Direct cytoplasmic delivery of RNAi therapeutics through a non-lysosomal pathway for enhanced gene therapy.

The first approved RNAi therapeutics, ONPATTRO, in 2017 moves the concept of RNA interference (RNAi) therapy from research to clinical reality, raising the hopes for the treatment of currently incurable diseases. However, RNAi therapeutics are still facing two main challenges-susceptibility to enzymatic degradation and low ability to escape from endo/lysosome into the cytoplasm. Therefore, we developed disulfide-based nanospheres (DBNPs) as universal vehicles to achieve efficient RNA delivery to address these problems. Notably, the DBNPs possess unique and desirable features, including improved resistance to nuclease degradation, direct cytoplasmic delivery through thiol-mediated cellular uptake, and cytosolic environment-responsive release, greatly enhancing the bioavailability of RNA therapeutics. Additionally, DBNPs are superior in terms of overcoming formidable physiological barriers, including vascular barriers and impermeable tumor tissues. Owning to these advantages, the DBNPs exhibit efficient gene silencing effect when delivering either small interfering RNA (siRNA) or microRNA in various cell lines and generate remarkable growth inhibition in the zebrafish and mouse model of pancreatic tumors as compared to traditional delivery vectors, such as PEI. Therefore, DBNPs have potential application prospect in RNAi therapy both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: RNA interference (RNAi) therapeutics could target and alter any disease-related mRNA translation, thus have great potential in clinical application. Delivery efficiency of RNA modalities into cell cytoplasm is the main problem that currently limit RNAi therapeutics to release their full potential. Most of the known delivery materials suffer from the endo/lysosomal entrapment and enzymatic degradation during endocytosis-dependent uptake, resulting unsatisfied efficiency of the cytoplasmic release. Here, we developed disulfide-based nanospheres could directly transfer RNA modalities into the cytoplasm and significantly enhance the delivery efficiency, thus holding great potential in RNAi therapy.

The complete mitochondrial genome of Stibochiona nicea (Gray, 1846) (Lepidoptera: Nymphalidae) and phylogenetic analysis.

In this study, the complete mitochondrial genome (mitogenome) of Stibochiona nicea (Gray, 1846) (Lepidoptera: Nymphalidae) was first reported with 15,298 bp in size, containing 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes (rrnL and rrnS), and one control region. The nucleotide composition of the entire mitogenome is highly A + T biased (81.5%). The gene content and arrangement of the newly sequenced mitogenome are identical to those of the other available mitogenomes of Nymphalidae. All PCGs start with the conventional ATN codons, except for cox1 initiating with atypical CGA(R). Nine PCGs (atp8, atp6, cox3, nad1, nad2, nad3, nad4l, nad6, and cob) utilize a typical stop codon TAA, whereas the remaining PCGs (cox1, cox2, nad4, and nad5) end with an incomplete stop codon T-. Phylogenetic analysis revealed that S. nicea is closely related to Dichorragia nesimachus within Pseudergolinae, which further forms the sister group to the grouping of (Nymphalinae + (Cyrestinae + (Biblidinae + Apaturinae))). The complete mitogenome of S. nicea will provide useful genetic information for improving the taxonomic system and phylogenetics of Nymphalidae.

High summation of preoperative and postoperative Interleukin-6 levels predicts prolonged mechanical ventilation in patients with acute DeBakey type I aortic dissection: A single center retrospective study.

Objective: This study aimed to investigate the predictive effect of preoperative and postoperative interleukin-6 (IL-6) levels on the duration of mechanical ventilation in patients with acute DeBakey Type I aortic dissection (I-AAD) after emergency surgery. Methods: We retrospectively enrolled 381 patients with I-AAD who underwent surgery in our hospital, between June 2018 and June 2022. Patients were divided into two groups according to whether prolonged mechanical ventilation (PMV) occurred after surgery. The baseline data, biochemical indicators at admission, surgical data, biochemical indicators at postoperative 6 h, and the postoperative data of the two groups were recorded and analyzed. Results: The PMV group comprised 199 patients, and the non-PMV group 182. The postoperative in-hospital mortality was different between the two groups (11.1% vs. 3.3%, p = 0.004). The length of intensive care unit and hospitalization time in the PMV group were significantly longer than those in the non-PMV group. Multiple regression analysis showed postoperative IL-6 (post-IL-6) ≥67.1 pg/mL and summation of preoperative and postoperative IL-6 (total IL-6) ≥83.4 pg/mL were associated risk factors for PMV [odds ratio (OR) 3.259, 95% confidence interval (CI) 1.922-5.524, p < 0.001], [(OR) 4.515, 95% CI 2.241-9.098, p < 0.001]. Furthermore, determined by the receiver operating characteristics(ROC) curve, the cut-off point was total IL-6 ≥83.4 pg/mL (area under curve(AUC) = 0.825). The sensitivity and specificity of predicting postoperative PMV of patients with I-AAD were 91.5% and 78.2%, respectively (95% CI 0.782-0.868, p < 0.001). Conclusion: For predicting postoperative PMV in patients with I-AAD, post IL-6 ≥67.1 pg/mL is potentially valuable and summation of preoperative and postoperative IL-6 (total IL-6) ≥83.4 pg/mL has a more pronounced predictive value.

Ubiquitin-proteasome system reveals clinical subtypes with distinct molecular characteristics and prognoses in gastric cancer.

Modulators in ubiquitin-proteasome system (UPS) has been implicated in regulating cancer-related genes, immune responses, and oncogenesis. However, the global UPS expression pattern and its role in gastric cancer (GC) pathology remain elusive. Herein, we integrated the modulators in UPS and dissected their associations with tumor microenvironment (TME), therapeutic response and prognosis in GC. Ten eligible GC cohorts (n = 2161) were collected in this comprehensive analysis. Unsupervised clustering based on expression profile of ubiquitination regulators was performed to identify distinct expression pattern. Then, pathway activation, and TME characteristics and prognosis were explored for patients in each pattern. Finally, a UPS scoring system in GC, termed UPSGC, is developed for individualized quantification of UPS expression pattern. Two prognosis-distinctive UPS expression patterns were identified and validated. Multiple interdependent characteristics were found in each pattern. Patients in the pattern with poor prognosis were found with activation of EMT, TNFα/NF-κB and IL6/JAK/STAT3 signaling, and more infiltration of immunosuppressive M2 macrophages and Th2 cells in TME. And another pattern was characterized by upregulation of angiogenesis, Notch and Wnt-ß/catenin signaling, as well as enrichment of microvessels in TME. Based on the UPSGC system, two pattern-related clinical subtypes were identified. Finally, the UPSGC subtypes were validated as robust biomarker to predict patient's therapeutic responses and survival outcomes. In conclusion, this study proposes two previously unexplored UPS expression patterns in GC, in which patients have distinct survival outcomes and molecular characteristics. The findings provide new evidences to support the clinical relevance of ubiquitination with personalized therapy.

Activated peroxydisulfate by sorghum straw-based biochar for enhanced tartrazine degradation: Roles of adsorption and radical/nonradical processes.

Biochar obtained from biomass waste through pyrolysis has significant potential in wastewater treatment due to its large specific surface area and multi-functional active sites. In current study, sorghum straw (SS) was pyrolyzed to prepare various biochar under nitrogen atmosphere. Adsorption kinetics of prepared biochar toward tartrazine (TTZ) was systematically investigated, and the biochar was also characterized by using multiple techniques to explore the contribution of physicochemical properties to adsorption. Then, the biochar with optimum TTZ adsorption performance, was also applied as a catalyst for peroxydisulfate (PDS) activation to degrade TTZ. Factors including PDS concentration, solution pH, and reaction temperature were examined. The optimized degradation rate constant of TTZ (1.1627 min-1) was achieved under the conditions at 2 mM PDS, pH of 3, and 23 °C. In addition, the free radical trapping experiments and EPR spectra revealed that the reactive substances of electron (e-), 1O2, SO4•-, O2•-, and •OH contributed to TTZ degradation. Density Functional Theory (DFT) also concluded that the atoms C(6), O(12), N(16), N(17), C(18) and N(22) in TTZ molecule showed larger f0 values which are vulnerable to radical attack. Therefore, the synergistic mechanism embodying adsorption and radical/non-radical processes were proposed. Besides, the degradation pathways of TTZ were identified with the aid of HPLC/MS technique, indicating that multiple reaction processes containing the symmetrical cleavage of azo bonds, the asymmetrical cleavage of C-N, desulfonation, and benzene-like structure cracking were involved. Therefore, this study provides a simple and effective catalytic system for TTZ degradation, and also realizes the resource utilization of solid waste.

Efficacy of non-pharmacological interventions in pain relief and opioid consumption after cardiac surgery: A systematic review and Bayesian network meta-analysis.

OBJECTIVE: To investigate and rank the evidence for the efficacy of non-pharmacological interventions in relieving pain after cardiac surgery using comprehensive comparisons. BACKGROUND: Although several previous systematic reviews and meta-analyses showed that non-pharmacological interventions effectively control and reduce pain after cardiac surgery, none quantitatively compared the effect of these different types of interventions. DESIGN: Systematic review and Bayesian network meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analysis guidelines. METHODS: Six databases were searched from inception to April 2021 to collect all published evidence from randomised clinical trials. One author extracted the relevant information from the eligible trials; a second author independently reviewed the data. Before analysing the extracted data, two investigators independently assessed the quality of the included studies. Conventional meta-analysis was conducted using either fixed- or random-effects models according to statistical heterogeneity. The Bayesian network meta-analysis was conducted using the consistency model. RESULTS: We identified 42 randomised clinical trials comparing 14 groups with 4253 patients. Transcutaneous electrical nerve stimulation, acupressure, music and massage were effective for pain relief, with transcutaneous electrical nerve stimulation being associated with the best probability of successful pain relief after cardiac surgery (cumulative ranking curve surface, 0.97; probability, 77.03%). Acupressure (cumulative ranking curve surface, 0.79; probability, 30.69%) was the second-best option. However, there was no evidence that any pair-up intervention significantly reduced opioid use or anxiety. CONCLUSIONS: These findings suggest that transcutaneous electrical nerve stimulation, acupressure, music and massage may effectively alleviate postoperative cardiac pain, with transcutaneous electrical nerve stimulation representing the best choice for pain relief. RELEVANCE TO CLINICAL PRACTICE: The results of this network meta-analysis can guide patients after cardiac surgery and healthcare providers to make optimal decisions in managing postoperative cardiac pain. TRIAL REGISTRATION: PROSPERO CRD42021246183.

The effect of sand fractional wettability on SDBS-enhanced PCE immiscible mobilization in porous media.

Fractional wettability is common in the dense non-aqueous phase liquids (DNAPL) contaminated sites. However, it is still unclear how fractional wettability affects surfactant-enhanced DNAPL immiscible mobilization in saturated porous media. The macro-contact angle of the fractional wettability media was measured. The results of column experiments showed that the entrapped tetrachloroethene (PCE) saturations after sodium dodecyl benzene sulfonate (SDBS) flooding were lower in the media where NAPL-wet sand was present compared with those in water-wet media. In the media which contained 25% octadecyltrichlorosilane (OTS)-treated sand, the entrapped PCE saturations decreased to the minimum, and the decrease was much larger in fine sand media. The SDBS-enhanced PCE recoveries were jointly affected by fractional wettability, particle size, and interfacial tension (IFT). When NAPL-wet sand was present and SDBS concentration was just 0.125 g⋅L-1, the SDBS-enhanced PCE recoveries increased significantly. As the SDBS concentration continues to increase to 0.5 g⋅L-1, they only increased slightly. In the fine sand media, the SDBS-enhanced PCE recoveries were higher, and they increased more obviously with the increase of NAPL-wet sand fractions. The influence weight of fractional wettability on SDBS-enhanced PCE recoveries was the largest (47.09%) under the experimental conditions. These findings indicate that it is important to consider fractional wettability characteristics when establishing a DNAPL immiscible mobilization strategy, because it is not sufficient to consider only IFT reduction, especially in media with finer pore structures.

Opposite effects of high- and low-dose di-(2-ethylhexyl) phthalate (DEHP) exposure on puberty onset, oestrous cycle regularity and hypothalamic kisspeptin expression in female rats.

Di-(2-ethylhexyl) phthalate (DEHP) is ubiquitous in the environment and has been proposed to lead to reproductive disruption. In this study, we systematically investigated the effects of different doses of DEHP exposure on female hypothalamic-pituitary-gonadal axis development. Female Sprague-Dawley rats were gavaged with vehicle (corn oil) or DEHP (5 or 500mgkg-1 day-1) during postnatal Days (PNDs) 22-28 or PNDs 22-70. Results demonstrated that the low and high doses of DEHP exerted opposite effects on puberty onset, circulating luteinising hormone, serum oestradiol and progesterone levels, with the low dose (5mgkg-1) promoting and the high dose (500mgkg-1) inhibiting these parameters. Significant dose-related differences were also found in the D500 group with longer oestrous cycle duration, lower ovarian/bodyweight ratio, fewer corpus lutea and more abnormal ovarian stromal tissue in comparison with the oil or D5 groups. Molecular data showed that the hypothalamic Kiss1 mRNA expression in the anteroventral periventricular but not in the arcuate nucleus significantly decreased in the D500 rats and increased in the D5 rats relative to the rats in the oil group. These findings suggested that the kisspeptin system is a potential target for DEHP to disrupt reproductive development and function.

Toxicity and Its Mechanism Study of Arecae semen Aqueous Extract in Wistar Rats by UPLC-HDMS-Based Serum Metabolomics.

BACKGROUND: Arecae semen (AS) is officially recorded in Chinese Pharmacopoeia and it is known for its multiple functions, including antidepressive, antioxidant, anti-inflammatory, and cholesterol-lowering effects, which have been confirmed by modern pharmacological study. Previous study in our laboratory showed that long-term oral administration of Arecae semen (AS) is officially recorded in Chinese Pharmacopoeia and it is known for its multiple functions, including antidepressive, antioxidant, anti-inflammatory, and cholesterol-lowering effects, which have been confirmed by modern pharmacological study. Previous study in our laboratory showed that long-term oral administration of Hypothesis. The aim of this work was to characterize the metabolome, evaluate the metabolic changes, and study the mechanisms of the toxicity induced by different treatment doses of ASAE via metabolomics. METHODS: Wistar rats were administered orally two different doses of ASAE (1500 and 4500 mg/kg/d) for 30 days. The investigation was carried out to evaluate the safety of ASAE. And, the UPLC-HDMS-based serum metabolomics in conjunction with multivariate statistical techniques was applied to investigate the serum metabolite profile and potential markers of toxicity induced by different doses of ASAE. RESULTS: Coupled with blood biochemistry and histopathology results, the significant difference in metabolic profiling was observed between 1500 and 4500 mg/kg/d dosages of ASAE-treated rats and normal rats by using pattern recognition analysis, indicating that changes in serum metabolites must have occurred. Some significant changed metabolites such as arachidonic acid, linoleic acid, stearic acid, and LPC (18 : 1) have been found and identified. These biochemical changes in serum metabolites are related to the perturbation of linoleic acid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, and purine metabolism, which may be helpful to further understand the cardiotoxicity and neurotoxicity of ASAE. CONCLUSION: The study shows that the metabolomic method may be a valuable tool for studying the essence of toxicity induced by traditional Chinese medicine.

[Effects of the construction of fertile and cultivated upland soil layer on soil fertility and maize yield in black soil region in Northeast China.] / 肥沃耕层构建对东北黑土区旱地土壤肥力和玉米产量的影响.

Organic amendment return could enhance soil fertility, improve soil structure, and increase crop yield. However, how construction of soil layers can affect soil fertility and crop yield are not fully understood. We examined the effects of constructions of fertile and cultivated soil layer on soil fertility and maize yield in the upland black soil region in Northeast China, to provide theoretical guidance in increasing soil fertility and sustainable development of agriculture. Based on the combination of field plot experiments and demonstration regions, nine study sites with different ecological characteristics were selected from Heilongjiang, Jilin and Liaoning provinces from northeast China, covering dark brown, black, meadow, chernozem, albic, brown and cinnamon soils. There were three treatments in each study site, including maize straw return within 0-35 cm soil layer (CFⅠ), the combination of maize straw and organic manure return within 0-35 cm soil layer (CFⅡ) and conventional agricultural practice without organic amendmentas control (CK). The rate of straw return in CFⅠ and CFⅡ treatments were 10000 kg·hm-2, and full straw for demonstration regions. The rate of organic manure in CFⅡ treatment was 30000 kg·hm-2. Considerable difference in soil fertility were recorded among the nine study sites with the trend of tillage layer > sub-tillage layer, especially for dark brown soil and albic soil. Soil fertility of tillage layer and sub-tillage layer was relatively low both for brown soil and cinnamon soil. The heavy clay and plow pan were pivotal limiting factors of soil fertility for the black soil and the meadow soil. Compared with CK, the concentrations of soil organic matter (SOM), available nitrogen (AN), available phosphorous (AP), and available potassium (AK) in tillage layers was increased on average by 1.85 g·kg-1, 20.16 mg·kg-1, 1.56 mg·kg-1 and 17.2 mg·kg-1 in the CFⅠ and CFⅡ treatments in five study sites with more than two years of treatments. The contents of SOM, AN, AP and AK in sub-tillage layer increased by 2.09 g·kg-1, 12.06 mg·kg-1, 2.18 mg·kg-1 and 3.84 mg·kg-1, compared with tillage layer. CFⅠ treatment significantly enhanced the contents of SOM and AP in both tested soil layers, while CFⅡ treatment significantly enhanced all fertility indices in both tested soil layers. This indicated that the increase of organic amendment return is an effective way to improve soil fertility. Maize yield fluctuated under the combined effect of climatic conditions and soil types. The significant differences in maize yield under CK, CFⅠ and CFⅡ treatments were observed with a trend of CFⅡ > CFⅠ > CK. This result indicated that the construction of fertile and cultivated soil layer could significantly increase maize yield independent of soil types. The construction of fertile and cultivated soil layer based on maize straw return or maize straw and organic manure combined return within 0-35 cm soil layer, could simultaneously increase soil fertility in both tillage and sub-tillage layer, as well as maize yield. We suggested that the selection of approaches of the constructions of fertile and cultivated soil layer should consider soil types and the sources of organic amendments. It should also give priority to soil layers rich in organic manure source to construct fertile and cultivated soil layers.

UPLC-HDMS-based on serum metabolomics reveals the toxicity of arecae semen.

ETHNOPHARMACOLOGICAL RELEVANCE: Arecae semen has been used as vermifuge and digestant in traditional Chinese medicine (TCM) for more than one thousand years. However, the toxicity effect of areca semen and its underlying mechanism are still unclear. THE AIM OF THE STUDY: This study was aimed to investigate the toxicity of arecae semen and to explore its mechanisms by serum metabolomics. MATERIALS AND METHODS: The male Wistar rats were divided into the control group and treated group (n = 6 in each group), which were given by gavage with distill water or arecae semen aqueous extract (ASAE) once a day for 30 days, respectively. Serum samples were collected from all the rats after treatment of 7-day, 14-day and 30-day for metabolomics analysis. Moreover, biochemistry analysis and histopathological examination were performed at the end of study. RESULTS: The phenomenon of diarrhea, less physical activity, tremors and body curl up were observed in the treated group. Additionally, the body weights of treated rats were significantly decreased compared with control rats from the 8th day after oral administration. Except the level of creatinekinase (CK) in the treated group significantly increased compared with the control group, there were no differences on biochemistry parameters and histopathological test in the two groups. Combined with the methods of principal component analysis (PCA), orthogonal projection to latent structure-discrimination analysis (OPLS-DA) and available databases, the treated and control rats were clearly distinguished from each other and 19 metabolites were identified as the potential biomarkers in the arecae semen treated rats. The identified biomarkers indicated that there were perturbations of the phospholipid metabolism, amino acid metabolism and fat acid metabolism in the treated group. CONCLUSIONS: This indicated that arecae semen possessed certain cardiotoxicity and inhibited the normal growth in Wistar male rats. In addition, the metabolomics approach is a useful tool to study the toxicity in TCM.

Whole genome bisulfite sequencing of human spermatozoa reveals differentially methylated patterns from type 2 diabetic patients.

AIMS/INTRODUCTION: The incidence of type 2 diabetes mellitus is increasing worldwide, and it might partly cause metabolic disorder and type 2 diabetes mellitus susceptibility in patients' offspring through epigenetic modification. However, the underlying mechanisms remain largely unclear. Recent studies have shown a potential link between deoxyribonucleic acid methylation in paternal sperm and susceptibility to type 2 diabetes mellitus in offspring, so this article focuses on whether the whole-genome methylation profiles of spermatozoa in type 2 diabetes mellitus patients have changed. MATERIALS AND METHODS: We investigated the genome-wide deoxyribonucleic acid methylation profiles in spermatozoa by comparing eight individuals with type 2 diabetes mellitus and nine non-diabetic controls using whole-genome bisulfite sequencing method. RESULTS: First, we found that the proportion of methylated cytosine in the whole genome of the type 2 diabetes mellitus group was slightly lower than that of the control group. Interestingly, the proportion of methylated cytosines in the CG context decreased, and the proportion of methylated cytosines in the CHG context (H = A, T or C) increased in the type 2 diabetes mellitus group, but the proportion of methylated cytosines in the CHH context (H = A, T or C) barely changed. The methylated cytosines in the CG context were mainly distributed at the high methylated level, whereas methylated cytosines in the CHG context and methylated cytosines in the CHH context were mainly distributed at the low and middle methylated level in both groups. Second, functional enrichment analysis showed that differentially methylated genes played a significant role in nervous system development and cell metabolism. Finally, we identified 10 top type 2 diabetes mellitus-related differentially methylated genes, including IRS1, PRKCE, FTO, PPARGC1A, KCNQ1, ATP10A, GHR, CREB1, PRKAR1A and HNF1B. CONCLUSIONS: Our study provides the first evidence for deoxyribonucleic acid methylation reprogramming in spermatozoa of type 2 diabetes mellitus patients, and provides a new basis for explaining the complex mechanism of type 2 diabetes mellitus susceptibility in offspring.

Concomitant lung adenocarcinoma and pulmonary cryptococcosis confirmed by pathologic examinations.

To describe the characteristics of concomitant lung cancer and pulmonary cryptococcosis (PC) cases.A total of 8 patients with lung cancer and coexisting PC, who were admitted to Fuzhou Pulmonary Hospital of Fujian from 1st January 2009 to 31st December 2015 and whose diagnoses were confirmed by pathological examinations, were studied.One patient had a history of diabetes mellitus and 1 had a history of treated with surgery. The lesions in 7 cases manifested as nodular shadows; only 1 case showed the lesion of the 2 diseases mergedmixed together, and it manifested as a large flake-like infiltrated shadow in the same lobe. The histological type in all of the patients was lung adenocarcinoma. Lung cancer stage was advanced (III-IV) in 25.0% of the cases. The 5 patients who received surgery and drug treatment are presently healthy following resection. Recurrence and metastasis of lung cancer following surgery occurred in 2 patients in whom the tumor was controlled again after anti-tumor treatment. One patient with advanced lung cancer and PC was treated with antifungal therapy in combination with antineoplastic chemotherapy, but she failed to improve and died 10 months after symptom onset during the follow-up period.PC coexisting with pulmonary carcinoma is rare. PC can manifest as pulmonary nodules and mimic malignant lesions, so it must be considered during a differential diagnosis of pulmonary nodules, especially in immunosuppressed patients.

Design, synthesis and antitumour and anti-angiogenesis evaluation of 22 moscatilin derivatives.

Two series of moscatilin derivatives were designed, synthesized and evaluated as anti-tumor and anti-angiogenesis agents. Most of these compounds showed moderate-to-obvious cytotoxicity against five cancer cell lines (A549, HepG2, MDA-MB-231, MKN-45, HCT116). Among these cell lines, compounds had obvious effects on HCT116. Especially for 8Ae, the IC50 was low to 0.25 µM. 8Ae can inhibit the viability and induce the apoptosis of HCT116 cells but exhibit no cytotoxic activity in noncancerous NCM460 colon cells. 8Ae can also arrest the G2/M cell cycle in HCT116 cells by inhibiting the α-tubulin expression. Zebrafish bioassay-guided screen showed the 22 moscatilin derivatives had potent anti-angiogenic activities and compound 8Ae had better activities than positive compound. Molecular docking indicated 8Ae interacted with tubulin at the affinity of -7.2 Kcal/mol. In conclusion, compound 8Ae was a potential antitumor and anti-angiogenesis candidate for further development.

First successful combination of extracorporeal membrane oxygenation (ECMO) with video-assisted thoracic surgery (VATS) of pulmonary bullae resection in the management of refractory pneumothorax in a critically ill patient with H7N9 pneumonia and acute respiratory distress syndrome: A case report.

RATIONALE: At present, data regarding refractory pneumothorax treated with video-assisted thoracic surgery (VATS) in combination with extracorporeal membrane oxygenation (ECMO) in critically ill patients with H7N9 pneumonia have never been reported. PATIENT CONCERNS: A laboratory-confirmed case of human infection with avian influenza A (H7N9) virus was treated in our hospital. Acute respiratory distress syndrome (ARDS) developed and the patient was oxygenated via veno-venous ECMO due to the failure of mechanical ventilation. Unfortunately, a right refractory pneumothorax occurred. Despite treatment with pleural drainage and select bronchial occlusion, the patient still failed to improve. DIAGNOSIS: Fatal H7N9 pneumonia complicated with severe ARDS, pulmonary bullae, and refractory pneumothorax. INTERVENTIONS: Successful combination of ECMO with VATS of pulmonary bullae resection was performed and pneumothorax was cured. OUTCOMES: One week after the operation, ECMO was removed. However, the patient finally developed multiorgan failure (MOF) complicated by refractory hypoxemia due to progressive lung fibrosis and died 36 days after admission. LESSONS: Although the patient died of MOF triggered by severe lung fibrosis at last, the successful treatment of refractory pneumothorax by combination of ECMO with VATS is encouraging. Thus, when refractory pneumothorax in a patient with severe pulmonary dysfunction fails to improve through routine therapy, the treatment of pneumothorax by VATS based on ECMO support can be considered as a feasible selection.

The kinetics, thermodynamics and mineral crystallography of CaCO3 precipitation by dissolved organic matter and salinity.

Calcium carbonate (CaCO3) precipitation is an important geochemical process. In the estuary zone and some arid shallow lakes, DOM (dissolved organic matter) and salinity are two frequent changing factors that may affect CaCO3 precipitation. The joint effect of DOM and salinity on CaCO3 precipitation kinetics and thermodynamics are still unclear. In this study, effects of DOM on CaCO3 precipitation process at 0.5‰ and 70‰ salinity were investigated by QCM (Quartz Crystal Microbalance) technique, real-time pH measurement and single-injection nanoliter ITC (isothermal titration calorimetry). The mineral crystallography was analyzed by SEM-EDS. Both DOM and salinity had inhibitory effect on CaCO3 precipitation. DOM had more pronounced inhibitory effect on CaCO3 precipitation at lower salinity. Regardless of DOM, 70‰ salinity inhibited CaCO3 precipitation >0.5‰ salinity. The CaCO3 precipitation kinetics followed the first-order kinetic model and the adhesion kinetics of the instantaneous nucleation and crystal growth stage could be well described by the exponential function. CaCO3 precipitation was an endothermic process and high salinity strongly hindered CaCO3 precipitation. The effect of DOM on the absorbed heat was significant at 0.5‰ salinity. At 70‰ salinity, regardless of the effect of DOM, CaCO3 precipitation rate was greatly slowed down because it needed much more heat. CaCO3 minerals were dominated by rhombohedral calcite while CaCO3 minerals were mainly shaped as spherical vaterite at 0.5‰ salinity and rhombohedral calcite at 70‰ salinity. The crystal phase changed during CaCO3 precipitation at 0.5‰ salinity. In conclusion, the presence of DOM had substantial impact on the micrograph of the CaCO3 minerals. The percentage of flawed crystals with rough surface increased significantly with increased DOM concentration.

Pro-angiogenic activity of isoliquiritin on HUVECs in vitro and zebrafish in vivo through Raf/MEK signaling pathway.

AIMS: Liquorice is a widely used herbal medicine for treating various diseases native to southern Europe and parts of Asia. Isoliquiritin (ISL), a licorice root-derived flavonoid, has been reported to exhibit antioxidant, anti-inflammatory, anti-genotoxic activity and anti-depression activities. This study was aimed to explore the pro-angiogenic activity of ISL and explicate the underlying mechanism. MAIN METHODS: In vitro, ISL-treated human umbilical vein endothelial cells (HUVECs) were analyzed for cell viability, cell migration and tube formation. In vivo, pro-angiogenic effects were evaluated for the intersegmental vessels (ISVs) formation in transgenic zebrafish embryos [Tg(fli-1: EGFP)]. Furthermore, a blocking assay with eight pathways-specific kinase inhibitors were also used to determine the potential pro-angiogenic mechanism of ISL. KEY FINDINGS: ISL counteracted tyrosine kinase inhibitor II (VRI)-induced endothelial cell apoptosis and promoted cell migration and tube formation in HUVECs. ISL markedly rescued ISVs loss induced by VRI in zebrafish embryos, probably by activating vascular endothelial growth factor receptor-2 (VEGFR-2), phosphoinositide 3-kinase (PI3K), Raf and mitogen-activated protein kinase (MEK)-dependent signaling pathways. SIGNIFICANCE: Our study first discovered and confirmed the pro-angiogenic activity of ISL both in HUVECs and zebrafish. Thus, ISL could be developed as a potential therapeutic agent by the role of pro-angiogenic activity for the treatment of cardiovascular diseases, cerebrovascular diseases and other vascular diseases.

Ca2+ complexation of dissolved organic matter in arid inland lakes is significantly affected by drastic seasonal change of salinity.

CaCO3 precipitation is one of the most common and important geochemical processes in the arid inland waters and it can be significantly affected by interaction of DOM with Ca2+. Effects of the drastic seasonal change of water salinity on interaction of DOM with Ca2+ in the arid inland waters were completely unknown. In the present study, complexation of DOM with Ca2+ in the freshwater (0.5‰ salinity) and hypersaline water (70‰ salinity) were comparatively examined by excitation-emission matrix (EEM) fluorescence quenching titration and isothermal titration calorimetry (ITC). The complexation of DOM with Ca2+ was significantly influenced by the drastic change of salinity. The ITC complexation is exothermic at 0.5‰ salinity but turns to an endothermic process at 70‰ salinity. More energy is needed for the complex reaction between DOM and Ca2+ under the hypersaline condition than in the fresh water. Fluorescence quenching titration indicates that DOM has stronger binding ability toward Ca2+ in the freshwater than in the saline water, and more fractions of DOM in the freshwater are accessible to Ca2+ than in the saline water. Ca2+ complexation in the DOM is dominated by the tryptophan-like components at both salinities and the complexation of Ca2+ with fulvic acid-like components is ignorable. The findings is important for understanding the aquatic geochemical processes in some lakes that seriously affected by irrigation water use in the arid zone.

1-Methoxycarbony-ß-carboline from Picrasma quassioides exerts anti-angiogenic properties in HUVECs in vitro and zebrafish embryos in vivo.

Angiogenesis is a crucial process in the development of inflammatory diseases, including cancer, psoriasis and rheumatoid arthritis. Recently, several alkaloids from Picrasma quassioides had been screened for angiogenic activity in the zebrafish model, and the results indicated that 1-methoxycarbony-ß-carboline (MCC) could effectively inhibit blood vessel formation. In this study, we further confirmed that MCC can inhibit, in a concentration-dependent manner, the viability, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, as well as the regenerative vascular outgrowth of zebrafish caudal fin in vivo. In the zebrafish xenograft assay, MCC inhibited the growth of tumor masses and the metastatic transplanted DU145 tumor cells. The proteome profile array of the MCC-treated HUVECs showed that MCC could down-regulate several angiogenesis-related self-secreted proteins, including ANG, EGF, bFGF, GRO, IGF-1, PLG and MMP-1. In addition, the expression of two key membrane receptor proteins in angiogenesis, TIE-2 and uPAR, were also down-regulated after MCC treatment. Taken together, these results shed light on the potential therapeutic application of MCC as a potent natural angiogenesis inhibitor via multiple molecular targets.

Anti-angiogenic and anticancer effects of baicalein derivatives based on transgenic zebrafish model.

Angiogenesis leads to tumor neovascularization by promoting tumor growth and metastatic spread, therefore, angiogenesis is considered as an attractive target for potential small molecule anticancer drug discovery. Herein, we report the structural modification and biological evaluation of baicalein derivatives, among which compound 42 had potent in vivo anti-angiogenic activity and wide security treatment window in transgenic zebrafish model. Further, 42 exhibited the most potent inhibitory activity on HUVEC proliferation, migration and tube formation in vitro. Moreover, 42 significantly inhibited growth of human lung cancer A549 cells and weak influence on human normal fibroblast L929 cells. The present research demonstrated that the significant anti-angiogenic and anticancer effects, which provided the supportive evidence for 42 could be used as a potential compound of cancer therapy.