cytokines. These nanovaccines serve a dual purpose as both therapeutic and preventive. By inducing an immune response, activating cytotoxic T cells, and promoting macrophage M1 polarization, they effectively inhibit melanoma growth and enhance survival in mouse models. When combined with αPD-1, the CS-TEMPO-OVA nanovaccines significantly bolster the infiltration of cytotoxic T lymphocytes (CTLs) within tumors, sparking a powerful systemic antitumor response that effectively curbs tumor metastasis. The ability of these nanovaccines to control both primary (subcutaneous) and metastatic B16-OVA tumors highlights their remarkable efficacy. Furthermore, the CS-TEMPO-OVA nanovaccine can be administered in vivo via both intravenous and intramuscular routes, both of which effectively enhance the T1 contrast of magnetic resonance imaging in tumor tissue. This study offers invaluable insights into the integrated application of these nanovaccines in both clinical diagnostics and treatment, marking a significant stride in cancer research and patient care.

Beyond lung cancer: air pollution and bladder, breast and prostate cancer incidence.

BACKGROUND: The carcinogenicity of air pollution and its impact on the risk of lung cancer is well known; however, there are still knowledge gaps and mixed results for other sites of cancer. METHODS: The current study aimed to evaluate the associations between ambient air pollution [fine particulate matter (PM2.5) and nitrogen oxides (NOx)] and cancer incidence. Exposure assessment was based on historical addresses of >900 000 participants. Cancer incidence included primary cancer cases diagnosed from 2007 to 2015 (n = 30 979). Cox regression was used to evaluate the associations between ambient air pollution and cancer incidence [hazard ratio (HR), 95% CI]. RESULTS: In the single-pollutant models, an increase of one interquartile range (IQR) (2.11 µg/m3) of PM2.5 was associated with an increased risk of all cancer sites (HR = 1.51, 95% CI: 1.47-1.54), lung cancer (HR = 1.73, 95% CI: 1.60-1.87), bladder cancer (HR = 1.50, 95% CI: 1.37-1.65), breast cancer (HR = 1.50, 95% CI: 1.42-1.58) and prostate cancer (HR = 1.41, 95% CI: 1.31-1.52). In the single-pollutant and the co-pollutant models, the estimates for PM2.5 were stronger compared with NOx for all the investigated cancer sites. CONCLUSIONS: Our findings confirm the carcinogenicity of ambient air pollution on lung cancer and provide additional evidence for bladder, breast and prostate cancers. Further studies are needed to confirm our observation regarding prostate cancer. However, the need for more research should not be a barrier to implementing policies to limit the population's exposure to air pollution.

[Personal nitrogen oxides exposure levels and related influencing factors in adults over 35 years old in Tianjin and Shanghai].

OBJECTIVE: To investigate personal exposures to nitrogen oxides (NOX) and nitrogen di-oxide (NO2) and the influence of baseline personal characteristics, living environment and daily activity patterns of the participants on the exposures among adults over 35 in Tianjin and Shanghai. METHODS: In this panel study, 91 healthy nonsmoking adults aged over 35 from Tianjin and Shanghai participated in our study. The study was conducted in summer and winter. The participants were followed for three times with an interval of at least two weeks. Only participants in Shanghai were followed once in winter because of the COVID-19 pandemic. Twenty-seven participants completed follow-up visits in both seasons. We measured their 24 h personal exposures to NOX and NO2and collected their baseline and time-activity information through questionnaire/diary. The linear mixed model was used to analyze the associations between potential influencing factors and personal NOX and NO2 exposure levels. RESULTS: There were 349 follow-up visits with valid 24 h personal NO2 and NOX exposure measurements in the two cities. The ave-rage 24 h personal exposures to NO2 and NOX (volume fraction) in Tianjin participants were 18.0×10-9 and 26.2×10-9 in summer, and 31.0×10-9 and 54.9×10-9 in winter, respectively; and the average 24 h personal exposures to NO2 and NOX in Shanghai participants were 38.7×10-9 and 100.0×10-9 in summer, and 45.5×10-9 and 139.2×10-9 in winter, respectively. The results of univariate regression analysis showed that their personal NOX exposure levels were significantly associated with city, season, gender, average daily cooking times, and ambient NO2 concentrations measured at fixed-site monitoring stations. In addition to the above factors, the personal NOX exposure levels were also significantly associated with educational level and the personal NO2 exposure levels were also significantly associated with passive smoking, average daily home time, cooking energy type, residential distance from main traffic road, and use of kitchen ventilators. Multivariate regression analysis showed that the personal exposure levels of NO2 and NOX were significantly lower in Tianjin than that in Shanghai, were significantly lower in summer than that in winter, and were significantly and positively associated with ambient NO2 concentrations measured at fixed-site monitoring stations. In addition, personal NOX exposure levels were significantly lower in females than in males, and personal NO2 exposure levels were significantly positively associated with average daily cooking times and significantly inversely associated with average daily home time. For every interquartile range (IQR) increase (12.7×10-9) in ambient NO2, the personal NO2 exposure levels increased by 27.5% (95%CI: 17.0%-38.9%), and personal NOX exposure levels increased by 16.1% (95%CI: 7.1%-25.8%). CONCLUSION: Season, city and ambient NO2 concentrations are significant influencing factors of personal exposure levels of NO2and NOX. At the same time, the personal exposures levels of NO2are also affected by lifestyle factors. Our study provides scientific evidence for making precise air pollution control decisions and reducing the exposure levels of NOX in the population.

Associations of ambient air pollution exposure and lifestyle factors with incident dementia in the elderly: A prospective study in the UK Biobank.

OBJECTIVE: Dementia is an important disease burden among the elderly, and its occurrence may be profoundly affected by environmental factors. Evidence of the relationship between air pollution and dementia is emerging, but the extent to which this can be offset by lifestyle factors remains ambiguous. METHODS: This study comprised 155,828 elder adults aged 60 years and above in the UK Biobank who were dementia-free at baseline. Cox proportional hazard models were conducted to examine the associations of annual average levels of air pollutants in 2010, including nitrogen dioxide (NO2), nitrogen oxides (NOX), particulate matter (PM2.5, PM10, and PMcoarse) and lifestyle factors recorded at baseline [physical activity (PA), sleep patterns, or smoking status] with incident risk of dementia, and their interactions on both multiplicative and additive scales. RESULTS: During a 12-year period of follow-up, 4,389 incidents of all-cause dementia were identified. For each standarddeviationincrease in ambient NO2, NOX or PM2.5, all-cause dementia risk increases by 1.07-fold [hazard ratio (HR) and 95 % confidence interval (CI) = 1.07 (1.04, 1.10)], 1.05-fold (95 % CI: 1.02, 1.08) and 1.07-fold (95 % CI: 1.04, 1.10), whereas low levels of PA, poor sleep patterns, and smoking are associated with an elevated risk of dementia [HR (95 % CI) = 1.17 (1.09, 1.26), 1.13 (1.00, 1.27), and 1.14 (1.07, 1.21), respectively]. Furthermore, these air pollutants show joint effects with low PA, poor sleep patterns, and smoking on the onset of dementia. The moderate to high levels of PA could significantly or marginally significantly modify the associations between NO2, NOX or PM2.5 (P-int = 0.067, 0.036, and 0.067, respectively) and Alzheimer's disease (AD), but no significant modification effects are found for sleep patterns or smoking status. CONCLUSION: The increased exposures of NO2, NOX, or PM2.5 are associated with elevated risk of dementia among elderly UK Biobank population. These air pollutants take joint effects with low PA, poor sleep patterns, and smoking on the development of dementia. In addition, moderate to high levels of PA could attenuate the incident risk of AD caused by air pollution. Further prospective researches among other cohort populations are warranted to validate these findings.

Effects of Nitrosyl Iron Complexes with Thiol, Phosphate, and Thiosulfate Ligands on Hemoglobin.

Nitrosyl iron complexes are remarkably multifactorial pharmacological agents. These compounds have been proven to be particularly effective in treating cardiovascular and oncological diseases. We evaluated and compared the antioxidant activity of tetranitrosyl iron complexes (TNICs) with thiosulfate ligands and dinitrosyl iron complexes (DNICs) with glutathione (DNIC-GS) or phosphate (DNIC-PO4-) ligands in hemoglobin-containing systems. The studied effects included the production of free radical intermediates during hemoglobin (Hb) oxidation by tert-butyl hydroperoxide, oxidative modification of Hb, and antioxidant properties of nitrosyl iron complexes. Measuring luminol chemiluminescence revealed that the antioxidant effect of TNICs was higher compared to DNIC-PO4-. DNIC-GS either did not exhibit antioxidant activity or exerted prooxidant effects at certain concentrations, which might have resulted from thiyl radical formation. TNICs and DNIC-PO4- efficiently protected the Hb heme group from decomposition by organic hydroperoxides. DNIC-GS did not exert any protective effects on the heme group; however, it abolished oxoferrylHb generation. TNICs inhibited the formation of Hb multimeric forms more efficiently than DNICs. Thus, TNICs had more pronounced antioxidant activity than DNICs in Hb-containing systems.

Rational design of Near-Infrared fluorescent probe for monitoring HNO in plants.

Nitroxyl (HNO), a reactive nitrogen species (RNS), is essential for plant growth. However, the action of HNO in plants has been difficult to understand due to the lack of highly sensitive and real-time in-situ monitoring tools. Herein, we presented a near-infrared fluorescent probe, DCI-HNO, based on dicyanoisophorone fluorophore, for real-time mapping HNO in plants. The introduction of a phosphine moiety as a specific HNO recognition unit can inhibit the intramolecular charge transfer (ICT) of probe DCI-HNO. However, in the presence of HNO, the ICT process occurred, leading to the emission at 665 nm. Probe DCI-HNO exhibited high sensitivity (97 nM), rapid response time (8 min), large Stokes shift (135 nm) for detection of HNO in plants. The novel developed probe has successfully imaged endogenous HNO produced during NO/H2S cross-talk in plant tissues. Additionally, the up-regulated in HNO levels during tobacco aging and in response to stress has been confirmed. Therefore, probe DCI-HNO has provided a reliable method for monitoring the NO/H2S cross-talk and revealing the role of HNO in plants.

Insight into the photodynamic mechanism and protein binding of a nitrosyl iron-sulfur [Fe2S2(NO)4]2- cluster.

Iron-sulfur cluster conversion and nitrosyl modification are involved in regulating their functions and play critical roles in signaling for biological systems. Hereby, the photo-induced dynamic process of (Me4N)2[Fe2S2(NO)4] was monitored using time-resolved electron paramagnetic resonance (EPR) spectra, MS spectra and cellular imaging methods. Photo-irradiation and the solvent affect the reaction rates and products. Spectroscopic and kinetic studies have shown that the process involves at least three intermediates: spin-trapped NO free radical species with a gav at 2.040, and two other iron nitrosyl species, dinitrosyl iron units (DNICs) and mononitrosyl iron units (MNICs) with gav values at 2.031 and 2.024, respectively. Moreover, the [Fe2S2(NO)4]2- cluster could bind with ferritin and decompose gradually, and a binding state of dinitrosyl iron coordinated with Cys102 of the recombinant human heavy chain ferritin (rHuHF) was finally formed. This study provides insight into the photodynamic mechanism of nitrosyl iron - sulfur clusters to improve the understanding of physiological activity.

Quantifying air quality co-benefits to industrial decarbonization: the local Air Emissions Tracking Atlas.

Introduction: Many decarbonization technologies have the added co-benefit of reducing short-lived climate pollutants, such as particulate matter (PM), nitrogen oxides (NOx), and sulfur dioxide (SO2), creating a unique opportunity for identifying strategies that promote both climate change solutions and opportunities for air quality improvement. However, stakeholders and decision-makers may struggle to quantify how these co-benefits will impact public health for the communities most affected by industrial air pollution. Methods: To address this problem, the LOCal Air Emissions Tracking Atlas (LOCAETA) fills a data availability and analysis gap by providing estimated air quality benefits from industrial decarbonization options, such as carbon capture and storage (CCS). These co-benefits are calculated using an algorithm that connects disparate datasets that separately report greenhouse gas emissions and other pollutants at U.S. industrial facilities. Results: Version 1.0 of LOCAETA displays the estimated primary PM2.5 emission reduction co-benefits from additional pretreatment equipment for CCS on industrial and power facilities across the state of Louisiana, as well as the potential for VOC and NH3 generation. The emission reductions are presented in the tool alongside facility pollutant emissions information and relevant air quality, environmental, demographic, and public health datasets, such as air toxics cancer risk, satellite and in situ pollutant measurements, and population vulnerability metrics. Discussion: LOCAETA enables regulators, policymakers, environmental justice communities, and industrial and commercial users to compare and contrast quantifiable public health benefits due to air quality impacts from various climate change mitigation strategies using a free and publicly-available tool. Additional pollutant reductions can be calculated using the same methodology and will be available in future versions of the tool.

Association between air pollution and skin cutaneous melanoma: A Mendelian randomization study.

There has been a consistent and notable increase in the global prevalence of skin cutaneous melanoma (SKCM). Although genetic factors are closely associated with the occurrence and development of melanoma, the potential influence of environmental factors cannot be overlooked. The existing literature lacks a definitive consensus on the correlation between air pollution and the incidence rate of SKCM. This study seeks to investigate the causal relationship between air pollution, specifically focusing on particulate matter (PM) 2.5, PM2.5-10, PM10, and nitrogen oxides, and the risk of SKCM. A 2-sample Mendelian randomization (MR) method was applied, utilizing extensive publicly accessible genome-wide association studies summary datasets within European populations. The primary analytical method employed was the inverse variance weighted method. Supplementary methods, including the weighted median model, MR-Egger, simple model, and weighted model, were chosen to ensure robust analysis. Heterogeneity assessment was conducted using Cochran's Q test. To identify potential pleiotropy, both MR-Egger regression and the MR-PRESSO global test were employed. Additionally, a sensitivity analysis was performed using the leave-one-out method. The analysis revealed no statistically significant association between air pollution and SKCM risk, with specific findings as follows: PM2.5 (P = .485), PM2.5-10 (P = .535), PM10 (P = .136), and nitrogen oxides (P = .745). While some results exhibited heterogeneity, all findings demonstrated an absence of pleiotropy. This study did not find substantive evidence supporting a causal relationship between air pollution and the risk of SKCM within European populations. The comprehensive MR analysis, encompassing various pollutants, suggests that environmental factors such as air pollution may not be significant contributors to the development of SKCM.

Ambient air pollution, lifestyle, and genetic predisposition on all-cause and cause-specific mortality: A prospective cohort study.

BACKGROUND: Although it is widely acknowledged that long-term exposure to ambient air pollution is closely related to the risk of mortality, there were inconsistencies in terms of cause-specific mortality and it is still unknown whether lifestyle and genetic susceptibility could modify the association. METHODS: This population-based prospective cohort study involved 461,112 participants from the UK Biobank. The land-use regression model was used to estimate the concentrations of particulate matter (PM2.5, PMcoarse, PM10), and nitrogen oxides (NO2 and NOx). The association between air pollution and mortality was evaluated using Cox proportional hazard models. Furthermore, a lifestyle score incorporated with smoking status, physical activity, alcohol consumption, and diet behaviors, and polygenic risk score using 12 genetic variants, were developed to assess the modifying effect of air pollution on mortality outcomes. RESULTS: During a median follow-up of 14.0 years, 33,903 deaths were recorded, including 17,083 (2835; 14,248), 6970, 2429, and 1287 deaths due to cancer (lung cancer, non-lung cancer), cardiovascular disease (CVD), respiratory and digestive disease, respectively. Each interquartile range (IQR) increase in PM2.5, NO2 and NOx was associated with 7 %, 6 % and 5 % higher risk of all-cause mortality, respectively. Specifically, for cause-specific mortality, each IQR increase in PM2.5, NO2 and NOx was also linked to mortality due to cancer (lung cancer and non-lung cancer), CVD, respiratory and digestive disease. Furthermore, additive and multiplicative interactions were identified between high ambient air pollution and unhealthy lifestyle on mortality. In addition, associations between air pollution and mortality were modified by lifestyle behaviors. CONCLUSION: Long-term exposure to air pollutants increased the risk of all-cause and cause-specific mortality, which was modified by lifestyle behaviors. In addition, we also revealed a synergistically detrimental effect between air pollution and an unhealthy lifestyle, suggesting the significance of joint air pollution management and adherence to a healthy lifestyle on public health.

Activation of Transcription Factor Nrf2 in HeLa Cells under the Action of Nitrosyl Iron Complex with N-Ethylthiourea.

We studied the effect of an NO donor, nitrosyl iron complex with N-ethylthiourea, on Nrf2-dependent antioxidant system activation of tumor cells in vitro. The complex increased intracellular accumulation of Nrf2 transcription factor and induced its nuclear translocation. It was shown that both heme oxygenase-1 gene and protein expression increased significantly under the influence of the complex. Nrf2 activation was accompanied by a decrease in the intracellular accumulation of proinflammatory transcription factor NF-κB p65 subunit and expression of its target genes. The cytotoxic effect of N-ethylthiourea leads to induction of Nrf2/HO-1 antioxidant response and suppression of NF-κB-dependent processes in tumor cells.

Air Pollution Exposure and Interstitial Lung Features in SPIROMICS Participants with Chronic Obstructive Pulmonary Disease.

Rationale: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives: To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between -600 and -250 Hounsfield units), respectively. We assessed for effect modification by MUC5B-promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results: Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (P value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (P value interaction term for NOx = 0.05; NO2 = 0.01; and ozone = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NOx, 2.41; 95% confidence interval [CI], 0.97-6.0; and RR per 4 µg ⋅ m-3 PM2.5, 1.43; 95% CI, 0.93-2.2, respectively). With higher exposure to NO2, former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0-2.7). Conclusions: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Contrast Agents Based on Human Serum Albumin and Nitroxides for 1H-MRI and Overhauser-Enhanced MRI.

In cancer diagnostics, magnetic resonance imaging (MRI) uses contrast agents to enhance the distinction between the target tissue and background. Several promising approaches have been developed to increase MRI sensitivity, one of which is Overhauser dynamic nuclear polarization (ODNP)-enhanced MRI (OMRI). In this study, a macromolecular construct based on human serum albumin and nitroxyl radicals (HSA-NIT) was developed using a new synthesis method that significantly increased the modification to 21 nitroxide residues per protein. This was confirmed by electron paramagnetic resonance (EPR) spectroscopy and matrix-assisted laser desorption/ionization time-of-flight (MALDI ToF) mass spectrometry. Gel electrophoresis and circular dichroism showed no significant changes in the structure of HSA-NITs, and no oligomers were formed during modification. The cytotoxicity of HSA-NITs was comparable to that of native albumin. HSA-NITs were evaluated as potential "metal-free" organic radical relaxation-based contrast agents for 1H-MRI and as hyperpolarizing contrast agents for OMRI. Relaxivities (longitudinal and transversal relaxation rates r1 and r2) for HSA-NITs were measured at different magnetic field strengths (1.88, 3, 7, and 14 T). Phantoms were used to demonstrate the potential use of HSA-NIT as a T1- and T2-weighted relaxation-based contrast agent at 3 T and 14 T. The efficacy of 1H Overhauser dynamic nuclear polarization (ODNP) in liquids at an ultralow magnetic field (ULF, B0 = 92 ± 0.8 µT) was investigated for HSA-NIT conjugates. The HSA-NITs themselves did not show ODNP enhancement; however, under the proteolysis conditions simulating cancer tissue, HSA-NIT conjugates were cleaved into lower-molecular-weight (MW) protein fragments that activate ODNP capabilities, resulting in a maximum achievable enhancement |Emax| of 40-50 and a radiofrequency power required to achieve half of Emax, P1/2, of 21-27 W. The HSA-NIT with a higher degree of modification released increased the number of spin probes upon biodegradation, which significantly enhanced the Overhauser effect. Thus, HSA-NITs may represent a new class of MRI relaxation-based contrast agents as well as novel cleavable conjugates for use as hyperpolarizing contrast agents (HCAs) in OMRI.

A Crucial Role of Proteolysis in the Formation of Intracellular Dinitrosyl Iron Complexes.

Dinitrosyl iron complexes (DNICs) stabilize nitric oxide in cells and tissues and constitute an important form of its storage and transportation. DNICs may comprise low-molecular-weight ligands, e.g., thiols, imidazole groups in chemical compounds with low molecular weight (LMWDNICs), or high-molecular-weight ligands, e.g., peptides or proteins (HMWDNICs). The aim of this study was to investigate the role of low- and high-molecular-weight ligands in DNIC formation. Lysosomal and proteasomal proteolysis was inhibited by specific inhibitors. Experiments were conducted on human erythroid K562 cells and on K562 cells overexpressing a heavy chain of ferritin. Cell cultures were treated with •NO donor. DNIC formation was monitored by electron paramagnetic resonance. Pretreatment of cells with proteolysis inhibitors diminished the intensity and changed the shape of the DNIC-specific EPR signal in a treatment time-dependent manner. The level of DNIC formation was significantly influenced by the presence of protein degradation products. Interestingly, formation of HMWDNICs depended on the availability of LMWDNICs. The extent of glutathione involvement in the in vivo formation of DNICs is minor yet noticeable, aligning with our prior research findings.