Aldehyde Dehydrogenase 2 Deficiency Aggravates Lung Fibrosis through Mitochondrial Dysfunction and Aging in Fibroblasts.

Idiopathic pulmonary fibrosis, a fatal interstitial lung disease, is characterized by fibroblast activation and aberrant extracellular matrix accumulation. Effective therapeutic development is limited because of incomplete understanding of the mechanisms by which fibroblasts become aberrantly activated. Here, we show aldehyde dehydrogenase 2 (ALDH2) in fibroblasts as a potential therapeutic target for pulmonary fibrosis. A decrease in ALDH2 expression was observed in patients with idiopathic pulmonary fibrosis and bleomycin-treated mice. ALDH2 deficiency spontaneously induces collagen accumulation in the lungs of aged mice. Furthermore, young ALDH2 knockout mice exhibited exacerbated bleomycin-induced pulmonary fibrosis and increased mortality compared with that in control mice. Mechanistic studies revealed that transforming growth factor (TGF)-ß1 induction and ALDH2 depletion constituted a positive feedback loop that exacerbates fibroblast activation. TGF-ß1 down-regulated ALDH2 through a TGF-ß receptor 1/Smad3-dependent mechanism. The subsequent deficiency in ALDH2 resulted in fibroblast dysfunction that manifested as impaired mitochondrial autophagy and senescence, leading to fibroblast activation and extracellular matrix production. ALDH2 overexpression markedly suppressed fibroblast activation, and this effect was abrogated by PTEN-induced putative kinase 1 (PINK1) knockdown, indicating that the profibrotic effects of ALDH2 are PINK1- dependent. Furthermore, ALDH2 activated by N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) reversed the established pulmonary fibrosis in both young and aged mice. In conclusion, ALDH2 expression inhibited the pathogenesis of pulmonary fibrosis. Strategies to up-regulate or activate ALDH2 expression could be potential therapies for pulmonary fibrosis.

Metal-Organic Framework PCN-224 Combined Cobalt Oxide Nanoparticles for Hypoxia Relief and Synergistic Photodynamic/Chemodynamic Therapy.

Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are promising tumor treatments mediated by reactive oxygen species (ROS), which have the advantages of being minimally invasive. However, the hypoxia of tumor microenvironment and poor target ability often reduce the therapeutic effect. Here we propose a tumor targeted nanoplatform PCN-224@Co3O4-HA for enhanced PDT and synergistic CDT, constructed by hyaluronate-modified Co3O4 nanoparticles decorated metal-organic framework PCN-224. Co3O4 can catalyze the decomposition of highly expressed H2O2 in tumor cells to produce oxygen and alleviate the problem of hypoxia. It can also produce hydroxyl radicals according to the Fenton-like reaction for chemical dynamic therapy, significantly improving the therapeutic effect. The cell survival experiment showed that after in vitro treatment, 4T1 and MCF-7 cancer cells died in a large area under the anaerobic state, while the survival ability of normal cell L02 was nearly unchanged. This result effectively indicated that PCN-224@Co3O4-HA could effectively relieve tumor hypoxia and improve the effect of PDT and synergistic CDT. Cell uptake experiments showed that PCN-224@Co3O4-HA had good targeting properties and could effectively aggregate in tumor cells. In vivo experiments on mice, PCN-224@Co3O4-HA presented reliable biosafety performance, and can cooperate with PDT and CDT therapy to prevent the growth of tumor.

The accuracy of electromagnetic navigation bronchoscopy compared to fluoroscopy in navigation of transbronchial lung cryobiopsy in patients with interstitial lung disease.

BACKGROUND: Safely implementing transbronchial lung cryobiopsy (TBLC) in patients with interstitial lung disease (ILD) requires accurate navigation. Traditional fluoroscopy falls short in reducing the risk of post-procedure pneumothorax. The potential of electromagnetic navigation bronchoscopy (ENB) as a more precise navigation method warrants further exploration. METHODS: A prospective cohort study was conducted on ILD patients undergoing TBLC. Patients were assigned either fluoroscopy or ENB for cryoprobe positioning. Navigation accuracy was evaluated using cone beam computed tomography (CBCT) images as the standard. Safety and diagnostic yield were also observed. RESULTS: Seventeen patients underwent TBLC, with 10 guided by fluoroscopy and seven by ENB. Fluoroscopy-guided cryoprobe navigation required more adjustments [9/15 (60%) v.s. 1/9 (11%), p = 0.018] for subsequent TBLC compared to ENB, as confirmed by CBCT images. Clinical characteristics, post-procedure complications, and biopsy specimen size showed no significant differences between the groups. Fourteen patients obtained a pathological diagnosis, and 15 received a multidisciplinary discussion (MDD) diagnosis. In the fluoroscopy group, three patients failed to obtain a pathological diagnosis, and two failed to obtain an MDD diagnosis. CONCLUSIONS: ENB demonstrates significantly superior accuracy in TBLC navigation compared to traditional fluoroscopy when CBCT images are used as a reference. Further studies are necessary to determine the value of ENB in TBLC navigation for ILD patients.

Feasibility of spheno-occipital synchondrosis fusion stages as an indicator for the assessment of maxillomandibular growth: A mixed longitudinal study.

OBJECTIVES: This study aimed to assess the relative growth rates (RGRs) of the maxilla and mandible at varying fusion stages of the spheno-occipital synchondrosis (SOS), thereby elucidating the potential of SOS stages in predicting maxillomandibular growth. MATERIALS AND METHODS: A total of 320 subjects (171 boys and 149 girls), aged 6 to 18 years, were retrospectively included. Each subject had a minimum of two longitudinal cone-beam computed tomography (CBCT) images, with no more than one interval of SOS fusion stage change between the two scans. Subjects were categorized based on their SOS fusion stages and genders. The RGRs of the maxilla and mandible at various SOS fusion stages were measured and compared using longitudinal CBCT images. RESULTS: Significant statistical differences were observed in maxillomandibular RGRs across various SOS fusion stages. In girls, the sagittal growth of the maxilla remained stable and active until SOS 3, subsequently exhibited deceleration in SOS 4-5 (compared to SOS 3-4, P < .05) and continued to decrease in SOS 5-6. Whereas in boys, the sagittal growth of the maxilla remained stable until SOS 4, and a deceleration trend emerged starting from SOS 5 to 6 (P < .01 compared to SOS 4-5). Mandibular growth patterns in both genders exhibited a progression of increasing-accelerating-decelerating rates from SOS 2 to 6. The highest RGRs for total mandibular length were observed in SOS 3-4 and SOS 4-5. CONCLUSION: Spheno-occipital synchondrosis fusion stages can serve as a valid indicator of maxillomandibular growth maturation.

Three-dimensional analysis of the positional relationship between the dentition and basal bone region in patients with skeletal Class I and Class II malocclusion with mandibular retrusion.

Objective: This study aimed to determine the maxillary and mandibular basal bone regions and explore the three-dimensional positional relationship between the dentition and basal bone regions in patients with skeletal Class I and Class II malocclusions with mandibular retrusion. Methods: Eighty patients (40 each with Class I and Class II malocclusion) were enrolled. Maxillary and mandibular basal bone regions were determined using cone-beam computed tomography images. To measure the relationship between the dentition and basal bone region, the root position and root inclination were calculated using the coordinates of specific fixed points by a computer program written in Python. Results: In the Class II group, the mandibular anterior teeth inclined more labially (P < 0.05), with their apices positioned closer to the external boundary. The apex of the maxillary anterior root was positioned closer to the external boundary in both groups. Considering the molar region, the maxillary first molars tended to be more lingually inclined in females (P = 0.037), whereas the mandibular first molars were significantly more labially inclined in the Class II group (P < 0.05). Conclusions: Mandibular anterior teeth in Class II malocclusion exhibit a compensatory labial inclination trend with the crown and apex relative to the basal bone region when mandibular retrusion occurs. Moreover, as the root apices of the maxillary anterior teeth are much closer to the labial side in Class I and Class II malocclusion, the range of movement at the root apex should be limited to avoid extensive labial movement.

Removal of dyes from wastewater using Eucalyptus wood fiber loaded nanoscale zero-valent iron: Characterization and removal mechanism.

Wood fiber as a natural and renewable material has low cost and plenty of functional groups, which owns the ability to adsorb dyes. In order to improve the application performance of wood fiber in dye-pollution wastewater, Eucalyptus wood fiber loaded nanoscale zero-valent iron (EWF-nZVI) was developed to give EWF magnetism and the ability to degrade dyes. EWF-nZVI was characterized via FTIR, XRD, zeta potential, VSM, SEM-EDS and XPS. Results showed that EWF-nZVI owned a strong magnetism of 96.51 emu/g. The dye removal process of EWF-nZVI was more in line with the pseudo-second-order kinetics model. In addition, the Langmuir isotherm model fitting results showed that the maximum removal capacities of Congo red and Rhodamine B by EWF-nZVI were 714.29 mg/g and 68.49 mg/g at 328 K, respectively. After five adsorption-desorption cycles, the regeneration efficiencies of Congo red and Rhodamine B were 74 % and 42 % in turn. The dye removal mechanisms of EWF-nZVI included redox degradation (Congo red and Rhodamine B) and electrostatic adsorption (Congo red). In summary, EWF-nZVI is a promising biomass-based material with high dye removal capacities. This work is beneficial to promote the large-scale application of wood fiber in water treatment.

PKD knockdown mitigates Ang II-induced cardiac hypertrophy and ferroptosis via the JNK/P53 signaling pathway.

BACKGROUND: Cardiac hypertrophy is studied in relation to energy metabolism, autophagy, and ferroptosis, which are associated with cardiovascular adverse events and chronic heart failure. Protein kinase D (PKD) has been shown to play a degenerative role in cardiac hypertrophy. However, the role of ferroptosis in PKD-involved cardiac hypertrophy remains unclear. METHODS: A cardiac hypertrophy model was induced by a subcutaneous injection of angiotensin II (Ang II) for 4 weeks. Adeno-associated virus serotype 9 (AAV9)-PKD or AAV9-Negative control were injected through the caudal vein 2 weeks prior to the injection of Ang II. The degree of cardiac hypertrophy was assessed using echocardiography and by observing cardiomyocyte morphology. Levels of ferroptosis and protein expression in the Jun N-terminal kinase (JNK)/P53 signaling pathway were measured both in vivo and in vitro. RESULTS: The results indicated that PKD knockdown reduces Ang II-induced cardiac hypertrophy, enhances cardiac function and inhibits ferroptosis. The involvement of the JNK/P53 pathway in this process was further confirmed by in vivo and in vitro experiments. CONCLUSION: In conclusion, our findings suggest that PKD knockdown mitigates Ang II-induced cardiac hypertrophy and ferroptosis via the JNK/P53 signaling pathway.

Coumestrol facilitates apoptosis in colorectal cancer cells by interacting with ZIP8 protein via the ferroptosis pathway.

Objective: So far, there have been no reports of coumestrol inhibiting colorectal cancer (CRC) through the ferroptosis pathway. This study is to investigate the mechanism of the traditional Chinese medicine monomer coumestrol in the treatment of CRC. Methods: Data on CRC transcriptome sequencing was obtained from the GEO database and TCGA database. Bioinformatics analyses were conducted to screen for CRC prognostic-related key genes and their potential binding monomers in traditional Chinese medicine. The inhibitory effect of coumestrol on CRC cell lines (COLO 205 & HCT 116) was determined using the CCK-8 assay, and cell apoptosis was assessed by flow cytometry. The content of ferrous ions was measured using the Ferrous Ion Content Assay Kit. The expression of ferroptosis pathway-related genes SLC39A8, NCOA4, VDAC2, and NOX2 before and after small interference RNA (siRNA) was examined through real-time PCR and Western blotting. Results: SLC39A8 was found to be associated with CRC clinical progression staging, and its encoded protein ZIP8 may bind to coumestrol. KEGG enrichment analysis suggested that ZIP8 plays a role in iron transmembrane transport and may affect the expression of ferroptosis pathway-related genes NCOA4, VDAC2, and NOX2. Coumestrol was found to induce apoptosis in CRC cell lines by upregulating the expression of ferroptosis pathway-related genes SLC39A8, NCOA4, VDAC2, and NOX2. However, coumestrol was unable to upregulate the expression of ferroptosis pathway-related genes in CRC cell lines after SLC39A8 interference. Conclusion: Coumestrol facilitates apoptosis in CRC cells by interacting with ZIP8 protein via the ferroptosis pathway.

Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria-Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism.

The heart primarily derives its energy through lipid oxidation. In cardiomyocytes, lipids are stored in lipid droplets (LDs) and are utilized in mitochondria, although the structural and functional connections between these two organelles remain largely unknown. In this study, visible evidence have presented indicating that a complex is formed at the mitochondria-LD membrane contact (MLC) site, involving mitochondrion-localized Mfn2 and LD-localized Hsc70. This complex serves to tether mitochondria to LDs, facilitating the transfer of fatty acids (FAs) from LDs to mitochondria for ß-oxidation. Reduction of Mfn2 induced by lipid overload inhibits MLC, hinders FA transfer, and results in lipid accumulation. Restoring Mfn2 reinstates MLC, alleviating myocardial lipotoxicity under lipid overload conditions both in-vivo and in-vitro. Additionally, prolonged lipid overload induces Mfn2 degradation through the ubiquitin-proteasome pathway, following Mfn2 acetylation at the K243 site. This leads to the transition from adaptive lipid utilization to maladaptive lipotoxicity. The experimental findings are supported by clinical data from patients with obesity and age-matched non-obese individuals. These translational results make a significant contribution to the molecular understanding of MLC in the heart, and offer new insights into its role in myocardial lipotoxicity.

Single-molecule detection assisted by the target-triggered signal amplification strategy for ultrasensitive quantitative analysis of intracellular telomerase activity.

We developed a multiplex single-molecule quantitative assay of intracellular telomerase that used target-triggered signal amplification to enhance sensitivity, substrate reaction to increase signal stability, and quantum dots to enhance signal-to-noise ratio, obtaining an LOD of 5 × 10-14 IU for intracellular telomerase and LOD of 3 cells for multiple cancer cells.

Sustained amphiregulin expression in intermediate alveolar stem cells drives progressive fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.

Assessment of lung deformation in patients with idiopathic pulmonary fibrosis with elastic registration technique on pulmonary three-dimensional ultrashort echo time MRI.

OBJECTIVE: To assess lung deformation in patients with idiopathic pulmonary fibrosis (IPF) using with elastic registration algorithm applied to three-dimensional ultrashort echo time (3D-UTE) MRI and analyze relationship of lung deformation with the severity of IPF. METHODS: Seventy-six patients with IPF (mean age: 62 ± 6 years) and 62 age- and gender-matched healthy controls (mean age: 58 ± 4 years) were prospectively enrolled. End-inspiration and end-expiration images acquired with a single breath-hold 3D-UTE sequence were registered using elastic registration algorithm. Jacobian determinants were calculated from deformation fields and represented on color maps. Jac-mean (absolute value of the log means of Jacobian determinants) and the Dice similarity coefficient (Dice) were compared between different groups. RESULTS: Compared with healthy controls, the Jac-mean of IPF patients significantly decreased (0.21 ± 0.08 vs. 0.27 ± 0. 07, p < 0.001). Furthermore, the Jac-mean and Dice correlated with the metrics of pulmonary function tests and the composite physiological index. The lung deformation in IPF patients with dyspnea Medical Research Council (MRC) ≥ 3 (Jac-mean: 0.16 ± 0.03; Dice: 0.06 ± 0.02) was significantly lower than MRC1 (Jac-mean: 0. 25 ± 0.03, p < 0.001; Dice: 0.10 ± 0.01, p < 0.001) and MRC 2 (Jac-mean: 0.22 ± 0.11, p = 0.001; Dice: 0.08 ± 0.03, p = 0.006). Meanwhile, Jac-mean and Dice correlated with health-related quality of life, 6 min-walk distance, and the extent of pulmonary fibrosis. Jac-mean correlated with pulmonary vascular-related indexes on high-resolution CT. CONCLUSION: The decreased lung deformation in IPF patients correlated with the clinical severity of IPF patients. Elastic registration of inspiratory-to-expiratory 3D UTE MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. CRITICAL RELEVANCE STATEMENT: This prospective study demonstrated that lung deformation decreased in idiopathic pulmonary fibrosis (IPF) patients and correlated with the severity of IPF. Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. KEY POINTS: • Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI could evaluate lung deformation. • Lung deformation significantly decreased in idiopathic pulmonary fibrosis (IPF) patients, compared with the healthy controls. • Reduced lung deformation of IPF patients correlated with worsened pulmonary function and the composite physiological index (CPI).

Echocardiographic evaluation of the right atrial size and function: Relevance for clinical practice.

Right atrial (RA) structural and functional evaluations have recently emerged as powerful biomarkers for adverse events in various cardiovascular conditions. Quantitative analysis of the right atrium, usually performed with volume changes or speckle-tracking echocardiography (STE), has markedly changed our understanding of RA function and remodeling. Knowledge of reference echocardiographic values and measurement methods of RA volumes and myocardial function is a prerequisite to introduce RA quantitation in the clinical routine. This review describes the methodology, benefits and pitfalls of measuring RA size and function by echocardiography based on the current understanding of right atrial anatomy and physiological function and provides the current knowledge of right atrial function in related cardiac diseases.