Neferine mitigates angiotensin II-induced atrial fibrillation and fibrosis via upregulation of Nrf2/HO-1 and inhibition of TGF-ß/p-Smad2/3 pathways.

BACKGROUND: Atrial fibrillation (AF) is often associated with atrial fibrosis and oxidative stress. Neferine, a bisbenzylisoquinoline alkaloid, has been reported to exert an antiarrhythmic effect. However, its impact on Angiotensin II (Ang II) infusion-induced AF and the underlying mechanism remains unclear. This study aimed to investigate whether neferine alleviates Ang II-induced AF and explore the underlying mechanisms. METHODS: Mice subjected to Ang II infusion to induce AF were concurrently treated with neferine or saline. AF incidence, myocardial cell size, fibrosis, and oxidative stress were then examined. RESULTS: Neferine treatment inhibited Ang II-induced AF, atrial size augmentation, and atrial fibrosis. Additionally, we observed that Ang II increased reactive oxygen species (ROS) generation, induced mitochondrial membrane potential depolarization, and reduced glutathione (GSH) and superoxide dismutase (SOD) levels, which were reversed to some extent by neferine. Mechanistically, neferine activated the Nrf2/HO-1 signaling pathway and inhibited TGF-ß/p-Smad2/3 in Ang II-infused atria. Zinc Protoporphyrin (ZnPP), an HO-1 inhibitor, reduced the anti-oxidative effect of neferine to some extent and subsequently abolished the beneficial effect of neferine on Ang II-induced AF. CONCLUSIONS: These findings provide hitherto undocumented evidence that the protective role of neferine in Ang II-induced AF is dependent on HO-1.

Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor ß type II receptor.

BACKGROUND: The transforming growth factor ß (TGFß) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFß type II receptor (TGFßR2), followed by the recruitment of TGFßR1 finally triggering downstream signaling pathway. AIM: To find drugs targeting TGFßR2 that inhibit TGFßR1/TGFßR2 complex formation, theoretically inhibit TGFß signaling pathway, and thereby ameliorate liver fibrosis. METHODS: Food and Drug Administration-approved drugs were screened for binding affinity with TGFßR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect. RESULTS: We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFß induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFßR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFßR2 disrupted the binding of TGFßR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson's trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver. CONCLUSION: DHE alleviates liver fibrosis by binding to TGFßR2 thereby suppressing TGFß signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

Population genomics reveals that natural variation in PRDM16 contributes to cold tolerance in domestic cattle.

Environmental temperature serves as a major driver of adaptive changes in wild organisms. To discover the mechanisms underpinning cold tolerance in domestic animals, we sequenced the genomes of 28 cattle from warm and cold areas across China. By characterizing the population structure and demographic history, we identified two genetic clusters, i.e., northern and southern groups, as well as a common historic population peak at 30 kilo years ago. Genomic scan of cold-tolerant breeds determined potential candidate genes in the thermogenesis-related pathways that were under selection. Specifically, functional analysis identified a substitution of PRDM16 (p.P779L) in northern cattle, which maintains brown adipocyte formation by boosting thermogenesis-related gene expression, indicating a vital role of this gene in cold tolerance. These findings provide a basis for genetic variation in domestic cattle shaped by environmental temperature and highlight the role of reverse mutation in livestock species.

Ultrathin sulfate-intercalated NiFe-layered double hydroxide nanosheets for efficient electrocatalytic oxygen evolution.

As an important two-dimensional material, layered double hydroxides (LDHs) show considerable potential in electrocatalytic reactions. However, the great thickness of the bulk LDH materials significantly limits their catalytic activity. In this work, we report ultrathin NiFe-LDH nanosheets with sulfate interlayer anions (Ni6Fe2(SO4)(OH)16·7H2O) (U-LDH(SO4 2-)), which can be synthesized in gram-scale by a simple solvothermal method. The U-LDH(SO4 2-) shows excellent stability and great electrocatalytic performance in OER with a current density of 10 mA cm-2 at a low overpotential of 212 mV and a small Tafel slope of 65.2 mV dec-1, exhibiting its great potential for a highly efficient OER electrocatalyst.

A randomized controlled trial of a guided self-disclosure intervention to facilitate benefit finding in Chinese breast cancer patients: Study protocol.

AIM: To describe a protocol that examines the feasibility and effectiveness of a face-to-face guided self-disclosure intervention for facilitating benefit finding and other related psychological outcomes for breast cancer patients. BACKGROUND: Benefit finding can promote a positive attitude among patients facing disease. However, limited studies have focused on improving benefit finding among breast cancer patients. Previous research has been based on group interventions, which may not suit all patients. Self-disclosure was recognized as a strong predictor of benefit finding. This protocol is based on a brief face-to-face disclosure intervention to improve benefit finding for breast cancer patients. DESIGN: A non-blinded randomized controlled trial. METHODS: A total of 154 patients with breast cancer who have undergone radical mastectomy will be randomly assigned to either the experimental group, which will participate in a six-session face-to-face individual intervention, or the control group at a ratio of 1:1. Baseline assessments will take place after the breast cancer diagnosis, with follow-up assessments at 3, 6 and 9 months after baseline. The primary outcome is benefit finding; other outcomes are self-disclosure, cognitive reappraisal, social support, optimism and medical coping modes. DISCUSSION: This study is to design a protocol for guided self-disclosure interventions to promote benefit finding in Chinese breast cancer patients. If this intervention is feasible and effective, it could be implemented in clinical practice. IMPACT: This study will provide useful advice for health professionals to guide breast cancer patients in benefit finding during stressful events. If it is effective, it will be implemented broadly in clinical practice.

On-line Identification of chiral ofloxacin in milk with an extraction/ionization device coupled to Electrospray Mass Spectrometry.

The direct separation and analysis of chiral drugs in the complex matrix systems are meaningful and challenging. As the most common broad-spectrum antibiotic, levofloxacin has a strong antibacterial ability, but its enantiomer, dextrofloxacin can cause serious harm to human health. In this work, we reported a rapid on-line extraction/ionization device coupled with Electrospray Mass Spectrometry (ESI-MS) for chiral analysis of ofloxacin enantiomers in complex matrix of milk. Since ofloxacin is difficult to dissolve in water and most organic solvents, the procedure of separating ofloxacin in complex system is often complicated. Using the homemade apparatus, the sample pretreatment process was greatly simplified. Milk sample was directly injected and chiral ofloxacin in the sample was extracted at PTFE membrane for further ionization. It took less than 10s to finish all the procedures including sampling, extraction, reagents mixing, ionization and mass analysis. Utilizing reaction thermodynamics method, trimeric cluster ion [NiΙΙ(ref)2Ofloxacin-H]+ was formed and collisionally dissociated to get chiral resolution of levofloxacin and dextrofloxacin due to the different relative stabilities of the two diastereomeric clusters produced through the dissociation of NiΙΙ bound trimeric clusters. With the proposed method, qualitative and quantitative chiral analysis of ofloxacin in milk was successfully achieved in a simple and fast way.

The flavonoid TL-2-8 induces cell death and immature mitophagy in breast cancer cells via abrogating the function of the AHA1/Hsp90 complex.

The flavonoid quercetin exhibits significant anticancer activities with few side effects. In the current study, we characterized TL-2-8, a quercetin derivative, as a novel anticancer agent in vitro and in vivo. Cell proliferation and viability were assessed using Cell Counting Kit-8 and CellTiter-Blue assay, respectively. Cell death was examined using PI staining or a TUNEL assay. Mitophagy was determined by measuring autophagic flux and by confocal imaging. Protein expression was examined by Western blotting. We found that TL-2-8 selectively inhibited the proliferation and decreased the viability of various cancer cells (the anti-proliferation IC50 values in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells at 72 h were 8.28, 8.56, and 9.58 µmol/L, respectively), and it displayed only slight cytotoxicity against normal MCF-10A and HEK-293 cells. In MDA-MB-231 and MDA-MB-468 breast cancer cells, TL-2-8 treatment induced the degradation of multiple Hsp90 client proteins without inducing Hsp70. TL-2-8 (3, 6, 12 µmol/L) dose-dependently inhibited the expression of AHA1, an activator of Hsp90 ATPase, and decreased Hsp90-AHA1 complex formation, leading to decreased Hsp90 chaperone function and reduced polo-like kinase 1 (PLK1) signaling. Consequently, impaired mitophagy was induced via the downregulation of lysosomal-associated membrane protein 2 (LAMP2). The in vivo anticancer effects of TL-2-8 were evaluated in an MDA-MB-231 breast cancer xenograft model, which was treated with TL-2-8 (25, 50, 100 mg·kg-1·d-1, po). Administration of TL-2-8 resulted in tumor growth inhibition rates of 37.9%, 58.9% and 70.9%, respectively, whereas quercetin treatment (100 mg·kg-1·d-1, po) produced only a lower tumor growth inhibition rate (49.5%). Furthermore, TL-2-8 treatment significantly extended the lifespan of mice bearing MDA-MB-231 breast cancer cell xenografts. Our results demonstrate that TL-2-8 induces significant cell death and immature mitophagy in breast cancer cells in vitro and in vivo via AHA1 abrogation.

Effect of Nanoemitters on Suppressing the Formation of Metal Adduct Ions in Electrospray Ionization Mass Spectrometry.

In the work, we showed that the use of nanoemitters (tip dimension <1 µm, typically ∼100 nm) could dramatically reduce the nonspecific metal adduction to peptide or protein ions as well as improve the matrix tolerance of electrospray ionization mass spectrometry (ESI-MS). The proton-enriched smaller initial droplets are supposed to have played a significant role in suppressing the formation of metal adduct ions in nanoemitters. The proton-enrichment effect in the nanoemitters is related to both the exclusion-enrichment effect (EEE) and the ion concentration polarization effect (ICP effect), which permit the molecular ions to be regulated to protonated ones. Smaller initial charged droplets generated from nanoemitters need less fission steps to release the gas-phase ions; thus, the enrichment effect of salt was not as significant as that of microemitters (tip dimension >1 µm), resulting in the disappearing of salt cluster peaks in high mass-to-charge (m/z) region. The use of nanoemitters demonstrates a novel method for tuning the distribution of the metal-adducted ions to be in a controlled manner. This method is also characterized by ease of use and high efficiency in eliminating the formation of adduct ions, and no pretreatment such as desalting is needed even in the presence of salt at millimole concentration.

Synchronized Polarization Induced Electrospray: Comprehensively Profiling Biomolecules in Single Cells by Combining both Positive-Ion and Negative-Ion Mass Spectra.

In this work, a synchronized polarization induced electrospray ionization (SPI-ESI) method is developed and applied for the analysis of single-cell samples. In SPI-ESI, periodic alternating current square wave voltage (AC-SWV) is applied to induce the bipolar spray and both positive-ion and negative-ion mass spectra are obtained through one measurement by synchronizing the mode of mass analyzer with the bipolar spray process. Compared with conventional nanoelectrospray ionization (nESI, flow rate < 1000 nL/min), ultralow spray flow rate (pico-electrospray ionization, pESI, flow rate < 1000 pL/min) is achieved in SPI-ESI without loss of its sensitivity. The decrease of flow rate prolongs the MS signal duration from single-cell samples to acquire ms(2) data for components determination. To our knowledge, this is the first time to successfully achieve comprehensive analysis of single-cell samples by combining both positive-ion and negative-ion mass spectra. Ultimately, 86 components are profiled from single Allium cepa cells and 94 components are profiled from single PC-12 cells.

Mediating effect of anxiety and depression on the relationship between Attention-deficit/hyperactivity disorder symptoms and smoking/drinking.

Attention-deficit/hyperactivity disorder (ADHD) has been often found to be comorbid with other disorders, including anxiety, depression, and unhealthy behaviors such as drinking alcohol and smoking. These factors were often discussed separately, and the mediating effects of mental health on substance use are unknown. To study the mediating effects of anxiety and depression on the relationship between ADHD and drinking/smoking behaviors, we conducted a cross-sectional study of 1870 college students from Shanghai, China. The Adult ADHD Self-Report Scale (ASRS-v1.1) and Wender Utah Rating Scale (WURS) were used to identify the current and past ADHD. Structural Equation Modeling was carried out to clarify the mediating effect of anxiety and depression on the relationship between core ADHD symptoms and smoking/drinking behaviors. We found that inattention as one of the core symptoms of ADHD was associated with an increased risk of depression as a direct effect, as well as slightly increased risk of smoking/drinking behaviors by an indirect effect of depression. Hyperactivity-impulsivity, as another core symptom of ADHD had a robust impact on smoking and drinking behaviors, while being mediated by anxiety and depression. In conclusion, anxiety and depression was associated with further increased risk behaviors of smoking/drinking alcohol among those students with ADHD.

DNA methylation and histone acetylation regulate the expression of MGMT and chemosensitivity to temozolomide in malignant melanoma cell lines.

Malignant melanoma is an aggressive, highly lethal dermatological malignancy. Chemoresistance and rapid metastasis limit the curative effect of multimodal therapies like surgery or chemotherapy. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes adducts from the O6-position of guanine to repair DNA damage. High MGMT expression is associated with resistance to therapy in melanoma. However, it is unknown if MGMT is regulated by DNA methylation or histone acetylation in melanoma. We examined the effects of the DNA methylation inhibitor 5-Aza-2'-deoxycytidine and histone deacetylase inhibitor Trichostatin A alone or in combination on MGMT expression and promoter methylation and histone acetylation in A375, MV3, and M14 melanoma cells. This study demonstrates that MGMT expression, CpG island methylation, and histone acetylation vary between melanoma cell lines. Combined treatment with 5-Aza-2'-deoxycytidine and Trichostatin A led to reexpression of MGMT, indicating that DNA methylation and histone deacetylation are associated with silencing of MGMT in melanoma. This study provides information on the role of epigenetic modifications in malignant melanoma that may enable the development of new strategies for treating malignant melanoma.

Meta-analysis of ceftriaxone compared with penicillin for the treatment of syphilis.

Penicillin is the gold standard for treating syphilis. However, allergic reactions, poor drug tolerance and limited efficacy in patients remain a challenging problem. The objective of this meta-analysis was to compare the efficacy of ceftriaxone and penicillin based on data obtained from published randomised controlled trials (RCTs). The Cochrane Library, Medline, EBSCO, EMBASE and Ovid databases were searched for RCTs of ceftriaxone vs. penicillin for the treatment of syphilis. Estimated risk ratios (RRs) and 95% confidence intervals (CIs) were used to investigate the following outcome measures: 3-month response rate; 6-month response rate; 12-month response rate; relapse rate; serofast rate; and failure rate. Seven RCTs involving 281 participants (159 patients who received ceftriaxone and 122 patients who received penicillin) were included in the meta-analysis. There were no significant differences in 3-month response rate (RR=1.12, 95% CI 0.89-1.42), 6-month response rate (RR=1.02, 95% CI 0.75-1.38), 12-month response rate (RR=1.04, 95% CI 0.82-1.32), relapse rate (RR=0.91, 95% CI 0.45-1.84), serofast rate (RR=0.69, 95% CI 0.22-2.12) or failure rate (RR=0.66, 95% CI 0.03-15.76) in patients treated with ceftriaxone compared with those treated with penicillin. In conclusion, there is no evidence in the literature that ceftriaxone is less efficient than penicillin.

Recreational screen-time among Chinese adolescents: a cross-sectional study.

BACKGROUND: Rapid urbanization in China has led to a proliferation of electronic entertainment media among youth. Prolonged screen time (ST; includes watching television and playing on computers, video game consoles, or mobile phones) is linked to poor health profiles. The aim of this study was to report recreational ST behaviors and ST correlates among Chinese adolescents living in two regions with different degrees of urbanization. METHODS: A cross-sectional, school-based survey (n = 3461 adolescents; aged 12-14 years old) living in inner-city Shanghai and a peri-urban region of Hangzhou. Students completed a questionnaire including family characteristics, daily ST, and information on family environment related to screen use. Recreational ST was categorized into two groups according to recommendations by the American Academy of Pediatrics (< or ≥2 h/day). Parents reported their own ST and also reported educational attainment as a proxy for socioeconomic status. RESULTS: ST was higher among boys than girls and on weekends than weekdays. Peri-urban girls were more likely to exceed 2 h/day ST compared to inner-city girls on weekends. Having a father with no university degree, mother's TV viewing ≥2 h/day, no ST rules at home, and eating meals in front of the TV were associated with higher ST on both weekdays and weekends, and regional differences were found for weekend ST. CONCLUSIONS: TV viewing and playing on the computer were the most prevalent ST behaviors among Chinese adolescents. Mobile phone playing was less prevalent but persistent throughout the week. More population-level surveillance and research is needed to monitor the trends in ST behaviors and to better understand the characteristics of those who are at risk.

High prevalence of overweight and obesity among inner city Chinese children in Shanghai, 2011.

BACKGROUND: In China, the prevalence of overweight and obesity appears to be increasing at unacceptable levels among young people living in major cities undergoing rapid economic growth. OBJECTIVE: To report the prevalence of overweight and obesity among Shanghai inner city youth using the recently published International Obesity Task Force (IOTF) Asian definition. METHODS: Secondary analysis of children aged 8-15 years who participated in the Shanghai Schools' Physical Fitness Examinations, a representative school-based survey. Height and weight were measured and body mass index (kg/m(2)) was calculated. The prevalence of overweight and obesity was determined using the IOTF children's BMI cut-points for Asian populations, equivalent to an adult BMI of 23 g/m(2) (overweight) and 27 kg/m(2) (obese). RESULTS: The prevalence of combined overweight and obesity was 49.1% for boys and 30.8% for girls aged 8-15-years. Almost one-in-five boys were obese, compared with 8.4% of girls. In boys the prevalence of overweight appeared to increase from age 10 years. CONCLUSION: The high prevalence of combined overweight and obesity among urban Chinese youth, especially among boys, requires immediate health promotion intervention.

Use of mobile phone text messaging to deliver an individualized smoking behaviour intervention in Chinese adolescents.

We evaluated the effectiveness of a mobile phone text-messaging based smoking cessation intervention package among Chinese adolescent smokers. Students aged 16-19 years were recruited from six vocational high schools located in Shanghai. We assigned the six schools to an intervention group or a control group by cluster randomization. The 92 participants in the intervention group were given tailored information via mobile phone text-messaging for 12 weeks. The 87 participants in the control group were provided with a self-help pamphlet about smoking cessation instead. After the intervention, attitudes towards the disadvantages of smoking were significantly improved, and the level of nicotine dependence and cigarette dependence significantly decreased in the intervention group. The intervention group had a relatively higher self-reported 7-day abstinence compared to the control group and 30-day abstinence, but the differences were not significant. However, the intervention group had a significantly higher rate of smoking reduction (66% vs. 35%) and moving forward in quitting stages (52% vs. 18%) compared to the control group. The interactive and tailored assistance provided by the mobile phone text-messaging was effective in smoking behaviour intervention in Chinese adolescent smokers.

MTA2 expression is a novel prognostic marker for pancreatic ductal adenocarcinoma.

The aim of this study was to detect MTA2 expression in pancreatic ductal adenocarcinoma (PDA) and to analyze its association with prognosis of PDA patients. MTA2 mRNA and protein expression were determined by real-time quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry in specimens of primary cancer and their adjacent noncancerous tissues in PDA patients. We found that MTA2 mRNA and protein expression levels were both significantly upregulated in PDA lesions compared with adjacent noncancerous tissues. Immunohistochemistry showed that high MTA2 expression was correlated with poor tumor differentiation, TNM stage, and lymph node metastasis. Kaplan-Meier survival analysis showed that patients with high expression levels of MTA2 showed lower overall survival rate than those with low expression levels. Multivariate analysis showed that high MTA2 protein expression was an independent prognostic factor for PDA patients. Our study suggests that overexpression of MTA2 may play an important role in the progression of PDA and MTA2 expression may serve as a biomarker for poor prognosis for PDA.

[Effect of puerarin preconditioning on cytokine levels in patients undergoing cardiopulmonary bypass in perioperative period].

OBJECTIVE: To study the effect and acting mechanism of puerarin preconditioning (PP) on blood level of cytokines in patients undergoing cardiopulmonary bypass (CPB) in perioperative period. METHODS: Forty patients with heart diseases scheduled to take surgical operation were randomized into the control group and the PP group equally. They were treated with the same program, excepting that 0.6 g of puerarin was given to the PP group by adding in 5% glucose solution 250 mL for intravenous dripping every day for one week before operation, but to the control group, normal saline was given instead. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 6, 8 and 10 (IL-6, IL-8, IL-10) in arterial blood were measured at 5 time points in the process of CPB, namely, anesthetic induction (T1), 10 min after the clamp of the ascending aorta (T2), 10 min, 2 h and 12 h after the Clamped aorta is unclamped (T3, T4 and T5). RESULTS: All the above-mentioned indexes (TNF-alpha, IL-6, IL-8 and IL-10) gradually increased after beginning CPB, reached the peak at T4, then lowered gradually but still presented the higher levels at T5 than those at T1 (P < 0.05). Comparison between the two groups showed that levels of TNF-alpha, IL-6 and IL-8 were significantly lower (P < 0.05 or P < 0.01) and level of IL-10 was higher in the PP group than those in the control group respectively at all the time points (P < 0.01). CONCLUSION: Injecting puerarin before CPB could effectively suppress the pro-inflammatory cytokines like TNF-alpha, IL-6 and IL-8; and enhance the expression of anti-inflammatory cytokines like IL-10, thus to alleviate the inflammatory reaction induced by CPB.