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Background: To develop effective strategies for controlling asthma, a thorough assessment of its disease burden is essential. In this study, we examined long-term trends in the asthma burden in China over the past three decades and analyzed its epidemiological features. Methods: We assessed the burden of asthma in China via the global burden of disease (GBD) 2021 database, focusing on prevalence, incidence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs). Additionally, we employed joinpoint analysis and age-period-cohort (apc) methods to interpret the epidemiological characteristics of asthma. Finally, we analyzed the attributable burden of asthma to gain a comprehensive understanding of its impact. Results: The age-standardized incidence rate (ASIR) and mortality rate (ASMR) for both sexes in China shifted from 524.81 (95% UI: 421.31, 672.76) to 314.17 (95% UI: 283.22, 494.10) and from 5.82 (95% UI: 4.46, 8.50) to 1.47 (95% UI: 1.15, 1.79) per 100,000 population between 1990 and 2021. According to joinpoint analysis, the average annual percentage change (AAPC) in the age-standardized incidence rate was – 1.2 (95% CI: – 1.4, – 1.1), indicating a gradual but fluctuating decline (with significant turning points in 2005 and 2014). The apc fitting results suggest that the prevalence is now lower than it was in the past and that the relative prevalence risk is high among adolescents and middle-aged to elderly individuals, possibly due to different pathophysiological mechanisms. In 2021, the primary asthma-related burdens were metabolic risks, especially obesity. Conclusions: In conclusion, we found that the disease burden of asthma in China has significantly decreased. However, it remains a major concern among adolescents and elderly individuals. Metabolic risk factors, particularly obesity, are the main contributors to the asthma burden. It is essential to address specific risk factors and develop targeted public health strategies for different age groups. [ABSTRACT FROM AUTHOR]

Background: CFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor–tezacaftor–ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution remains unknown. Methods: We used an unbiased proteomics approach to measure the effect of ETI on inflammatory proteins. Plasma from 20 pediatric pwCF and 20 non-CF (NCF) was collected during routine examination and 3 months after ETI initiation. Protein screening was performed with an inflammation panel (Target 96, Olink®). Bioinformatics analysis was used to determine changes in protein expression. Results: There were significantly fewer pulmonary exacerbations after ETI initiation, along with sustained improvement in lung function and reduced bacterial colonization. Unpaired analysis of CF pre-ETI and NCF resulted in 34 significantly different proteins. Of these, CCL20, MMP-10, EN-RAGE, and AXIN1 had a log2 fold change of 1.2 or more. There was a modest shift in overall CF protein profiles post-ETI toward the NCF cluster. Unpaired analysis of protein differential expression between NCF and CF post-ETI identified a total of 24 proteins significantly impacted by ETI therapy (p -value ≤ 0.05), with only CCL20 having a log2 fold change higher than 1.2. Paired analysis (CF pre- and CF post-ETI) of differential protein expression demonstrated significant expression changes of MMP-10, EN-RAGE, and IL-17A. Pathway analysis identified significantly impacted pathways such as the NF-κB pathway. Conclusion: This study showed that ETI in a pediatric cohort had a modest effect on several inflammatory proteins with potential as biomarkers. Pathways significantly impacted by ETI can be further studied for future therapies to combat persistent inflammation and dysregulated immunity. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis (CF) is characterized by chronic neutrophilic inflammation in the airways. Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has demonstrably improved clinical outcomes and quality of life in people with CF (pwCF), but its effects on systemic inflammatory parameters remain unclear. Objective: To evaluate the impact of ETI on systemic inflammation in children and adolescents with CF. Design: Retrospective, dual-center observational, propensity score-matching study of pediatric pwCF on ETI. Methods: PwCF aged ⩽ 18 years treated with ETI at two Italian reference centers were included in this study. Data on immunoglobulins (Ig) (A, G, and M), γ-globulin, leukocyte levels, percent predicted forced expiratory volume in the first second (ppFEV1), sweat chloride (SC) concentration, and sputum cultures were collected at baseline, 12, and 24 months of treatment. Laboratory data of a control group (pwCF, not in ETI therapy, same demographic characteristics as the study group) were also collected. Results: Sixty-six patients (30 males, median age: 12 years, F508del homozygous: 23) were included. Mean IgG levels (SD) significantly decreased (p = 0.001) from 1168.20 mg/dl (344.41) at baseline to 1093.05 mg/dl (258.73; 12 months) and 1092.87 mg/dl (232.42; 24 months). Similar reductions were observed for IgA and γ-globulin; IgM reduction was not statistically significant. Leukocyte levels also decreased significantly from 8.04 × 103/µl (3.23 × 103) at baseline to 6.61 × 103/µl (1.74 × 103) (12 months) and 6.45 × 103/µl (1.70 × 103; 24 months). As for the control group, no significant changes in the levels of Ig, leukocytes, and γ-globulin were detected throughout the study period (p > 0.05). The mean (SD) ppFEV1 and the overall mean (SD) SC concentration significantly decreased during the follow-up. Regarding cultures, 18 (27%) of the 27 patients positive (41%) for Staphylococcus aureus at baseline became negative during treatment. Three patients (4%) with persistently positive cultures for Pseudomonas aeruginosa during the first 12 months, became negative after 24 months. One patient (1.5%), with a baseline positive culture for Pseudomonas Aeruginosa, showed negative cultures after 12 months. Conclusion: ETI treatment improved respiratory outcomes and significantly reduced values of IgG, IgA, γ-globulin, and leukocytes, suggesting an effect on the systemic inflammatory response. Further research is warranted to elucidate the role of inflammatory parameters in monitoring response to therapy. Plain language summary: Inflammation in cystic fibrosis: impact of a new therapy in children and adolescents. • Inflammation plays a pivotal role in Cystic Fibrosis (CF) progression • The new combination therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) improves lung function, nutritional status, and quality of life in eligible CF patients. Limited data exists on the impact of ETI on inflammation in CF. • This retrospective study demonstrates that ETI appears to positively impact inflammation markers in children and adolescents with CF. • Further research is needed to better understand how inflammation parameters can help monitor the response to therapy [ABSTRACT FROM AUTHOR]

Manganese(III) (3d4, S = 2) coordination complexes have been widely studied by high-frequency and -field EPR (HFEPR) for their own inherent chemical interest and for providing information for the burgeoning area of molecular magnetism. In the present study, we demonstrate how a stable, easily handled complex of MnIII, [MnLKNO3], where L3− is a hexadentate tripodal ligand, trianion of 1,1,1-tris[(3- methoxysalicylideneamino)methyl]ethane, can be used for another purpose entirely. This purpose is as a field and frequency standard for HFEPR that is superior to a "traditional" standard such as an organic radical (e.g., DPPH) with its single, g = 2.00 signal, or to atomic hydrogen, which is less readily available than DPPH and provides only two signals for calibration purposes (Stoll et al. in J Magn Reson 207:158–163, 2010). By contrast, polycrystalline [MnLKNO3] (1) orients in the external magnetic field of an HFEPR spectrometer (three different spectrometers were employed in this study). The crystal structure of 1 allows determination of the exact, reproducible molecular orientation of 1 in the applied field. This phenomenon provides multiple, well-defined resonances over a broad field sweep range (0–36 T) at any of a wide range of frequencies (tested up to 1 THz so far) allowing accurate calibration of magnetic field in a multi-frequency HFEPR study. [ABSTRACT FROM AUTHOR]

Designing new nanozyme systems as a simple substitute of natural enzymes with higher catalytically active sites and stability has attracted growing research interests for widespread applications especially in environmental remediation. Laccases belong to a group of multicopper-containing enzymes that show significant potential in diverse biotechnological and bioremediation applications. In this paper, a facile strategy is reported for the preparation of an efficient laccase mimic inspired by structural features and electron transfer mechanism of natural laccase, via Cu2+ ions doping in ZIF8 framework (denoted as Cu-ZIF8). Cu-ZIF8 nanozyme showed laccase-like activity and significant catalytic performance in the oxidation of a wide range of phenolic pollutants such as 2,4-dichlorophenol, phenol, catechol, hydroquinone, and o-nitrophenol. Kinetic studies were carried out to estimate the kinetic parameters of the as-prepared Cu-ZIF8 nanozyme including apparent Michaelis–Menten constant (Km) and maximum velocity (Vmax). The Km and Vmax were calculated to be 0.28 mM and 0.017 mM min−1, respectively. In addition, Cu-ZIF8 nanozyme was robust over a wide range of temperature (30–90 °C), at extreme pH and high salt concentration. In addition, Cu-ZIF8 nanozyme can catalyze the oxidation of dopamine to a brown product, where an absorption band at 290 nm was observed. Accordingly, a simple colorimetric assay has been established for detection of dopamine in the linear range of 0.01–0.44 mM with a detection limit of 1.1 × 10−3 mM (S/N = 3). The developed colorimetric method showed good selectivity and high sensitivity in measuring dopamine among potential interfering components. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the effects of Parkin (Prkn) knockout in a juvenile mouse model of asthma. Methods: Prkn knockout (KO) and wild type (WT) mice were utilized to establish a juvenile mouse asthma model. The asthma model involved exposure to hyperoxia/ovalbumin (OVA), encompassing hyperoxia from postnatal day 1 (P1) to P7, sensitization on P21 and P28, and challenge from P36 to P42. Room air/phosphate-buffered saline (PBS) served as the control condition. Following airway resistance measurement, bronchoalveolar lavage fluid (BALF) was collected for cellular analysis, and lung tissues were subjected to histological examination and oxidative stress assessment. Serum levels of ovalbumin-specific immunoglobulin E (IgE), total IgE, interleukin-4 (IL-4), IL-5, and IL-13 were quantified using enzyme-linked immunosorbent assay (ELISA). Results: WT mice exposed to hyperoxia/OVA showed decreased body weight and increased airway resistance compared to those exposed to control condition. Conversely, KO mice exhibited increased body weight under asthma conditions. KO mice with asthma had reduced total cell counts, along with lower levels of lymphocytes, eosinophils, and neutrophils, compared to WT asthma mice. Histological assessment showed attenuated inflammation and reduced collagen deposition in KO mice relative to WT mice, with lower serum levels of inflammatory markers and improved lung oxidative stress profiles. No significant differences were observed between KO and WT mice under room air/PBS conditions. Conclusions: Parkin knockout in juvenile mice mitigates asthma-related alterations in airway resistance, histopathological changes, inflammation status, and oxidative stress. These findings highlight a protective role of Parkin deficiency against asthma-associated pathologies. [ABSTRACT FROM AUTHOR]

Background: Chronic respiratory diseases (CRD) represents a series of lung disorders and is posing a global health burden. Systemic inflammation and phenotypic ageing have been respectively reported to associate with certain CRD. However, little is known about the co-exposures and mutual associations of inflammation and ageing with CRD. Here, we aim to systematically elucidate the joint and mutual mediating associations of systemic immune-inflammation index (SII) and phenotypic age acceleration (PhenoAgeAccel) with CRD based on data from National Health and Nutrition Examination Survey (NHANES). Methods: Data for this study was obtained from NHANES 2007–2010 and 2015–2018. The single and combined associations of SII and PhenoAgeAccel with CRD were analyzed using multivariable logistic regression models. The dose-response relationship between exposures and outcomes was determined by restricted cubic splines (RCS) regression. Subgroup and mediation analyses were further conducted. Results: Totally, 15,075 participants were enrolled in this study including 3,587 CRD patients. Compare with controls, CRD patients tended to be older, females and present higher SII and PhenoAgeAccel values. Single-index analysis indicated that either SII or PhenoAgeAccel demonstrated a significantly positive association with CRD via logistic regressions and RCS curves. Furthermore, the joint-indexes analysis revealed that compared to individuals with lower SII and PhenoAgeAccel, those with higher SII and PhenoAgeAccel exhibited remarkably stronger associations with CRD (adjusted OR [aOR], 1.56; 95% CI, 1.31–1.85; P < 0.001), chronic obstructive pulmonary disease (aOR, 1.56; 95% CI, 1.22-2.00; P = 0.001) and asthma (aOR, 1.40; 95% CI, 1.16–1.70; P = 0.001), which were predominant among those aged above 40 years, females and smokers. Eventually, mediation analyses suggested the mutual mediating effects of SII and PhenoAgeAccel on CRD and PhenoAgeAccel mediated SII resulting in CRD more significantly. Conclusion: This study confirmed the coexposure effect and mutual mediation between SII and PhenoAgeAccel on CRD. We recommend that the joint assessment may conduce to the accurate identification for populations susceptible to CRD and early prevention of chronic respiratory diseases. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to systematically investigate the different phenotypes and functional analyses of macrophages in lung tissue. Data sources: A search was performed using three databases (Web of Science, Science Direct, and MEDLINE) for all relevant studies published from January 1, 2019, to December 31, 2023. Study selections: This systematic review complied with the PRlSMA document's requirements, including studies related to the signaling pathway relationship between pulmonary macrophages and asthma phenotype. The search includedstudies published in English or French lanquage, and was based on title, abstract, and complete textDocuments not meeting inclusion requirements were excluded Results: We have identified studies published within the past five years that meet the criteria for inclusion in this review. We found that asthma is a heterogeneous chronic inflammatory lung disease, and lung tissue macrophages are important immune cells in the respiratory tract. Pulmonary macrophages are also heterogeneous, as they have different subgroups with varying effector functions depending on the environment. They have different phenotypes and biological functions in different disease environments. The phenotypic changes of pulmonary macrophages occur during asthma, and the study of the different phenotypes and functions of macrophages in lung tissue is of great significance for treatment. Conclusions: This review summarizes current literature and provides a detailed introduction to the role of macrophages as key inflammatory mediators in the pathogenesis of asthma, as well as existing knowledge gaps. In addition, we propose that regulatory macrophages may prevent the development of asthma by producing IL-10, and regulating the polarization of pulmonary macrophages may be a new direction for asthma treatment. [ABSTRACT FROM AUTHOR]

Purpose: Ischemia-reperfusion injury (IRI) is a major challenge in lung transplantation often causing graft dysfunction and chronic airway illnesses in recipients. To prevent potential transplant related complications, strict guidelines were put in place to choose viable donor lungs with minimal risk of IRI. These regulations deem most of the donor organs unfit for transplant which then are donated for research to understand the mechanisms of health and diseases in human. However, resected organs that are being transported undergo cold ischemia that can negatively affect the tissue architecture and other cellular functions under study. Thus, it is important to assess how cold ischemia time (CIT) affects the physiological mechanism. In this respect, we are interested in studying how CIT affects cellular senescence in normal aging and various pulmonary pathologies. We thus hypothesized that prolonged CIT exhibits cell-type specific changes in lung cellular senescence in mice. Methods: Lung lobes from C57BL/6J (n = 5–8) mice were harvested and stored in UW Belzer cold storage solution for 0, 4-, 9-, 12-, 24-, and 48-h CIT. Lung cellular senescence was determined using fluorescence (C12FdG) assay and co-immunolabelling was performed to identify changes in individual cell types. Results: We found a rapid decline in the overall lung cellular senescence after 4-h of CIT in our study. Co-immunolabelling revealed the endothelial cells to be most affected by cold ischemia, demonstrating significant decrease in the endothelial cell senescence immediately after harvest. Annexin V-PI staining further revealed a prominent increase in the number of necrotic cells at 4-h CIT, thus suggesting that most of the cells undergo cell death within a few hours of cold ischemic injury. Conclusions: We thus concluded that CIT significantly lowers the cellular senescence in lung tissues and must be considered as a confounding factor for mechanistic studies in the future. [ABSTRACT FROM AUTHOR]

The combination of elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) reverses the primary defect in cystic fibrosis (CF) by improving CFTR-mediated Cl− and HCO3− secretion by airway epithelial cells (AECs), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, have numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression, we exposed primary human AEC to ETI for 48 h and interrogated the transcriptome by RNA-seq and qPCR. ETI increased CFTR Cl− secretion, and defensin gene expression (DEFB1), an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI decreased MMP10 and MMP12 gene expression, suggesting that ETI may reduce proteolytic-induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase (HMOX1). qPCR analysis confirmed DEFB1, HMOX1, MMP10, and MMP12 gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation, and MHC class II antigen presentation. Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug-induced increases in DEFB1 and that ETI may reduce lung damage by reducing MMP10 and MMP12 gene expression. Moreover, pathway analysis also identified several other genes responsible for the ETI-induced reduction in inflammation observed in pwCF. NEW & NOTEWORTHY: Gene expression responses by CF AECs exposed to ETI suggest that in addition to improving CFTR channel function, ETI is likely to enhance resistance to bacterial infection by increasing levels of beta-defensin 1 (hBD-1). ETI may also reduce lung damage by suppressing MMP10 and MMP12 and reduce airway inflammation by repressing proinflammatory cytokine secretion by CF AECs. [ABSTRACT FROM AUTHOR]

This paper reviews our historical developments of broken-symmetry (BS) and beyond BS methods that are applicable for theoretical investigations of metalloenzymes such as OEC in PSII. The BS hybrid DFT (HDFT) calculations starting from high-resolution (HR) XRD structure in the most stable S1 state have been performed to elucidate structure and bonding of whole possible intermediates of the CaMn4Ox cluster (1) in the Si (i = 0 ~ 4) states of the Kok cycle. The large-scale HDFT/MM computations starting from HR XRD have been performed to elucidate biomolecular system structures which are crucial for examination of possible water inlet and proton release pathways for water oxidation in OEC of PSII. DLPNO CCSD(T0) computations have been performed for elucidation of scope and reliability of relative energies among the intermediates by HDFT. These computations combined with EXAFS, XRD, XFEL, and EPR experimental results have elucidated the structure, bonding, and reactivity of the key intermediates, which are indispensable for understanding and explanation of the mechanism of water oxidation in OEC of PSII. Interplay between theory and experiments have elucidated important roles of four degrees of freedom, spin, charge, orbital, and nuclear motion for understanding and explanation of the chemical reactivity of 1 embedded in protein matrix, indicating the participations of the Ca(H2O)n ion and tyrosine(Yz)-O radical as a one-electron acceptor for the O–O bond formation. The Ca-assisted Yz-coupled O–O bond formation mechanisms for water oxidation are consistent with recent XES and very recent time-resolved SFX XFEL and FTIR results. [ABSTRACT FROM AUTHOR]

Flash-induced absorption changes in the Soret region arising from the [PD1PD2]+ state, the chlorophyll cation radical formed upon light excitation of Photosystem II (PSII), were measured in Mn-depleted PSII cores at pH 8.6. Under these conditions, TyrD is i) reduced before the first flash, and ii) oxidized before subsequent flashes. In wild-type PSII, when TyrD● is present, an additional signal in the [PD1PD2]+-minus-[PD1PD2] difference spectrum was observed when compared to the first flash when TyrD is not oxidized. The additional feature was "W-shaped" with troughs at 434 nm and 446 nm. This feature was absent when TyrD was reduced, but was present (i) when TyrD was physically absent (and replaced by phenylalanine) or (ii) when its H-bonding histidine (D2-His189) was physically absent (replaced by a Leucine). Thus, the simple difference spectrum without the double trough feature at 434 nm and 446 nm, seemed to require the native structural environment around the reduced TyrD and its H bonding partners to be present. We found no evidence of involvement of PD1, ChlD1, PheD1, PheD2, TyrZ, and the Cytb559 heme in the W-shaped difference spectrum. However, the use of a mutant of the PD2 axial His ligand, the D2-His197Ala, shows that the PD2 environment seems involved in the formation of "W-shaped" signal. [ABSTRACT FROM AUTHOR]

Asthma poses a major threat to human health. The aim of this study was to identify genetic markers of severe asthma and analyze the relationship between key genes and immune infiltration. Differentially expressed genes (DEGs) were first screened by downloading the training set GSE69683 and validation set GSE137268 from the GEO dataset. SVM-RFE analysis and the LASSO regression model were used to screen key genes, and CIBERSORT was used to assess immune infiltration in the samples. A total of 20 DEGs were identified in this study, mainly enriched for lymph node-like receptors, b-cell receptors, and neutrophil extracellular trap pathway. Comparative validation set GSE137268 identified thioredoxin (TXN) and coagulation factor V (F5) were identified as diagnostic markers of severe asthma. CIBERSORT analysis revealed that TXN and F5 are associated with multiple immune cell infiltrates. In addition, we identified miRNA and TF at the transcriptional level that may regulate F5 and TXN, and found that several commonly used drugs may exert therapeutic effects by targeting F5 and TXN. Taken together, TXN and F5 may be key genes in the development of severe asthma and are associated with immune infiltration. Our study can help to better understand the pathogenesis of asthma and provide new ideas for clinical treatment. [ABSTRACT FROM AUTHOR]

Laccase is an enzyme known for its eco-friendly uses in environmental cleanup and biotechnology. However, it has limitations such as low stability, high cost, and complex recycling. So, there is a need for laccase mimics that can effectively imitate its properties. Herein, we created copper formate–lysine nanoparticles (Cuf-Lys) that mimic laccase's activity. The developed Cuf-Lys demonstrated remarkable polyphenol oxidase-like activity, stability, and recyclability, making them suitable for the fabrication of efficient colorimetric sensors for the detection of epinephrine. These sensors had a specific response and could accurately measure epinephrine concentrations ranging from 2.5 to 50 μM, with a detection limit as low as 1 μM. Furthermore, the biosensor demonstrated high sensitivity and selectivity when applied to the detection of rutin. The limit of detection for rutin was determined to be 0.16 μM while in the linear concentration range of 0.25 to 150.0 μM. We believe that Cuf-Lys provide a new route for the design of laccase mimics, showing potential applications for biomedical diagnosis and environmental monitoring. [ABSTRACT FROM AUTHOR]

Electrocatalytic carbon dioxide (CO2) reduction by CO2 reductases is a promising approach for biomanufacturing. Among all known biological or chemical catalysts, hydrogen-dependent carbon dioxide reductase from Thermoanaerobacter kivui (TkHDCR) possesses the highest activity toward CO2 reduction. Herein, we engineer TkHDCR to generate an electro-responsive carbon dioxide reductase considering the safety and convenience. To achieve this purpose, a recombinant Escherichia coli TkHDCR overexpression system is established. The formate dehydrogenase is obtained via subunit truncation and rational design, which enables direct electron transfer (DET)-type bioelectrocatalysis with a near-zero overpotential. By applying a constant voltage of −500 mV (vs. SHE) to a mediated electrolytic cell, 22.8 ± 1.6 mM formate is synthesized in 16 h with an average production rate of 7.1 ± 0.5 μmol h−1cm−2, a Faradaic efficiency of 98.9% and a half-cell energy efficiency of 94.4%. This study provides an enzyme candidate for high efficient CO2 reduction and opens up a way to develop paradigm for CO2-based bio-manufacturing. Thermoanaerobacter kivui-drived CO2 reductase (TkHDCR) requires hydrogen as substrate, which can lead to safety issue. Here, the authors engineered TkHDCR into an electro-responsive carbon dioxide reductase to harvest electrons from either an external mediator or a polarized electroactive surface. [ABSTRACT FROM AUTHOR]

Background: Bronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology. Objective: The purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation. Methods: We used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into the highest and lowest bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high (N = 277) vs. low (N = 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed. Results: We identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR = 2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways. Conclusion: MiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients. Trial registration: LOCCS cohort [ClinicalTrials.gov number NCT00156819, Registration date 20050912], GACRS cohort [ClinicalTrials.gov number NCT00021840]. [ABSTRACT FROM AUTHOR]

Introduction: Ulcerative colitis, a subtype of chronic inflammatory bowel disease (IBD), is characterized by relapsing colonic inflammation and ulcers. The traditional Chinese herbal formulation Huang Lian Jie Du (HLJD) decoction is used clinically to treat diarrhea and colitis. However, the mechanisms associated with the effects of treatment remain unclear. This study aims to elucidate the molecular mechanistic effects of HLJD formulation on colitis. Methods: Chronic colitis in mice was induced by adding 1% dextran sulfate sodium (DSS) to their drinking water continuously for 8 weeks, and HLJD decoction at the doses of 2 and 4 g/kg was administered orally to mice daily from the second week until experimental endpoint. Stool consistency scores, blood stool scores, and body weights were recorded weekly. Disease activity index (DAI) was determined before necropsy, where colon tissues were collected for biochemical analyses. In addition, the fecal microbiome of treated mice was characterized using 16S rRNA amplicon sequencing. Results: HLJD decoction at doses of 2 and 4 g/kg relieved DSS-induced chronic colitis in mice by suppressing inflammation through compromised macrophage activity in colonic tissues associated with the colony-stimulating factor 1 receptor (Csf1r)/Src pathway. Furthermore, the HLJD formula could modify the gut microbiota profile by decreasing the abundance of Bacteroides, Odoribacter, Clostridium_sensu_stricto_1, and Parasutterella. In addition, close correlations between DAI, colon length, spleen weight, and gut microbiota were identified. Discussion: Our findings revealed that the HLJD formula attenuated DSSinduced chronic colitis by reducing inflammation via Csf1r/Src-mediated macrophage infiltration, as well as modulating the gut microbiota profile. [ABSTRACT FROM AUTHOR]

CD4+ T cells play a central role in orchestrating the immune response in asthma, with dysregulated ion channel profiles and altered metabolic signatures contributing to disease progression and severity. An important classification of asthma is based on the presence of T-helper cell type 2 (Th2) inflammation, dividing patients into Th2-high and Th2-low endotypes. These distinct endotypes have implications for disease severity, treatment response, and prognosis. By elucidating how ion channels and energy metabolism control Th cells in asthma, this review contributes to the pathophysiological understanding and the prospective development of personalized therapeutic treatment strategies for patients suffering from distinct asthma endotypes. [ABSTRACT FROM AUTHOR]

The article highlights ongoing challenges in managing cystic fibrosis (CF) in patients despite advancements in modulator therapies. Topics include the persistence of chronic bacterial infections within the lungs and airways that remain a hallmark of CF, the limitations of current therapies in fully controlling infection and inflammation, and the need for further research to enhance treatment efficacy for patients who do not respond optimally to modulators.

Phenotype distortion of lung resident mesenchymal stem cells (MSC) in preterm infants is a hallmark event in the pathogenesis of bronchopulmonary dysplasia (BPD). Here, we evaluated the impact of cyclic mechanical stretch (CMS) and hyperoxia (HOX). The negative action of HOX on proliferation and cell death was more pronounced at 80% than at 40%. Although the impact of CMS alone was modest, CMS plus HOX displayed the strongest effect sizes. Exposure to CMS and/or HOX induced the downregulation of PDGFRα, and cellular senescence preceded by p21 accumulation. p21 interference interfered with cellular senescence and resulted in aggravated cell death, arguing for a prosurvival mechanism. HOX 40% and limited exposure to HOX 80% prevailed in a reversible phenotype with reuptake of proliferation, while prolonged exposure to HOX 80% resulted in definite MSC growth arrest. Our mechanistic data explain how HOX and CMS induce the effects on MSC phenotype disruption. The results are congruent with the clinical observation that preterm infants requiring supplemental oxygen plus mechanical ventilation are at particular risk for BPD. Although inhibiting p21 is not a feasible approach, limiting the duration and magnitude of the exposures is promising. NEW & NOTEWORTHY: Rarefication of lung mesenchymal stem cells (MSC) due to exposure to cyclic mechanical stretch (CMS) during mechanical ventilation with oxygen-rich gas is a hallmark of bronchopulmonary dysplasia in preterm infants, but the pathomechanistic understanding is incomplete. Our studies identify a common signaling mechanism mediated by p21 accumulation, leading to cellular senescence and cell death, most pronounced during the combined exposure with in principle reversible phenotype change depending on strength and duration of exposures. [ABSTRACT FROM AUTHOR]

Asthma is a complex chronic respiratory inflammatory disease affected by both genetic and environmental factors. Therefore, our study explored the influence of TRIM11 on asthma and its underlying mechanisms. Our research involved patients diagnosed with asthma and healthy volunteers recruited from our hospital. We observed a reduction in serum TRIM11 expression in asthma patients, which positively correlated with the levels of anti-IgE or IgE. Additionally, both TRIM11 mRNA and protein expression in lung tissue were diminished. The introduction of the TRIM11 gene resulted in a reduction in inflammation in an in vitro asthma model and prevented the development of asthma in a mouse model. Moreover, the TRIM11 gene exhibited a suppressive effect on Ferroptosis and mitigated ROS-induced mitochondrial damage in the asthma model. TRIM11 was found to stimulate UBE2N-TAX1BP1 signaling in the asthma model, with UBE2N being identified as the specific target for TRIM11's effects on Ferroptosis. Furthermore, TRIM11 protein interacted with UBE2N protein and facilitated the dissociation of UBE2N-UBE2N in the asthma model. In conclusion, TRIM11 plays a vital role in preventing Ferroptosis in the asthma model through UBE2N-TAX1BP1 signaling. This indicates that targeting the TRIM11 mechanism could serve as a promising strategy for anti-Ferroptosis immunotherapy in asthma treatment. [ABSTRACT FROM AUTHOR]

Background: In asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R's signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R−/−) mice. Methods: C57BL/6J WT (Kiss1R+/+) and Kiss1R−/− mice, both male and female, were intranasally challenged with mixed-allergen (MA) and/or phosphate-buffered saline (PBS). We used flexiVent analysis to assess airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and cytokine analysis. Histology staining was performed using hematoxylin and eosin (H&E) for morphological analysis and Masson's Trichrome (MT) for collagen deposition. Additionally, lung sections were processed for immunofluorescence (IF) of Ki-67, α-smooth muscle actin (α-SMA), and tenascin-c. Results: Interestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R−/− female mice. MA-challenged Kiss1R−/− mice showed a significant increase in immune cell infiltration and proinflammatory cytokine levels. Importantly, the loss of Kiss1R aggravated Th2/Th17 biased cytokines in MA-challenged mice. Furthermore, histology of lung sections from Kiss1R−/− mice showed increased collagen deposition on airway walls and mucin production in airway cells compared to Kiss1R+/+ mice. In addition, immunofluorescence analysis showed loss of Kiss1R significantly aggravated airway remodeling and subsequently AHR. Conclusions: These findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma. [ABSTRACT FROM AUTHOR]

Tetrapyrroles such as heme, chlorophyll, and vitamin B12 are essential for various metabolic pathways. They derive from 5-aminolevulinic acid (5-ALA), which can be synthesized by a single enzyme (5-ALA synthase or AlaS, Shemin pathway) or by a two-enzyme pathway. The genomes of some bacteriophages from aquatic environments carry various tetrapyrrole biosynthesis genes. Here, we analyze available metagenomic datasets and identify alaS homologs (viral alaS, or valaS) in sequences corresponding to marine and freshwater phages. The genes are found individually or as part of complete or truncated three-gene loci encoding heme-catabolizing enzymes. Amino-acid sequence alignments and three-dimensional structure prediction support that the valaS sequences likely encode functional enzymes. Indeed, we demonstrate that is the case for a freshwater phage valaS sequence, as it can complement an Escherichia coli 5-ALA auxotroph, and an E. coli strain overexpressing the gene converts the typical AlaS substrates glycine and succinyl-CoA into 5-ALA. Thus, our work identifies valaS as an auxiliary metabolic gene in phage sequences from aquatic environments, further supporting the importance of tetrapyrrole metabolism in bacteriophage biology. Tetrapyrroles such as heme and chlorophyll, which are essential for various metabolic pathways, are synthesized from 5-aminolevulinic acid (5-ALA). Here, the authors identify functional 5-ALA synthase genes in bacteriophage sequences from aquatic environments, thus highlighting the importance of tetrapyrrole metabolism in phage biology. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible respiratory disease with limited therapeutic options. A hallmark of IPF is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We performed an unbiased, next-generation sequencing (NGS) screen to identify signaling pathways involved in stiffness-dependent lung fibroblast activation. Adipocytokine signaling was downregulated in primary lung fibroblasts (PFs) cultured on stiff matrices. Re-activating adipocytokine signaling with adiponectin suppressed stiffness-dependent activation of human PFs. Adiponectin signaling depended on CDH13 expression and p38 mitogen-activated protein kinase gamma (p38MAPKγ) activation. CDH13 expression and p38MAPKγ activation were strongly reduced in lungs from IPF donors. Our data suggest that adiponectin-signaling via CDH13 and p38MAPKγ activation suppresses profibrotic activation of fibroblasts in the lung. Targeting of the adiponectin signaling cascade may provide therapeutic benefits in IPF. NEW & NOTEWORTHY: A hallmark of idiopathic pulmonary fibrosis (IPF) is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We found that activation of the adipocytokine signaling pathway halts and reverses stiffness-induced, profibrotic fibroblast activation. Specific targeting of this signaling cascade may therefore provide therapeutic benefits in IPF. [ABSTRACT FROM AUTHOR]

Single-molecule magnets (SMMs) are a kind of nanosized magnetic materials that are capable of storing massive bytes of information. Strongly coupling the spin centers in a proper manner is a usual approach to promote the working temperature (or blocking temperature) for SMMs. Electron delocalized radicals have been widely employed to accomplish this job. Here, we show a new manner by using weak but multiple B–Hδ− ⋯ Dy3+ inverse hydrogen bonding (IHB) interactions to control the magnetic couplings in a series of dimeric dysprosiacaborane SMMs. This approach leads to a record high TB100s of 10 K among non-radical bridged dimeric SMMs, which is mainly ascribed to strong ferromagnetic coupling (4.38 cm−1) and the proper alignment of the magnetic principle axes of the adjacent dysprosium(III) ions. In verifying by theoretical calculations, these results demonstrate that IHB interactions can be used to construct strong axial ferromagnetic coupling and enhancing magnetic blocking temperature for SMMs. [ABSTRACT FROM AUTHOR]

In the pursuit of high-performance single-molecule magnets (SMMs), incorporating intramolecular magnetic coupling emerges as a pivotal strategy. Among these, d-f SMMs have garnered significant attention due to their remarkable versatility, which lies in their ability to tune coordination environments and facilely substitute metal centers. However, achieving performance-centric d-f SMMs through the synergistic interplay between highly anisotropic f ions and d-f magnetic interactions remains a formidable challenge. While mononuclear hexagonal bipyramidal (D6h) DyIII SMMs have been successfully isolated, the exploration of d-f SMMs featuring D6h-lanthanide metal centers remains uncharted territory. In this study, we employed planar bipodal ligands in conjunction with "staple-like" axial phenoxide ligands to synthesize the first hexagonal bipyramidal d-f SMM. Remarkably, this compound exhibits alternating-current magnetic susceptibilities peaking up to 68 K with an energy barrier surpassing 1,200 K, thus establishing a new benchmark within the heterometallic d-f SMM landscape inclusive of complexes with diamagnetic d metals and paramagnetic f ions. Notably, the ferromagnetic interaction at the d-f sites engenders oscillating relaxation times contingent on the magnetic field — a characteristic distinct from mononuclear SMMs. These findings shed light on a deliberate design approach for d-f SMMs, emphasizing the cooperative utilization of high-barrier lanthanide modules alongside d ions through magnetic interactions. This synergy significantly enhances and diversifies the magnetic dynamics of these intriguing molecular systems. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the underlying mechanism of miR-9-5p in airway smooth muscle cells (ASMCs) of asthmatic mice. An asthmatic mouse model was established through the intraperitoneal injection of ovalbumin. Histopathological changes in lung tissues of asthmatic mice were observed using HE staining. ASMCs was identified using immunofluorescence staining and cell morphology. The mRNA expressions of miR-9-5p, KLF5, and IL-1β were measured using RT-qPCR. Additionally, CCK8 assay and flow cytometry were applied for ASMC proliferation and apoptosis, respectively. The protein levels of OPN, KLF5, and IL-1β were assessed using western blotting. The results showed that miR-9-5p was abnormally downregulated in lung tissues and ASMCs of asthmatic mice. Dual-Luciferase Reporter Assay and Chromatin immunoprecipitation confirmed that miR-9-5p targeted KLF5 that bounds to IL-1β promoter. Besides, miR-9-5p negatively regulated IL-1β mRNA and protein level via KLF5. Moreover, miR-9-5p was found to positively regulate ASMC apoptosis, negatively regulate ASMC proliferation and OPN protein expression, albeit with partial reversal by KLF5. Mechanistically, the regulation of ASMC proliferation and apoptosis by miR-9-5p is achieved by targeting KLF5/IL-1β axis. [ABSTRACT FROM AUTHOR]

We examine the electron paramagnetic resonance (EPR) and electron-nuclear double resonance (ENDOR) spectroscopy of three quite distinct high-spin Mn(II) systems and describe experimental techniques and methods of analysis that are useful in their study. We demonstrate that this S = 5/2 metal center provides useful orientation-selection through the Zero-Field Splitting (ZFS) tensor that enables determination of a 13C hyperfine-coupling tensor with extremely small hyperfine interaction. We also demonstrate that Mims suppression effects can be used in concert with orientation-selection to edit complex [1,2]H ENDOR patterns that can be produced by even a 'simple' center with a single Mn(II). We develop a perturbation-based approach to understanding second-order shifts in Mn(II) ENDOR responses that occur in systems with intermediate ZFS values, and show that these shifts can be used to estimate the values of the ZFS tensors. [ABSTRACT FROM AUTHOR]

Eighty years ago, the advent of electron paramagnetic resonance (EPR) revolutionized our ability to observe the physical world of unpaired electron spins. The inception of EPR spawned multiple scientific areas with a focus on discerning the roles of paramagnetic metals and organic radicals in an array of processes and materials. More recently, the emergence of site-directed spin labeling combined with distance measurement technology and molecular modeling has harnessed the power of EPR, to 'watch proteins move'. Spin labels have enabled the measurement of distance constraints and site-specific dynamics in biomolecules to provide rich details of structure and structural changes that are tightly linked to biological function. Historically, nitroxide radicals are the most common spin labels. However, decades of method development and technological innovation have created a plethora of spin label types to extend the reach of EPR throughout the realm of biophysics. In this review we overview recent developments that improve the sensitivity of distance measurements using Cu(II) labels. These achievements over the last three years promise advancements in the ability of EPR to measure structural and dynamical constraints beyond what is possible using common spin labels. First, we briefly discuss pulsed and continuous-wave EPR techniques that discern the coordination of Cu(II) to monitor spin-labeling efficiency and binding in biological environments. Next, we outline the bottlenecks that impact sensitivity in pulsed dipolar spectroscopy and the strategic steps taken to remove these bottlenecks to collect distance measurements in hours. More precisely, we focus on the fast-spin phase memory relaxation time, the broad EPR spectrum due to anisotropy, and orientational selectivity effects inherent to Cu(II). Finally, we showcase the versatile application of Cu(II) spin labels in biological systems and the advantages of Cu(II) in pulsed dipolar spectroscopy to access nanomolar protein concentrations. [ABSTRACT FROM AUTHOR]

This review aimed to explore the pivotal role of the immune system in COPD and its therapeutic potential. Methods: We conducted a review of immunity and COPD published within the past decade in the Web of Science and PubMed databases, sorting through and summarizing relevant literature. Results: This article examines the pivotal roles of the immune system in COPD. Understanding the specific functions and interactions of these immune cells could facilitate the development of novel therapeutic strategies and interventions aimed at controlling inflammation, enhancing immune function, and mitigating the impact of respiratory infections in COPD patients. [ABSTRACT FROM AUTHOR]

This experiment was conducted for 10 weeks (40 to 52 weeks old) to investigate the effect of different sources and levels of zinc on the immune and antioxidant performance of laying hens. For this purpose, 240 high-line laying hens (36-W) were used in a completely randomized design, with 8 treatments and 5 replications (6 birds per replication). The experimental treatments include 1- control (without zinc supplement), treatment 2, 3, and 4, respectively, including the control diet + 80, 120, and 160 mg/kg of zinc sulfate with a purity of 34%, and treatment 5, 6 and 7, respectively The control diet included 50, 75 and 100 mg/kg zinc hydroxy chloride with 55% purity, and treatment 8 included the control diet + 124 mg/kg zinc-methionine complex. The findings showed that, in general, different levels of zinc supplementation in organic and hydroxy form caused significant improvement in feed conversion ratio, shell weight, Haugh unit, and blood glucose reduction compared to other treatments. During the test, organic and hydroxy sources increased antibodies against the influenza vaccine (P<0.05). Also, treatments containing zinc supplements increased superoxide dismutase and total antioxidant capacity (P<0.05). This increase was associated with a decrease in serum malondialdehyde (P<0.05). Different levels and sources of zinc had no significant effect on shape index, yolk color, and glutathione peroxidase level (P<0.05). The results show that adding hydroxy chloride at 100 mg/kg can improve the antioxidant and safety indicators of eggs. [ABSTRACT FROM AUTHOR]

Cross talk between T cells and airway smooth muscle (ASM) may play a role in modulating asthmatic airway inflammation and remodeling. Infiltrating T cells have been observed within the ASM bundles of asthmatics, and a wide range of direct and indirect interactions between T cells and ASM has been demonstrated using various in vitro and in vivo model systems. Contact-dependent mechanisms such as ligation and activation of cellular adhesion and costimulatory molecules, as well as the formation of lymphocyte-derived membrane conduits, facilitate the adhesion, bidirectional communication, and transfer of materials between T and ASM cells. T cell-derived cytokines, particularly of the Th1, Th2, and Th17 subsets, modulate the secretome, proliferation, and contractility of ASM cells. This review summarizes the mechanisms governing T cell-ASM cross talk in the context of asthma. Understanding the underlying mechanistic basis is important for directing future research and developing therapeutic interventions targeted toward this complex interaction. [ABSTRACT FROM AUTHOR]

Objective: At present, targeting molecular-pharmacological therapy is still difficult in neutrophilic asthma. The investigation aims to identify and validate mitochondrion-related gene signatures for diagnosis and specific targeting therapeutics in neutrophilic asthma. Methods: Bronchial biopsy samples of neutrophilic asthma and healthy people were identified from the GSE143303 dataset and then matched with human mitochondrial gene data to obtain mitochondria-related differential genes (MitoDEGs). Signature mitochondria-related diagnostic markers were jointly screened by support vector machine (SVM) analysis, least absolute shrinkage, and selection operator (LASSO) regression. The expression of marker MitoDEGs was evaluated by validation datasets GSE147878 and GSE43696. The diagnostic value was evaluated by receiver operating characteristic (ROC) curve analysis. Meanwhile, the infiltrating immune cells were analyzed by the CIBERSORT. Finally, oxidative stress level and mitochondrial functional morphology for asthmatic mice and BEAS-2B cells were evaluated. The expression of signature MitoDEGs was verified by qPCR. Results: 67 MitoDEGs were identified. Five signature MitoDEGs (SOD2, MTHFD2, PPTC7, NME6, and SLC25A18) were further screened out. The area under the curve (AUC) of signature MitoDEGs presented a good diagnostic performance (more than 0.9). There were significant differences in the expression of signature MitoDEGs between neutrophilic asthma and non-neutrophilic asthma. In addition, the basic features of mitochondrial dysfunction were demonstrated by in vitro and in vivo experiments. The expression of signature MitoDEGs in the neutrophilic asthma mice presented a significant difference from the control group. Conclusions: These MitoDEGs signatures in neutrophilic asthma may hold potential as anchor diagnostic and therapeutic targets in neutrophilic asthma. [ABSTRACT FROM AUTHOR]

Background: Carbon monoxide (CO), hypothetically linked to prebiotic biosynthesis and possibly the origin of the life, emerges as a substantive growth substrate for numerous microorganisms. In anoxic environments, the coupling of CO oxidation with hydrogen (H2) production is an essential source of electrons, which can subsequently be utilized by hydrogenotrophic bacteria (e.g., organohalide-respring bacteria). While Dehalococcoides strains assume pivotal roles in the natural turnover of halogenated organics and the bioremediation of chlorinated ethenes, relying on external H2 as their electron donor and acetate as their carbon source, the synergistic dynamics within the anaerobic microbiome have received comparatively less scrutiny. This study delves into the intriguing prospect of CO serving as both the exclusive carbon source and electron donor, thereby supporting the reductive dechlorination of trichloroethene (TCE). Results: The metabolic pathway involved anaerobic CO oxidation, specifically the Wood-Ljungdahl pathway, which produced H2 and acetate as primary metabolic products. In an intricate microbial interplay, these H2 and acetate were subsequently utilized by Dehalococcoides, facilitating the dechlorination of TCE. Notably, Acetobacterium emerged as one of the pivotal collaborators for Dehalococcoides, furnishing not only a crucial carbon source essential for its growth and proliferation but also providing a defense against CO inhibition. Conclusions: This research expands our understanding of CO's versatility as a microbial energy and carbon source and unveils the intricate syntrophic dynamics underlying reductive dechlorination. 3ez2V3iuLHAKAp3AxS5o4q Video Abstract [ABSTRACT FROM AUTHOR]

Extracellular traps (ETs) are a specialized form of innate immune defense in which leukocytes release ETs composed of chromatin and active proteins to eliminate pathogenic microorganisms. In addition to the anti-infection effect of ETs, researchers have also discovered their involvement in the pathogenesis of inflammatory disease, tumors, autoimmune disease, and allergic disease. Asthma is a chronic airway inflammatory disease involving multiple immune cells. The increased level of ETs in asthma patients suggests that ETs play an important role in the pathogenesis of asthma. Here we review the research work on the formation mechanism, roles, and therapeutic strategies of ETs released by neutrophils, eosinophils, and macrophages in asthma. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous disease, and its development is the result of a combination of factors, including genetic factors, environmental factors, immune dysfunction and other factors. Its specific mechanism has not yet been fully investigated. With the improvement of disease models, research on the pathogenesis of asthma has made great progress. Immunological disorders play an important role in asthma. Previously, we thought that asthma was mainly caused by an imbalance between Th1 and Th2 immune responses, but this theory cannot fully explain the pathogenesis of asthma. Recent studies have shown that T-cell subsets such as Th1 cells, Th2 cells, Th17 cells, Tregs and their cytokines contribute to asthma through different mechanisms. For the purpose of the present study, asthma was classified into distinct phenotypes based on airway inflammatory cells, such as eosinophilic asthma, characterized by predominant eosinophil aggregates, and neutrophilic asthma, characterized by predominant neutrophil aggregates. This paper will examine the immune mechanisms underlying different types of asthma, and will utilize data from animal models and clinical studies targeting specific immune pathways to inform more precise treatments for this condition. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively. [ABSTRACT FROM AUTHOR]

Sargassum horneri (S. horneri), a brown seaweed excessively proliferating along Asian coastlines, are damaging marine ecosystems. Thus, this study aimed to enhance nutritional value of S. horneri through lactic acid bacteria fermentation to increase S. horneri utilization as a functional food supplement, and consequently resolve coastal S. horneri accumulation. S. horneri supplemented fermentation was most effective with Lactiplantibacillus pentosus SH803, thus this product (F-SHWE) was used for further in vitro studies. F-SHWE normalized expressions of oxidative stress related genes NF-κB, p53, BAX, cytochrome C, caspase 9, and caspase 3, while non-fermented S. horneri (SHWE) did not, in a H2O2-induced HT-29 cell model. Moreover, in an LPS-induced HT-29 cell model, F-SHWE repaired expressions of inflammation marker genes ZO1, IL1β, IFNγ more effectively than SHWE. For further functional assessment, F-SHWE was also treated in 3T3-L1 adipocytes. As a result, F-SHWE decreased lipid accumulation, along with gene expression of adipogenesis markers PPARγ, C/EBPα, C/EBPβ, aP2, and Lpl; lipogenesis markers Lep, Akt, SREBP1, Acc, Fas; inflammation markers IFN-γ and NF-κB. Notably, gene expression of C/EBPβ, IFN-γ and NF-κB were suppressed only by F-SHWE, suggesting the enhancing effect of fermentation on obesity-related properties. Compositional analysis attributed the protective effects of F-SHWE to acetate, an organic acid significantly higher in F-SHWE than SHWE. Therefore, F-SHWE is a novel potential anti-obesity agent, providing a strategy to reduce excess S. horneri populations along marine ecosystems. [ABSTRACT FROM AUTHOR]

Loss of proteostasis and cellular senescence have been previously established as characteristics of aging; however, their interaction in the context of lung aging and potential contributions to aging-associated lung remodeling remains understudied. In this study, we aimed to characterize endoplasmic reticulum (ER) stress response, cellular senescence, and their interaction in relation to extracellular matrix (ECM) production in lung fibroblasts from young (25–45 yr) and old (>60 yr) humans. Fibroblasts from young and old patients without significant preexisting lung disease were exposed to vehicle, MG132, etoposide, or salubrinal. Afterward, cells and cell lysates or supernatants were analyzed for ER stress, cellular senescence, and ECM changes using protein analysis, proliferation assay, and senescence-associated beta-galactosidase (SA-b-Gal) staining. At baseline, fibroblasts from aging individuals showed increased levels of ER stress (ATF6 and PERK), senescence (p21 and McL-1), and ECM marker (COL1A1) compared to those from young individuals. Upon ER stress induction and etoposide exposure, fibroblasts showed an increase in senescence (SA-b-Gal, p21, and Cav-1), ER stress (PERK), and ECM markers (COL1A1 and LUM) compared to vehicle. Additionally, IL-6 and IL-8 levels were increased in the supernatants of MG132- and etoposide-treated fibroblasts, respectively. Finally, the ER stress inhibitor salubrinal decreased the expression of p21 compared to vehicle and MG132 treatments; however, salubrinal inhibited COL1A1 but not p21 expression in MG132-treated fibroblasts. Our study suggests that ER stress response plays an important role in establishment and maintenance of a senescence phenotype in lung fibroblasts and therefore contributes to altered remodeling in the aging lung. NEW & NOTEWORTHY The current study establishes functional links between endoplasmic reticulum (ER) stress and cellular senescence per se in the specific context of aging human lung fibroblasts. Recognizing that the process of aging per se is complex, modulated by the myriad of lifelong and environmental exposures, it is striking to note that chronic ER stress may play a crucial role in the establishment and maintenance of cellular senescence in lung fibroblasts. [ABSTRACT FROM AUTHOR]

Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5- trisphosphate (IP3) and diacylglycerol (DAG). This is a point for second-messenger bifurcation where DAG via protein kinase C (PKC) and IP3 via calcium activate distinct protein targets and regulate cellular functions. IP3 signaling is regulated by multiple calcium influx and efflux proteins involved in calcium homeostasis. A family of lipid kinases belonging to DAG kinases (DGKs) converts DAG to phosphatidic acid (PA), negatively regulating DAG signaling and pathophysiological functions. PA, through a series of biochemical reactions, is recycled to produce new molecules of PIP2. Therefore, DGKs act as a central switch in terminating DAG signaling and resynthesis of membrane phospholipids precursor. Interestingly, calcium and PKC regulate the activation of α and ζ isoforms of DGK that are predominantly expressed in airway and immune cells. Thus, DGK forms a feedback and feedforward control point and plays a crucial role in fine-tuning phospholipid stoichiometry, signaling, and functions. In this review, we discuss the previously underappreciated complex and intriguing DAG/DGK-driven mechanisms in regulating cellular functions associated with asthma, such as contraction and proliferation of airway smooth muscle (ASM) cells and inflammatory activation of immune cells. We highlight the benefits of manipulating DGK activity in mitigating salient features of asthma pathophysiology and shed light on DGK as a molecule of interest for heterogeneous diseases such as asthma. [ABSTRACT FROM AUTHOR]

Nitrogen fixation is a complex process involving the transfer of six electrons and protons. Diverging from the conventional Haber-Bosch process, which relies on hydrogen (H2) to provide both electrons and protons to reduce nitrogen (N2), homogeneous transition metal complex-catalyzed N2 reduction reactions (NRR) employ an array of electron and proton donors or even electron donors combined with silanes. As the synthesis of diverse catalytic progress, the categories of donors have seen rapid expansion. However, existing literature only provides summaries regarding the metal, ligands, and mechanism. Despite the significance of electron and proton donor combinations in nitrogen reduction reactions, no literature has thoroughly reviewed this aspect. Therefore, we hereby compiled a comprehensive list of commonly used reagents in N2 reduction and classified them according to their specific donor combinations. This review presents clear and organized information about these combinations, along with a summary of their general performance trend in NRR with related catalysts. Finally, we conclude the discussion by highlighting key points for researchers to consider when selecting catalysts and donor combinations, with the ultimate goal of advancing the field of nitrogen fixation. [ABSTRACT FROM AUTHOR]

Archaea possess characteristic membrane-spanning lipids that are thought to contribute to the adaptation to extreme environments. However, the biosynthesis of these lipids is poorly understood. Here, we identify a radical S-adenosyl-L-methionine (SAM) enzyme that synthesizes glycerol monoalkyl glycerol tetraethers (GMGTs). The enzyme, which we name GMGT synthase (Gms), catalyzes the formation of a C(sp3)–C(sp3) linkage between the two isoprenoid chains of glycerol dialkyl glycerol tetraethers (GDGTs). This conclusion is supported by heterologous expression of gene gms from a GMGT-producing species in a methanogen, as well as demonstration of in vitro activity using purified Gms enzyme. Additionally, we show that genes encoding putative Gms homologs are present in obligate anaerobic archaea and in metagenomes obtained from oxygen-deficient environments, and appear to be absent in metagenomes from oxic settings. The biosynthesis of membrane-spanning lipids in archaea is poorly understood. Here, Li et al. identify an archaeal enzyme that forms a C(sp3)–C(sp3) linkage between isoprenoid chains for the synthesis of membrane-spanning GMGT lipids, and show that the corresponding gene is exclusively found in obligate anaerobic archaea and in metagenomes from oxygen-deficient environments. [ABSTRACT FROM AUTHOR]

Two coordination complexes were synthesized using vanadyl(IV) acetylacetonate and H2denm/H4dpim in MeOH/CHCl3 and characterized. The complexes were [VO(denm)(H2O)]·CH3OH (1) and [VO(H2dpim)(CH3COONa)]·CH3OH (2) (H2denm = 2,2′-[[(1R,2R)-1,2-diphenyl-1,2-ethanediyl]bis[(E)-nitrilomethylidyne]]bis[6-methoxyphenol]; H4dpim = [(2,2-dimethyl-1,3-propanediyl)bis(iminomethylene)bis(6-methoxyphenol)]. The vanadyl(IV) species of 1 and 2 exhibited distorted octahedral geometries with two N and two O atoms of each ligand and aqua/acetate ligand. Complex 1 did not exhibit emissions in the solid and solution states, whereas complex 2 exhibited strong band maxima in the solid state and a dimethyl sulfoxide solution. The magnetic properties and electron paramagnetic resonance spectra of 1 and 2 revealed that they were S = 1/2 spin systems. The antioxidant activity of 2 was higher than those of 1 and ascorbic acid. [ABSTRACT FROM AUTHOR]