Hesperetin ameliorates lipopolysaccharide-induced acute lung injury via the miR-410/SOX18 axis.

Hesperetin (Hesp), a dihydroflavone, has a wide range of pharmacological activities, including antioxidant, anti-inflammatory, and antitumor effects, as well as cardiovascular protection. It also has protective effects against acute lung injury (ALI); however, the exact mechanism remains unclear. In the present study, the protective effects and mechanism of Hesp in the lungs were investigated. Hematoxylin and eosin staining was used to examine pathological changes in the lungs. Enzyme-linked immunosorbent assay was used to detect proinflammatory cytokine levels. In addition, reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to observe the transcription and translation changes in the related genes, respectively. The results indicate that Hesp not only improves histopathological changes in the lungs but decreases the wet/dry ratio. In addition, total cell counts and the number of neutrophils and macrophages were lower in the bronchoalveolar fluid after Hesp treatment, consistent with the change in proinflammatory cytokine levels. MicroRNA-410 (miR-410) levels were significantly lower in the lung tissues of ALI mice and were reversed after Hesp treatment. Furthermore, miR-410 overexpression due to injection with agomiR-410 produced similar protective effects as Hesp. However, blocking miR-410 inhibited the protective effects of Hesp in the lungs of ALI mice. In addition, miR-410 has been shown to target the inhibition of sex determining region Y-box 18 (SOX18), indicating that Hesp might alleviate inflammatory secretion by blocking the miR-410/SOX18 axis. Thus, Hesp might be a potential agent for the treatment of ALI.

Sequential occurrence of eclampsia-associated posterior reversible encephalopathy syndrome and reversible splenial lesion syndrome (a case report): proposal of a novel pathogenesis for reversible splenial lesion syndrome.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a rare clinic-radiological entity characterized by headache, an altered mental status, visual disturbances, and seizures. Reversible splenial lesion syndrome (RESLES) is a new clinic-radiological syndrome characterized by the presence of reversible lesions with transiently restricted diffusion (cytotoxic edema) in the splenium of the corpus callosum (SCC) on magnetic resonance (MR) images. Here we report a rare case involving a 23-year-old pregnant woman with eclampsia who sequentially developed PRES and RESLES. CASE PRESENTATION: The patient, a 23-year-old pregnant woman, presented with sudden-onset headache, dizziness, and severe hypertension (blood pressure, 170/110 mmHg). Brain MR imaging (MRI) revealed T2 hyperintense lesions in the posterior circulation territories. Immediate cesarean section was performed, and the patient received intravenous infusion of mannitol (125 ml, q8h) for 8 days for the treatment of PRES. Ten days later, or 1 day after the discontinuation of mannitol, T2-weighted MRI showed that the hyperintense lesions (vasogenic edema) had disappeared. However, diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping revealed an isolated lesion in the splenium of the corpus callosum (SCC) that was accompanied by restricted diffusion (cytotoxic edema); these findings indicated reversible splenial lesion syndrome (RESLES). Five days after the discontinuation of mannitol, she had no abnormal symptoms and was discharged from our hospital. Brain MRI performed 29 days after the clinical onset of symptoms showed no abnormalities. CONCLUSION: The sequential occurrence of the two reversible diseases in our patient prompted us to propose a novel pathogenesis for RESLES. Specifically, we believe that the vasogenic edema in PRES was reduced with mannitol treatment, which increased the hyperosmotic stress and opened the blood-brain barrier; meanwhile, upregulation of aquaporin-4 expression secondary to the increased osmotic pressure resulted in cytotoxic edema in the astrocytes in SCC (RESLES). Further research is necessary to confirm this possible pathogenesis.

Combined effect of salt and drought on boron toxicity in Puccinellia tenuiflora.

Boron toxicity is a worldwide problem, usually accompanied by salt (NaCl) and drought. The combined stresses may induce complex toxicity to the plant. The aim of the present study was to investigate how the combined stresses of salt and drought affect B toxicity in plants. Puccinellia tenuiflora seedlings were planted in vermiculite. A three (B) × three (salt) × three (drought) factorial experiment (for a total of 27 treatments) was conducted. After a 30-day cultivation, plants were harvested to determine dry weight and the concentrations of B, Na+, K+, Ca2+, and Mg2+. Plant growth was inhibited by B toxicity, which was alleviated by salt and drought. B stress enhanced B uptake and transport of the plant, which was inhibited by salt and drought. B stress had a little effect on K+ and Na+ concentration and caused Ca2+ and Mg2+ accumulation in the plant. Salt addition increased Na+ concentration and inhibited Ca2+ and Mg2+ accumulation. Drought addition inhibited Na+ accumulation and enhanced Ca2+ and Mg2+ accumulation. The combined stresses of salt and drought had a greater alleviation on the inhibition of dry weight caused by B than individual salt and drought. Besides, the combined stresses of salt and drought also enhanced B uptake and inhibited B transport. The results indicate that salt, drought, and the combined stresses of salt and drought all can alleviate B toxicity in P. tenuiflora, the main mechanism of which is the restriction of B and Na+ uptake caused by salt and drought. The combined stresses of salt and drought have a greater effect on B toxicity than individual salt and drought.

Clinical Efficiency of Metagenomic Next-Generation Sequencing in Sputum for Pathogen Detection of Patients with Pneumonia According to Disease Severity and Host Immune Status.

Purpose: Severe pneumonia causes the highest mortality rate in immunocompromised patients. This study aimed to investigate the pathogen diagnostic efficacy of metagenomic next-generation sequencing (mNGS) using sputum sample in patients with pneumonia according to patients' disease severity and immune conditions. Patients and Methods: A total of 180 patients suffering from pneumonia were recruited, and sputum samples were collected in duplicate for pathogen detection by both conventional microbiological tests (CMT) and mNGS. Then, the performance of pathogen identification was examined between two methods, according to disease severity and patients' immune status. Results: In comparison to CMT, mNGS had higher positivity rates in all patients with pneumonia (85.0% vs 62.2%, P=9.445e-07). The most commonly detected microorganism in sputum of pneumonia patients was Acinetobacter baumannii (42/180, 23.3%) in bacterum level, Candida albicans in fungus level (44/180, 24.4%), and Human herpesvirus 1 (39/180, 27.5%) in virus level. However, for mNGS results, Candida albicans in 34.9% of positive patients, and Human herpesvirus 1 in 7.7% of positive cases were confirmed as pathogens causing pneumonia. Acinetobacter baumannii detected by mNGS in 75% of positive patients was diagnosed as pathogen of pneumonia. The microorganism profile of sputum mNGS differed according to disease severity and immune status of patients. Pneumocystis jirovecii was more likely to infect immunocompromised patients (P=0.002). Pseudomonas aeruginosa (14.8% vs 0.0%, P=0.008) and Human herpesvirus 1 (26.1% vs 5.3%, P=0.004) had higher infection rate in patients with severe pneumonia compared with non-severe cases. mNGS had overwhelming advantages over CMT in detecting a lot of microorganisms including Streptococcus pneumoniae, Enterococcus faecium, Pneumocystis jirovecii, and majority of viruses. Conclusion: mNGS is a complementary tool of CMT for detecting suspected pathogens for patients with lower respiratory infections. The interpretation of opportunistic pathogens identified by mNGS is challenging, and needs comprehensive consideration of sequencing data and clinical factors.

A semi-supervised classification RBM with an improved fMRI representation algorithm.

BACKGROUND AND OBJECTIVE: Training an effective and robust supervised learning classifier is not easy due to the limitations of acquiring and labeling considerable human functional magnetic resonance imaging (fMRI) data. Semi-supervised learning uses unlabeled data for feature learning and combines them into labeled data to build better classification models. METHODS: Since no premises or assumptions are required, a restricted Boltzmann machine (RBM) is suitable for learning data representation of neuroimages. In our study, an improved fMRI representation algorithm with a hybrid L1/L2 regularization method (HRBM) was proposed to optimize the original model for sparsity. Different from common semi-supervised classification models that treat feature learning and classification as two separate training steps, we then constructed a new semi-supervised classification RBM based on a joint training algorithm with HRBM, named Semi-HRBM. This joint training algorithm jointly trains the objective function of feature learning and classification process, so that the learned features can effectively represent the original fMRI data and adapt to the classification tasks. RESULTS: This study uses fMRI data to identify categories of visual stimuli. In the fMRI data classification task under four visual stimuli (house, face, car, and cat), our HRBM has satisfactory feature representation capabilities and better performance for multiple classification tasks. Taking the supervised RBM (sup-RBM) as an example, our Semi-HRBM classification model improves the average accuracy of the four-classification task by 7.68%, and improves the average F1 score of each visual stimulus task by 8.90%. In addition, the generalization ability of the model was also improved. CONCLUSION: This research might contribute to enrich solutions for insufficiently labeled neuroimaging samples, which could help to identify complex brain states under different stimuli or tasks.

Development of liquiritigenin-phospholipid complex with the enhanced oral bioavailability.

In the present study, liquiritigenin-phospholipid complex (LPC) was developed and evaluated to increase the oral bioavailability of liquiritigenin. A single-factor test methodology was applied to optimize the formulation and process for preparing LPC. The effects of solvent, drug concentration, reaction time, temperature and drug-to-phospholipid ratio on encapsulation efficiency were investigated. LPCs were characterized by UV-visible spectroscopy, differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR), and powder X-ray diffractometry (PXRD). The apparent solubility and n-octanol/water partition coefficient were tested. The pharmacokinetic characteristics and bioavailability of the LPC were investigated after oral administration in rats in comparison with liquiritigenin alone. An LPC was successfully prepared. The optimum level of various parameters for liquiritigenin-phospholipid complex was obtained at the drug concentration of 8 mg·mL-1, reaction time for 15 min, reaction temperature of 30 ℃, a ratio of 1∶4.5 (W/W) drug-to-phospholipid and anhydrous ethanol as reaction solvent. Compared to liquiritigenin, the AUC0-t of the LPC was increased by 239%. The liquiritigenin-phospholipid complex significantly increase the lipid solubility and bioavailability of liquiritigenin, suggesting that it is an effective formulation for further development and clinical applications.

Gene Variations of Sixth Complement Component Affecting Tacrolimus Metabolism in Patients with Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: Orthotopic liver transplantation (OLT) improves the prognosis of patients with hepatocellular carcinoma (HCC). Moreover, the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis. However, studies correlating the complement system with tacrolimus metabolism after OLT are scarce. In this study, the role of single nucleotide polymorphisms (SNPs) associated with the sixth complement component (C6) in tacrolimus metabolism was investigated during the early stages of liver transplantation. METHODS: The study enrolled 135 adult patients treated with OLT for HCC between August 2011 and October 2013. Ten SNPs in C6 gene and rs776746 in cytochrome P450 3A5 (CYP3A5) gene were investigated. The tacrolimus levels were monitored daily during 4 weeks after transplantation. RESULTS: Both donor and recipient CYP3A5 rs776746 allele A were correlated with decreased concentration/dose (C/D) ratios. Recipient C6 rs9200 allele G and donor C6 rs10052999 homozygotes were correlated with lower C/D ratios. Recipient CYP3A5 rs776746 allele A (yielded median tacrolimus C/D ratios of 225.90 at week 1 and 123.61 at week 2), C6 rs9200 allele G (exhibited median tacrolimus C/D ratios of 211.31 at week 1, 110.23 at week 2, and 99.88 at week 3), and donor CYP3A5 rs776746 allele A (exhibited median C/D ratios of 210.82 at week 1, 111.06 at week 2, 77.49 at week 3, and 85.60 at week 4) and C6 rs10052999 homozygote (exhibited median C/D ratios of 167.59 at week 2, 157.99 at week 3, and 155.36 at week 4) were associated with rapid tacrolimus metabolism. With increasing number of these alleles, patients were found to have lower tacrolimus C/D ratios at various time points during the 4 weeks after transplantation. In multiple linear regression analysis, recipient C6 rs9200 group (AA vs. GG/GA) was found to be related to tacrolimus metabolism at weeks 1, 2, and 3 (P = 0.005, P = 0.045, and P = 0.033, respectively), whereas donor C6 rs10052999 group (CC/TT vs. TC) was demonstrated to be correlated with tacrolimus metabolism only at week 4 (P = 0.001). CONCLUSIONS: Recipient C6 gene rs9200 polymorphism and donor C6 gene rs10052999 polymorphism are new genetic loci that affect tacrolimus metabolism in patients with HCC after OLT.

Developmental toxicity of doxorubicin hydrochloride in embryo-larval stages of zebrafish.

Doxorubicin hydrochloride is widely used to treat various types of cancers. Its therapeutic and side effects are well documented. However, the developmental toxicity of doxorubicin has not been previously described. Lethal and sublethal effects on embryo-larval stages of zebrafish in a study of the developmental toxicity of doxorubicin were observed. Zebrafish embryos were exposed to different concentrations (0-100 mg/L) of doxorubicin between 4 and 120 h post fertilization, and zebrafish larvae were exposed to different concentrations (0-200 mg/L) of doxorubicin for 96 h. The markers about the development toxicity of doxorubicin in zebrafish were observed under a stereomicroscope. Higher doxorubicin concentrations mainly caused acute lethal effects, and lower doxorubicin concentrations mainly caused sublethal effects, such as multiple malformations in embryos and larvae. Moreover, with the increase of doxorubicin concentration, the malformation rate increased. The heart rate of embryos was accelerated at lower concentrations of doxorubicin (≤ 10 mg/L) and decelerated at higher concentrations (≥ 25 mg/L). The hatching rate and body length were inhibited at higher concentrations of doxorubicin (≥ 25 mg/L).In conclusion, doxorubicin has serious developmental toxicity and this raises a concern for developmental effects of doxorubicin in clinical practice.