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The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.

Objectives: Our study aimed to investigate the effects of alprostadil and Salvia miltiorrhiza extract on myocardial ischemia-reperfusion injury (IRI) and related underlying molecular mechanisms. Methods: A myocardial IRI model was established in Wistar rats via surgical ligation of the left anterior descending coronary artery followed by loosening of the occlusion. The rats were divided into four groups: saline, sham, alprostadil, and S. miltiorrhiza. Rats in the saline and sham groups were injected with normal saline by tail vein once daily for 10 consecutive days. Rats in the S. miltiorrhiza and alprostadil groups were injected with S. miltiorrhiza extract (20 μg/kg) or alprostadil. Histological differences in myocardial tissues between rats in the sham group and in the myocardial IRI model were observed by hematoxylin and eosin staining. India ink perfusion was used to quantify the number of capillary microvessels. Real-time quantitative reverse transcription polymerase chain reaction was used to determine serum expression levels of soluble intercellular adhesion molecule (sICAM), soluble vascular adhesion molecule (sVCAM), CD11b and CD18. Results: The alprostadil and S. miltiorrhiza groups had significantly higher numbers of microvessels than the saline group. Serum sICAM and sVCAM expression was significantly reduced in the alprostadil and S. miltiorrhiza groups. Meanwhile, sICAM and sVCAM in the alprostadil group were markedly lower than in the S. miltiorrhiza group. Moreover, the alprostadil group had markedly lower mRNA expression of CD11b and CD18, which were clearly lower than in the S. miltiorrhiza group. Conclusion: Alprostadil may have cardioprotective effects for myocardial IRI, with down-regulated expression of sICAM, sVCAM, CD11b, and CD18. Resumo: Objetivos: Investigar os efeitos do alprostadil e do extrato de Salvia miltiorrhiza na lesão da reperfusão da isquemia do miocárdio (RIM) e os mecanismos moleculares subjacentes relacionados. Métodos: O modelo RIM foi estabelecido através de sutura cirúrgica da artéria descendente anterior esquerda, seguida de diminuição da oclusão. Os ratos Wistar utilizados foram divididos em quatro grupos: salino, sham, alprostadil e Salvia miltiorrhiza. Os ratos do grupo salino e do grupo sham foram injetados com soro fisiológico l por veia caudal uma vez por dia durante 10 dias consecutivos. Os ratos do grupo Salvia miltiorrhiza e do grupo alprostadil foram injetados com extrato de Salvia miltiorrhiza (20 μg/kg) ou com alprostadil. As alterações histológicas nos tecidos miocárdicos entre os ratos do grupo sham e os ratos do modelo RIM foram analisadas por coloração de hematoxilina e eosina (H&E). A perfusão foi realizada para contar o número de microvasos capilares. A PCR quantitativa em tempo real foi utilizada para determinar os níveis de expressão sérica da molécula de adesão intercelular solúvel (sICAM) e da molécula de adesão vascular solúvel (sVCAM), CD11b e CD18 utilizadas. Resultados: O grupo alprostadil e o grupo Salvia miltiorrhiza tinham um número significativamente maior de microvasos do que os ratos do grupo salino. As expressões séricas sICAM e sVCAM foram significativamente menores no grupo alprostadil e no grupo Salvia miltiorrhiza. No entanto, o sICAM e o sVCAM no grupo alprostadil foram claramente mais baixos do que os do grupo Salvia miltiorrhiza. Além disso, o grupo alprostadil revelou expressões marcadamente inferiores de mRNA de CD11b e de CD18, que foram obviamente menores do que as do grupo Salvia miltiorrhiza. Conclusão: O alprostadil pode ter efeitos cardioprotetores na RIM, incluindo expressões down-regulated de sICAM, sVCAM, CD11b, e CD18.

Ischemic stroke is the most common type of cerebrovascular disease with high disability rate and mortality. The blood-brain barrier (BBB) protects the homeostasis of the brain’s microenvironment and impedes the penetration of 98% of drugs. Therefore, effective treatment requires the better drug transport across membranes and increased drug distribution. Nanoparticles are a good choice for drugs to cross BBB. The main pathways of nano delivery systems through BBB include passive diffusion, adsorption-mediated endocytosis, receptor-mediated transport, carrier-mediated transport, etc. At present, the materials used in brain-targeted delivery can be divided into natural polymer, synthetic polymers, inorganic materials and phospholipid. In this review, we first introduced several ways of nano delivery systems crossing the BBB, and then summarized their applications in ischemic stroke. Based on their potential and challenges in the treatment of ischemic stroke, new ideas and prospects are proposed for designing feasible and effective nano delivery systems.

Pulmonary vascular endothelial cells (VECs) are the main damaged cells in the pathogenesis of various respiratory diseases and they mediate the development and regulation of the diseases. Effective intervention targeting pulmonary VECs is of great significance for the treatment of respiratory diseases. A variety of cell markers are expressed on the surface of VECs, some of which can be specifically combined with the drugs or carriers modified by corresponding ligands such as ICAM-1, PECAM-1, and P-selectin, to achieve effective delivery of drugs in lung tissues. In addition, the great endothelial surface area of the pulmonary vessels, the “first pass effect” of venous blood in lung tissues, and the high volume and relatively slow blood perfusion rate of pulmonary capillaries further promote the drug distribution in lung tissues. This review summarizes the representative markers at the onset of respiratory diseases, drug delivery systems designed to target these markers and their therapeutic effects.

Background: The RESORCE trial reported that regorafenib was effective as the second-line treatment for patients with hepatocellular carcinoma (HCC) after progression on sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice.Objective: We aimed to evaluate the efficacy and safety of regorafenib after disease progression with sorafenib in Chinese patients with advanced HCC.Patients and Methods: A total of 41 patients with advanced HCC who did not respond to sorafenib and followed a regorafenib regimen were enrolled in this retrospective study. Overall survival (OS), progression-free survival (PFS), radiological responses, and adverse events (AEs) were evaluated. Survival curves were compared by using the log-rank test and constructed with the Kaplan–Meier method.Results: The median PFS with regorafenib was 6.6 months (range: 5.0–8.2 months), and the median OS with regorafenib was not reached. The 1-year OS rate of regorafenib was 66.4%. The median OS of sequential sorafenib to regorafenib treatment was 35.3 months [95% confidence interval (CI), 24.3–46.3], and the 2-year OS rate of sequential sorafenib to regorafenib treatment was 74.4%. The most common AEs of regorafenib treatment were elevated aspartate aminotransferase [17/41 patients (41.5%)], elevated alanine aminotransferase [16/41 patients (39%)] and hand-foot syndrome [14/41 patients (34.1%)].Conclusion: Regorafenib appears to be safe and clinically effective in patients with advanced HCC who progressed on first-line sorafenib.

Anxiety prevails in financial markets. In accordance with psychological research, anxious traders’ hesitant behavior differs from the frequently dissected herding and speculative behaviors. This paper examines the interactions between agent anxiety and price inertia in an artificial financial market. We incorporate an evolutionary mechanism to analyze the strategic benefit of the boundedly rational anxious agent. According to our simulation results, deviations in asset prices from their fundamentals increase with the behavioral hesitation of the anxious agent. The investment rigidity from the anxious agent’s lack of confidence mitigates the possibility of price reversal. Moreover, the average strategic benefit of the anxious agent is close to zero. To ensure the reliability of our finding, we further include the irrationality of the anxious agent in our evolutionary setting. Such an endeavor again demonstrates that the strategic benefit of the fundamentalist agent is inferior to that of the anxious agent. Since the anxious agent is characterized by an intolerance for uncertainty, we also investigate the artificial market under various degrees of risk aversion. We perceive that it is less possible for price reversal to emerge when considering higher levels of hesitation. The behavioral hesitation of the anxious agent enables the agent to cleverly evade the risk raised by the speculator.

Objectives We aimed to determine predictors of mortality within 90 days and develop a simple score for patients with mechanical thrombectomy (MT).Design Analysis of a multicentre prospective registry.Setting In six participating centres, patients who had an acute ischaemic stroke (AIS) treated by MT between March 2017 and May 2018 were documented prospectively.Participants 224 patients with AIS were treated by MT.Results Of 224 patients, 49 (21.9%) patients died, and 87 (38.8%) were independent. Variables associated with 90-day mortality were age, previous stroke, admission National Institutes of Health Stroke Scale (NIHSS), fasting blood glucose and occlusion site. Logistic regression identified four variables independently associated with 90-day mortality: age ≥80 years (OR 3.26, 95% CI 1.45 to 7.33), previous stroke (OR 2.33, 95% CI 1.04 to 5.21), admission NIHSS ≥18 (OR 2.37, 95% CI 1.13 to 4.99) and internal carotid artery or basilar artery occlusion (OR 2.92, 95% CI 1.34 to 6.40). Using these data, we developed predicting 90-day mortality of AIS with MT (PRACTICE) score ranging from 0 to 6 points. The receiver operator curve analysis found that PRACTICE score (area under the curve (AUC)=0.744, 95% CI 0.669 to 0.820) was numerically better than iScore (AUC=0.661, 95% CI 0.577 to 0.745) and Predicting Early Mortality of Ischemic Stroke score (AUC=0.638, 95% CI 0.551 to 0.725) for predicting 90-day mortality.Conclusions We developed a simple score to estimate the 90-day mortality of patients who had an AIS treated with MT. But the score needs to be prospectively validated.Trial registration number Chinese Clinical Trial Registry (ChiCTR-OOC-17013052).

We show the effect of investor anxiety on momentum in the Chinese stock market. In this market dominated by retail investors, we examine the momentum profits in 900 types of daily testing periods. We find prevalent price reversals in the long formation and holding periods in the Chinese A-share market. Compared to Goyal and Wahal (2015), Wang and Xie (2010), and Kang et al. (2002) who found no momentum, our novel finding from a daily basis is that the A-share market presents price momentum within the short formation and holding periods. We first test the momentum profits under different strengths of anxiety in the A-share market. The stocks held by the least anxious investors elicit the strongest price momentum, whereas the stocks held by the most anxious investors encounter much weaker price momentum in the A-share market. According to our empirical outcomes, the A-share market overall exhibits higher anxiety and weaker momentum, whereas the B-share market embodies milder anxiety and stronger momentum. From the results of single market and cross-market comparisons, the intrinsic anxiety of retail investors is an essential factor stimulating the Chinese stock market to be prone to price reversals.

Acute lung injury (ALI) is a critical illness without effective therapeutic modalities currently. Recent studies indicated potential efficacy of statins for ALI, while high-dose statins was suggested to be significant for attenuating inflammation in vivo. Therefore, a lung-targeted drug delivery system (DDS) delivering simvastatin (SV) for ALI therapy was developed, attempting to improve the disease with a decreased dose and minimize potential adverse effects. SV-loaded nanostructured lipid carriers (SV/NLCs) with different size were prepared primarily. With particle size increasing from 143.7 nm to 337.8 nm, SV/NLCs showed increasing drug-encapsulated efficiency from 66.70% to 91.04%. Although larger SV/NLCs exhibited slower in vitro cellular uptake by human vascular endothelial cell line EAhy926 at initial stage, while in vivo distribution demonstrated higher pulmonary accumulation of the larger ones. Thus, the largest size SV/NLCs (337.8 nm) were conjugated with intercellular adhesion molecule 1 (ICAM-1) antibody (anti-ICAM/SV/NLCs) for lung-targeted study. The anti-ICAM/SV/NLCs exhibited ideal lung-targeted characteristic in lipopolysaccharide-induced ALI mice. In vivo i.v. administration of anti-ICAM/SV/NLCs attenuated TNF-α, IL-6 and inflammatory cells infiltration more effectively than free SV or non-targeted SV/NLCs after 48-h administration. Significant histological improvements by anti-ICAM/SV/NLCs were further revealed by H&E stain. Therefore, ICAM-1 antibody-conjugated NLCs may represent a potential lung-targeted DDS contributing to ALI therapy by statins.

In an attempt to improve therapeutic efficacy of dexamethasone (DXM)-loaded solid lipid nanoparticles (NPs) for renal ischemia-reperfusion injury (IRI)-induced acute renal injury (AKI), sialic acid (SA) is used as a ligand to target the inflamed vascular endothelium. DXM-loaded SA-conjugated polyethylene glycol (PEG)ylated NPs (SA-NPs) are prepared via solvent diffusion method and show the good colloidal stability. SA-NPs reduce apoptotic human umbilical vein endothelial cells (HUVECs) via downregulating oxidative stress-induced Bax, upregulating Bcl-xL, and inhibiting Caspase-3 and Caspase-9 activation. Cellular uptake results suggest SA-NPs can be specifically internalized by the inflamed vascular endothelial cells (H2O2-pretreated HUVECs), and the mechanism is associated with the specific binding between SA and E-selectin receptor expressed on the inflamed vascular endothelial cells. Bio-distribution results further demonstrated the enhanced renal accumulation of DXM is achieved in AKI mice treated with SA-NPs, and its content is 2.70- and 5.88-fold higher than those treated with DXM and NPs at 6 h after intravenous administration, respectively. Pharmacodynamic studies demonstrate SA-NPs effectively ameliorate renal functions in AKI mice, as reflected by improved blood biochemical indexes, histopathological changes, oxidative stress levels and pro-inflammatory cytokines. Moreover, SA-NPs cause little negative effects on lymphocyte count and bone mineral density while DXM leads to severe osteoporosis. It is concluded that SA-NPs provide an efficient and targeted delivery of DXM for ischemia-reperfusion-induced injury-induced AKI, with improved therapeutic outcomes and reduced adverse effects.

Objective To analyse the location of pathogenic genes of autosomal dominant Charcot⁃Marie⁃Tooth disease (CMT, peroneal atrophy) in a Chinese pedigree. Methods The pedigree of autosomal dominant Charcot ⁃ Marie ⁃ Tooth disease was confirmed by genetic pattern, clinical manifestation and neuromuscular electrophysiological and laboratory examinations. Linkage analysis was performed by using 37 microsatellite genetic markers for the autosomal dominant Charcot⁃Marie⁃Tooth disease pedigree. Thirty⁃ seven microsatellite genetic markers covering 16 genetic loci were linked to 20 kinds of known autosomal dominant Charcot ⁃ Marie ⁃ Tooth disease. The 16 genetic loci were 17p11.2 ⁃ p12 (D17S839, D17S122, D17S793), 1q22 (D1S426, D1S2771), 16p12.3⁃p13.1 (D16S764, D16S3137), 10q21.1 (D10S546, D10S561, D10S581), 1p36.2 (D1S2845, D1S2893, D1S2660), 3q21 (D3S1273, D3S1292), 12q23 (D12S1329, D12S105), 7p15 (D7S2562, D7S516), 8p21 (D8S552, D8S265), 7q11⁃q21 (D7S634, D7S669), 12q12⁃q13 (D12S1663, D12S368, D12S1632), 8q13 ⁃ q21 (D8S286, D8S548), 12q24.3 (D12S1679, D12S86), 10q24 (D10S554, D10S571, D10S1863), 19p12 ⁃ p13 (D19S916, D19S433) and 1p34 ⁃ p35 (D1S489, D1S432). Results All microsatellite genetic markers were amplified successfully, and polymorphisms were presented on every genetic loci. The examined pedigree of Charcot ⁃ Marie ⁃ Tooth disease was autosomal dominant inheritance. Three patients did not present the same allele on the 16 genetic loci. Linkage analysis indicated that the pathogenic genes in all the members of this pedigree did not link with the 16 known pathogenic genetic loci in autosomal dominant Charcot ⁃ Marie ⁃ Tooth disease. Conclusion The diagnosis of autosomal dominant Charcot ⁃ Marie⁃Tooth disease in this pedigree is confirmed, but do not coincide with the diagnostic criteria of the known types of this disease recommended by European Neuromuscular Center (ENMC). It is suggested that autosomal dominant Charcot⁃Marie⁃Tooth disease in this Chinese pedigree may be a new type caused by other pathogenic genes. DOI：10.3969/j.issn.1672-6731.2010.03.018

Chemoresistance is still a major obstacle for lung cancer treatment. Increasing studies have demonstrated that microRNAs (miRNAs) are essential meditators of chemoresistance during cancer progression. MiR-451a is reported to be a tumor suppressor during cancer development. However, its effects on lung cancer and drug resistance in lung cancer are still unclear. In the study, the results showed that miR-451a exhibited a significant role in suppressing the drug resistance in lung cancer cells when treated with doxorubicin (DOX) through alleviating epithelialmesenchymal transition (EMT), as evidenced by the markedly reduced expression of N-cadherin and Vimentin, while the enhanced expression of E-cadherin. In addition, miR-451a over-expression markedly promoted the sensitivity of lung cancer cells to DOX treatments, and also disrupted the EMT of lung cancer cells. Mechanistically, miR-451a was found to directly target c-Myc to affect the EMT and drug resistance in lung cancer cells in response to DOX incubation. Furthermore, c-Myc knockdown markedly elevated the sensitivity of lung cancer cells to DOX, whereas over-expressing c-Myc markedly reversed the anti-tumor role of DOX, which was slightly diminished by miR-451a mimic. The in vivo experiments confirmed that miR-451a promoted the sensitivity of lung cancer cells-derived tumors to DOX treatment by reducing c-Myc. Therefore, our results revealed a new insight into DOX resistance of lung cancer cells and miR-451a could be considered as a potential therapeutic target to overcome drug resistance in lung cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier Masson SAS.)