Safety and effectiveness of butorphanol in epidural labor analgesia: A protocol for a systematic review and meta-analysis.

BACKGROUND: Epidural analgesia is the most effective analgesic method during labor. Butorphanol administered epidurally has been shown to be a successful analgesic method during labor. However, no comprehensive study has examined the safety and efficacy of using butorphanol as an epidural analgesic during labor. AIM: To assess butorphanol's safety and efficacy for epidural labor analgesia. METHODS: The PubMed, Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure, and Google Scholar databases will be searched from inception. Other types of literature, such as conference abstracts and references to pertinent reviews, will also be reviewed. We will include randomized controlled trials comparing butorphanol with other opioids combined with local anesthetics for epidural analgesia during labor. There will be no language restrictions. The primary outcomes will include the visual analog scale score for the first stage of labor, fetal effects, and Apgar score. Two independent reviewers will evaluate the full texts, extract data, and assess the risk of bias. Publication bias will be evaluated using Egger's or Begg's tests as well as visual analysis of a funnel plot, and heterogeneity will be evaluated using the Cochran Q test, P values, and I2 values. Meta-analysis, subgroup analysis, and sensitivity analysis will be performed using RevMan software version 5.4. This protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocols statement, and the PRISMA statement will be used for the systematic review. RESULTS: This study provides reliable information regarding the safety and efficacy of using butorphanol as an epidural analgesic during labor. CONCLUSION: To support clinical practice and development, this study provides evidence-based findings regarding the safety and efficacy of using butorphanol as an epidural analgesic during labor.

Prunolactones A-G, proangiogenic isocoumarin derivatives with an unusual 6/6/6/6/6 spiropentacyclic skeleton from the endophytic fungus Phomopsis prunorum.

Seven novel isocoumarins, prunolactones A-G (1-7), featuring an unusual 6/6/6/6/6 spiropentacyclic skeleton, together with two biosynthetic precursors phomopsilactone (8) and methyl 3-epi-shikimate (9), were isolated from the endophytic fungus Phomopsis prunorum guided by UPLC-QTOF-MS and 1H NMR spectroscopic analytical techniques. Their structures including absolute configurations of 1-7 were elucidated based on extensive spectroscopic data, X-ray diffraction analysis, and ECD calculations. Biogenetically, compounds 1-7 are proposed to be derived from polyketide and shikimate pathways via key intermolecular Diels - Alder reactions. Compounds 2, 3, and 7 showed significant in vivo proangiogenic activity in transgenic zebrafish.

Distribution fractions and potential ecological risk assessment of heavy metals in mangrove sediments of the Greater Bay Area.

The restoration of mangrove in coastal wetlands of China has been started since the 1990s. However, various pollutants, especially for heavy metals (HMs), contained in wastewater might present a significant risk to mangrove forests during the restoration. In this study, sediments of five typical mangrove wetlands with varying restoration years and management measures in the Greater Bay Area were collected to evaluate the distribution fractions and potential ecological risk of HMs. Cd (0.2-1.6 mg/kg) was found in high concentrations in the exchangeable fraction (37.8-71.5%), whereas Cu (54.2-94.8 mg/kg), Zn (157.6-332.6 mg/kg), Cr (57.7-113.6 mg/kg), Pb (36.5-89.9 mg/kg), and Ni (29.7-69.5 mg/kg) primarily presented in residual fraction (30.8-91.9%). According to the geo-accumulation index (Igeo) analysis, sediment Cd presented a high level of pollution (3 ≤ Igeo ≤ 4), while Zn and Cu were associated with moderately pollution (1 ≤ Igeo ≤ 2). Besides, high ecological risk of Cd was found in sediments of five mangroves, with risk assessment code (RAC) ranging from 45.9 to 84.2. Redundancy analysis revealed that the content of NO3--N was closely related to that of HMs in sediments and, pH value and NO3--N concentration affected the distribution of HMs geochemical fractions. High concentration of HMs in QA and NS sampling sites was caused by the formerly pollutants discharge, resulting in these sediments still with a higher HM pollution level after the plant of mangrove for a long period. Fortunately, strict drainage standards for industrial activities in Shenzhen significantly availed for decreasing HMs contents in mangrove sediments. Therefore, future works on mangrove conversion and restoration should be linked to the water purification in the GBA.

Reducing the inhibitive effect of fluorine and heavy metals on nitrate reduction by hydroxyapatite substrate in constructed wetlands.

Bio-toxic inorganic pollutants, e.g., fluorine (F) and heavy metals (HMs), in wastewaters are the potential threats to nitrate (NO3--N) reduction by microorganisms in constructed wetlands (CWs). Selection of suitable substrate with high F and HMs adsorption efficiency and capacity is a potential alternative for simultaneous removal of these pollutants in CWs. Herein, this study investigated the feasibility of applying hydroxyapatite (HA)-gravel media for F and HMs adsorption and its effect on NO3--N reduction in CWs (HA CWs) by comparing the CWs filled with gravel substrate (CK CWs). The results indicated that the removal efficiency of F, Cr, As, and NO3--N in HA CWs increased by 113.6-, 3.3-, 2.7-, and 0.6-folds, respectively, compared to CK CWs. The NO3--N reduction rate decreased by 11-46% in CK CWs after the presence of F and HMs in influent, while for HA CWs, it was only 13-22%. Excellent F and HMs adsorption capacity of HA substrate availed for wetland plants resisting F/HMs toxicity and making catalase activity lower. The HA substrate in CWs resulted in the certain succession of nitrogen-transforming bacteria, e.g., nitrifiers (Nitrospira) and denitrifiers (Thiobacillus and Desulfobacterium). More importantly, key functional genes, including nirK/nirS, korA/korB, ChrA/ChrD, arsA/arsB, catalyzing the processes of nitrogen biotransformation, energy metabolism, NO3--N and metal ions reduction were also enriched in HA CWs. This study highlights HA substrate reduce the inhibitive effect of F and HMs on NO3--N reduction, and provides new insights into how microbiota structurally and functionally respond to different substrates in CWs.

Interactive effects of aquatic nitrogen and plant biomass on nitrous oxide emission from constructed wetlands.

Understanding of mechanisms in nitrous oxide (N2O) emission from constructed wetland (CW) is particularly important for the establishment of related strategies to reduce greenhouse gas (GHG) production during its wastewater treatment. However, plant biomass accumulation, microbial communities and nitrogen transformation genes distribution and their effects on N2O emission from CW as affected by different nitrogen forms in aquatic environment have not been reported. This study investigated the interactive effects of aquatic nitrogen and plant biomass on N2O emission from subsurface CW with NH4+-N (CW-A) or NO3--N (CW-B) wastewater. The experimental results show that NH4+-N and NO3--N removal efficiencies from CW mesocosms were 49.4% and 87.6%, which indirectly lead to N2O emission fluxes of CW-A and CW-B maintained at 213 ± 67 and 462 ± 71 µg-N/(m2·h), respectively. Correlation analysis of nitrogen conversion dynamic indicated that NO2--N accumulation closely related to N2O emission from CW. Aquatic NH4+-N could up-regulate plant biomass accumulation by intensifying citric acid cycle, glycine-serine-threonine metabolism etc., resulting in more nitrogen uptake and lower N2O emission/total nitrogen (TN) removal ratio of CW-A compared to CW-B. Although the abundance of denitrifying bacteria and N2O reductase nosZ in CW-B were significantly higher than that of CW-A, after fed with mixed NH4+-N and NO3--N influent, N2O fluxes and N2O emission/TN removal ratio in CW-A were extremely close to that of CW-B, suggesting that nitrogen form rather than nitrogen transformation microbial communities and N2O reductase nosZ determines N2O emission from CW. Hence, the selection of nitrate-loving plants will play an important role in inhibiting N2O emission from CW.

Sleep Quality, Sleep Duration, and the Risk of Adverse Clinical Outcomes in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries.

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous entity with varying underlying etiologies and occurs in ~5-10% of patients with acute myocardial infarction. Sleep disorders and short sleep duration are common phenomena experienced by patients with coronary heart disease and are associated with poor clinical outcomes. However, the association between sleep quality, sleep duration, and the MINOCA prognosis is less clear. Methods: We performed a prospective observational study of 607 patients with MINOCA between February 2016 and June 2018. The mean follow-up period was 3.9 years. Sleep quality and sleep duration were measured by the Chinese version of the Pittsburgh Sleep Quality Index. The primary endpoint was all-cause mortality, and the secondary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke and heart failure hospitalization. Results: During the follow-up period, all-cause death occurred in 69 participants and 105 participants developed MACE. The Kaplan-Meier survival analysis demonstrated a significant association between poor sleep quality and all-cause mortality (log-rank P = 0.005) and MACE (log-rank P = 0.004). Multivariable Cox regression model indicated that poor sleep quality was an independent predictor of all-cause mortality as well as MACE [adjusted hazard ratio (HR) = 1.649; 95% confidence interval (CI), 1.124-2.790; P < 0.001; and adjusted HR = 1.432; 95% CI, 1.043-2.004; P = 0.003, respectively]. For sleep duration, short sleep duration (<6 h/d) was significantly associated with an increased risk of all-cause mortality and MACE (adjusted HR = 1.326; 95% CI, 1.103-1.812; P = 0.004; and adjusted HR = 1.443; 95% CI, 1.145-1.877; P < 0.001, respectively), whereas long sleep duration was not (>8 h/d). A poorer sleep profile (including poor sleep quality and short sleep duration) was associated with a 149.4% increased risk of death (HR = 2.494; 95% CI, 1.754-4.562; P < 0.001) and a 96.7% increased risk of MACE (HR = 1.967; 95% CI, 1.442-3.639; P < 0.001) than those with neither. Conclusion: Sleep disorders were common among Chinese patients with MINOCA. Poor sleep quality and short sleep duration were independently associated with an increased risk of all-cause mortality and MACE in the MINOCA population. Meanwhile, a poor sleep profile has an additive effect with regard to cardiovascular risks; in these populations, efforts should be made to improve both sleep quality and sleep duration for secondary cardiovascular prevention. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000040701.

MiR-20b-5p modulates inflammation, apoptosis and angiogenesis in severe acute pancreatitis through autophagy by targeting AKT3.

BACKGROUND: Severe acute pancreatitis (SAP) is a common acute abdominal disease with high morbidity and mortality. However, the mechanism underlying SAP is still unclear. METHODS: Cerulean and LPS (Cer-LPS) was used to establish a rat model and an in vitro model of SAP. qRT-PCR, western blot and IHC were determined to analyse the expression of mRNA and proteins. IL-1ß, TNF-α and IL-6 levels were measured applying ELISA. H&E staining was determined to observe the pathological changes. Apoptosis was tested by AV-PI staining using flow cytometry. CCK8 assay was taken to detect cell viability. Cell migration was assessed by transwell assay. Tube formation assay was conducted to evaluate angiogenesis. Luciferase assay was used to detect relationship of miR-20b-5p and AKT3. RESULTS: MiR-20b-5p was lowly expressed in SAP models both in vivo and in vitro. Overexpression of miR-20b-5p restrained inflammation and apoptosis in Cer-LPS treated pancreatic acinar cells. Furthermore, miR-20b-5p promoted the angiogenesis of vascular endothelial cells, since the viability, migration and the capability of tube formation were increased by miR-20b-5p. Mechanically, miR-20b-5p directly targeted AKT3 to promote autophagy. Furthermore, miR-20b-5p could prevent the inflammation, apoptosis and enhance angiogenesis via enhancing autophagy, which was verified in vivo. CONCLUSION: This study demonstrated miR-20b-5p attenuates SAP through directly targeting AKT3 to regulate autophagy, subsequently inhibit inflammation and apoptosis, and promote angiogenesis. Our findings suggested a novel target of miR-20b-5p for the therapy of SAP.

Genome-Wide Association Study for Grain Micronutrient Concentrations in Wheat Advanced Lines Derived From Wild Emmer.

Wheat is one of the important staple crops as the resources of both food and micronutrient for most people of the world. However, the levels of micronutrients (especially Fe and Zn) in common wheat are inherently low. Biofortification is an effective way to increase the micronutrient concentration of wheat. Wild emmer wheat (Triticum turgidum ssp. dicoccoides, AABB, 2n = 4x = 28) is an important germplasm resource for wheat micronutrients improvement. In the present study, a genome-wide association study (GWAS) was performed to characterize grain iron, zinc, and manganese concentration (GFeC, GZnC, and GMnC) in 161 advanced lines derived from wild emmer. Using both the general linear model and mixed linear model, we identified 14 high-confidence significant marker-trait associations (MTAs) that were associated with GFeC, GZnC, and GMnC of which nine MTAs were novel. Six MTAs distributed on chromosomes 3B, 4A, 4B, 5A, and 7B were significantly associated with GFeC. Three MTAs on 1A and 2A were significantly associated with GZnC and five MTAs on 1B were significantly associated with GMnC. These MTAs show no negative effects on thousand kernel weight (TKW), implying the potential value for simultaneous improvement of micronutrient concentrations and TKW in breeding. Meanwhile, the GFeC, GZnC and GMnC are positively correlated, suggesting that these traits could be simultaneously improved. Genotypes containing high-confidence MTAs and 61 top genotypes with a higher concentration of grain micronutrients were recommended for wheat biofortification breeding. A total of 38 candidate genes related to micronutrient concentrations were identified. These candidates can be classified into four main groups: enzymes, transporter proteins, MYB transcription factor, and plant defense responses proteins. The MTAs and associated candidate genes provide essential information for wheat biofortification breeding through marker-assisted selection (MAS).

Integration of CW-MFC and anaerobic granular sludge to explore the intensified ammonification-nitrification-denitrification processes for nitrogen removal.

The integration of constructed wetland-microbial fuel cell (CW-MFC) and anaerobic granular sludge (AGS) is an important way to promote its ammonification efficiency and decrease the land use scale. This study explored the integration of CW-MFC and AGS for nitrogen removal via the intensified ammonification-nitrification-denitrification processes with initial NH3-N, NO3-N, Org-N and total nitrogen (TN) concentrations of 10.5, 13.8, 21.4, and 45.7 mg L-1 in wastewater. Two reactors with AGS inoculated with a separated area (R1) and directly inoculated into gravel substrate (R2) were designed, respectively. Results showed that chemical oxygen demand (COD) removal efficiency could reach 85% in R1 and 81% in R2, and the conversion of Org-N to NH3-N and NO3-N to gaseous nitrogen were 80% and 90%, respectively. Although the conversion efficiency of NH3-N to NO2-N/NO3-N via nitrification process was only 18%, it could reach 45%, 94%, and 98% with the aeration rates of 50-, 100-, and 200-mL min-1. According to microstructural property and microbial community analyses, the separation gravel substrate and AGS areas in R1 availed for stable particle size of AGS, archaeal diversity, and metabolic activity even with a 1.5 times daily wastewater treatment capacity than that of R2. Overall, although the intensified ammonification-nitrification-denitrification processes for nitrogen removal could be achieved with supplementary aeration, further investigation is still needed to explore other substrate materials and high CW-MFC/AGS volume ratio for intensified nitrification process in CW-MFC associated with AGS.

Comparative analysis of developing grain transcriptome reveals candidate genes and pathways improving GPC in wheat lines derived from wild emmer.

The grain protein content (GPC) in modern wheat is inherently low. Wild emmer wheat (Triticum turgidum ssp. dicoccoides, 2n = 4x = 28, AABB) gene pool harbors wide genotypic variations in GPC. However, the characterization of candidate genes associated with high GPC is a challenge due to the complex characteristic of this trait. In the current study, we performed RNA-seq analysis on developing grains of wild emmer genotype D1, common wheat CN16, and their hexaploid wide hybrid BAd107-4 with contrasting GPC. We have found a total of 39,795 expressed genes on chromosomes A and B, of which 24,152 were shared between D1, CN16, and BAd107-4. From 1744 differentially expressed genes (DEGs), 1203 were downregulated and 541 were upregulated in the high GPC (D1+BAd107-4) compared with low GPC (CN16) groups. The majority of DEGs were associated with protein processing in endoplasmic reticulum, starch and sucrose metabolism, galactose metabolism, and protein export pathways. Expression levels of nine randomly selected genes were verified by qRT-PCR, which was consistent with the transcriptome data. The present database will help us to understand the potential regulation networks underlying wheat grain protein accumulation and provide the foundation for simultaneous improvement of grain protein content and yield in wheat breeding programs.

Relationship between fluoroquinolones and the risk of aortic diseases: a meta-analysis of observational studies.

BACKGROUND: Our aim was to determine the relationship between the use of fluoroquinolones and the risk of aortic diseases. METHODS: PubMed, EMBASE and the Web of Science were searched from inception to July 6, 2019, to identify observational studies that evaluated the risk of aortic diseases associated in users of fluoroquinolones compared with nonusers or users of other antibiotics. The primary outcome was the first occurrence of aortic diseases. We used the GRADE approach to rate the strength of evidence. We used the inverse variance method random-effect model to estimate the odds ratios (ORs) with 95% CIs, and statistical heterogeneity was assessed by the I2 statistic. RESULTS: This meta-analysis enrolled 2,829,385 patients reported the relationship between fluoroquinolones and the risk of aortic diseases. Compared with nonusers or users of other antibiotics, users of fluoroquinolone had a significantly increased risk of aortic diseases (adjusted OR, 2.10; 95% CI, 1.65-2.68; P = .000, I2 = 16.4%). The quality of evidence was moderate, and the number needed to harm (NNH) for aortic diseases among patients was estimated to be 1301. CONCLUSIONS: The fluoroquinolone use in patients significantly increases the risk of new-onset aortic diseases. Clinicians need to pay attention to these severe adverse events when considering fluoroquinolone use.

Prognostic value of preoperative carcinoembryonic antigen/tumor size in rectal cancer.

BACKGROUND: Carcinoembryonic antigen (CEA) is a commonly used biomarker in colorectal cancer. However, controversy exists regarding the insufficient prognostic value of preoperative serum CEA alone in rectal cancer. Here, we combined preoperative serum CEA and the maximum tumor diameter to correct the CEA level, which may better reflect the malignancy of rectal cancer. AIM: To assess the prognostic impact of preoperative CEA/tumor size in rectal cancer. METHODS: We retrospectively reviewed 696 stage I to III rectal cancer patients who underwent curative tumor resection from 2007 to 2012. These patients were randomly divided into two cohorts for cross-validation: training cohort and validation cohort. The training cohort was used to generate an optimal cutoff point and the validation cohort was used to further validate the model. Maximally selected rank statistics were used to identify the optimum cutoff for CEA/tumor size. The Kaplan-Meier method and log-rank test were used to plot the survival curve and to compare the survival data. Univariate and multivariate Cox regression analyses were used to determine the prognostic value of CEA/tumor size. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively. RESULTS: In all, 556 patients who satisfied both the inclusion and exclusion criteria were included and randomly divided into the training cohort (2/3 of 556, n = 371) and the validation cohort (1/3 of 556, n = 185). The cutoff was 2.429 ng/mL per cm. Comparison of the baseline data showed that high CEA/tumor size was correlated with older age, high TNM stage, the presence of perineural invasion, high CEA, and high carbohydrate antigen 19-9 (CA 19-9). Kaplan-Meier curves showed a manifest reduction in 5-year OS (training cohort: 56.7% vs 81.1%, P < 0.001; validation cohort: 58.8% vs 85.6%, P < 0.001) and DFS (training cohort: 52.5% vs 71.9%, P = 0.02; validation cohort: 50.3% vs 79.3%, P = 0.002) in the high CEA/tumor size group compared with the low CEA/tumor size group. Univariate and multivariate analyses identified CEA/tumor size as an independent prognostic factor for OS (training cohort: hazard ratio (HR) = 2.18, 95% confidence interval (CI): 1.28-3.73, P = 0.004; validation cohort: HR = 4.83, 95%CI: 2.21-10.52, P < 0.001) as well as DFS (training cohort: HR = 1.47, 95%CI: 0.93-2.33, P = 0.096; validation cohort: HR = 2.61, 95%CI: 1.38-4.95, P = 0.003). CONCLUSION: Preoperative CEA/tumor size is an independent prognostic factor for patients with stage I-III rectal cancer. Higher CEA/tumor size is associated with worse OS and DFS.

Long non-coding RNA NEAT1 modulates hypoxia/reoxygenation-induced cardiomyocyte injury via targeting microRNA-520a.

In the present study, a hypoxia/reoxygenation (H/R) model of cardiomyocytes was established to investigate the effects of long non-coding RNA (LncRNA) Nuclear Enriched Abundant Transcript 1 (NEAT1) and microRNA (miR)-520a on H/R-induced cardiomyocyte apoptosis. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were used to evaluate cell apoptosis. Luciferase activity assay was used to investigate whether miR-520a targets NEAT1. Results revealed that NEAT1 was significantly upregulated and miR-520a was downregulated in the ischemia/reperfusion myocardium and the cardiomyocytes that received H/R treatment. Further study demonstrated that knockdown of NEAT1 and overexpression of miR-520a serves a protective role against H/R-induced cardiomyocyte apoptosis. miR-520a directly targets NEAT1 and its expression level is negatively correlated with that of NEAT1. The findings suggested that NEAT1 and miR-520a may protect cardiomyocytes from apoptosis through regulating apoptotic proteins B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein, and altering cleaved caspase3 expression levels.

Brucine Suppresses Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cell Line MDA-MB-231.

Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.

MicroRNA-98 attenuates cardiac ischemia-reperfusion injury through inhibiting DAPK1 expression.

Cardiovascular ischemic disease is a large class of diseases that are harmful to human health. The significant role of microRNAs (miRNAs) in terms of controlling cardiac injury has been reported in latest studies. MiR-98 is very important in regulating the apoptosis, the differentiation, the growth as well as the metastasis of cells. Nevertheless, the effect of miR-98 in the cardiac ischemia reperfusion (I/R) injury has rarely been investigated. In the current research, we found that the miR-98 expression was down-regulated in the cardiomyocytes subjected to hypoxia/reoxygenation (H/R) and in the myocardium of the I/R rats. In addition, over-expression of miR-98 could significantly reduce the myocardial oxidative stress and ischemic injury as well as cell apoptosis. In agreement, similar findings were demonstrated in H9c2 cells subjected to H/R injury. Bioinformatic analysis using MiRanda and TargetScan and luciferase activity assay confirmed death-associated protein kinase 1 (DAPK1) as a direct target of miR-98. These findings suggest that miR-98 may be exploited as a novel molecular marker or therapeutic target for myocardial I/R injury. © 2018 IUBMB Life, 71(1):166-176, 2019.

miR-190 protects cardiomyocytes from apoptosis induced by H2O2 through targeting MAPK8 and regulating MAPK8/ERK signal pathway.

MicroRNAs (miRs) have been demonstrated to regulate physiological and pathological processes. Numerous miRsprotect against cardiomyocyte injury induced by oxidative stress. However, the function of miR-190 still remains unclear. Here, we determined the expression level of miR-190 in H9c2 cells under H2O2 treatment and found that miR-190 expression was significantly inhibited by H2O2. Further study indicated that miR-190 significantly reduced cell apoptosisand the LDH and MDA levels of H9c2 cells induced by H2O2. Luciferase activity assay, quantitative real-time-PCR, and Western blot demonstrated that miR-190 directly targets MAPK8. Rescue experiment confirmed this hypothesis. Further study has revealed that miR-190 protects H9c2 cells from oxidative stress injury through inhibiting the MAPK8/ERK signal pathway. In conclusion, these data suggest that miR-190 protects against oxidative stress injury of H9c2 cells induced by H2O2 through inhibiting MAPK8 expression and the MAPK8/ERK pathway. Our findings provide a potential therapeutic target to promote functional recovery after cardiac ischemia/reperfusion.

Clinical efficacy, onset time and safety of bright light therapy in acute bipolar depression as an adjunctive therapy: A randomized controlled trial.

BACKGROUND: Bright light therapy (BLT) is an effective treatment for seasonal affective disorder and non- seasonal depression. The efficacy of BLT in treating patients with bipolar disorder is still unknown. AIMS: The aim of this study is to examine the efficacy, onset time and clinical safety of BLT in treating patients with acute bipolar depression as an adjunctive therapy (trial registration at ClinicalTrials.gov: NCT02009371). METHODS: This was a multi-center, single blind, randomized clinical trial. Seventy-four participants were randomized in one of two treatment conditions: BLT and control (dim red light therapy, dRLT). Sixty-three participants completed the study (33 BLT, 30 dRLT). Light therapy lasted for two weeks, one hour every morning. All participants were required to complete several scales assessments at baseline, and at the end of weeks 1 and 2. The primary outcome measures were the clinical efficacy of BLT which was assessed by the reduction rate of HAMD-17 scores, and the onset time of BLT which was assessed by the reduction rate of QIDS-SR16 scores. The secondary outcome measures were rates of switch into hypomania or mania and adverse events. RESULTS: 1) Clinical efficacy: BLT showed a greater ameliorative effect on bipolar depression than the control, with response rates of 78.19% vs. 43.33% respectively (p < 0.01). 2) Onset day: Median onset day was 4.33 days in BLT group. 3) BLT-emergent hypomania: No participants experienced symptoms of hypomania. 4) Side effects: No serious adverse events were reported. CONCLUSION: BLT can be considered as an effective and safe adjunctive treatment for patients with acute bipolar depression.

MicroRNAs Involved in Asthma After Mesenchymal Stem Cells Treatment.

Administration of human bone marrow-derived mesenchymal stem cells (BM-MSCs) significantly alleviates allergic airway inflammation. There are no studies that refer to the role of microRNAs (miRNAs) after the BM-MSCs treatment in airway allergic inflammation. We induced a mouse model of asthma and performed the transplantation of BM-MSCs. We analyzed aberrant miRNAs and key immune regulators using both miRNA and messenger RNA (mRNA) polymerase chain reaction (PCR) arrays. We identified that 296 miRNAs were differently expressed after the induction of asthma and/or the treatment of BM-MSCs, in which 14 miRNAs presented the reverse variation tendency between asthma induction and BM-MSCs transplantation. Mmu-miR-21a-3p, mmu-miR-449c-5p, and mmu-miR-496a-3p were further confirmed to be differently expressed with additional samples and quantitative real-time PCR. With an mRNA PCR array, we identified 19 genes to be involved in the allergy induction and the administration of BM-MSCs. Further target genes analysis revealed that mmu-miR-21a-3p was significantly correlated with the immune regulator activin A receptor, Type IIA (Acvr2a). Mmu-miR-21a-3p had opposite expression with Acvr2a after asthma and BM-MSCs treatment. Acvr2a had binding sites for miR-21a for both mice and human, suggesting that miR-21/Acvr2a axis is conserved between human and mice. Dual-luciferase reporter assay showed that mmu-miR-21a-3p negatively regulated the transcript of Acvr2a. In addition, has-miR-21a inhibitor significantly increased the expression of Acvr2a mRNA in BEAS-2B cells under lipopolysaccharide stimulation. Our results suggest that there were different miRNA and mRNA profiles after asthma induction and BM-MSCs treatment, and the miR-21/Acvr2a axis is an important mechanism for the induction of asthmatic inflammation.

Connexin 43 Upregulation in Mouse Lungs during Ovalbumin-Induced Asthma.

BACKGROUND: Connexin (Cx)-based gap junction channels play important roles in the inflammatory response. Cx43 is involved in the pathogenesis of some lung diseases such as acute lung injury. However, the Cx43 expression in asthma is unclear. In the present study, we used a murine model of ovalbumin (OVA)-induced allergic airway disease to examine the levels of Cx43 and analyze the relationship between Cx43 and airway inflammation in allergic airway disease. METHODS: Asthma was induced in mice via sensitization and challenge with OVA. Cx43 mRNA and protein expression levels were investigated via QT-PCR, western blot, and immunohistochemistry 0 h, 8 h, 1 d, 2 d and 4 d after the first challenge. The relationship between Cx43 protein levels and inflammatory cell infiltration, cytokine levels was analyzed. RESULTS: The OVA-induced mice exhibited typical pathological features of asthma, including airway hyper-responsiveness; strong inflammatory cell infiltration surrounding the bronchia and vessels; many inflammatory cells in the bronchoalveolar lavage fluid (BALF); higher IL-4, IL-5 and IL-13 levels; and high OVA specific IgE levels. Low Cx43 expression was detected in the lungs of control (PBS) mice. A dramatic increase in the Cx43 mRNA and protein levels was found in the asthmatic mice. Cx43 mRNA and protein expression levels increased in a time-dependent manner in asthma mice, and Cx43 was mostly localized in the alveolar and bronchial epithelial layers. Moreover, lung Cx43 protein levels showed a significant positive correlation with inflammatory cell infiltration in the airway and IL-4 and IL-5 levels in the BALF at different time points after challenge. Interestingly, the increase in Cx43 mRNA and protein levels occurred prior to the appearance of the inflammatory cell infiltration. CONCLUSION: Our data suggest that there is a strong upregulation of Cx43 mRNA and protein levels in the lungs in asthma. Cx43 levels also exhibited a positive correlation with allergic airway inflammation. Cx43 may represent a target to treat allergic airway diseases in the future.

AVP modulation of the vestibular nucleus via V1b receptors potentially contributes to the development of motion sickness in rat.

BACKGROUND: Arginine vasopressin (AVP) is considered to be an etiologic hormone in motion sickness (MS). The present study was designed to investigate whether individual differences in AVP expression in the paraventricular nucleus (PVN) and in modulation on the vestibular nucleus (VN) are involved in MS. Systemic application or microinjection of AVP into rat VN and rotatory stimulus were used to induce conditioned taste aversion (CTA) to 0.15 % saccharin sodium solution as a model of MS. RESULTS: Intra-VN use of SSR149415, an antagonist of V1b receptors (V1bRs), blunted CTA. AVP inhibited Ca(2+) influxes through L-type Ca(2+) channels and NMDA receptor channels in cultured VN neurones, but antagonised by SSR149415. More AVP and V1bRs were expressed respectively in the PVN and VN after rotatory stimulus, especially in rats susceptible to MS. In the VN, AVP content was low, the AVP mRNA was less expressed, a few AVP-positive fibres were sparsely distributed, and fewer AVP/synaptophysin-positive terminals were identified. Almost no fluoro-ruby-labelled AVP-positive neurones in the PVN were found with retrograde tracing from the VN. SNP analysis of the reported 9 sites of the AVP gene showed significant difference between the groups susceptible and insusceptible to MS at the site rs105235842 in the allele frequencies and genotypes. However, there was not any difference between these two groups in the SNP of the reported 38 sites of V1bR gene. CONCLUSIONS: AVP, through its modulatory, possibly humoral action on the VN neurones via the mediation of V1bR, may contribute to the development of motion sickness in rats; AVP gene polymorphisms may contribute to the individual difference in the responsive expression of AVP in the PVN; and higher expressions of AVP in the PVN and V1bRs in the VN may contribute to the development of motion sickness in rats after vestibular stimulation.