Search

Background and Objective: Pulmonary fibrosis (PF) is a chronic progressive disease with an extremely high mortality rate and is a complication of COVID-19. Inhalable microspheres have been increasingly used in the treatment of lung diseases such as PF in recent years. Compared to the direct inhalation of drugs, a larger particle size is required to ensure the sustained release of microspheres. However, the clinical symptoms of PF may lead to the easier deposition of microspheres in the upper respiratory tract. Therefore, it is necessary to understand the effects of PF on the deposition of microspheres in the respiratory tract., Methods: In this study, airway models with different degrees of PF in humans and mice were established, and the transport and deposition of microspheres in the airway were simulated using computational fluid dynamics., Results: The simulation results showed that PF increases microsphere deposition in the upper respiratory tract and decreases bronchial deposition in both humans and mice. Porous microspheres with low density can ensure deposition in the lower respiratory tract and larger particle size. In healthy and PF humans, porous microspheres of 10 µm with densities of 700 and 400 kg/m³ were deposited most in the bronchi. Unlike in humans, microspheres larger than 4 µm are completely deposited in the upper respiratory tract of mice owing to their high inhalation velocity. For healthy and PF mice, microspheres of 6 µm with densities of and 100 kg/m³ are recommended., Conclusions: The results showed that with the exacerbation of PF, it is more difficult for microsphere particles to deposit in the subsequent airway. In addition, there were significant differences in the deposition patterns among the different species. Therefore, it is necessary to process specific microspheres from different individuals. Our study can guide the processing of microspheres and achieve differentiated drug delivery in different subjects to maximize therapeutic effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Some chemotherapy can damage tumor cells, releasing damage-related molecular patterns including ATP to improve immunological recognition against the tumor by immunogenic cell death (ICD). However, the immune-stimulating ATP may be rapidly degraded into immunosuppressive adenosine by highly expressed CD39 and CD73 in the tumor microenvironment, which leads to immune escape. Based on the above paradox, a liposome nanoplatform combined with ICD inducer (oxaliplatin) and CD39 inhibitor (POM-1) is designed for immunochemotherapy. The liposomes efficiently load the phospholipid-like oxaliplatin prodrug, and the cationic charged surface could adsorb POM-1. Rationally designed DSPE-PEG n -pep, on the one hand, could cover and hide POM-1 to avoid systematic toxicity and, on the other, achieve a response and charge reversal to favor POM-1 shedding and tumor deep penetration. This combination maximizes the ICD effect, and takes two-pronged advantage of stimulating the immune response and relieving immune suppression. The designed POL can effectively inhibit the growth of in situ, lung metastasis and postoperative recurrence melanoma model and form long-term immune memory. With the powerful clinical transformation potential of nanoliposome platforms, this new synergistic strategy is expected to enhance anticancer effects safely and effectively., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: This study was undertaken to determine if coronary computed tomographic angiography (CCTA) can help to assess patent foramen ovale (PFO) with high accuracy and reproducibility when compared to transesophageal echocardiography (TEE)., Materials and Methods: In total, 75 suspected PFO cases (31 men, 44 women; mean age, 45 ± 9 years) were evaluated by coronary CTA and TEE. PFO tunnel length (TL) and the opening diameter of the left atrial entrance (ODLAE) and right atrial entrance (ODRAE), as well as contrast shunt (if present due to PFO), were measured by both modalities., Results: PFO was detected in 68 patients with TEE. The sensitivity for the detection of PFO with CCTA was 85.3%; specificity, 71.4%; positive predictive value, 96.7%; and negative predictive value, 33.3%. Both modalities demonstrated good agreement in measuring TL and ODLAE of PFO. However, the ODRAE of TEE was different from that of CCTA (1.14 ± 0.4 mm and 1.45 ± 0.5 mm, respectively, p = 0.04). The intra-observer and inter-observer variability and agreement for TL, ODRAE, and ODLAE of PFO were excellent between the two measurements., Conclusion: CCTA provided a method for detection of PFO with high accuracy and reproducibility compared with TEE. Therefore, CCTA is a practical and efficient alternative to TEE for PFO diagnosis., (© 2022. The Author(s) under exclusive licence to Japan Radiological Society.)

Background: When the heart rate of a patient exceeds the physical limits of a scanning device, even retrospective electrocardiography (ECG) gating technology cannot correct motion artifacts. The purpose of this study was to use deep learning methods to correct motion artifacts in coronary computed tomography angiography (CCTA) images acquired with retrospective ECG gating., Methods: To correct motion artifacts in CCTA images, we used a cycle Wasserstein generative adversarial network with a gradient penalty (WGAN-GP) to synthesize CCTA images without motion artifacts, and applied objective image indicators and clinical quantitative scores to evaluate the images. The objective image indicators included peak signal-to-noise ratio (PSNR), structural similarity (SSIM), and normalized mean square error (NMSE). For clinical quantitative scoring, we randomly selected 50 sets of images from the test data set as the scoring data set. We invited 2 radiologists from Zhongnan Hospital of Wuhan University to score the composite images., Results: In the test images, the PSNR, SSIM, NMSE and clinical quantitative score were 24.96±1.54, 0.769±0.055, 0.031±0.023, and 4.12±0.61, respectively. The images synthesized by cycle WGAN-GP performed better on objective image indicators and clinical quantitative scores than those synthesized by cycle least squares generative adversarial network (LSGAN), UNet, WGAN, and cycle WGAN., Conclusions: Our proposed method can effectively correct the motion artifacts of coronary arteries in CCTA images and performs better than other methods. According to the performance of the clinical score, correction of images by this method does not affect the clinical diagnosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-20-1400/coif). The authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Abnormal lipid accumulation in macrophages may lead to macrophages foaming, which is the most important pathological process of atherosclerosis. Atmospheric PM 2.5 could enter the blood circulation and further affect the lipid metabolism of macrophages. But the underlying mechanism is not unclear. This study was undertaken to clarify the effect of PM 2.5 on lipid metabolism in macrophages, and to explore the role of inflammatory reaction and JAK2/STAT3 signaling pathway in this process., Method: Macrophages derived from THP-1 cells were exposed to PM 2.5 (0,100,200,400 μg/mL) for 6 h and 12 h. STAT3 agonist ColivelinTFA is used to specifically excite STAT3. The survival rate of macrophages was detected by CCK-8. The lipid levels in macrophages were detected by colorimetry. The levels of inflammatory factors secreted by macrophages were detected by ELISA. Q-PCR was used to detect the mRNA expression levels, and Western Blot was used to detect the protein expression levels of JAK2/STAT3 pathway genes., Result: The survival rate of macrophages was reduced by PM 2.5 , and the levels of TG, T-CHO and LDL-C of macrophages exposed to PM 2.5 were increased. PM 2.5 led to the increasing level of IL-6 and the decreasing level of IL-4, and the JAK2/STAT3 signaling pathway was inhibited by PM 2.5 . Colivelin TFA significantly decreased the increasing levels of TG, T-CHO and LDL-C levels, and increased the decreasing mRNA levels of IL-4, and LPL induced by PM 2.5 (p < 0.05)., Discussion: PM 2.5 could cause the lipid accumulation of macrophages by inhibiting the JAK2/STAT3 signaling pathway, and inflammatory responses may be involved in this process., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

An increasing number of studies have shown that exposure to particulate matter with a diameter ≤ 2.5 μm (PM 2.5 ) could affect the onset and development of cardiovascular diseases. To explore the underlying mechanisms, the studies conducted in vitro investigations using different cell lines. In this review, we examined recently published reports cited by PubMed or Web of Science on the topic of cardiovascular toxicity induced by PM 2.5 that carried the term in vitro. Here, we summarized the suggested mechanisms of PM 2.5 leading to adverse effects and cardiovascular toxicity including oxidative stress; the increase of vascular endothelial permeability; the injury of vasomotor function and vascular reparative capacity in vascular endothelial cell lines; macrophage polarization and apoptosis in macrophage cell lines; and hypermethylation and apoptosis in the AC16 cell line and the related signaling pathways, which provided a new research direction of cardiovascular toxicity of PM 2.5 ., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Angelica root is the dry root of the Umbelliferae plant Angelica sinensis (oliv) Diels. Angelica organic acid (OA) is the main active ingredient in Angelica sinensis, and it exerts potential anti-atherosclerotic effects by preventing Oxidized low-density lipoprotein (Ox-LDL) induced endothelial injury. To study the protective effects of OA on ox-LDL-induced HUVECs autophagic flux dysfunction and inflammatory injury., Methods: OA were isolated by water extraction and alcohol precipitation, and then the content of ferulic acid (FA) in the OA was determined by high performance liquid chromatography. The ox-LDL-induced endothelial injury model was established. The effect of ferulic acid on the survival of Human umbilical vein endothelial cells (HVUECs) was detected by CCK-8 assay. HUVECs were pretreated with different concentrations of OA (20 μmol/L, 40 μmol/L, and 80 μmol/L), and Western Blot was used to detect the expressions of LC3II, p62, MCP-1, VCAM-1 and LOX-1. The autophagosomes in HUVECs were observed by transmission electron microscopy (TEM)., Results: 20 μmol/L OA could increase the expression of LC3II and decrease the expression of p62, MCP-1, VCAM-1 and LOX-1. The results of TEM showed that angelica organic acids promoted cell organelle degradation in autolysosomes., Conclusion: OA could reduce inflammation, protect endothelial cells and play an anti-atherosclerotic role by enhancing the autophagy flux of damaged endothelial cells, in which FA the major active ingredient of OA played a major role.

The clinical treatment of melanoma continues to present many challenges including poor prognosis because neither monotherapy nor combination therapies have shown maximal treatment efficacy. In this study, an enzyme-responsive nanoparticle was designed for tumor subtypes with the high expression of heparanase-1, since highly metastatic tumors such as melanoma generally express significant levels of heparanase-1. PTX-DOTAP@alloferon-1-heparin/protamine, an enzyme-responsive nanoparticle, has a particle size of 106.1 ± 1.113 nm and a ζ-potential of -45.1 ± 0.455 mV, which enables enrichment in the tumor site by passive targeting. Subsequently, heparanase-1, which is highly expressed in the extracellular matrix, rapidly recognizes and degrades heparin in the outer layer of the nanoparticle and releases encapsulated alloferon-1 by ion diffusion to activate inhibited NK cells in the tumor microenvironment. The size of the smart nanoparticle will eventually decrease to 59.30 ± 0.783 nm and the ζ-potential will reverse to 25.4 ± 0.257 mV, which is beneficial for deep penetration and tumor cell uptake (due to the high negative charge on the tumor cell surface) of PTX-DOTAP cores. Paclitaxel is released in the cytoplasm, and the tumor cells are arrested in the G2/M phase. The nanoparticle characterization experiment demonstrated that in vivo drug delivery could be completed. In subsequent cell and animal experiments, the experimental data demonstrated the efficient therapeutic effects of the nanoparticle. This study provides an excellent template nanoparticle for the treatment of highly metastatic tumors to enhance future prognosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Epidemiological studies have confirmed atmospheric PM 2.5 could affect asthma, and dyslipidemia may be related to pathogenesis of asthma. Recent studies show Notch ligands had lipid combination domains which are responsible for regulating lipid levels. However, the effect of PM 2.5 on asthmatic rats' lipid levels and the role of Notch signaling pathway is unclear., Methods: Rats were treat with ovalbumin (OVA) to establish asthma models. Notch signaling pathway inhibitor (DAPT) was injected intraperitoneally. Asthmatic and healthy rats were exposed to different concentrations of PM 2.5 . Lung tissues were collected and the expression of Hes1 protein was detected by Western Blot. Blood samples were collected to detect the serum lipid levels., Results: Hes1 expression levels in healthy and asthma pathway inhibition groups were lower than those in control groups. Compared with control group, rats exposed to PM 2.5 in middle and high dose, the levels of TG and TC were decreased. Similar results were observed after exposure to the same concentration of PM 2.5 in asthmatic rats. Rats, which were exposed to PM 2.5 after being established the asthma model successfully, could exhibit more significant dyslipidemia than those with direct exposure. After Notch signaling pathway inhibited, TC and LDL in asthma pathway inhibition group were lower than those in healthy group., Conclusions: PM 2.5 can affect the lipid levels of asthmatic rats through the Notch signaling pathway.

In recent years, immunotherapy has produced many unexpected breakthroughs in oncological therapy; however, it still has many deficiencies. For example, the number of patients who are unresponsive to anti-programmed death-ligand 1 (PD-L1), anti-cytotoxic T-like antigen-4 (CTLA4), and anti-programmed death-1 (PD1) therapies cannot be ignored, and the search for an undiscovered immunosuppressive pathway is imminent. Five decades ago, researchers found that activation of the adenosinergic pathway was negatively correlated with prognosis in many cancers. This review describes the entire process of the adenosinergic pathway in the tumor microenvironment and the mechanism of immunosuppression, which promotes tumor metastasis and drug resistance. Additionally, the review explores factors that regulate this pathway, including signaling factors secreted by the tumor microenvironment and certain anti-tumor drugs. Additionally, the combination of adenosinergic pathway inhibitors with chemotherapy, checkpoint blockade therapy, and immune cell-based therapy is summarized. Finally, certain issues regarding treatment via inhibition of this pathway and the use of targeted nanoparticles to reduce adverse reactions in patients are put forward in this review. Graphical Abstract The inhibitors of adenosinergic pathway loaded nanoparticles enter tumor tissue through EPR effect, and inhibit adenosinergic pathway to enhance or restore the effect of immune checkpoint blockade therapy, chemotherapies and immune cell-based therapy. Note: EPR means enhanced penetration and retention, × means blockade.

Low molecular weight heparin-modified isoliquiritigenin-loaded solid lipid nanoparticle (LMWH-ISL-SLN) was developed for injective application. The morphological observation, particle diameter and zeta potential of LMWH-ISL-SLN were characterized using transmission electron microscopy (TEM) and a Malvern Zetasizer. Its entrapment efficiency (EE) and drug loading (DL) were determined by ultracentrifuge. The in-vitro release experiments were performed by dialysis technique. The cytotoxic effects of LMWH-ISL-SLN on Hep-G2 cell lines were determined using an MTT assay. Pharmacokinetic and tissue distribution studies were conducted in kunming mice after intravenous administration of LMWH-ISL-SLN. The average drug entrapment efficiency for LMWH-ISL-SLN was (99.80 ± 3.27)%, drug loading was (18.68 ± 1.51)%, mean particle size was (217.53 ± 4.86) nm and zeta potential was (-18.24 ± 2.47) mV. The in-vitro release experiments demonstrated isoliquiritigenin release from LMWH-ISL-SLN was in line with Weibull's distribution law. Hemolysis test and dose-related toxic effects proved that LMWH-ISL-SLN was a safe and non toxic product when given by intravenous injection. The pharmacokinetics results of LMWH-ISL-SLN showed that the area under the concentration-time curve (AUC 0→∞ )of LMWH-ISL-SLN was greater than that for the isoliquiritigenin solution in plasma. Tissue distribution study indicated that ISL were mainly distributed in the liver and lung. In conclusion, low molecular weight heparin-modified SLN system is a promising carrier for the intravenous delivery of ISL.

A simple and rapid LC-MS/MS method was established for the determination of dihydroartemisinin (DHA) in plasma and tissues of rats. Sample preparation was achieved by liquid-liquid extraction with aether and analysis was performed on LC-MS/MS in positive ion mode using electrospray ionization (ESI) as an interface. Target compounds were quantified in a single ion-monitoring (SIM) mode. DHA was monitored at m/z 267.1 and the internal standard finasteride at m/z 305.2. Chromatography was carried out using a Synergi fusion RP 80 column with a mixture of ethanol and 0.1% formic acid mixture (75:25) as the mobile phase. The pharmacokinetics and tissue distribution after intravenous administration of DHA in nanostructured lipid carrier (NLC) and in solution were then compared. The mean residence times (MRT) of the DHA-NLC was much longer than that of the DHA solution. In the tested organs, the AUC values of the DHA-NLC were higher than that of the DHA solution in liver, spleen, lung, brain and muscle, and lower than the DHA solution in heart and kidney. DHA-NLC prepared in this study is a promising sustained-release and drug-targeting system for antitumor drugs. It may also allow a reduction in dosage and a decrease in systemic toxicity.