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Background To explore if chest high-resolution computed tomography (HRCT) can make higher accurate stages for thoracic sarcoidosis stage than X-ray (CRX) only. Methods Clinical data from medical records of consecutive patients with a confirmed diagnosis of pulmonary sarcoidosis at Shanghai Pulmonary Hospital from January 1 2012 to December 31 2016 and consecutive patients treated at the Sarcoidosis Center of University of Cincinnati Medical Center, Ohio, USA from January 1 2010 to December 31 2015 were reviewed. The clinical records of 227 patients diagnosed with sarcoidosis (140 Chinese and 87 American) were reviewed. Their sarcoidosis stage was determined by three thoracic radiologists based on CXR and HRCT presentations, respectively. The stage determined from CXR was compared with that determined from HRCT. Results Overall, 50.2% patients showed discordant sarcoidosis stage between CXR and HRCT (52.9% in Chinese and 44.8% in American, respectively). The primary reason for inconsistent stage between CXR and HRCT was failure to detect mediastinal lymph node enlargement in the shadow of the heart in CXR (22.1%) and small nodules because of the limited resolution of CXR (56.6%). Stage determined from HRCT negatively correlated with carbon monoxide diffusing capacity (DLCO) significantly ( P  < .01) but stage determined from CXR did not. Pleural involvement was detected by HRCT in 58 (25.6%) patients but only in 17 patients (7.5%) by CXR. Patients with pleural involvement had significantly lower forced vital capacity and DLCO than patients without it (both P  < .05). Conclusion Revised staging criteria based on HRCT presentations included 5 stages with subtypes in the presence of pleural involvement were proposed. Thoracic sarcoidosis can be staged more accurately based on chest HRCT presentations than based on CXR presentations. Pleural involvement can be detected more accurately by HRCT.

Background Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold. Aims To establish a mouse model of virus infection‐induced AE‐IPF and investigate the mechanism underlying the AE‐IPF. Methods Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild‐type (WT) and IL‐17A gene knockout (IL‐17A‐/‐) mice 21 days after intratracheal administration of bleomycin (BLM). Results HSV1 infection caused acute exacerbation in mice with BLM‐induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)‐related proteins in mice with BLM‐induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL‐17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE‐IPF. Compared with WT mice with BLM+HSV1, IL‐17A‐/‐ mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response. Conclusions HSV1 infection in addition to BLM‐induced IPF can successfully establish AE‐IPF in mice. IL‐17A and ERS promote lung inflammation in AE‐IPF development.

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

BackgroundPatients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold.AimsTo establish a mouse model of virus infection‐induced AE‐IPF and investigate the mechanism underlying the AE‐IPF.MethodsHerpes simplex virus 1 (HSV1) was inoculated intranasally to wild‐type (WT) and IL‐17A gene knockout (IL‐17A‐/‐) mice 21 days after intratracheal administration of bleomycin (BLM).ResultsHSV1 infection caused acute exacerbation in mice with BLM‐induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)‐related proteins in mice with BLM‐induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL‐17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE‐IPF. Compared with WT mice with BLM+HSV1, IL‐17A‐/‐ mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response.ConclusionsHSV1 infection in addition to BLM‐induced IPF can successfully establish AE‐IPF in mice. IL‐17A and ERS promote lung inflammation in AE‐IPF development.

Ovarian cancer, the deadliest gynecologic malignancy, is marked by high recurrence and poor prognosis. Exosome-like nanovesicles (ELNVs) derived from decocted traditional Chinese medicine (TCM) formulas encapsulate key bioactive components, and show promising therapeutic efficacy with good biocompatibility and targeting ability. However, research on ELNV extraction methodologies remains limited. Yiqi Huoxue Jiedu Decoction (YQHXJDD), an empirically validated TCM formula for ovarian cancer, lacks systematic investigation into its ELNV isolation protocols and therapeutic mechanisms. This study took YQHXJDD as the research subject, with a focus on extracting ELNVs from this TCM formula and validating their anti-ovarian cancer activity. YQHXJDD was extracted using varied decoction protocols. ELNVs were enriched by gradient and ultracentrifugation, resuspended in phosphate-buffered saline, and were characterized by size and concentration using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The number of ELNVs enriched per dose of YQHXJDD was calculated to screen the decoction method that maximized ELNV yield and aligned with clinical medication practices. The colloidal stability of YQHXJDD ELNVs was evaluated via zeta potential measurement, and the bioactive components of YQHXJDD ELNVs were identified using untargeted metabolomics and RNA sequencing. An ID8-Luc peritoneal tumor-bearing mouse model was established and randomized into three groups: model, YQHXJDD, and YQHXJDD ELNVs. Mice received oral gavage for 3 consecutive weeks. Tumor burden was monitored via small animal imaging. Immunofluorescence was used to quantify CD86, CD206, CD4, and CD8 fluorescence in omental tumors. Luminex xMAP® Multiplex Assay was used to detect 36 cytokines/chemokines in serum, and flow cytometry was used to analyze splenic immune cell proportions and activity. The creation efficiency of ELNVs formed during decoction is the highest with the optimal protocol, which is identified for maximizing YQHXJDD ELNV yield and involves 40 min of high-heat treatment followed by an additional 30 min of low-heat treatment. Zetaview-based zeta potential analysis demonstrated that YQHXJDD ELNVs by this protocol had an average zeta potential of -35.52 mV, indicating favorable colloidal stability. Untargeted metabolomics analysis revealed \"Lipids and lipid-like molecules\" as the most abundant metabolite superclass (34.98% of total metabolites), while \"Carboxylic acids and derivatives\" represented the dominant subclass (11.66%). Regarding small RNAs, those enriched in YQHXJDD ELNVs were confirmed to be typical, functionally active small RNAs. Notably, miR8783 and other miRNAs exhibited significantly high expression, along with high conservation and abundance across samples, suggesting they might act as core regulators of YQHXJDD ELNV biological functions. In assessments, compared with the model group, YQHXJDD ELNVs significantly inhibited ovarian cancer growth and metastasis, increased tumor necrosis factor-α (TNF-α) levels in mouse peripheral blood, and positively regulated the M1/M2 macrophage ratio and CD4 /CD8 T cell ratio in omental tissues (all < 0.05). However, YQHXJDD ELNVs had no significant effect on the proportions of splenic effector T cells, natural killer (NK) cells, activated CD8 T cells, and activated NK cells (all ≥ 0.05). The decoction ELNVs isolated from YQHXJDD can inhibit the growth and dissemination of ovarian cancer. The miRNAs and lipid components encapsulated in these ELNVs are presumed to be the critical mediators of these anti-ovarian cancer effects.

The significance of iron in myocardial mitochondria function cannot be underestimated, because deviations in iron levels within cardiomyocytes may have profound detrimental effects on cardiac function. In this study, we investigated the effects of ferroportin 1 (FPN1) on cardiac iron levels and pathological alterations in mice subjected to chronic intermittent hypoxia (CIH). The cTNT‐FPN1 plasmid was administered via tail vein injection to induce the mouse with FPN1 overexpression in the cardiomyocytes. CIH was established by exposing the mice to cycles of 21%–5% FiO2 for 3 min, 8 h per day. Subsequently, the introduction of hepcidin resulted in a reduction in FPN1 expression, and H9C2 cells were used to establish an IH model to further elucidate the role of FPN1. First, FPN1 overexpression ameliorated CIH‐induced cardiac dysfunction, myocardial hypertrophy, mitochondrial damage and apoptosis. Second, FPN1 overexpression attenuated ROS levels during CIH. In addition, FPN1 overexpression mitigated CIH‐induced cardiac iron accumulation. Moreover, the administration of hepcidin resulted in a reduction in FPN1 levels, further accelerating the CIH‐induced levels of ROS, LIP and apoptosis in H9C2 cells. These findings indicate that the overexpression of FPN1 in cardiomyocytes inhibits CIH‐induced cardiac iron accumulation, subsequently reducing ROS levels and mitigating mitochondrial damage. Conversely, the administration of hepcidin suppressed FPN1 expression and worsened cardiomyocyte iron toxicity injury.

Chronic intermittent hypoxia (CIH) could cause neuronal damage, accelerating the progression of dementia. However, safe and effective therapeutic drugs and delivery are needed for successful CIH therapy. To investigate the neuroprotective effect of Huperzine A (HuA) packaged with nanoliposomes (HuA-LIP) on neuronal damage induced by CIH. The stability and release of HuA-LIP in vitro were identified. Mice were randomly divided into the Control, CIH, HuA-LIP, and HuA groups. The mice in the HuA and HuA-LIP groups received HuA (0.1 mg/kg, i.p.), and HuA-LIP was administered during CIH exposure for 21 days. HuA-LIP contains the equivalent content of HuA. We prepared a novel formulation of HuA-LIP that had good stability and controlled release. First, HuA-LIP significantly ameliorated cognitive dysfunction and neuronal damage in CIH mice. Second, HuA-LIP elevated T-SOD and GSH-Px abilities and decreased MDA content to resist oxidative stress damage induced by CIH. Furthermore, HuA-LIP reduced brain iron levels by downregulating TfR1, hepcidin, and FTL expression. In addition, HuA-LIP activated the PKAα/Erk/CREB/BDNF signaling pathway and elevated MAP2, PSD95, and synaptophysin to improve synaptic plasticity. Most importantly, compared with HuA, HuA-LIP showed a superior performance against neuronal damage induced by CIH. HuA-LIP has a good sustained-release effect and targeting ability and efficiently protects against neural injury caused by CIH.

The objective of this study is to examine the potential protective effect of rosmarinic acid (RosA) encapsulated within nanoliposomes (RosA-LIP) on hepatic damage induced by iron overload. The characteristics, stability, and release of RosA-LIP in vitro were identified. The mice were randomly assigned to five groups: Control, Model, Model+DFO (DFO), Model+RosA (RosA), and Model+RosA-LIP (RosA-LIP). The iron overload model was induced by administering iron dextran (i.p.). The DFO, RosA, and RosA-LIP groups received iron dextran and were subsequently treated with DFO, RosA, and RosA-LIP for 14 days. We developed a novel formulation of RosA-LIP that exhibited stability and controlled release properties. Firstly, RosA-LIP improved liver function and ameliorated pathological changes in a mouse model of iron overload. Secondly, RosA-LIP demonstrated the ability to enhance the activities of T-SOD, GSH-Px, and CAT, while reducing the levels of MDA and 4-HNE, thereby effectively mitigating oxidative stress damage induced by iron overload. Thirdly, RosA-LIP reduced hepatic iron levels by downregulating FTL, FTH, and TfR1 levels. Additionally, RosA-LIP exerted a suppressive effect on hepcidin expression through the BMP6-SMAD1/5/8 signaling pathway. Furthermore, RosA-LIP upregulated FPN1 expression in both the liver and duodenum, thereby alleviating iron accumulation in these organs in mice with iron overload. Notably, RosA exhibited a comparable iron chelation effect, and RosA-LIP demonstrated superior efficacy in mitigating liver damage induced by excessive iron overload. RosA-LIP exhibited favorable sustained release properties, targeted delivery, and efficient protection against iron overload-induced liver damage. Graphical Abstract A schematic representation of the proposed protective mechanism of rosmarinic acid liposome during iron overload. Once RosA-LIP is transported into cells, RosA is released. On the one hand, RosA attenuates the BMP6-SMAD1/5/8-SMAD4 signaling pathway activation, leading to inhibiting hepcidin transcription. Then, the declined hepcidin contacted the inhibitory effect of FPN1 in hepatocytes and duodenum, increasing iron mobilization. On the other hand, RosA inhibits TfR1 and ferritin expression, which decreases excessive iron and oxidative damage.

Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular eye diseases, but responses are incomplete in some patients. Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. JP1, derived from an optimized seven-amino-acid fragment of JWA protein, is a polypeptide specifically targeting integrin αVβ3. In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization (CNV) and retinal vascular leakage. CNV mice received a single intravitreal (IVT) injection of JP1 (10, 20, 40 µg) or ranibizumab (RBZ, 10 µg). We showed that JP1 injection dose-dependently inhibited laser-induced CNV; the effect of RBZ was comparable to that of 20 µg JP1; a combined IVT injection of JP1 (20 μg) and RBZ (5 μg) exerted a synergistic effect on CNV. In the 3rd month after streptozotocin injection, diabetic mice receiving IVT injection of JP1 (40 µg) or RBZ (10 µg) once a week for 4 weeks showed significantly suppressed retinal vascular leakage. In both in vivo and in vitro experiments, JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells, and angiogenesis via modulating MEK1/2-SP1-integrin αVβ3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells. In addition, intraperitoneal injection of JP1 (1, 5 or 10 mg) once every other day for 3 times also dose-dependently inhibited CNV. After intraperitoneal injection of FITC-labeled JP1 (FITC-JP1) or FITC in laser-induced CNV mice, the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group, compared with that in FITC group, confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion. We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.

A 69-year-old Chinese male farmer suddenly developed severe lower back pain accompanied by persistent high fever during his recovery from carbon monoxide (CO) poisoning. Clinical examination revealed limited spinal mobility and significant tenderness in the L2–L4 vertebrae and bilateral paravertebral regions, with no palpable masses. Magnetic resonance imaging (MRI) showed fluid accumulation around the bilateral psoas muscles, confirming the presence of bilateral abscesses. We performed ultrasound-guided puncture and drainage of the affected area, and the culture of the drainage fluid identified Carbapenem-Resistant Enterobacteriaceae (CRE). The final diagnosis was bilateral primary psoas abscess (PPA), and targeted antimicrobial therapy for CRE infection was initiated.