Maternal antiviral treatment safeguards infants from hepatitis B transmission in contingencies of delayed immunoprophylaxis.

BACKGROUND & AIMS: Effectiveness of maternal antiviral prophylaxis in mother-to-child transmission of hepatitis B virus (HBV) has been extensively explored in studies where standard immunoprophylaxis is well secured to the newborns. This real-world study aims to test if maternal antiviral prophylaxis can safeguard the newborn when immunoprophylaxis administration was delayed or missed. METHODS: Hepatitis B surface antigen-positive pregnant women were categorized into mothers with HBV DNA levels ≥2 × 105 IU/mL receiving nucleos(t)ide analogue during the third trimester; mothers with HBV DNA levels ≥2 × 105 IU/mL without antiviral treatment; and those with HBV DNA levels <2 × 105 IU/mL without antiviral treatment. The immunoprophylaxis procedure was collected and verified by the delivery medical document and logbook of biological product usage. The primary end point was the rate of chronic HBV infection (CHB) in infants. RESULTS: From 2011 to 2017, 251 mother-child pairs were enrolled. Among 187 infants of mothers with HBV DNA levels ≥2 × 105 IU/mL, none developed CHB when mothers received antiviral treatment, as compared to 13.0% (10/77) of infants born to untreated mothers (P < .001). None of the infants of mothers with HBV DNA levels <2 × 105 IU/mL were infected. Stratified by the time of immunoprophylaxis administration after birth, maternal antiviral prophylaxis predominately benefited infants who failed to receive immunoprophylaxis within 24 hours (100% [6/6] vs 0% [0/2], P = .036) and those who received delayed immunoprophylaxis between 2 and 24 hours (18.8% [3/16] vs 0% [0/32], P = .032). CONCLUSIONS: Antiviral prophylaxis in high viraemic mothers is effective in contingencies of missed or delayed neonatal immunoprophylaxis.

Probucol-induced hERG Channel Reduction can be Rescued by Matrine and Oxymatrine in vitro.

BACKGROUND: The human ether-a-go-go-related gene (hERG) potassium channel is the rapidly activating component of cardiac delayed rectifier potassium current (IKr), which is a crucial determinant of cardiac repolarization. The reduction of hERG current is commonly believed to cause Long QT Syndrome (LQTs). Probucol, a cholesterol-lowering drug, induces LQTs by inhibiting the expression of the hERG channel. Unfortunately, there is currently no effective therapeutic method to rescue probucol-induced LQTs. METHODS: Patch-clamp recording techniques were used to detect the action potential duration (APD) and current of hERG. Western blot was performed to measure the expression levels of proteins. RESULTS: In this study, we demonstrated that 1 µM matrine and oxymatrine could rescue the hERG current and hERG surface expression inhibited by probucol. In addition, matrine and oxymatrine significantly shortened the prolonged action potential duration induced by probucol in neonatal cardiac myocytes. We proposed a novel mechanism underlying the probucol induced decrease in the expression of transcription factor Specificity protein 1 (Sp1), which is an established transactivator of the hERG gene. We also demonstrated that matrine and oxymatrine were able to upregulate Sp1 expression which may be one of the possible mechanisms by which matrine and oxymatrine rescued probucol-induced hERG channel deficiency. CONCLUSION: Our current results demonstrate that matrine and oxymatrine could rescue probucol-induced hERG deficiency in vitro, which may lead to potentially effective therapeutic drugs for treating acquired LQT2 by probucol in the future.

Expression signature of miRNAs and the potential role of miR-195-5p in high-glucose-treated rat cardiomyocytes.

MicroRNAs are endogenous small noncoding RNAs that posttranscriptionally regulate the expression of target genes and play crucial roles in diverse physiopathologic processes. In the current study, we examined the microRNA (miRNA) expression profile of high-glucose-treated neonatal rat cardiomyocytes and the potential mechanisms. Differentially expressed miRNAs were analyzed by a miRNA microarray and validated by a quantitative real-time polymerase chain reaction in high-glucose-treated rat cardiomyocytes. Based on the results of our previous study and the bioinformatics prediction, we identified miR-195-5p/SGK1/Nedd4-2/hERG as the top-ranked signal pathway in diabetes cell model in vitro. In summary, our present study provides novel insights into the regulatory mechanism of miR-195-5p/SGK1/Nedd4-2/hERG in rat cardiomyocytes under high-glucose stress, which may provide a novel idea for the development of diagnostic and therapeutic strategies for diabetic cardiomyopathy in the future.

Evaluation of cytochrome P450 3A4­mediated drug­drug interaction potential between P2Y12 inhibitors and statins.

Ticagrelor and prasugrel are widely used in the treatment of acute coronary syndrome. The co­administration of ticagrelor or prasugrel with statins in the clinic has already drawn a great deal of attention. The aims of the present study were to evaluate the safety and effectiveness, and guide the rational clinical use of, co­administration of ticagrelor or prasugrel with statins by exploring potential drug interactions. The activity of cytochrome P450 family 3 subfamily A member 4 (CYP3A4) was detected, and its protein and mRNA expression levels were measured in a rat model and liver microsomes to evaluate the effect of the drug combinations on CYP3A4. High performance liquid chromatography, western blotting and reverse transcription­quantitative PCR were used to perform these investigations. The in vitro experiments suggested that ticagrelor inhibited CYP3A4 activity, with IC50 and inhibitor constant (Ki) values of 68.74 and 26.47 µM, respectively; prasugrel also inhibited CYP3A4, activity with IC50 and Ki values of 16.24 and 10.84 µM, respectively. When different dosages of the antagonists were combined with simvastatin or atorvastatin, the metabolic rate was reduced more effectively at higher dosages when compared with lower dosages. An in vivo pharmacokinetic study demonstrated that the co­administration of ticagrelor or prasugrel with simvastatin caused an increase in the principal pharmacokinetic parameters of the probe drug dapsone [area under the concentration/time curve (AUC)0­t, AUC0­∞ and t1/2] and a decrease in clearance compared with ticagrelor, prasugrel or simvastatin alone. Additional studies confirmed that the two investigated P2Y12 inhibitors were able to decrease the protein level of CYP3A4 by promoting protein degradation through the proteasomal pathway, and combination with statins such as simvastatin had a synergistic inhibitory effect on CYP3A4 activity. These results demonstrated that the co­administration of P2Y12 inhibitors with simvastatin could markedly inhibit the activity of CYP3A4, and these findings will further influence the assessment of the clinical effectiveness (reduced or enhanced efficacy) and safety (bleeding and rhabdomyolysis) in the clinic.

Effects of As2O3 and Resveratrol on the Proliferation and Apoptosis of Colon Cancer Cells and the hERG-mediated Potential Mechanisms.

BACKGROUND: As2O3 and resveratrol have been widely considered to be effective in anti-cancer therapies and the underlying mechanisms have been reported extensively. However, the combined treatment effect and potential target of As2O3 and resveratrol in the treatment of tumors remains elusive. The purpose of this study was to investigate the benefits and efficacy of As2O3 in combination with resveratrol in the treatment of colon cancer, as well as looking for new targets that could provide alternative explanation of the efficacy of drugs. METHODS: The proliferation of cancer cells was measured by the MTT and EdU staining assay, while the apoptosis of cancer cells was determined by the flow cytometry. Western blot and immunoprecipitation were performed to measure the expression levels of proteins and the interaction between hERG and integrin ß1, respectively. RESULTS: In this study, we found that both As2O3 and resveratrol can effectively inhibit cell proliferation and promote cell apoptosis in colon cancer, and the combined effect of the two drugs on colon cancer cells is more preeminent. The combination of As2O3 with resveratrol, on the one hand reduced the expression of hERG channels on the membrane, and on the other hand weaken the binding between hERG and integrin ß 1, which may be the main cause of downstream signaling pathways alterations, including the activation of the apoptotic pathway. CONCLUSION: Taken together, hERG, as a subunit of potassium ion channel on the cell membrane, is highly likely to be involved in the As2O3 and resveratrol induced intracellular signaling cascade disorder, and this novel signaling pathway that sustains the progression of colon cancer may be a promising therapeutic target for human colon cancer treatment in the future.

A series of two-photon absorption pyridinium sulfonate inner salts targeting endoplasmic reticulum (ER), inducing cellular stress and mitochondria-mediated apoptosis in cancer cells.

In this study, a two-photon active DiphenthioER1 was screened from the four pyridinium sulfonate salt derivatives (TriphenER1-2 and DiphenthioER1-2) for imaging endoplasmic reticulum (ER) and tracking the dynamics of the ER morphology. The photophysical properties of TriphenER1-2 and DiphenthioER1-2 were systemically investigated both experimentally and theoretically, revealing that they possess large Stokes shifts, and large two-photon absorption cross-sections from 163 GM to 2023 GM in the near infrared region using a Z-scan method by avoiding spontaneous fluorescence, deep tissue penetration, and low cell damage in living cells. Among them, the DiphenthioER1 compound was found to exhibit the highest cellular uptake ability and two-photon fluorescence signals using confocal microscopy. DiphenthioER1 successfully targeted the ER and induced ER-stress, subsequently nuclear misshaping and mitochondria-mediated apoptosis have been displayed. This study thus provides great insights into designing novel two-photon fluorescent materials with dual functionality and offers tools to understand the ER-stress related mechanism for cell and chemical biologists.

[Simultaneous determination of 38 limited colorants in cosmetics by high performance liquid chromatography].

A method has been established for the simultaneous determination of 38 limited colorants in cosmetics by high performance liquid chromatography (HPLC). The samples were extracted by ultrasonic with tetrahydrofuran, methanol, ammonium acetate solution as extraction solvents. After centrifugation, nitrogen blow and redissolved in turn, the extracts were separated on an Agilent zorbax SB-Aq column (150 mm x 3.0 mm, 3.5 µm) using a gradient elution program with acetonitrile and 30 mmol/L ammonium acetate containing 0.075% (v/v) formic acid as mobile phases. The detection wavelengths were set at 254, 416, 484, 514, 590 and 620 nm. The linear ranges of the 38 target compounds were all in the range of 1 to 10 mg/L with correlation coefficients more than 0.999. The limits of quantification (LOQs) for the 38 colorants were in the range of 5-50 µg/g. The average recoveries at two spiked levels ranged from 93.2% to 107.6% with the relative standard deviations (RSDs) less than 10% (n = 6). This method is accurate, simple, sensitive and reliable, and can be used for the analysis of the 38 limited colorants in cosmetics.

3-(2-Methyl-1,3-benzo-thia-zol-3-ium-3-yl)propane-1-sulfonate monohydrate.

In the title hydrated zwitterion, C11H13NO3S2·H2O, the N-C-C-C and C-C-C-S torsion angles in the side-chain are 171.06 (14) and 173.73 (12)°, respectively. In the crystal, inversion-related mol-ecules are π-stacked with an inter-planar separation of 3.3847 (2) Å. O-H⋯O hydrogen bonds link inversion-related mol-ecules with a pair of water mol-ecules to form R 4 (2)(8) rings. The closest S⋯S contact is 3.4051 (15) Šbetween inversion-related mol-ecules.

Self-assembly of Terbium(III)-based metal-organic complexes with two-photon absorbing active.

Hybrid complexes based on D-π-A type dyes p-aminostyryl-pyridinum and Terbium(III) complex anion (1, 2) have been synthesized by ionic exchange reaction. Meanwhile two different alkyl-substituted amino groups were used as electron donors in organic dyes cations. The synthesized complexes were characterized by element analysis. In addition, the structural features of them were systematic studied by single crystal X-ray diffraction analysis. Their linear properties have been systematically investigated by absorption spectra and fluorescence, the results show that the energy transfer takes place from the trans-4-[4'-(N,N-diethylamino)styryl]-N-methyl pyridinium (2') cation to Tb(III). In addition, complex 2 exhibit a large two-photon absorption coefficient ß: 0.044cm/GW at 710nm.

High incidence of multiple viral infections identified in upper respiratory tract infected children under three years of age in Shanghai, China.

BACKGROUND: Upper respiratory tract infection (URTI) is a major reason for hospitalization in childhood. More than 80% of URTIs are viral. Etiological diagnosis of URTIs is important to make correct clinical decisions on treatment methods. However, data for viral spectrum of URTIs are very limited in Shanghai children. METHODS: Nasopharyngeal swabs were collected from a group of 164 children aged below 3 years who were hospitalized due to acute respiratory infection from May 2009 to July 2010 in Shanghai. A VRDAL multiplex PCR for 10 common respiratory viruses was performed on collected specimens compared with the Seeplex® RV15 ACE Detection kit for 15 respiratory viruses. RESULTS: Viruses were detected in 84 (51.2%) patients by VRDAL multiplex PCR, and 8 (4.9%) of cases were mixed infections. Using the Seeplex® RV15 ACE Detection kit, viruses were detected in 129 (78.7%) patients, 49 (29.9%) were co-infected cases. Identified viruses included 37 of human rhinovirus (22.6% of cases), 32 of influenza A virus (19.5%), 30 of parainfluenzavirus-2 (18.3%), 23 of parainfluenzavirus-3 (14.0%), 15 of human enterovirus (9.1%), 14 each of parainfluenzavirus-1, respiratory syncytial virus B and adenovirus (8.5%), 8 of coronavirus 229E/NL63 (4.9%), 6 of human bocavirus (3.7%), 5 each of influenza B virus and respiratory syncytial virus A (3.0%), 3 of parainfluenzavirus-4 (1.8%), 2 of coronavirus OC43/HKU1 (1.2%), and 1 human metapneumovirus (0.6%). CONCLUSIONS: A high frequency of respiratory infections (78.7%) and co-infections (29.9%) was detected in children with acute respiratory infection symptoms in Shanghai. The Seeplex® RV15 ACE detection method was found to be a more reliable high throughput tool than VRDAL method to simultaneously detect multiple respiratory viruses.

Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers.

HOXB13 is a homeodomain protein implicated to play a role in growth arrest in AR (androgen receptor)-negative prostate cancer cells. Expression of HOXB13 is restricted to the AR-expressing prostate cells. In this report, we demonstrate that the HDAC inhibitor NaB (sodium butyrate) was able to induce cell growth arrest and to increase HOXB13 expression in AR-negative prostate cancer cells. We also show that both HDAC4 and YY1 participated in the repression of HOXB13 expression through an epigenetic mechanism involving histone acetylation modification. Specifically, co-immunoprecipitation assays revealed that HDAC4 and YY1 formed a complex. The chromatin immunoprecipitation (ChIP) assays verified that HDAC4 was recruited to HOXB13 promoter by YY1. Moreover, promoter truncation and point mutation studies determined that the two proximal YY1 binding sites on the HOXB13 promoter were essential for the recruitments of YY1 and HDAC4. Data presented in this report suggest that YY1 and HDAC4 affected cell growth by repressing transcriptional regulation of HOXB13 through an epigenetic modification of histones.