Stella Chen

LIN28 Binds Messenger RNAs at GGAGA Motifs and Regulates Splicing Factor Abundance

LIN28 is a conserved RNA-binding protein implicated in pluripotency, reprogramming, and oncogenesis. It was previously shown to act primarily by blocking let-7 microRNA (miRNA) biogenesis, but here we elucidate distinct roles of LIN28 regulation via its direct messenger RNA (mRNA) targets. Through crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq) in human embryonic stem cells and somatic cells expressing exogenous LIN28, we have defined discrete LIN28-binding sites in a quarter of human transcripts. These sites revealed that LIN28 binds to GGAGA sequences enriched within loop structures in mRNAs, reminiscent of its interaction with let-7 miRNA precursors. Among LIN28 mRNA targets, we found evidence for LIN28 autoregulation and also direct but differing effects on the protein abundance of splicing regulators in somatic and pluripotent stem cells. Splicing-sensitive microarrays demonstrated that exogenous LIN28 expression causes widespread downstream alternative splicing changes. These findings identify important regulatory functions of LIN28 via direct mRNA interactions.

Endogenous generation of sulfur dioxide in rat tissues

While sulfur dioxide (SO(2)) has been previously known for its toxicological effects, it is now known to be produced endogenously in mammals from sulfur-containing amino acid L-cysteine. L-cysteine is catalyzed by cysteine dioxygenase (CDO) to L-cysteinesulfinate, which converts to β-sulfinylpyruvate through transamination by aspartate aminotransferase (AAT), and finally spontaneously decomposes to pyruvate and SO(2). The present study explored endogenous SO(2) production, and AAT and CDO distribution in different rat tissue. SO(2) content was highest in stomach, followed by tissues in the right ventricle, left ventricle, cerebral gray matter, pancreas, lung, cerebral white matter, renal medulla, spleen, renal cortex and liver. AAT activity and AAT1 mRNA expression were highest in the left ventricle, while AAT1 protein expression was highest in the right ventricle. AAT2 and CDO mRNA expressions were both highest in liver tissue. AAT2 protein expression was highest in the renal medulla, but CDO protein expression was highest in liver tissue. In all tissues, AAT1 and AAT2 were mainly distributed in the cytoplasm rather than the nucleus. These observed differences among tissues endogenously generating SO(2) and associated enzymes are important in implicating the discovery of SO(2) as a novel endogenous signaling molecule.

Flow-mediated vasodilation and endothelium function in children with postural orthostatic tachycardia syndrome.

The study was designed to explore flow-mediated vasodilation (FMD) and endothelium function in children with postural orthostatic tachycardia syndrome (POTS). The patient group consisted of 46 children 12 +/- 3 years of age who were diagnosed with POTS from June 2008 to January 2009 by head-up test or head-up tilt test at Peking University First Hospital. Twenty healthy children 12 +/- 4 years of age were selected for the control group. Plasma concentrations of nitric oxide (NO) and activity of NO synthase (NOS) were determined in the patient and control groups. FMD of each participants brachial artery was measured using color Doppler vascular ultrasound and a comparison of FMDs and plasma NO and NOS activities between the 2 groups was done using independent t test. No significant differences were found between the POTS and control groups in age, sex ratio, height, body weight, baseline blood pressure, heart rate, and baseline brachial artery diameter. Patients in the POTS group had larger FMD (10.8 +/- 4.4%) than children in the control group (5.7 +/- 2.2%), and this difference was significant (p <0.01). Plasma NO and NOS levels were significantly higher in the POTS group than in the control group (NO 74 +/- 19 micromol/L in POTS group vs 62 +/- 6 micromol/L in control group, p <0.01; NOS 21 +/- 3 U/mL in POTS group vs 15 +/- 1 U/mL in control group, p <0.01). In addition, there was a significant correlation between FMD and the NOS activity. In conclusion, augmented FMD and abnormal function of vascular endothelium may play an important role in POTS in children.

Sulfur dioxide derivatives depress L‐type calcium channel in rat cardiomyocytes

1. Sulfur dioxide (SO2) has recently been found to have various biological effects on the cardiovascular system. The present study was designed to explore the effects of SO2 derivatives on the L‐type calcium current (I Ca, L) in isolated rat ventricular cardiomyocytes.

Postural orthostatic tachycardia syndrome with increased erythrocytic hydrogen sulfide and response to midodrine hydrochloride.

OBJECTIVES To evaluate the use of erythrocytic hydrogen sulfide (H2S) in predicting the therapeutic efficacy of midodrine hydrochloride for children with postural orthostatic tachycardia syndrome (POTS). STUDY DESIGN Fifty-five children were included in this study, involving 28 children with POTS (POTS group) and 27 healthy children (control group). Children in the POTS group received midodrine hydrochloride treatment. Erythrocytic H2S production was measured; a receiver operating characteristic curve was used to assess if erythrocytic H2S could predict the therapeutic response to midodrine hydrochloride treatment. RESULTS H2S production from erythrocytes was significantly higher in the POTS group than in the control group (P < .01). H2S production was also significantly higher in responders to midodrine hydrochloride than in non-responders (P < .05). The change in symptom score and baseline erythrocytic H2S production had a positive linear relationship (P < .01). There was also a positive correlation with the change in heart rate (P < .05). The receiver operating characteristic curve showed an area under curve value of 0.813. Erythrocytic H2S production yielded a sensitivity of 78.9% and a specificity of 77.8% in predicting the efficacy of midodrine hydrochloride therapy for children with POTS. CONCLUSION Erythrocytic H2S could serve as a useful predictor of therapeutic response to midodrine hydrochloride in children with POTS.

Brg1-dependent epigenetic control of vascular smooth muscle cell proliferation by hydrogen sulfide

Hydrogen sulfide (H2S) can modulate the proliferation of vascular smooth muscle cells. This study was designed to investigate the epigenetic control of vascular smooth muscle cell proliferation in response to H2S. Microarray analysis indicated that Brahma-related gene 1 (Brg1) and proliferation-related genes including proliferating cell nuclear antigen (Pcna), neurotrophin 3 (Ntf3) and platelet-derived growth factor subunit A (Pdgfα) were significantly downregulated by H2S in endothelin-1-stimulated proliferative vascular smooth muscle cells. Brg1 is the central catalytic subunit of the SWI/SNF apparatus (an ATP-dependent chromatin remodeling complex). Overexpression and knockdown of Brg1 confirmed that Brg1 was crucial for H2S-induced inhibition of vascular smooth muscle cell proliferation. A luciferase reporter assay, real-time PCR and Western blotting demonstrated that H2S inhibited Brg1 transcription and expression. A DNase I hypersensitivity assay revealed that H2S reversed endothelin-1-stimulated Pcna, Ntf3 and Pdgfα chromatin remodeling and vascular smooth muscle cell proliferation. A chromatin immunoprecipitation assay indicated that H2S inhibited the recruitment of Brg1 to the Pcna, Ntf3 and Pdgfα promoters. The results of this study indicate that H2S inhibits vascular smooth muscle cell proliferation via an epigenetic mechanism involving the inhibition of Brg1 transcription and expression, and by reducing the recruitment of Brg1 to the Pcna, Ntf3 and Pdgfα promoter regions.

α-Adrenoceptor agonists for the treatment of vasovagal syncope: a meta-analysis of worldwide published data

Aim:  The present study was aimed at evaluating present randomized controlled trials (RCTs) regarding the effect of α‐adrenoceptor agonists on vasovagal syncope (VVS).

Flow-mediated vasodilation as a predictor of therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome.

This study was designed to explore the value of flow-mediated vasodilation (FMD) as a predictor of therapeutic response to midodrine hydrochloride (MD) in children with postural orthostatic tachycardia syndrome (POTS). One hundred and eight children diagnosed with POTS and 20 healthy control children were enrolled. All children with POTS received MD and were followed up for 3 months. FMD of brachial artery for each participant was measured by vascular ultrasound. Symptom scores, FMD values, and head-up test (HUT)/head-up tilt test (HUTT) outcomes were investigated before and after treatment. A receiver operating characteristic curve was used to explore the value of FMD as a predictor. Baseline FMD (%) and increased heart rate (beats per minute) during HUT/HUTT were significantly greater in children with POTS compared with control children (FMD: 11 ± 3% vs 6 ± 2%, p <0.001; increased heart rate: 38 ± 9 vs 7 ± 7 beats/min, p <0.001, respectively). Before treatment, MD responders had greater FMD values than MD nonresponders (p <0.05). Symptom scores, excessive increases in heart rate during HUT, and increased FMD values were all reduced significantly after treatment (all p <0.05). The receiver operating characteristic curve for the predictive value of FMD showed the area under the curve to be 0.790 (95% confidence interval: 0.679 to 0.902; p <0.001) at 1-month and 0.803 (95% confidence interval: 0.669 to 0.936; p <0.01) at 3-month therapy. FMD of 9.85% had a high sensitivity (1-month therapy: 71.6%; 3-month therapy: 74.4%) and specificity (1-month therapy 77.8%; 3-month therapy: 80%). In conclusion, FMD is a predictor of the efficacy of MD for treating children with POTS.

A meta-analysis of re-treatment for intravenous immunoglobulin-resistant Kawasaki disease

OBJECTIVE To determine the optimal drug therapy for intravenous immunoglobulin-resistant Kawasaki disease. METHODS Studies regarding drug therapy for intravenous immunoglobulin-resistant Kawasaki disease were selected from medical electronic databases including PubMed, Medline, Elsevier, and Springer Link. The effectiveness in terms of temperature recovery and coronary artery damage was compared between a second intravenous immunoglobulin treatment and glucocorticosteroid treatment for children with intravenous immunoglobulin-resistant Kawasaki disease using meta-analysis with Review Manager 5.3 software. Indices to evaluate the effects were body temperature, biomarker levels, and coronary artery lesions detected by echocardiography. Results are reported as relative risks or odds ratio with a 95% confidence interval and p<0.05. RESULTS Meta-analysis included 52 patients in the second intravenous immunoglobulin treatment group and 75 patients in the glucocorticosteroid treatment control group from four studies that met our inclusion criteria. Temperatures of patients who received glucocorticosteroid treatment were effectively controlled compared with those who received a second intravenous immunoglobulin treatment (relative risk=0.73, 95% confidence interval: 0.58-0.92, p=0.007). There were no differences, however, in the incidence of coronary artery lesions between the two groups (odds ratio=1.55, 95% confidence interval: 0.57-4.20, p=0.39). CONCLUSIONS Glucocorticosteroids are more effective in controlling body temperature compared with intravenous immunoglobulin re-treatment in intravenous immunoglobulin-resistant Kawasaki disease children; however, glucocorticosteroids and intravenous immunoglobulin re-treatment showed no difference in the prevention of coronary artery lesions.

Study on the reference values of serum lipids in children aged 3–18 years old in Beijing, China

Background:  The present study was designed to explore the reference values of serum lipids in children in Beijing.