An otoprotective role for the apoptosis inhibitor protein survivin

Hearing impairment caused by ototoxic insults, such as noise or gentamicin is a worldwide health problem. As the molecular circuitries involved are not yet resolved, current otoprotective therapies are rather empirical than rational. Here, immunohistochemistry and western blotting showed that the cytoprotective protein survivin is expressed in the human and guinea pig cochlea. In the guinea pig model, moderate noise exposure causing only a temporary hearing impairment transiently evoked survivin expression in the spiral ligament, nerve fibers and the organ of Corti. Mechanistically, survivin upregulation may involve nitric oxide (NO)-induced Akt signaling, as enhanced expression of the endothelial NO synthase and phosphorylated Akt were detectable in some surviving-positive cell types. In contrast, intratympanic gentamicin injection inducing cell damage and permanent hearing loss correlated with attenuated survivin levels in the cochlea. Subsequently, the protective activity of the human and the guinea pig survivin orthologs against the ototoxin gentamicin was demonstrated by ectopic overexpression and RNAi-mediated depletion studies in auditory cells in vitro. These data suggest that survivin represents an innate cytoprotective resistor against stress conditions in the auditory system. The pharmacogenetic modulation of survivin may thus provide the conceptual basis for the rational design of novel therapeutic otoprotective strategies

Indigenous use and bio-efficacy of medicinal plants in the Rasuwa District, Central Nepal

<p>Abstract</p> <p>Background</p> <p>By revealing historical and present plant use, ethnobotany contributes to drug discovery and socioeconomic development. Nepal is a natural storehouse of medicinal plants. Although several ethnobotanical studies were conducted in the country, many areas remain unexplored. Furthermore, few studies have compared indigenous plant use with reported phytochemical and pharmacological properties.</p> <p>Methods</p> <p>Ethnopharmacological data was collected in the Rasuwa district of Central Nepal by conducting interviews and focus group discussions with local people. The informant consensus factor (F_IC) was calculated in order to estimate use variability of medicinal plants. Bio-efficacy was assessed by comparing indigenous plant use with phytochemical and pharmacological properties determined from a review of the available literature. Criteria were used to identify high priority medicinal plant species.</p> <p>Results</p> <p>A total of 60 medicinal formulations from 56 plant species were documented. Medicinal plants were used to treat various diseases and disorders, with the highest number of species being used for gastro-intestinal problems, followed by fever and headache. Herbs were the primary source of medicinal plants (57% of the species), followed by trees (23%). The average F_IC value for all ailment categories was 0.82, indicating a high level of informant agreement compared to similar studies conducted elsewhere. High F_ICvalues were obtained for ophthalmological problems, tooth ache, kidney problems, and menstrual disorders, indicating that the species traditionally used to treat these ailments are worth searching for bioactive compounds: <it>Astilbe rivularis</it>, <it>Berberis asiatica</it>, <it>Hippophae salicifolia, Juniperus recurva</it>, and <it>Swertia multicaulis</it>. A 90% correspondence was found between local plant use and reported plant chemical composition and pharmacological properties for the 30 species for which information was available. Sixteen medicinal plants were ranked as priority species, 13 of which having also been prioritized in a country-wide governmental classification.</p> <p>Conclusions</p> <p>The <it>Tamang </it>people possess rich ethnopharmacological knowledge. This study allowed to identify many high value and high priority medicinal plant species, indicating high potential for economic development through sustainable collection and trade.</p

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis