PD protects Müller cells through the SIRT1/NLRP3 inflammasome pathway.

PURPOSE: Polydatin (PD) has widely pharmacological activities. However, the effects of PD on high glucose (HG)-induced Müller cells in diabetic retinopathy (DR) are rarely studied. METHODS: The protective effects of PD were evaluated in HG-induced human retinal Müller cells. The levels of pro-angiogenic factors and pro-inflammatory factors were detected using the ELISA kits. The expressions of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) and sirtuin-1 (SIRT1) were determined by western blot. RESULTS: PD inhibited proliferation and activation of HG-induced MIO-M1 cells. PD treatment reduced the levels of pro-angiogenic factors, pro-inflammatory factors, and oxidative stress, while these effects were attenuated by NLRP3 agonist ATP in HG-induced MIO-M1 cells. Furthermore, PD inhibited the activation of NLRP3 inflammasome by regulating the SIRT1 expression after HG stimulation, and knockdown of SIRT1 reversed the inhibition effects of PD on NLRP3 inflammasome, pro-angiogenic factors, pro-inflammatory factors, and oxidative stress in HG-induced MIO-M1 cells. CONCLUSION: PD may inhibit HG-induced Müller cells proliferation and activation and suppress pro-angiogenic factors, pro-inflammatory factors, and oxidative stress through the SIRT1/NLRP3 inflammasome pathway. In summary, PD treatment may be an effective therapeutic strategy for DR.

The identification of key metabolites and mechanisms during isoniazid/rifampicin-induced neurotoxicity and hepatotoxicity in a mouse model by HPLC-TOF/MS-based untargeted urine metabolomics.

The co-administration of isoniazid (INH) and rifampicin (RIF) is associated with hepatotoxicity and neurotoxicity. To systematically investigate the mechanisms of hepatotoxicity and neurotoxicity induced by INH/RIF, we used high performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF/MS)-based untargeted metabolomics to analyze urine from a mouse model and screened a range of urinary biomarkers. Mice were orally co-administered with INH (120 mg/kg) and RIF (240 mg/kg) and urine samples were collected on days 0, 7, 14 and 21. Hepatotoxicity and neurotoxicity were assessed by samples of liver, brain and kidney tissue which were harvested for histological analysis. Toxicity analysis revealed that INH/RIF caused hepatotoxicity and neurotoxicity in a time-dependent manner; compared with day 0, the levels of 35, 82 and 86 urinary metabolites were significantly different on days 7, 14 and 21, respectively. Analysis showed that by day 21, exposure to INH+RIF had caused disruption in vitamin B6 metabolism; the biosynthesis of unsaturated fatty acids; tyrosine, taurine, hypotaurine metabolism; the synthesis of ubiquinone and other terpenoid-quinones; and the metabolism of tryptophan, nicotinate and nicotinamide. Nicotinic acid, nicotinuric acid and kynurenic acid were identified as sensitive urinary biomarkers that may be useful for the diagnosis and evaluation of toxicity.

Safety and Efficacy of Ticagrelor versus Clopidogrel in East Asian Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention Treated with Dual Antiplatelet Therapy: A Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The treatment strategy for dual antiplatelet therapy (DAPT) with ticagrelor has been controversial in East Asian patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Our meta-analysis aimed to demonstrate whether intensified antithrombotic regimens with ticagrelor plus aspirin have more beneficial effects and fewer adverse events compared to those of clopidogrel plus aspirin in East Asian patients with ACS undergoing PCI. METHODS: We searched PubMed, Embase, Web of Science, ScienceDirect, Clinical Trials, Cochrane Library, and Chinese Clinical Trial Registry for randomized controlled trials (RCTs) comparing the efficacy of DAPT with ticagrelor or clopidogrel plus aspirin for secondary prevention of ACS in East Asian patients undergoing PCI. Risk ratios (RRs) and 95% confidence intervals (CIs) were used as the metrics of choice for assessing treatment effects. The primary endpoint was bleeding events, and the secondary endpoints were major adverse cardiovascular and cerebrovascular events (MACCEs, including cardiovascular death, nonfatal myocardial infarction [MI], and stroke), all-cause death, and definite/probable/possible stent thrombosis. The I2 index was used to assess heterogeneity. RESULTS: Six RCTs involving a total of 2,725 patients met the inclusion criteria. The incidence of all bleeding events with ticagrelor was higher than that with clopidogrel (RR, 1.65; 95% CI, 1.31-2.07), but the incidence of MACCE was not significantly different between the two groups (RR, 1.08; 95% CI, 0.54-2.16). All-cause death (RR, 1.10; 95% CI, 0.67-1.79), cardiovascular death (RR, 1.42; 95% CI, 0.68-2.98), nonfatal MI (RR, 0.92; 95% CI, 0.48-1.78), stroke (RR, 1.00; 95% CI, 0.40-2.50), and stent thrombosis (RR, 0.76; 95% CI, 0.19-2.98) were not statistically different between the two groups. CONCLUSION: Ticagrelor increased the risk of bleeding and did not increase treatment efficacy compared to that of clopidogrel in the East Asian population who have ACS treated with PCI.

Thoracic Endovascular Aortic Repair versus Optimal Medical Treatment in Patients with Type B Intramural Hematoma: A Meta-Analysis.

PURPOSE: We intended to study the effect of thoracic endovascular aortic repair (TEVAR) and optimal medical treatment (OMT) on type B intramural hematoma (BIMH). METHODS: We searched PubMed, EMbase, Cochrane Library, and China National Knowledge Infrastructure databases that compared TEVAR and OMT in patients with BIMH. Two authors independently assessed the risk of bias using the Newcastle-Ottawa Scale. The rate ratio (RR) and 95% confidence interval were used to calculate the outcome. The primary endpoints were aortic-related death and regression/resolution. Secondary endpoints were all-cause death, progression to dissection, and secondary intervention. RESULTS: Eight observational studies were included in the analysis. TEVAR reduced aortic-related death (RR 0.22, 95% CI 0.08-0.56, P = 0.002, I² = 24%) and promoted hematoma regression/resolution (RR 1.48, 95% CI 1.05-2.10, P <0.05, I² = 71%) compared to OMT. Moreover, TEVAR was associated with a reduction in progression to dissection (RR 0.32, 95% CI 0.13-0.81, P <0.02, I² = 39%) and secondary intervention (RR 0.18, 95% CI 0.09-0.37, P <0.00001, I² = 38%) compared to OMT. However, all-cause death has no significant difference between the two groups (RR 0.45, 95% CI 0.17-1.19, P = 0.11, I² = 58%). CONCLUSIONS: The results of this meta-analysis suggested that TEVAR is an effective treatment for BIMH, which can delay the progression of intramural hematoma and promotes regression/resolution. More research about indications of TEVAR is still needed.

Integration of metabolomics and proteomics analysis to explore the mechanism of neurotoxicity induced by receipt of isoniazid and rifampicin in mice.

Isoniazid (INH) and rifampicin (RIF) are co-administered in tuberculosis treatment but can cause neurotoxicity, and the mechanism is not known. To explore this mechanism, we employed an integrated approach using metabolomics analysis (MA) and proteomics analysis (PA). Male mice were divided into three groups and administered vehicle (control group), or co-administered INH (120 mg/kg) and RIF (240 mg/kg), for 7 or 14 days. Mice brains were collected for mass spectrometry-based PA and MA plus lipidomics analysis. Measurement of brain levels of malondialdehyde and superoxide dismutase revealed time-dependent brain injury after exposure to INH+RIF for 7 and 14 days. Also, 422 proteins, 35 metabolites, and 21 lipids were dysregulated and identified. MA demonstrated "purine metabolism," "phenylalanine, tyrosine and tryptophan biosynthesis," "biosynthesis of unsaturated fatty acids," "phenylalanine metabolism," and "arginine biosynthesis" to be disturbed significantly. PA demonstrated pathways such as "lipids," "amino acids," and "energy metabolism" to be disrupted. Peroxisome proliferator-activated receptor (PPAR) pathways were changed in energy metabolism, which led to the neurotoxicity induced by INH+RIF. Immunohistochemical analyses of PPARs in mice brains verified that PPAR-α and -γ expression was downregulated. PPAR-α and -γ activation might be a key target for alleviating INH+RIF-induced neurotoxicity.

Pulmonary effects of exposure to indium and its compounds: cross-sectional survey of exposed workers and experimental findings in rodents.

BACKGROUND: Many studies have shown that occupational exposure to indium and its compounds could induce lung disease. Although animal toxicological studies and human epidemiological studies suggest indium exposure may cause lung injury, inflammation, pulmonary fibrosis, emphysema, pulmonary alveolar proteinosis, and even lung cancer, related data collected from humans is currently limited and confined to single workplaces, and the early effects of exposure on the lungs are not well understood. OBJECTIVES: This study combined population studies and animal experiments to examine the links of indium with pulmonary injury, as well as its mechanism of action. A cross-sectional epidemiological study of indium-exposed workers from China was conducted to evaluate associations between occupational indium exposure and serum biomarkers of early effect. This study also compares and analyzes the causal perspectives of changes in human serum biomarkers induced by indium compound exposure and indium exposure-related rat lung pathobiology, and discusses possible avenues for their recognition and prevention. METHODS: This is a study of 57 exposed (at least 6 h per day for one year) workers from an indium ingot production plant, and 63 controls. Indium concentration in serum, urine, and airborne as exposure indices were measured by inductively coupled plasma-mass spectrometry. Sixteen serum biomarkers of pulmonary injury, inflammation, and oxidative stress were measured using ELISA. The associations between serum indium and 16 serum biomarkers were analyzed to explore the mechanism of action of indium on pulmonary injury in indium-exposed workers. Animal experiments were conducted to measure inflammatory factors levels in bronchoalveolar lavage fluid (BALF) and lung tissue protein expressions in rats. Four different forms of indium compound-exposed rat models were established (intratracheal instillation twice per week, 8 week exposure, 8 week recovery). Model I: 0, 1.2, 3, and 6 mg/kg bw indium tin oxide group; Model II: 0, 1.2, 3, and 6 mg/kg bw indium oxide (In2O3) group; Model III: 0, 0.523, 1.046, and 2.614 mg/kg bw indium sulfate (In2(SO4)3) group; Model IV: 0, 0.065, 0.65, and 1.3 mg/kg bw indium trichloride (InCl3) group. Lung pathological changes were assessed by hematoxylin & eosin, periodic acid Schiff, and Masson's staining, transmission electron microscopy, and the protein changes were determined by immunohistochemistry. RESULTS: In the production workshop, the airborne indium concentration was 78.4 µg/m3. The levels of serum indium and urine indium in indium-exposed workers were 39.3 µg/L and 11.0 ng/g creatinine. Increased lung damage markers, oxidative stress markers, and inflammation markers were found in indium-exposed workers. Serum indium levels were statistically and positively associated with the serum levels of SP-A, IL-1ß, IL-6 in indium-exposed workers. Among them, SP-A showed a duration-response pattern. The results of animal experiments showed that, with an increase in dosage, indium exposure significantly increased the levels of serum indium and lung indium, as well as the BALF levels of IL­1ß, IL­6, IL­10, and TNF­α and up-regulated the protein expression of SP-A, SP-D, KL-6, GM-CSF, NF-κB p65, and HO-1 in all rat models groups. TEM revealed that In2(SO4)3 and InCl3 are soluble and that no particles were found in lung tissue, in contrast to the non-soluble compounds (ITO and In2O3). No PAS-staining positive substance was found in the lung tissue of In2(SO4)3 and InCl3 exposure groups, whereas ITO and In2O3 rat models supported findings of pulmonary alveolar proteinosis and interstitial fibrosis seen in human indium lung disease. ITO and InCl3 can accelerate interstitial fibrosis. Findings from our in vivo studies demonstrated that intra-alveolar accumulation of surfactant (immunohistochemistry) and characteristic cholesterol clefts granulomas of indium lung disease (PAS staining) were triggered by a specific form of indium (ITO and In2O3). CONCLUSIONS: In indium-exposed workers, biomarker findings indicated lung damage, oxidative stress and an inflammatory response. In rat models of the four forms of indium encountered in a workplace, the biomarkers response to all compounds overall corresponded to that in humans. In addition, pulmonary alveolar proteinosis was found following exposure to indium tin oxide and indium oxide in the rat models, and interstitial fibrosis was found following exposure to indium tin oxide and indium trichloride, supporting previous report of human disease. Serum SP-A levels were positively associated with indium exposure and may be considered a potential biomarker of exposure and effect in exposed workers.

Now or never: Organizational forgetting as a determinant of knowledge sharing and cross-boundary innovation.

This study constructs a theoretical model to test and prove that organizational forgetting influences cross-boundary innovation and testifies to the moderating role of Institutionalized organizational mission in the said relationship. Data was collected through a convenient sampling technique from 353 middle and senior managers of entrepreneurial enterprises in China through online and offline modes. Additionally, we used confirmatory factor analysis, multiple regression, and bootstrap analysis to verify hypotheses using Analysis of a moment structures and Statistical Package for the Social Sciences latest versions. The results show that organizational forgetting has a significantly positive impact on cross-boundary innovation and binary knowledge sharing plays a mediating role in the relationship between organizational forgetting and cross-boundary innovation. Moreover, the mediating effect of exploitative knowledge sharing on the relationship between organizational forgetting and cross-boundary innovation is more substantial than exploratory knowledge sharing. This study separates the impact mechanism of exploitative and exploratory knowledge sharing as a mediator unanimously and proves that Institutionalized organizational mission has a significant moderating role in the relationship between organizational forgetting and cross-boundary innovation. This research offers significant implications for Chinese enterprises to bolster cross-boundary innovation to achieve growth.

Exploration of the underlying mechanisms of isoniazid/rifampicin-induced liver injury in mice using an integrated proteomics and metabolomics approach.

The hepatotoxic mechanism resulting from coadministration of isoniazid (INH) and rifampicin (RIF) are complex and studies remain inconclusive. To systematically explore the underlying mechanisms, an integrated mass-based untargeted metabolomics and label-free quantitative proteomics approach was used to clarify the mechanism of INH/RIF-induced liver injury. Thirty male mice were randomly divided into three groups: control (receiving orally administered vehicle solution), INH (150 mg/kg) + RIF (300 mg/kg) orally administered for either 7 or 14 days, respectively. Serum was collected for the analysis of biochemical parameters and liver samples were obtained for mass spectrum-based proteomics, metabolomics, and lipidomics analysis. Overall, 511 proteins, 31 metabolites, and 23 lipids were dysregulated and identified, and disordered biological pathways were identified. The network of integrated multiomics showed that glucose, lipid, and amino acid metabolism as well as energy metabolism were mainly dysregulated and led to oxidative stress, inflammation, liver steatosis, and cell death induced by INH and RIF. Coadministration of INH and RIF can induce liver injury by oxidative stress, inflammation, liver steatosis, and cell death, and the reduction in glutathione levels may play a critical role in these systematic changes and warrants further study.

Music Recognition Using Blockchain Technology and Deep Learning.

The purposes are to recognize and classify different music characteristics and strengthen the copyright protection system for original digital music in the big data era. Deep learning (DL) and blockchain technology are applied and researched herein. Based on CNN (Convolutional Neural Network), a music recognition method combined with hashing learning is proposed. The error generated when outputting the binary hash code is considered, and the semantic similarity of the hash code is ensured. Besides, the application of blockchain technology in the current intellectual property protection in original music is discussed. According to digital music property rights protection needs, the system is divided into modules, and its functions are designed. The system ensures its various functions by applying the application protocol designed in the Algor and network. In the experiments, the MagnaTagATune dataset is selected to verify the performance of the proposed CRNNH (Convolutional Recurrent Neural Network Hashing) algorithm. The algorithm shows the best music recognition performance under different bit numbers. When the number of connections is about 100, the QPS value of the blockchain-based music property rights protection system can be stabilized at about 20,000. At any number of threads, the system pressure will increase dramatically with the increase in the number of analog connections. The music recognition algorithm based on DL and hash method discussed is of great significance in improving the classification accuracy of music recognition. The application of blockchain technology in the copyright protection platform of original music works can protect the copyright of digital music and ensure the operation performance of the system.

The Re-integration of College Innovation and Entrepreneurship Education Under Young Entrepreneurs' Enterprising Spirit and Professional Music Education.

The purpose is to coordinate the relationship between innovation and entrepreneurship education (IEE) and professional education. This exploration is based on the entrepreneurial spirit of young entrepreneurs and the re-integration of IEE and music education in colleges. First, the IEE is studied in theory. Then, the basic criteria for integrating IEE and professional education are studied, and 305 students from a music college in Xi'an are taken as the survey sample. The questionnaire is adopted to investigate the current situation of the integration of IEE and professional education. The results show that 52.1% of students believe that IEE is closely related to professional education. In terms of self entrepreneurship awareness, males' awareness of self entrepreneurship is higher than females', and the willingness of self entrepreneurship from freshman to senior is 3.1, 15.5, 26.1, and 30.8%, respectively. For the dominant position in the integrated curriculum, 55.6% hold that professional courses should dominate innovative professional courses, and 25.9% believe that innovation and entrepreneurship courses should be dominated. Besides, 16.5% think that the proportion of the two should be the same, and 2% hold that it doesn't matter. For the enthusiasm of innovative professional courses, only 14.1% of students are very positive. The survey results show that the integration of IEE and professional education needs to be improved, and there is a lack of pertinence and guidance for students of different genders and grades. Students are not clear about the position of IEE and lack enthusiasm. Finally, reasonable suggestions are put forward in view of the above problems. The results are conducive to promoting and accelerating the process of talent training mode combining professional education and IEE. It has a certain reference value for college education and teaching reform.

Untargeted metabolomics analysis of omeprazole-enhanced chemosensitivity to cisplatin in mice with non-small cell lung cancer.

Drug resistance of tumors remains a major barrier in cisplatin (CDDP)-based chemotherapy. Omeprazole (OME) is often utilized during chemotherapy to alleviate gastrointestinal symptoms. In a previous investigation, we demonstrated a protective effect of OME against CDDP-induced kidney injury. To further establish whether OME could enhance chemosensitivity to CDDP and the underlying mechanisms, an in vivo tumor-bearing mouse model with CDDP-resistant A549 non-small cell lung cancer (A549/CDDP) was established in the current study. A high-performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF/MS)-based untargeted metabolomics approach for tumor tissue and serum was employed to explore the mechanisms underlying the enhanced therapeutic effects of co-administration of CDDP and OME. Notably, tumor weights of mice in the CDDP + OME group were significantly decreased compared with those treated with CDDP alone. HE and TUNEL staining revealed more significant apoptosis of tumor cells in the group co-administered CDDP + OME relative to CDDP alone. Overexpression of multidrug resistance-associated protein 2 in CDDP-resistant tumors was significantly reversed upon treatment with CDDP + OME. PCA score plots of the groups co-treated with CDDP + OME were clearly separated from those treated with CDDP alone in metabolomics analysis for tumor and serum samples, clearly suggesting that co-administration of OME enhances the antitumor effect of CDDP. Subsequently, 10 and 7 metabolites in CDDP + OME group with significant changes in tumor and serum compared with CDDP group, respectively, were identified. Pathway analysis both in tumor and serum samples revealed regulation of the metabolism of purines, several amino acids and riboflavin in enhanced chemotherapy with both OME and CDDP. The collective findings provide beneficial novel insights into drug-drug interactions, which could improve the application of CDDP in clinical practice.

Deficient Rnf43 potentiates hyperactive Kras-mediated pancreatic preneoplasia initiation and malignant transformation.

BACKGROUND: Largely due to incidental detection, asymptomatic pancreatic cystic lesions (PCLs) have become prevalent in recent years. Among them, intraductal papillary mucinous neoplasm (IPMN) infrequently advances to pancreatic ductal adenocarcinoma (PDAC). Conservative surveillance versus surgical intervention is a difficult clinical decision for both caregivers and PCL patients. Because RNF43 loss-of-function mutations and KRAS gain-of-function mutations concur in a subset of IPMN and PDAC, their biological significance and therapeutic potential should be elucidated. METHODS: Pancreatic Rnf43 knockout and Kras activated mice (Rnf43-/-; KrasG12D) were generated to evaluate their clinical significance in pancreatic pre-neoplastic initiation and malignant transformation. RESULTS: Loss of Rnf43 potentiated the occurrence and severity of IPMN and PDAC in oncogenic Kras mice. The Wnt/ß-catenin signaling pathway was activated in pancreatic KrasG12D and Rnf43 knockout mice and the PORCN inhibitor LGK974 blocked pancreatic IPMN initiation and progression to PDAC accordingly. CONCLUSIONS: Rnf43 is a tumor suppressor in the prevention of pancreatic malignant transformation. This genetically reconstituted autochthonous pancreatic Rnf43-/-; KrasG12D preclinical cancer model recapitulates the pathological process from pancreatic cyst to cancer in humans and can be treated with inhibitors of Wnt/ß-catenin signaling. Since the presence of RNF43 and KRAS mutations in IPMNs predicts future development of advanced neoplasia from PCLs, patients with these genetic anomalies warrant surveillance, surgery, and/or targeted therapeutics such as Wnt/ß-catenin inhibitors.

Polypharmacy and potentially inappropriate medications among elderly patients in the geriatric department at a single-center in China: A retrospective cross-sectional study.

ABSTRACT: The aging of the population has become a worldwide concern, especially in China. Polypharmacy and potentially inappropriate medications (PIMs) are prominent issues in elderly patients. Therefore, the aim of this study was to investigate the prevalence of polypharmacy and PIMs in older inpatients and further to explore the factors associated with PIM use.A retrospective, single-center, cross-sectional study was conducted. A total of 1200 inpatients aged 65 years or older admitted from January 2015 to December 2015 were included. The prevalence of polypharmacy (5-9 medications) and hyperpolypharmacy (10 or more medications) was calculated. The 2019 American Geriatric Society Beers criteria were applied to assess PIMs use. Multivariate logistic regression was used to determine the independent factors of PIM use, while zero-inflated negative binomial regression was performed to evaluate the relationship between polypharmacy and PIM use.The median age of the study population was 76 years (interquartile range = 71-81). The median number of medications was 9 (interquartile range = 7-12). 91.58% of the patients took 5 or more medications simultaneously, and 30.08% of the patients were subjected to one or more PIMs. Spironolactone, furosemide, and zopiclone were the top 3 most frequently encountered PIMs. Hyperpolypharmacy and older age were identified as independent factors associated with PIM use. The risk of PIMs rises with the number of medications prescribed.Polypharmacy and PIM use were common in our study, and the risk of PIM use correlated with an increase in the number of medications already prescribed.

Huaiqihuang (HQH) granule alleviates cyclophosphamide-induced nephrotoxicity via suppressing the MAPK/NF-κB pathway and NLRP3 inflammasome activation.

CONTEXT: Severe nephrotoxicity greatly limits the clinical use of the common effective chemotherapeutic agent cyclophosphamide (CYP). Huaiqihuang (HQH) is a Chinese herbal complex with various pharmacological activities, widely used for treating kidney disease. OBJECTIVE: This study estimates the protective effect of HQH against CYP-induced nephrotoxicity in rats. MATERIALS AND METHODS: Four groups of 10 Sprague-Dawley rats were pre-treated with once-daily oral gavage of 3 and 6 mg/kg HQH for 5 days before receiving a single dose of CYP (200 mg/kg i.p.) on the 5th day; the control group received equivalent dose of saline. Renal function indices, morphological changes, oxidative stress, apoptosis and inflammatory mediators were measured. In addition, phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were analysed. RESULTS: Both doses of HQH reduced the levels of serum creatinine (31.27%, 43.61%), urea nitrogen (22.66%, 32.27%) and urine protein (12.87%, 15.98%) in the CYP-treated rats, and improved histopathological aberrations. Additionally, HQH decreased the production of MDA (37.02%, 46.18%) and increased the activities of antioxidant enzyme CAT (59.18%, 112.25%) and SOD (67.10%, 308.34%) after CYP treatment. HQH protected against CYP-induced nephrotoxicity by modulating apoptosis-related protein and suppressing the inflammatory responses. Furthermore, the phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were significantly boosted in CYP-treated rats, which was also abrogated by HQH treatment. CONCLUSIONS: HQH effectively protected against CYP-induced nephrotoxicity, which was associated with regulating oxidative stress, apoptosis and inflammation, and so HQH may be a useful agent for treating nephrotoxicity caused by CYP.

Uplift resistance capacity of anchor piles used in marine aquaculture.

Anchor piles are widely used in marine aquaculture, and the safety is largely determined by the uplift resistance capacity,especially in harsh ocean environments. However, there are few practical guides to the design and installation of the anchor piles for mooring the body of marine aquaculture equipment. Laboratory experiments were conducted to investigate the effect of the initial tension angle, pile diameter, embedded depth, and pile configuration on the uplift resistance capacity of anchor piles under oblique loads. CCD camera and load cell were utilized to measure the corresponding displacement and load, respectively. The results show that increasing the initial tension angle of circular and square single piles can significantly improve the uplift resistance capacity. The failure load of the square single pile was slightly higher than that of the circular single pile. Increasing the pile diameter can effectively improve the failure load and delay the development speed of the pile top displacement. Increasing the embedded depth can effectively improve the failure load and increase the lateral displacement of the pile top. The uplift resistance capacity of the dual anchor piles was better than that of the single anchor piles. The layout configuration has little effect on the failure load, but has a large effect on the displacement development.

Ginsenoside Rg3 attenuates cisplatin-induced kidney injury through inhibition of apoptosis and autophagy-inhibited NLRP3.

The NOD-like receptor family pyrin domain-containing (NLRP3) inflammasomes is centrally implicated in cisplatin (CP)-induced kidney injury. Autophagy is critical for inhibiting production of NLRP3 protein that effectively reduces the inflammatory response. Ginsenoside Rg3 (SY), an active component extracted from ginseng, is reported to protect against CP-induced nephrotoxicity. However, the mechanisms underlying renoprotection by SY have not been established to date. Our results indicate that SY attenuated CP-induced apoptosis and damage in vivo and in vitro, as evidenced by increased cell viability, decreased the proportion of late apoptotic cells, elevated mitochondrial membrane potential, and ameliorated histopathological damage of the kidney. SY ameliorated CP-induced human renal tubular (HK-2) cells and kidney injury through upregulation of LC3II/I and beclin-1, inhibition of p62, NLRP3, ASC, caspase-1, and interleukin-1ß. However, blockade of autophagy by 3-methyladenine reversed the suppression of SY on NLRP3 inflammasome activation and the protection of SY on HK-2 cells. Our collective results support the utility of SY as a therapeutic agent that effectively protects against CP-induced kidney injury by activating the autophagy-mediated NLRP3 inhibition pathway.

Mutational profiling in acute lymphoblastic leukemia by RNA sequencing and chromosomal genomic array testing.

BACKGROUND: Comprehensive molecular and cytogenetic profiling of acute lymphoblastic leukemia (ALL) is important and critical to the current standard of care for patients with B-acute lymphoblastic leukemia (B-ALL). Here we propose a rapid process for detecting gene fusions whereby FusionPlex RNA next-generation sequencing (NGS) and DNA chromosome genomic array testing (CGAT) are combined for a more efficient approach in the management of patients with B-ALL. METHODS: We performed RNA NGS and CGAT on 28 B-ALL samples and, in four patients, compared fixed cell pellets to paired cryo-preserved samples as a starting material to further assess the utility of cytogenetic fixed pellets for gene expression analysis. RESULTS: Among the fixed specimens, when using alternative techniques as references, including karyotype, fluorescence in situ hybridization, CGAT, and RT-qPCR, fusions were detected by RNA NGS with 100% sensitivity and specificity. In the four paired fixed versus fresh cryopreserved samples, fusions were also 100% concordant. Four of the 28 patients showed mutations that were detected by RNA sequencing and three of four of these mutations had well-known drug resistance implications. CONCLUSIONS: We conclude that FusionPlex is a robust and reliable anchored multiplex RNA sequencing platform for use in the detection of fusions in both fresh cryopreserved and cytogenetic fixed pellets. Gene expression data could only be obtained from fresh samples and although limited variant data are available, critical hotspot variants can be determined in conjunction with the fusions.

Altered metabolic profiles and biomarkers associated with astragaloside IV-mediated protection against cisplatin-induced acute kidney injury in rats: An HPLC-TOF/MS-based untargeted metabolomics study.

Cisplatin (CDDP)-induced acute kidney injury (AKI) limits the therapeutic use of CDDP, which urgently needs to be addressed. Our previous study demonstrated that astragaloside IV (AS IV), an active compound of the traditional Chinese herb Astragalus membranaceus, alleviated CDDP-induced AKI. To explore the mechanism, we performed a metabolomics study to explore the altered metabolic pathways and screen for sensitive biomarkers. Twenty-four rats were randomly divided into three groups, which were treated with vehicle solutions (Control), intraperitoneally injected CDDP, and intraperitoneally injected CDDP plus oral AS IV, respectively. Metabolic profiles of serum, urine, and kidney samples were analyzed by high-performance liquid chromatography-time of flight mass spectrometry. There were 38 key metabolites in the urine samples, 20 in the serum samples, and 16 in the kidney samples that were significantly altered due to AS IV-mediated protection against CDDP-induced AKI relative to CDDP-only treatment. CDDP + AS IV co-treatment significantly altered two pathways in the blood (biosynthesis of unsaturated fatty acids and alanine, aspartate, and glutamate metabolism), five pathways in the urine (phenylalanine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; arginine and proline metabolism; and histidine metabolism), and five pathways in the kidneys (glutathione metabolism; alanine, aspartate, and glutamate metabolism; glyoxylate and dicarboxylate metabolism; arginine and proline metabolism; and D-glutamine and D-glutamate metabolism). The metabolic pathways were mainly associated with improvements in inflammatory responses, oxidative stress, and energy metabolism. Adrenic acid in serum and L-histidine and L-methionine in urine were identified as sensitive biomarkers. This study provides new insights to understand the mechanism of AS IV-mediated protection against CDDP-induced AKI and has identified three candidate biomarkers to evaluate preventative treatment and assess therapeutic effectiveness.

Genome-wide identification, and phylogenetic and expression profiling analyses, of XTH gene families in Brassica rapa L. and Brassica oleracea L.

BACKGROUND: Xyloglucan endotransglucosylase/hydrolase genes (XTHs) are a multigene family and play key roles in regulating cell wall extensibility in plant growth and development. Brassica rapa and Brassica oleracea contain XTHs, but detailed identification and characterization of the XTH family in these species, and analysis of their tissue expression profiles, have not previously been carried out. RESULTS: In this study, 53 and 38 XTH genes were identified in B. rapa and B. oleracea respectively, which contained some novel members not observed in previous studies. All XTHs of B. rapa, B. oleracea and Arabidopsis thaliana could be classified into three groups, Group I/II, III and the Early diverging group, based on phylogenetic relationships. Gene structures and motif patterns were similar within each group. All XTHs in this study contained two characteristic conserved domains (Glyco_hydro and XET_C). XTHs are located mainly in the cell wall but some are also located in the cytoplasm. Analyses of the mechanisms of gene family expansion revealed that whole-genome triplication (WGT) events and tandem duplication (TD) may have been the major mechanisms accounting for the expansion of the XTH gene family. Interestingly, TD genes all belonged to Group I/II, suggesting that TD was the main reason for the largest number of genes being in these groups. B. oleracea had lost more of the XTH genes, the conserved domain XET_C and the conserved active-site motif EXDXE compared with B. rapa, consistent with asymmetrical evolution between the two Brassica genomes. A majority of XTH genes exhibited different tissue-specific expression patterns based on RNA-seq data analyses. Moreover, there was differential expression of duplicated XTH genes in the two species, indicating that their functional differentiation occurred after B. rapa and B. oleracea diverged from a common ancestor. CONCLUSIONS: We carried out the first systematic analysis of XTH gene families in B. rapa and B. oleracea. The results of this investigation can be used for reference in further studies on the functions of XTH genes and the evolution of this multigene family.