Perinatal nicotine exposure alters lung development and induces HMGB1-RAGE expression in neonatal mice.

BACKGROUND: Maternal nicotine exposure during gestation and lactation adversely affect lung development of their children. High-mobility group box 1 (HMGB1) is the encoded non-histone, nuclear DNA-binding protein that regulates transcription, and is involved in organization of DNA. Receptors for advanced glycation end products (RAGE) is a receptor for HMGB1 and activates nuclear factor-κB (NF-κB) signaling. Animal and human studies have found cigarette smoke exposure upregulates RAGE expression, suggesting that the HMGB1-RAGE pathway might be involved in maternal nicotine-induced lung injury. METHODS: This study evaluated prenatal and perinatal nicotine effects on lung development and HMGB1 and RAGE expression in mouse offspring. Nicotine was administered to pregnant mice by subcutaneous osmotic mini-pump at a dose of 6 mg kg-1 day-1 from gestational Day 14 to birth (prenatal) or to postnatal Day 21 (perinatal). A control group received an equal volume of saline by the same route. Three study groups were obtained: prenatal normal saline (NS), prenatal nicotine, and perinatal nicotine groups. The mice were euthanized on postnatal Day 21, and the lung tissues were collected for histological and Western blot analyses. RESULTS: Mice exposed to prenatal nicotine exhibited significantly higher lung mean chord length and oxidative stress marker 8-hydroxy-2'-deoxyguanosine and NF-κB expression compared to mice exposed to NS. Perinatal nicotine exposure further enhanced these harmful effects. These perinatal nicotine effects on lung development were associated with increased HMGB1 and RAGE expression. CONCLUSIONS: HMGB1-RAGE pathway may be involved in the pathogenesis of altered lung development induced by perinatal nicotine exposure.

Psychotropic medications prescribing trends in adolescents: A nationwide population-based study in Taiwan.

OBJECTIVE: To describe psychotropic medications prescription patterns among adolescents in Taiwan; focusing on age, gender, duration of treatments and various classes of psychotropic medications. DESIGN: A retrospective description analysis. SETTING: Taiwan National Health Insurance Database. PARTICIPANTS: Twelve to seventeen years' patients treated with psychotropic medications. INTERVENTION: None. MAIN OUTCOME MEASURE(S): Percentage and duration of treatment with psychotropic medications during the study periods by medication classes and age groups were calculated. In addition, top three prescribed psychotropic medications were also determined. RESULTS: A total of 3,120 patients were prescribed psychotropic drugs. The percentage of adolescent patients that received anxiolytics and antidepressants in 2002-2012 were 2.89% and 2.15%, respectively. Also, 851 patients (1.21%) were prescribed hypnotics and 638 (0.91%) were given sedatives. The prevalence rate of the prescription of psychotropic drugs increased steadily with age and females were more treated than males except antipsychotic. Among psychotropic drugs, antidepressants (mean: 8.6 times) were refilled more but antipsychotics (mean 188 days) were the long-term treatment drugs. Additionally, the trend of hospital visits fluctuated over the year while May and December showed a higher rate of visits. CONCLUSIONS: These findings show that the prevalence of psychotropic drug prescriptions in Taiwanese adolescents is even low but increasing trends in the prescription of these medications raises some concern. As the evidence of psychotropic drug safety and effectiveness in adolescents is still inadequate; we recommend that healthcare providers should consider psychotropic drugs therapy, continuously monitor for outcomes and empower their patients to improve their knowledge, therapeutic outcomes and quality of life.

Regulating repression: roles for the sir4 N-terminus in linker DNA protection and stabilization of epigenetic states.

Silent information regulator proteins Sir2, Sir3, and Sir4 form a heterotrimeric complex that represses transcription at subtelomeric regions and homothallic mating type (HM) loci in budding yeast. We have performed a detailed biochemical and genetic analysis of the largest Sir protein, Sir4. The N-terminal half of Sir4 is dispensable for SIR-mediated repression of HM loci in vivo, except in strains that lack Yku70 or have weak silencer elements. For HM silencing in these cells, the C-terminal domain (Sir4C, residues 747-1,358) must be complemented with an N-terminal domain (Sir4N; residues 1-270), expressed either independently or as a fusion with Sir4C. Nonetheless, recombinant Sir4C can form a complex with Sir2 and Sir3 in vitro, is catalytically active, and has sedimentation properties similar to a full-length Sir4-containing SIR complex. Sir4C-containing SIR complexes bind nucleosomal arrays and protect linker DNA from nucleolytic digestion, but less effectively than wild-type SIR complexes. Consistently, full-length Sir4 is required for the complete repression of subtelomeric genes. Supporting the notion that the Sir4 N-terminus is a regulatory domain, we find it extensively phosphorylated on cyclin-dependent kinase consensus sites, some being hyperphosphorylated during mitosis. Mutation of two major phosphoacceptor sites (S63 and S84) derepresses natural subtelomeric genes when combined with a serendipitous mutation (P2A), which alone can enhance the stability of either the repressed or active state. The triple mutation confers resistance to rapamycin-induced stress and a loss of subtelomeric repression. We conclude that the Sir4 N-terminus plays two roles in SIR-mediated silencing: it contributes to epigenetic repression by stabilizing the SIR-mediated protection of linker DNA; and, as a target of phosphorylation, it can destabilize silencing in a regulated manner.

BOLD signals correlate with ensemble unit activities in rat's somatosensory cortex.

Evoked neural activity (ensemble single-unit activity and evoked field potential) and functional magnetic resonance imaging (fMRI) changes of the primary somatosensory cortex in response to electrical stimulation of the hind paw were studied in rats under anesthesia. The effects of stimulation frequency (ranging from 0.3 to 10 Hz) and types of anesthetics (alpha-chloralose and sodium pentobarbital) on blood oxygen level dependent (BOLD) activation and neural activation were compared. Both ensemble single-unit activity and BOLD signal changes achieved maximal activation at 3 Hz of stimulation and responses were significantly stronger under alpha-chloralose anesthesia. The maximal activation of the integral evoked potential (sigmaEP), in contrast, was the highest at 10 Hz; and the values were similar for alpha-chloralose and pentobarbital. These analyses revealed that fMRI image changes were better correlated with ensemble single-unit activity than with sigmaEP during somatosensory stimulations.