RESPIRATORY RESEARCH
·
2025
·
IF 5
De-zhi Sun,Xi-ru Yang,Cong-shu Huang,Zhi-jie Bai,Pan Shen,Zhe-xin Ni,Chao-ji Huang-fu,Yang-yi Hu,Ning-ning Wang,Xiang-lin Tang,Yong-fang Li,Yue Gao,Wei Zhou
Background High altitude pulmonary edema (HAPE) poses a significant medical challenge to individuals ascending rapidly to high altitudes. Hypoxia-induced cellular morphological changes in the alveolar-capillary barrier such as mitochondrial structural alterations and cytoskeletal reorganization, play a crucial role in the pathogenesis of HAPE. These morphological changes are critical in understanding the cellular response to hypoxia and represent potential therapeutic targets. However, there is still a lack of effective and valid drug discovery strategies for anti-HAPE treatments based on these cellular morphological features. This study aims to develop a pipeline that focuses on morphological alterations in Cell Painting images to identify potential therapeutic agents for HAPE interventions. Methods We generated over 100,000 full-field Cell Painting images of human alveolar adenocarcinoma basal epithelial cells (A549s) and human pulmonary microvascular endothelial cells (HPMECs) under different hypoxic conditions (1%~5% of oxygen content). These images were then submitted to our newly developed segmentation network (SegNet), which exhibited superior performance than traditional methods, to proceed to subcellular structure detection and segmentation. Subsequently, we created a hypoxia scoring network (HypoNet) using over 200,000 images of subcellular structures from A549s and HPMECs, demonstrating outstanding capacity in identifying cellular hypoxia status. Results We proposed a deep neural network-based drug screening pipeline (CPHNet), which facilitated the identification of two promising natural products, ferulic acid (FA) and resveratrol (RES). Both compounds demonstrated satisfactory anti-HAPE effects in a 3D-alveolus chip model (ex vivo) and a mouse model (in vivo). Conclusion This work provides a brand-new and effective pipeline for screening anti-HAPE agents by integrating artificial intelligence (AI) tools and Cell Painting, offering a novel perspective for AI-driven phenotypic drug discovery. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-025-03173-1.
研究领域:
医学
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生物信息学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
·
2023
·
IF 3.8
Ya Xu,Huiyang Li,Nan Sun,Bingmei Yao,Wenjin Dai,Jian Wang,Sujia Si,Shuo Liu,Liqun Jiang
Background High Altitude Pulmonary Edema (HAPE) seriously threatens the health of people at high altitudes. There are drug treatments for HAPE, and dry powder formulations (DPFs) represent a rapid and accessible delivery vehicle for these drugs. However, there are presently no reports on the inhalability of DPFs in low-pressure environments. Given the reduced atmospheric pressure typical at high altitudes, conventional DPFs might not be suitable for inhalation. Therefore, it is necessary to elucidate the deposition behaviors of dry powder in the respiratory tract at low pressure, as well as to improve their pulmonary deposition efficiency via adjustments to their formulation and design. Methods The effect of air pressure, inspiratory velocity, and particle properties (such as size, density, and aerodynamic diameter) on pulmonary deposition of DPFs was calculated by a computational fluid dynamics (CFD)-coupled discrete phase model. DPFs of various aerodynamic diameters were prepared by spray drying, and the inhalability of these DPFs in a low-pressure environment was evaluated in mice. Finally, a mouse model of HAPE was established, and the treatment of HAPE by nifedipine-loaded DPFs with small aerodynamic diameter was validated. Results CFD results showed that low pressure decreased the deposition of DPFs in the lungs. At 0.5 standard atmosphere, DPFs with aerodynamic diameter of ∼2.0 μm could not enter the lower respiratory tract; however, a decrease in the physical diameter, density, and, consequently, the aerodynamic diameter of the DPFs was able to enhance pulmonary deposition of these powders. To validate the CFD results, three kinds of dry powder with aerodynamic diameters of 0.66, 0.98, and 2.00 μm were prepared by spray drying. Powders with smaller aerodynamic diameter could be inhaled into the lungs of mice more effectively, and, consequently could ameliorate the progression of HAPE more effectively than conventional powders. These results were consistent with the CFD results. Conclusions Low atmospheric pressure can prevent the pulmonary deposition of DPFs at high altitudes. Compared with conventional DPFs, powders with smaller aerodynamic diameter can be effectively inhaled at these pressures and thus might be more suitable for the treatment the HAPE.
研究领域:
药剂学
·
呼吸病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Microbiology Spectrum
·
2025
·
IF 3.8
Xianduo Sun,Gaosheng Hu,Yuting Li,Wenjing Li,Yong Wang,Hui Yan,Guoqing Long,Long Zhao,Anhua Wang,Jingming Jia
Gut microbiota have been found to promote hypoxia-induced intestinal injury. However, the role of gut microbiota in high-altitude pulmonary edema (HAPE), the preventive effect of synbiotic on HAPE, and the mechanisms by which they might work remain unknown. In this study, we aimed to investigate the role of gut microbiota in the pathogenesis of HAPE and to explore the underlying mechanisms involved. We performed a fecal microbiome analysis and found a significant decrease in intestinal Klebsiella and Escherichia-Shigella, along with a notable increase in intestinal Bifidobacterium and Lactobacillus, as volunteers recovered from acute mountain sickness (AMS). Gavage colonization with Klebsiella pneumoniae and Escherichia coli induced plasma inflammation, increased plasma lysophosphatidylcholine (LPC) levels, and contributed to HAPE in rats at a simulated altitude of 6,500 m. Conversely, a synbiotic containing Bifidobacterium, Lactiplantibacillus, fructooligosaccharides, and isomaltose-oligosaccharides significantly reduced the severity of HAPE. Cellular experiments and molecular dynamics simulations revealed that LPCs can cause damage and permeability to human pulmonary microvascular endothelial cell (HPMEC) and human pulmonary alveolar epithelial cell (HPAEpiC) monolayers under hypoxic conditions by disrupting cell membrane integrity. In addition, tail vein injection of LPCs promoted HAPE in mice at a simulated altitude of 6,500 m. In conclusion, this study describes a gut microbiota-LPCs/inflammation-HAPE axis, an important new insight into HAPE that will help open avenues for prevention and treatment approaches.
研究领域:
医学
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微生物学
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生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineered
·
2021
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IF 3.269
Haibo Xie,Hanfei Chai,Xiaohong Du,Rongna Cui,Yinan Dong
Sepsis, resulting from infections, is a systemic inflammatory response syndrome with a high fatality rate. The present study revolves around probing into the function and molecular mechanism of long non-coding RNA OIP5 antisense RNA 1 (lncRNA OIP5-AS1) in modulating acute lung injury (ALI) mediated by sepsis. Here, a sepsis model was constructed using cecal ligation and puncture (CLP) surgery in vivo. The alveolar macrophage cell line NR8383 and the alveolar type II cell line RLE-6TN were dealt with lipopolysaccharide (LPS) for in-vitro experiments. We discovered that OIP5-AS1 and Sirtuin1 (SIRT1) were markedly down-regulated in sepsis models elicited by CLP or LPS, while miR-128-3p experienced a dramatic up-regulation. OIP5-AS1 overexpression attenuated NR8383 and RLE-6TN cell apoptosis triggered by LPS and suppressed the expressions of nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in NR8383 and RLE-6TN cells, whereas miR-128-3p overexpression resulted in the opposite phenomenon. Moreover, OIP5-AS1 overexpression relieved lung edema, lung epithelial cell apoptosis, infiltration of myeloperoxidase (MPO)-labeled polymorphonuclear neutrophils (PMN), inflammatory responses triggered by CLP in vivo. Mechanistically, miR-128-3p, which targeted SIRT1, was hobbled by OIP5-AS1. All in all, OIP5-AS1 overexpression enhanced sepsis-induced ALI by modulating the miR-128-3p/SIRT1 pathway, which helps create new insights into sepsis treatment.
研究领域:
分子生物学
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传染病学
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呼吸病学
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重症医学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2022
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IF 4.631
Renhui Huang,Qi Shi,Shutian Zhang,Hong Lin,Chengzhi Han,Xinyi Qian,Yijun Huang,Xiaorong Ren,Jiayuan Sun,Nana Feng,Chunmei Xia,Meng Shi
Purpose: Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS.Methods: We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system.Results: In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats.Conclusion: Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.
研究领域:
免疫学
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病理生理学
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呼吸医学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-21
·
IF 9.429
Qian ZhiZhi,Wang QianYi,Qiu ZhaoShun,Li DanYang,Zhang ChenCheng,Xiong XiYu,Zheng ZiHui,Ruan QinLi,Guo YiChen,Guo Jun
Acute respiratory distress syndrome (ARDS), caused by noncardiogenic pulmonary edema (PE), contributes significantly to Coronavirus 2019 (COVID-19)-associated morbidity and mortality. We explored the effect of transmembrane osmotic pressure (OP) gradients in PE using a fluorescence resonance energy transfer-based Intermediate filament (IF) tension optical probe. Angiotensin-II- and bradykinin-induced increases in intracellular protein nanoparticle (PN)-OP were associated with inflammasome production and cytoskeletal depolymerization. Intracellular protein nanoparticle production also resulted in cytomembrane hyperpolarization and L-VGCC-induced calcium signals, which differed from diacylglycerol-induced calcium increment via TRPC6 activation. Both pathways involve voltage-dependent cation influx and OP upregulation via SUR1-TRPM4 channels. Meanwhile, intra/extracellular PN-induced OP gradients across membranes upregulated pulmonary endothelial and alveolar barrier permeability. Attenuation of intracellular PN, calcium signals, and cation influx by drug combinations effectively relieved intracellular OP and pulmonary endothelial nonselective permeability, and improved epithelial fluid absorption and PE. Thus, PN-OP is pivotal in pulmonary edema in ARDS and COVID-19, and transmembrane OP recovery could be used to treat pulmonary edema and develop new drug targets in pulmonary injury. Graphical Abstract
研究领域:
肺病学
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药理学
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细胞生物学
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传染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2024
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IF 5.5
Wali Muhammad,Min Liang,Beiduo Wang,Jieqi Xie,Wajiha Ahmed,Changyou Gao
N-Acetyl cysteine (NAC) is an essential molecule that boosts acute lung injury (ALI) defense via its direct antioxidant capability. Nevertheless, the therapeutic use of NAC is limited due to its poor bioavailability and short half-life. In this study, NAC was grafted to the polyurethane consisting of poly(propylene fumarate), poly(thioketal), and 1,6-hexamethylene diisocyanate (PFTU) to reduce excessive oxidative stress and inflammatory factors in ALI. The NAC-grafted polymer nanoparticles (NPT@NPs) were prepared as a drug delivery system, which could effectively scavenge free radicals and reduce inflammation in vitro. The administration of NPT@NPs exhibited notable efficacy in ameliorating pulmonary edema, attenuating the presence of inflammatory cells, suppressing myeloperoxidase expression, diminishing the levels of pro-inflammatory cytokines, and reversing cell apoptosis in an ALI model induced by lipopolysaccharide (LPS). The NPT@NPs demonstrated significantly better efficacy compared to the free NAC in mitigating the deleterious effects of LPS on pulmonary tissue, thereby providing more effective protection against pulmonary inflammation.
研究领域:
药理学
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纳米技术
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肺科学
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炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Shuang Xie,Yu Li,Wenxiong Cao,Jiawen Peng,Kun Huang,Jie Meng,Xiaohong Li
Intracellular bacteria are the major cause of serious infections including sepsis and peritonitis, but face great challenges in fighting against the stubborn intracellular small colony variants (SCVs). Herein, the authors have developed nanogels (NGs) to destroy both planktonic bacteria and SCVs and eliminate excessive inflammations for peritonitis and sepsis therapies. Free gentamicin (GEN) and hydroxyapatite nanoparticles (NPs) with GEN loading and mannose grafts (mHA G ) are inoculated into ε-polylysine NGs to obtain NG@G1-mHA G2 through crosslinking with phenylboronic acid and tannic acid. The H 2 O 2 consumption after reaction with phenylboronic esters and the elimination of free radicals by tannic acid alleviates the escalated inflammatory status to promote sepsis therapy. After mannose-mediated uptake into macrophages, the acid-triggered degradation of mHA G NPs generates Ca 2+ to destabilize lysosomes and the efficient lysosomal escape leads to reversion of hypometabolic SCVs into normal phenotype and their sensitivity to GEN. In a peritonitis mouse model, NG@G1-mHA G2 treatment provides strong and persistent bactericidal effects against both extracellular bacteria and intracellular SCVs and extends survival of peritonitis mice without apparent hepatomegaly, splenomegaly, pulmonary edema, and inflammatory cell infiltration. Thus, this study demonstrates a concise and versatile strategy to eliminate SCVs and relieve inflammatory storms for peritonitis and sepsis therapies without infection recurrence.
研究领域:
纳米技术
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药学
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传染病学
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生物医学工程
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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