Pulmonary pharmacology & therapeutics最新文献

{"title":"Knockdown of HDAC10 inhibits POLE2-mediated DNA damage repair in NSCLC cells by increasing SP1 acetylation levels","authors":"Hua Guo ,&nbsp;Hui Ren ,&nbsp;Kun Han ,&nbsp;Jianying Li ,&nbsp;Yu Dong ,&nbsp;Xuan Zhao ,&nbsp;Chunqi Li","doi":"10.1016/j.pupt.2023.102250","DOIUrl":"10.1016/j.pupt.2023.102250","url":null,"abstract":"<div><p><span><span>HDAC10 has been reported to be associated with poor prognosis </span>in patients with non-small cell lung cancer (NSCLC), however, the regulatory role and mechanisms of HDAC10 in NSCLC have not been investigated. In this study, we found that HDAC10 was increased in NSCLC patients and cell lines. And high expression of HDAC10 is linked to poor survival in NSCLC patients. The results showed that knockdown of HDAC10 triggered DNA damage, </span><em>S</em><span><span>-phase arrest, and proliferation inhibition in A549 and H1299<span> cells. In addition, knockdown of HDAC10 promoted cell ferroptosis<span> by enhancing ROS, </span></span></span>MDA and Fe</span>²⁺<span> levels. Mechanistically, HDAC10 knockdown reduced SP1<span> expression and elevated the acetylation<span> level of SP1, which inhibited the binding of SP1 to the promoter of POLE2, resulting in reduced POLE2 expression. Overexpression of SP1 or POLE2 partially reversed the effects of HDAC10 deletion on NSCLC cell proliferation and ferroptosis. In conclusion, knockdown of HDAC10 inhibited the proliferation of NSCLC cells and promoted their ferroptosis by regulating the SP1/POLE2 axis. HDAC10 might be a promising target for the treatment of NSCLC.</span></span></span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10245137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydroquercetin (DHQ) ameliorates LPS-induced acute lung injury by regulating macrophage M2 polarization through IRF4/miR-132-3p/FBXW7 axis","authors":"Chen Li,&nbsp;Jianhua Liu,&nbsp;Changhong Zhang,&nbsp;Liang Cao,&nbsp;Fang Zou,&nbsp;Zhihua Zhang","doi":"10.1016/j.pupt.2023.102249","DOIUrl":"10.1016/j.pupt.2023.102249","url":null,"abstract":"<div><h3>Background</h3><p><span>Acute lung injury (ALI) is a common complication of </span>sepsis<span>. Dihydroquercetin (DHQ) has been found to attenuate lipopolysaccharide (LPS)-induced inflammation. However, the effect of DHQ on LPS-challenged ALI remains unclear.</span></p></div><div><h3>Methods</h3><p><span>Pulmonary HE and TUNEL staining<span><span> and lung wet/dry ratio were detected in LPS-treated Balb/c mice. IL-1β, IL-6 and TNF-α levels were determined utilizing ELISA assay. RAW264.7 cell </span>apoptosis<span><span> and macrophage markers (CD86, CD206) were tested using flow cytometry. TC-1 viability was analyzed by MTT assay. </span>Western blot<span><span> measured protein expression of macrophage markers. Interactions of miR-132–3p, </span>IRF4 and FBXW7 were explored utilizing </span></span></span></span>ChIP<span>, RNA pull-down and dual luciferase reporter assays.</span></p></div><div><h3>Results</h3><p>DHQ alleviated histopathological change, pulmonary edema<span><span> and apoptosis in LPS-treated mice. DHQ affected LPS-induced M2 macrophage polarization<span> and TC-1 cell injury-related indicators, such as decreased cell activity, decreased LDH levels, and increased apoptosis. </span></span>LPS inhibited IRF4 and miR-132–3p expression, activated Notch pathway and increased FBXW7 level, which were overturned by DHQ. IRF4 transcriptionally activated miR-132–3p expression. FBXW7 was a downstream target of miR-132–3p.</span></p></div><div><h3>Conclusion</h3><p>DHQ alleviated LPS-induced lung injury through promoting macrophage M2 polarization via IRF4/miR-132–3p/FBXW7 axis, which provides a new therapeutic strategy for ALI.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10199282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relative bioavailability of budesonide/glycopyrrolate/formoterol fumarate triple therapy delivered using next generation propellants with low global warming potential","authors":"Magnus Aurivillius ,&nbsp;Artur Bednarczyk ,&nbsp;Marek Kokot ,&nbsp;Jonathan Madriaga ,&nbsp;Jie Mei ,&nbsp;Kathryn Collison ,&nbsp;Raulin Surujbally ,&nbsp;James Archbell ,&nbsp;Vidya Joshi ,&nbsp;Michael Gillen","doi":"10.1016/j.pupt.2023.102245","DOIUrl":"10.1016/j.pupt.2023.102245","url":null,"abstract":"<div><h3>Introduction</h3><p>The climate crisis poses an immediate threat to human health and well-being, demanding urgent adaptions across sectors, including healthcare. The development of pressurized metered dose inhalers (MDIs) with greater sensitivity to the climate emergency using novel propellants with lower global warming potentials (GWPs), but comparable pharmacokinetic (PK) parameters to currently marketed MDIs, is a vital step toward reducing the impact of healthcare for respiratory disorders on climate change. This study evaluated the relative bioavailabilities of the individual components of a fixed-dose combination of budesonide/glycopyrrolate/formoterol fumarate (BGF) 160/9/4.8 μg per actuation between three different propellant formulations.</p></div><div><h3>Methods</h3><p>Healthy male participants (aged 18–60 years) were randomized into a single-blind, three-period, single-dose, single-center, crossover study (NCT04600505). The PK and safety and tolerability profiles of BGF MDI formulated with two novel propellants with low GWP (hydrofluoroolefin-1234ze [HFO]; hydrofluorocarbon-152a [HFC]) were compared with BGF MDI formulated with the propellant used in the currently marketed reference product (hydrofluoroalkane-134a [HFA]). The study included a screening period, three treatment periods (with 3- to 7-day washout periods between each dose), and a follow-up. The primary PK parameters assessed were maximum observed plasma concentration (C_max), area under the plasma concentration curve (AUC) from time zero extrapolated to infinity (AUC_inf), and AUC from time zero to the time of the last quantifiable analyte concentration (AUC_last). The study was not powered to statistically demonstrate bioequivalence.</p></div><div><h3>Results</h3><p>Forty-seven participants completed the study, and 24 participants were evaluable for PK assessments. Systemic exposure, based on geometric mean ratios (90% confidence interval), to each BGF component from the test propellants delivered in a standard MDI was comparable with the reference propellant for AUC_last (HFO vs. HFA: budesonide, 107.30 [94.53, 121.90]; glycopyrrolate, 106.10 [86.18, 130.60]; formoterol, 98.13 [86.44, 111.40]; HFC vs. HFA: budesonide, 98.80 [84.59, 115.40]; glycopyrrolate, 99.71 [80.84, 123.00]; formoterol, 107.00 [88.82, 128.90]); AUC_inf (where evaluable) and C_max followed the same trend. There were no serious adverse events or adverse events leading to treatment discontinuation. No new safety signals were observed.</p></div><div><h3>Conclusions</h3><p>Systemic BGF component exposure was similar for both test propellants (HFO and HFC) compared with the HFA reference propellant, with an acceptable safety profile in the studied population. Therefore, both novel low GWP propellants show strong potential as candidates for development of MDIs with greater sensitivity to the climate crisis, a vital step toward amelioratin","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10226716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nebulized amphotericin B for preventing exacerbations in allergic bronchopulmonary aspergillosis: A systematic review and meta-analysis","authors":"Valliappan Muthu ,&nbsp;Sahajal Dhooria ,&nbsp;Inderpaul Singh Sehgal ,&nbsp;Kuruswamy Thurai Prasad ,&nbsp;Shivaprakash M. Rudramurthy ,&nbsp;Ashutosh N. Aggarwal ,&nbsp;Arunaloke Chakrabarti ,&nbsp;Ritesh Agarwal","doi":"10.1016/j.pupt.2023.102226","DOIUrl":"10.1016/j.pupt.2023.102226","url":null,"abstract":"<div><h3>Background</h3><p>Allergic bronchopulmonary aspergillosis<span> (ABPA) is complicated by exacerbations in more than one-third of the subjects. Whether nebulized amphotericin B (NAB) therapy prevents ABPA exacerbations remains unclear.</span></p></div><div><h3>Objectives</h3><p>The primary objective of this systematic review and meta-analysis was to determine the frequency of subjects remaining exacerbation-free, one year after initiating NAB. The key secondary objectives were the time to first exacerbation and the safety of NAB therapy.</p></div><div><h3>Methods</h3><p>We searched the PubMed and Embase databases for studies evaluating ≥5 subjects of ABPA managed with NAB. We report the pooled proportion of ABPA subjects remaining exacerbation free after one year. For the randomized controlled trials (RCTs), we estimate the pooled risk difference (RD) of exacerbation-free status at one year with NAB versus the control arm.</p></div><div><h3>Results</h3><p>We included five studies for our analysis; three were observational (n = 28) and two RCTs (n = 160). The pooled proportion (95% confidence interval [CI]) of subjects remaining exacerbation free with NAB at one year was 76% (62–88). The pooled RD (95% CI) of an exacerbation-free status at one year was 0.33 (−0.12 to 0.78) and was not significantly different between the NAB and control arms. The time to first exacerbation was longer with NAB than with the standard therapy. No serious adverse events were reported with NAB.</p></div><div><h3>Conclusion</h3><p>NAB does not improve exacerbation-free status at one year; however, weak evidence suggests it delays ABPA exacerbations. More research using different dosing regimens is required.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9795047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amygdalin epimers exert discrepant anti-pulmonary fibrosis activity via inhibiting TGF-β1/Smad2/3 pathway","authors":"Haoyan Jiao ,&nbsp;Shuyu Li ,&nbsp;Qingfa Tang","doi":"10.1016/j.pupt.2023.102230","DOIUrl":"10.1016/j.pupt.2023.102230","url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis<span> (IPF) represents a chronic and progressive tissue repair<span> response that leads to irreversible scarring and lung remodeling. The decoction<span><span> of bitter almond usually contains amygdalin<span><span> epimers in traditional clinical application for lung disease<span>. To reveal the differences of cytotoxicity and antifibrotic effect between amygdalin epimers, and potential mechanism is also explored. The cytotoxicity of amygdalin epimers were evaluated with MRC-5 cells in vitro. Their antifibrotic activities were evaluated in bleomycin-induced C57BL/6 mice and TGF-β1-induced MRC-5 cells. Here we demonstrated that L-amygdalin is more toxic of the amygdalin epimers in MRC-5 cells, and D-amygdalin is more effective in anti-pulmonary fibrosis among the amygdalin epimers in bleomycin-induced C57BL/6 mice. Herein, it was observed that D-amygdalin had a stronger inhibitory effect on inflammation than L-amygdalin, and had similar results in inhibiting the mRNA and </span></span>protein expression levels of fibrosis-related biomarkers. The mechanism of anti-pulmonary fibrosis showed that amygdalin epimers suppressing expression of phosphorylation of Smads2/3, which implying deactivation of the TGF-β1induced Smads2/3 </span></span>signal pathway. This study evaluates the amygdalin epimers cytotoxicity and antifibrotic effect, and its mechanisms were related to the TGF-β1/Smads2/3 signal pathway. It provides a reference for clinical safety and effectiveness of amygdalin epimers.</span></span></span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9803079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic obstructive pulmonary disease and emerging ER stress-related therapeutic targets","authors":"Jia Wen Yeap ,&nbsp;Irfhan Ali Hyder Ali ,&nbsp;Baharudin Ibrahim ,&nbsp;Mei Lan Tan","doi":"10.1016/j.pupt.2023.102218","DOIUrl":"10.1016/j.pupt.2023.102218","url":null,"abstract":"<div><p><span>COPD<span><span><span><span> pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major </span>unfolded protein response (UPR) branches in the </span>ER stress pathway may provide pharmacotherapeutic selection strategies for treating COPD and enable relief from its symptoms. In this study, we aimed to systematically review the potential role of the ER stress inhibitors of major UPR branches (IRE1, PERK, and ATF6) in COPD-related studies and determine the current stage of knowledge in this field. The </span>systematic review was carried out adhering to the PRISMA checklist based on published studies obtained from specific keyword searches of three databases, namely PubMed, ScienceDirect and Springer Database. The search was limited to the year 2000–2022 which includes all </span></span><em>in vitro</em> studies, <em>in vivo</em><span> studies and clinical trials<span> related to the application of ER stress inhibitors toward COPD-induced models and disease. The risk of bias was evaluated using the QUIN, SYRCLE, revised Cochrane risk of bias tool for randomized trials (RoB 2.0) and NIH tool respectively. A total of 7828 articles were screened from three databases and a final total of 37 studies were included in the review. The ER stress and UPR pathways are potentially useful to prevent COPD progression and attenuate the exacerbation of COPD and related symptoms. Interestingly, the off-target effects from inhibition of the UPR pathway may be desirable or undesirable depending on context and therapeutic applications. Targeting the UPR pathway could have complex consequences as the production of ER molecules involved in folding may be impaired which could continuously provoke misfolding of proteins. Although several emerging compounds were noted to be potentially useful for targeted therapy against COPD, clinical studies have yet to be thoroughly explored.</span></span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10152261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S1PR1 attenuates pulmonary fibrosis by inhibiting EndMT and improving endothelial barrier function","authors":"Wenfang Xiong ,&nbsp;Shuhua Chen ,&nbsp;Hong Xiang ,&nbsp;Shaoli Zhao ,&nbsp;Jie Xiao ,&nbsp;Jialing Li ,&nbsp;Yulan Liu ,&nbsp;Zhihao Shu ,&nbsp;Jie Ouyang ,&nbsp;Jing Zhang ,&nbsp;Huiqin Liu ,&nbsp;Xuewen Wang ,&nbsp;Hang Zou ,&nbsp;Ying Chen ,&nbsp;Alex Chen ,&nbsp;Hongwei Lu","doi":"10.1016/j.pupt.2023.102228","DOIUrl":"10.1016/j.pupt.2023.102228","url":null,"abstract":"<div><h3>Background</h3><p>Idiopathic pulmonary fibrosis<span><span> (IPF) is a chronic fatal disease of unknown etiology. Its pathological manifestations include excessive proliferation and activation of fibroblasts and deposition of extracellular matrix. Endothelial cell-mesenchymal transformation (EndMT), a novel mechanism that generates fibroblast during IPF, is responsible for fibroblast-like phenotypic changes and activation of fibroblasts into hypersecretory cells. However, the exact mechanism behind EndMT-derived fibroblasts and activation is uncertain. Here, we investigated the role of sphingosine 1-phosphate receptor 1 (S1PR1) in EndMT-driven </span>pulmonary fibrosis.</span></p></div><div><h3>Methods</h3><p><span>We treated C57BL/6 mice with bleomycin (BLM) in vivo and pulmonary microvascular endothelial cells with TGF-β1 </span><em>in vitro</em><span>. Western blot<span>, flow cytometry, and immunofluorescence<span> were used to detect the expression of S1PR1 in endothelial cells. To evaluate the effect of S1PR1 on EndMT and endothelial barrier and its role in lung fibrosis and related signaling pathways, S1PR1 agonist and antagonist were used </span></span></span><em>in vitro</em> and in vivo.</p></div><div><h3>Results</h3><p><span>Endothelial S1PR1 protein expression was downregulated in both </span><em>in vitro</em><span> and in vivo models of pulmonary fibrosis induced by TGF-β1 and BLM, respectively. Downregulation of S1PR1 resulted in EndMT, indicated by decreased expression of endothelial markers CD31 and VE-cadherin, increased expression of mesenchymal markers α-SMA and nuclear transcription factor Snail, and disruption of the endothelial barrier. Further mechanistic studies found that stimulation of S1PR1 inhibited TGF-β1-mediated activation of the Smad2/3 and RhoA/ROCK1 pathways. Moreover, stimulation of S1PR1 attenuated Smad2/3 and RhoA/ROCK1 pathway-mediated damage to endothelial barrier function.</span></p></div><div><h3>Conclusions</h3><p>Endothelial S1PR1 provides protection against pulmonary fibrosis by inhibiting EndMT and attenuating endothelial barrier damage. Accordingly, S1PR1 may be a potential therapeutic target in progressive IPF.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10154937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and efficacy of transitioning from selexipag to oral treprostinil in pulmonary arterial hypertension: Findings from the ADAPT registry.","authors":"D. Lachant, R. Minkin, J. Swisher, Mohammed Mogri, R. Zolty, Stephanie S. Hwang, S. Seaman, M. Broderick, S. Sahay","doi":"10.2139/ssrn.4361306","DOIUrl":"https://doi.org/10.2139/ssrn.4361306","url":null,"abstract":"PURPOSE\u0000Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or side effects while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil.\u0000\u0000\u0000METHODS\u0000ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions.\u0000\u0000\u0000RESULTS\u0000Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging.\u0000\u0000\u0000CONCLUSION\u0000Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48971892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amygdalin epimers exert discrepant anti-pulmonary fibrosis activity via inhibiting TGF-β1/Smad2/3 pathway.","authors":"Haoyan Jiao, Shuyu Li, Qing-fa Tang","doi":"10.2139/ssrn.4357033","DOIUrl":"https://doi.org/10.2139/ssrn.4357033","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) represents a chronic and progressive tissue repair response that leads to irreversible scarring and lung remodelling. The decoction of bitter almond usually contains amygdalin epimers in traditional clinical application for lung disease. To reveal the differences of cytotoxicity and antifibrotic effect between amygdalin epimers, and potential mechanism is also explored. The cytotoxicity of amygdalin epimers were evaluated with MRC-5 cells in vitro. Their antifibrotic activities were evaluated in bleomycin-induced C57BL/6 mice and TGF-β1-induced MRC-5 cells. Here we demonstrated that L-amygdalin is more toxic of the amygdalin epimers in MRC-5 cells, and D-amygdalin is more effective in anti-pulmonary fibrosis among the amygdalin epimers in bleomycin-induced C57BL/6 mice. Herein, it was observed that D-amygdalin had a stronger inhibitory effect on inflammation than L-amygdalin, and had similar results in inhibiting the mRNA and protein expression levels of fibrosis-related biomarkers. The mechanism of anti-pulmonary fibrosis showed that amygdalin epimers suppressing expression of phosphorylation of Smads2/3, which implying deactivation of the TGF-β1induced Smads2/3 signal pathway. This study evaluates the amygdalin epimers cytotoxicity and antifibrotic effect, and its mechanisms were related to the TGF-β1/Smads2/3 signal pathway. It provides a reference for clinical safety and effectiveness of amygdalin epimers.","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45923832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional factor MAZ promotes cisplatin-induced DNA damage repair in lung adenocarcinoma by regulating NEIL3","authors":"Tao Wang,&nbsp;Xu Zhu,&nbsp;Kai Wang,&nbsp;Jianglun Li,&nbsp;Xiao Hu,&nbsp;Peng Lin,&nbsp;Jian Zhang","doi":"10.1016/j.pupt.2023.102217","DOIUrl":"10.1016/j.pupt.2023.102217","url":null,"abstract":"<div><h3>Background</h3><p><span>Cisplatin remains a common chemotherapy </span>drug<span><span><span> for lung adenocarcinoma (LUAD) in clinical </span>treatment. Long-term use of cisplatin </span>in patients<span> may lead to acquired drug resistance, resulting in poor prognoses of patients. NEIL3 was a glycosylase-encoding gene highly expressed in LUAD. NEIL3 can repair telomerase DNA damage in the S phase. Nevertheless, there are few reports on whether NEIL3 is involved in cisplatin resistance and its related mechanisms in LUAD.</span></span></p></div><div><h3>Methods</h3><p><span><span>The expression of NEIL3 in LUAD patients was analyzed by bioinformatics. The regulator upstream of NEIL3 was predicted via hTFtarget. The possibly involved pathways of NEIL3 were obtained by performing Gene Set Enrichment Analysis. qRT-PCR and </span>western blot were applied to test the expression level of genes and protein LUAD cells. Dual</span><strong>-</strong><span>luciferase<span> assay and chromatin immunoprecipitation (ChIP) assay were conducted to validate the binding relationship between MAZ and NEIL3. Cell function assays were performed to test the DNA damage, cell viability, cell migration and invasion, and cell cycle of LUAD cells in the treatment group.</span></span></p></div><div><h3>Results</h3><p><span>NEIL3 and its upstream regulatory factor MAZ were highly expressed in LUAD tissue, and NEIL3 was enriched in cell cycle and mismatch repair pathways. Dual-luciferase assay and ChIP assay proved that MAZ could target NEIL3. Cell experiments identified that MAZ/NEIL3 axis could repress DNA damage to advance cisplatin resistance of </span>cancer cells, and foster cell migration and invasion in LUAD.</p></div><div><h3>Conclusion</h3><p>MAZ-activated NEIL3 could propel the cisplatin resistance in LUAD by repressing DNA damage.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9628173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}