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Cancer Innovation Jun 2024Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular... (Review)
Review
Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.
PubMed: 38947757
DOI: 10.1002/cai2.114 -
Frontiers in Immunology 2024Chronic obstructive pulmonary disease (COPD) is currently listed as the 3 leading cause of death in the United States. Accumulating data shows the association between...
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is currently listed as the 3 leading cause of death in the United States. Accumulating data shows the association between COPD occurrence and the usage of electronic nicotine delivery systems (ENDS) in patients. However, the underlying pathogenesis mechanisms of COPD have not been fully understood.
METHODS
In the current study, bENaC-overexpressing mice (bENaC mice) were subjected to whole-body ENDS exposure. COPD related features including emphysema, mucus accumulation, inflammation and fibrosis are examined by tissue staining, FACS analysis, cytokine measurement. Cell death and ferroptosis of alveolar epithelial cells were further evaluated by multiple assays including staining, FACS analysis and lipidomics.
RESULTS
ENDS-exposed mice displayed enhanced emphysema and mucus accumulation, suggesting that ENDS exposure promotes COPD features. ENDS exposure also increased immune cell number infiltration in bronchoalveolar lavage and levels of multiple COPD-related cytokines in the lungs, including CCL2, IL-4, IL-13, IL-10, M-CSF, and TNF-α. Moreover, we observed increased fibrosis in ENDS-exposed mice, as evidenced by elevated collagen deposition and a-SMA+ myofibroblast accumulation. By investigating possible mechanisms for how ENDS promoted COPD, we demonstrated that ENDS exposure induced cell death of alveolar epithelial cells, evidenced by TUNEL staining and Annexin V/PI FACS analysis. Furthermore, we identified that ENDS exposure caused lipid dysregulations, including TAGs (9 species) and phospholipids (34 species). As most of these lipid species are highly associated with ferroptosis, we confirmed ENDS also enhanced ferroptosis marker CD71 in both type I and type II alveolar epithelial cells.
DISCUSSION
Overall, our data revealed that ENDS exposure exacerbates features of COPD in bENaC mice including emphysema, mucus accumulation, abnormal lung inflammation, and fibrosis, which involves the effect of COPD development by inducing ferroptosis in the lung.
Topics: Animals; Ferroptosis; Pulmonary Disease, Chronic Obstructive; Mice; Nicotine; E-Cigarette Vapor; Disease Models, Animal; Cytokines; Mice, Inbred C57BL; Electronic Nicotine Delivery Systems; Male; Mice, Transgenic
PubMed: 38947318
DOI: 10.3389/fimmu.2024.1429946 -
European Clinical Respiratory Journal 2024Bronchiectasis is a disease with predominantly neutrophilic inflammation. As a readily available biomarker, there is little evidence to support the use of blood...
BACKGROUND
Bronchiectasis is a disease with predominantly neutrophilic inflammation. As a readily available biomarker, there is little evidence to support the use of blood neutrophil-to-lymphocyte ratio (NLR) to predict bronchiectasis exacerbation severe enough to warrant hospitalization.
METHODS
A registry-based retrospective cohort study was conducted at a in Hong Kong. Chinese patients with non-cystic fibrosis (CF) bronchiectasis were retrospectively reviewed and subsequently followed up to investigate the association of NLR and the need for hospitalization for bronchiectasis exacerbation. Data on the NLR for patients in a clinically stable state in 2018 were collected and patients followed up from 1 January 2019 to 31 December 2022. The primary outcome was the need for hospitalization due to bronchiectasis exacerbation over the next 4 years.
RESULTS
We reviewed 473 Chinese patients with non-CF bronchiectasis, of whom 94 required hospitalization for bronchiectasis exacerbation during the 4-year follow-up period. Multi-variable logistic regression adjusted for E-FACED score (Exacerbation, Forced expiratory volume in 1 s (FEV), Age, Chronic colonization, Extension, and Dyspnea score), gender, age, smoking status, and presence of co-existing chronic obstructive pulmonary disease (COPD) was conducted to compare patients with highest and lowest quartile NLR. Results revealed that those with NLR at the highest quartile were at increased risk of hospitalization for bronchiectasis exacerbation with an adjusted odds ratio (aOR) of 2.02 (95% confidence interval = 1.00-4.12, = 0.05).
CONCLUSION
Blood NLR may serve as a marker to predict the need for hospitalization due to bronchiectasis exacerbation.
PubMed: 38946716
DOI: 10.1080/20018525.2024.2372901 -
Current Opinion in Pulmonary Medicine Jul 2024Pulmonary fibrosis (PF) negatively influences health-related quality of life (HRQOL). Patients living with PF have voiced the desire for a focus on symptoms and HRQOL in...
PURPOSE OF REVIEW
Pulmonary fibrosis (PF) negatively influences health-related quality of life (HRQOL). Patients living with PF have voiced the desire for a focus on symptoms and HRQOL in both disease monitoring and treatment decisions.
RECENT FINDINGS
Currently available disease modifying treatments do little to impact HRQOL. Newer studies evaluating pharmacologic and nonpharmacologic therapies targeting symptoms and HRQOL in PF have been conducted with some promising results. There is increasing recognition of the importance of incorporating HRQOL as a higher tier endpoint in clinical trials. Disease-specific measure of HRQOL have been developed for those living with PF, and there is ongoing work to better understand the validity and reliability characteristics of these tools. In addition to research, there is recognition of the potential benefits of measuring HRQOL and symptoms in clinical practice in facilitate integrating patient perspective into care and allow for more personalized treatment approaches.
SUMMARY
There is increased momentum to discover treatments that impact HRQOL in PF. More work is desperately needed to identify better treatment targets, and to incorporate HRQOL and symptoms as higher tier endpoints in clinical trials. Further work is also needed to address the practicalities of integrating HRQOL measurement into clinical care.
PubMed: 38946547
DOI: 10.1097/MCP.0000000000001095 -
Experimental & Molecular Medicine Jul 2024The senescence of alveolar type II (AT2) cells impedes self-repair of the lung epithelium and contributes to lung injury in the setting of idiopathic pulmonary fibrosis...
The senescence of alveolar type II (AT2) cells impedes self-repair of the lung epithelium and contributes to lung injury in the setting of idiopathic pulmonary fibrosis (IPF). Yes-associated protein 1 (YAP1) is essential for cell growth and organ development; however, the role of YAP1 in AT2 cells during pulmonary fibrosis is still unclear. YAP1 expression was found to be downregulated in the AT2 cells of PF patients. Deletion of YAP1 in AT2 cells resulted in lung injury, exacerbated extracellular matrix (ECM) deposition, and worsened lung function. In contrast, overexpression of YAP1 in AT2 cells promoted alveolar regeneration, mitigated pulmonary fibrosis, and improved lung function. In addition, overexpression of YAP1 alleviated bleomycin (BLM) -induced senescence of alveolar epithelial cells both in vivo and in vitro. Moreover, YAP1 promoted the expression of peroxiredoxin 3 (Prdx3) by directly interacting with TEAD1. Forced expression of Prdx3 inhibited senescence and improved mitochondrial dysfunction in BLM-treated MLE-12 cells, whereas depletion of Prdx3 partially abrogated the protective effect of YAP1. Furthermore, overexpression of Prdx3 facilitated self-repair of the injured lung and reduced ECM deposition, while silencing Prdx3 attenuated the antifibrotic effect of YAP1. In conclusion, this study demonstrated that YAP1 alleviates lung injury and pulmonary fibrosis by regulating Prdx3 expression to improve mitochondrial dysfunction and block senescence in AT2 cells, revealing a potential novel therapeutic strategy for pulmonary fibrosis.
PubMed: 38945958
DOI: 10.1038/s12276-024-01277-0 -
Journal of Hazardous Materials Jun 2024Next-generation risk assessment (NGRA) has emerged as a promising alternative to non-animal studies owing to the increasing demand for the risk assessment of inhaled...
Next-generation risk assessment (NGRA) has emerged as a promising alternative to non-animal studies owing to the increasing demand for the risk assessment of inhaled toxicants. In this study, NGRA was used to assess the inhalation risks of two biocides commonly used as humidifier disinfectants: polyhexamethylene guanidine phosphate (PHMG-p) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT). Human bronchial epithelial cell transcriptomic data were processed based on adverse outcome pathways and used to establish transcriptome-based points of departure (tPODs) for each biocide. tPOD values were 0.00500-0.0510 μg/cm and 0.0342-0.0544 μg/cm for PHMG-p and CMIT/MIT, respectively. tPODs may provide predictive power comparable to that of traditional animal-based PODs (aPODs). The tPOD-based NGRA determined that both PHMG-p and CMIT/MIT present a high inhalation risk. Moreover, the identified PHMG-p posed a higher risk than CMIT/MIT, and children were identified as more susceptible population compared to adults. This finding is consistent with observations from actual exposure events. Our findings suggest that NGRA with transcriptomics offers a reliable approach for risk assessment of specific humidifier disinfectant biocides, while acknowledging the limitations of current models and in vitro systems, particularly regarding uncertainties in pharmacokinetics (PK) and pharmacodynamics (PD).
PubMed: 38944992
DOI: 10.1016/j.jhazmat.2024.134986 -
Advances in Gerontology = Uspekhi... 2024Research on the condition of the lungs in senile people is an urgent task. This is due to the fact that degenerative or age-associated changes in the respiratory system...
Research on the condition of the lungs in senile people is an urgent task. This is due to the fact that degenerative or age-associated changes in the respiratory system play an important role in the formation of senile asthenia syndrome and a decrease in the age-related viability of the body as a whole. CT-scans of patients aged 80-90 years were analyzed (n=31). Age-associated changes were evaluated: the presence of linear fibrosis, increased pulmonary pattern by the type of reticular (reticular) changes, the presence of gross fibrous reticular changes with cystic cavities and air bullae (by the type of «cellular lung»), as well as the presence of pulmonary emphysema. Most naturally, senile people show changes characteristic of linear pulmonary fibrosis and emphysema. The progression of the process leads to diffuse reticular changes in the interalveolar and intersegmental septa and, in adverse cases, to the formation of gross changes in the type of «cellular lung». Fibro-emphysematous changes are significantly more common in men. A microbiological study of the microbiota of the lower respiratory tract in elderly people was also carried out (n=16). When studying the microbiocenosis of the lower respiratory tract in elderly people, the following data were obtained: resident microflora was found in 71% and clinically significant microorganisms were found in 29%.
Topics: Humans; Aged, 80 and over; Male; Female; Pulmonary Emphysema; Microbiota; Lung; Tomography, X-Ray Computed; Pulmonary Fibrosis; Aging
PubMed: 38944785
DOI: No ID Found -
Cellular Signalling Jun 2024Silicosis, one of the occupational health illnesses is caused by inhalation of crystalline silica. Deposition of extracellular matrix and fibroblast proliferation in...
BACKGROUND AND OBJECTIVES
Silicosis, one of the occupational health illnesses is caused by inhalation of crystalline silica. Deposition of extracellular matrix and fibroblast proliferation in lungs are linked to silicosis development. Mitochondrial dysfunction plays critical role in some diseases, but how these processes progress and regulated in silicosis, remains limited. Detailed study of silica induced pulmonary fibrosis in mouse model, its progression and severity may be helpful in designing future therapeutic strategies.
METHODS
In present study, mice model of silicosis has been developed after repeated silica exposures which may closely resemble clinical symptoms of silicosis in human. In addition to efficiently mimicking the acute/chronic transformation processes of silicosis, this is practical and efficient in terms of time and output, which avoids mechanical injury to the upper respiratory tract due to surgical interventions. Sonicated sterile silica suspension (120 mg/kg) was administered through intranasal route thrice a week at regular intervals (21, 28 and 35 days).
RESULTS
Presence of minute to larger silicotic nodules in H&E-stained lung sections were observed in all silica induced model groups. Enhanced ECM deposition was noted in MT stained lung sections of silica exposure groups as compared to control which were confirmed by significantly higher MMP9 expression levels and hydroxyproline content in silica 35 days group. Increase in Reactive oxygen species (ROS), inflammatory cell recruitment mainly, neutrophils and macrophage were observed in all three silica exposure groups. Transmission electron microscopic analysis has confirmed presence of many aberrant shaped mitochondria (swollen, round shape) in 35 days model where autophagosomes were minimum. Western blot analysis of mitophagy and autophagy markers such as Pink1, Parkin, Cytochrome c, SQSTM1/p62, the ratio of light chain LC3B II/LC3B I was found higher in 21 and 28 days which were significantly reduced in 35 days silica model.
CONCLUSIONS
Higher MMP9 activity and MMP9 /TIMP1 ratio demonstrate excessive extracellular matrix damage and deposition in 35 days model. Significantly reduced expressions of autophagy and mitophagy markers have also confirmed progression in fibrosis severity and its association with repeated silica exposures in 35 days model group.
PubMed: 38944258
DOI: 10.1016/j.cellsig.2024.111272 -
Pathology, Research and Practice Jun 2024Usual Interstitial Pneumonia (UIP) a fibrosing pneumonia is associated with idiopathic pulmonary fibrosis, chronic autoimmune disease (AID), or hypersensitivity...
BACKGROUND
Usual Interstitial Pneumonia (UIP) a fibrosing pneumonia is associated with idiopathic pulmonary fibrosis, chronic autoimmune disease (AID), or hypersensitivity pneumonia. Oxygen radicals, due to tobacco smoke, can damage DNA and might upregulate PARP1. Cytosolic DNA from dying pneumocytes activate cytosolic GMP-AMP-synthase-stimulator of interferon genes (cGAS-STING) pathway and TREX1. Prolonged inflammation induces senescence, which might be inhibited by phagocytosis, eliminating nuclear debris. We aimed to evaluate activation of cGAS-STING-TREX1 pathway in UIP, and if phagocytosis and anti-phagocytosis might counteract inflammation.
METHODS
44 cases of UIP with IPF or AID were studied for the expression of cGAS, pSTING, TREX1 and PARP1. LAMP1 and Rab7 expression served as phagocytosis markers. CD47 protecting phagocytosis and p16 to identify senescent cells were also studied.
RESULTS
Epithelial cells in remodeled areas and macrophages expressed cGAS-pSTING, TREX1; epithelia but not macrophages stained for PARP1. Myofibroblasts, endothelia, and bronchial/bronchiolar epithelial cells were all negative except early myofibroblastic foci expressing cGAS. Type II pneumocytes expressed cGAS and PARP1, but less pSTING. TREX1 although expressed was not activated. Macrophages and many regenerating epithelial cells expressed LAMP1 and Rab7. CD47, the 'don't-eat-me-signal', was expressed by macrophages and epithelial cells including senescence cells within the remodeled areas.
CONCLUSIONS
The cGAS-STING pathway is activated in macrophages and epithelial cells within remodeled areas. LikelyTREX1 because not activated cannot sufficiently degrade DNA fragments. PARP1 activation points to smoking-induced oxygen radical release, prolonging inflammation and leading to fibrosis. By expressing CD47 epithelial cells within remodeled areas protect themselves from being eliminated by phagocytosis.
PubMed: 38944022
DOI: 10.1016/j.prp.2024.155432 -
Biomedicine & Pharmacotherapy =... Jun 2024Idiopathic pulmonary fibrosis is an aging-related, chronic lung disease, with unclear pathogenesis and no effective treatment. One of the triggering factors in cell...
Idiopathic pulmonary fibrosis is an aging-related, chronic lung disease, with unclear pathogenesis and no effective treatment. One of the triggering factors in cell aging is oxidative stress and it is known to have a role in idiopathic pulmonary fibrosis. In this paper, the protective effect of the E-CG-01 (3,4-lacto-cycloastragenol) molecule in terms of its antioxidant properties was evaluated in the bleomycin induced mice lung fibrosis model. Bleomycin sulfate was administered as a single dose (2.5 U/kg body weight) intratracheally to induce lung fibrosis. E-CG-01 was administered intraperitoneally in three different doses (2 mg/kg/day, 6 mg/kg/day, and 10 mg/kg/day) for 14 days, starting three days before the bleomycin administration. Fibrosis was examined by Hematoxylin-Eosin, Masson Trichrome, and immunohistochemical staining for TGF-beta1, Type I collagen Ki-67, and gama-H2AX markers. Activity analysis of catalase and Superoxide dismutase enzymes, measurement of total oxidant, total glutathione, and Malondialdehyde levels. In histological analysis, it was determined that all three different doses of the molecule provided a prophylactic effect against the progression of fibrosis compared to the bleomycin control group. However, it was observed that only the molecule applied in the high dose decreased the total oxidant stress level. Lung weight ratio increased in the BLM group but significantly reduced with high-dose E-CG-01. E-CG-01 at all doses reduced collagen deposition, TGF-β expression, and Ki-67 expression compared to the BLM group. Intermediate and high doses of E-CG-01 also significantly reduced alveolar wall thickness and edema formation. These findings suggest that E-CG-01 has potential therapeutic effects in mitigating lung fibrosis through its antioxidant properties.
PubMed: 38943992
DOI: 10.1016/j.biopha.2024.117016