Brain-derived neurotrophic factor (BDNF) was recently identified as a factor produced by multiple myeloma (MM) cells, which may contribute to bone resorption and disease progression in MM, though the molecular mechanism of this process is not well understood. The purpose of this study was to test the effect of BDNF on bone disease and growth of MM cells both in vitro and in vivo. Co- and triple-culture systems were implemented. The in vitro results demonstrate that BDNF augmented receptor activator of nuclear factor kappa B ligand (RANKL) expression in human bone marrow stromal cells, thus contributing to osteoclast formation. To further clarify the effect of BDNF on myeloma bone disease in vivo, ARH-77 cells were stably transfected with an antisense construct to BDNF (AS-ARH) or empty vector (EV-ARH) to test their capacity to induce MM bone disease in SCID–rab mice. Mice treated with AS-ARH cells were preserved, exhibited no radiologically identifiable lytic lesions and, unlike the controls treated with EV-ARH cells, lived longer and showed reduced tumor burden. Consistently, bones harboring AS-ARH cells showed marked reductions of RANKL expression and osteoclast density compared to the controls harboring EV-ARH cells. These results provide further support for the potential osteoclastogenic effects of BDNF, which may mediate stromal–MM cell interactions to upregulate RANKL secretion, in myeloma bone diseases.

Background and Purpose

Ischemic stroke is a destructive cerebrovascular disease and a leading cause of death. Yet, no ideal neuroprotective agents are available, leaving prevention an attractive alternative. The extracts from the fruits of Lycium barbarum (LBP), a Chinese anti-aging medicine and food supplement, showed neuroprotective function in the retina when given prophylactically. We aim to evaluate the protective effects of LBP pre-treatment in an experimental stroke model.

Methods

C57BL/6N male mice were first fed with either vehicle (PBS) or LBP (1 or 10 mg/kg) daily for 7 days. Mice were then subjected to 2-hour transient middle cerebral artery occlusion (MCAO) by the intraluminal method followed by 22-hour reperfusion upon filament removal. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, immunohistochemical analysis, and Western blot experiments. Evans blue (EB) extravasation was determined to assess blood-brain barrier (BBB) disruption after MCAO.

Results

LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content. Fewer apoptotic cells were identified in LBP-treated brains by TUNEL assay. Reduced EB extravasation, fewer IgG-leaky vessels, and up-regulation of occludin expression were also observed in LBP-treated brains. Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains.

Conclusions

Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation. The present study suggests that LBP may be used as a prophylactic neuroprotectant in patients at high risk for ischemic stroke.

Regulatory T cells (Treg) contribute to the crucial immunological processes of self-tolerance and immune homeostasis. Genomic mechanisms that regulate cell fate decisions leading to Treg or conventional T cells (Tconv) lineages and those underlying Treg function remain to be fully elucidated, especially at the histone modification level. We generated high-resolution genome-wide distribution maps of monomethylated histone H3 lysine 4 (H3K4me1) and trimethylated H3K4 (H3K4me3) in human CD4+CD25+FOXP3+ Tregs and CD4+CD25+FOXP3− activated (a)Tconv cells by DNA sequencing-by-synthesis. 2115 H3K4me3 regions corresponded to proximal promoters; in Tregs, the genes associated with these regions included the master regulator FOXP3 and the chemokine (C-C motif) receptor 7 (CCR7). 41024 Treg-specific H3K4me1 regions were identified. The majority of the H3K4me1 regions differing between Treg and aTconv cells were located at promoter-distal sites, and in vitro reporter gene assays were used to evaluate and identify novel enhancer activity. We provide for the first time a comprehensive genome-wide dataset of lineage-specific H3K4me1 and H3K4me3 patterns in Treg and aTconv cells, which may control cell type-specific gene regulation. This basic principle is likely not restricted to the two closely-related T cell populations, but may apply generally to somatic cell lineages in adult organisms.

Introduction

Gonadotropin-releasing hormone analogs (GnRHa) are the treatment of choice for CPP. We investigated growth in GnRHa-naïve subjects, treated with leuprolide acetate 1-month depot for CPP.

Methods

This prospective, open-label study had a long-term, observational, follow-up period. Forty-nine females and 6 males were enrolled. Leuprolide acetate depot was administered intramuscularly every 28 days. Height and growth rate during and after treatment until adulthood were measured.

Results

Among 30 of 49 females having an adult height (AH) measurement, 29 had target heights available (mean = 163.8 cm) and 27 had pretreatment predicted adult heights (PAHs; mean = 157.4 cm). After treatment, the mean AH at mean age 21.8 years [range 13.7-26.7 years] was 162.5 cm, a mean height gain over baseline PAH of 4.0 cm. The mean height standard deviation score was -0.1 at AH.

Conclusions

Treatment of CPP with leuprolide acetate 1-month depot had beneficial effects on growth rate and preservation of AH.

Trial Registration

ClinicalTrials.gov: NCT00660010

Methods. This prospective US multicenter trial of leuprolide acetate 1-month depot (7.5–15 mg) for central precocious puberty utilized an open-label treatment period, long-term follow-up, and adult callback. Forty-nine females <9 years old with Tanner breast stage ≥2 before 8 years and 6 males <10 years old with Tanner genital stage ≥2 before 9 years with stimulated LH ≥10 IU/L and bone age advance ≥1 year were enrolled. Results. Subjects were treated for 3.9 ± 2.0 years. Mean peak GnRH-stimulated LH and FSH were prepubertal after the first dose and remained suppressed throughout treatment. During treatment, mean estradiol decreased to the limit of detection and mean testosterone decreased but remained above prepubertal norms. During posttreatment follow-up (3.5 ± 2.2 years), all patients achieved a pubertal hormonal response within 1 year and menses were reported in all females ≥12 years old. No impairment of reproductive function was observed at adulthood (mean age: 24.8 years).

Neuronal cell death, glial cell activation, retinal swelling and oxidative injury are complications in retinal ischemia/reperfusion (I/R) injuries. Lycium barbarum polysaccharides (LBP), extracts from the wolfberries, are good for “eye health” according to Chinese medicine. The aim of our present study is to explore the use of LBP in retinal I/R injury. Retinal I/R injury was induced by surgical occlusion of the internal carotid artery. Prior to induction of ischemia, mice were treated orally with either vehicle (PBS) or LBP (1 mg/kg) once a day for 1 week. Paraffin-embedded retinal sections were prepared. Viable cells were counted; apoptosis was assessed using TUNEL assay. Expression levels of glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), poly(ADP-ribose) (PAR) and nitrotyrosine (NT) were investigated by immunohistochemistry. The integrity of blood-retinal barrier (BRB) was examined by IgG extravasations. Apoptosis and decreased viable cell count were found in the ganglion cell layer (GCL) and the inner nuclear layer (INL) of the vehicle-treated I/R retina. Additionally, increased retinal thickness, GFAP activation, AQP4 up-regulation, IgG extravasations and PAR expression levels were observed in the vehicle-treated I/R retina. Many of these changes were diminished or abolished in the LBP-treated I/R retina. Pre-treatment with LBP for 1 week effectively protected the retina from neuronal death, apoptosis, glial cell activation, aquaporin water channel up-regulation, disruption of BRB and oxidative stress. The present study suggests that LBP may have a neuroprotective role to play in ocular diseases for which I/R is a feature.

Recently, magnetic nanoparticles of iron oxide (Fe3O4, γ-Fe2O3) have shown an increasing number of applications in the field of biomedicine, but some questions have been raised about the potential impact of these nanoparticles on the environment and human health. In this work, the three types of magnetic nanoparticles (DMSA-Fe2O3, APTS-Fe2O3, and GLU-Fe2O3) with the same crystal structure, magnetic properties, and size distribution was designed, prepared, and characterized by transmission electronic microscopy, powder X-ray diffraction, zeta potential analyzer, vibrating sample magnetometer, and Fourier transform Infrared spectroscopy. Then, we have investigated the effect of the three types of magnetic nanoparticles (DMSA-Fe2O3, APTS-Fe2O3, and GLU-Fe2O3) on smooth muscle cells (SMCs). Cellular uptake of nanoparticles by SMC displays the dose, the incubation time and surface property dependent patterns. Through the thin section TEM images, we observe that DMSA-Fe2O3 is incorporated into the lysosome of SMCs. The magnetic nanoparticles have no inflammation impact, but decrease the viability of SMCs. The other questions about metabolism and other impacts will be the next subject of further studies.

Recently, magnetic nanoparticles of iron oxide (Fe3O4, γ-Fe2O3) have shown an increasing number of applications in the field of biomedicine, but some questions have been raised about the potential impact of these nanoparticles on the environment and human health. In this work, the three types of magnetic nanoparticles (DMSA-Fe2O3, APTS-Fe2O3, and GLU-Fe2O3) with the same crystal structure, magnetic properties, and size distribution was designed, prepared, and characterized by transmission electronic microscopy, powder X-ray diffraction, zeta potential analyzer, vibrating sample magnetometer, and Fourier transform Infrared spectroscopy. Then, we have investigated the effect of the three types of magnetic nanoparticles (DMSA-Fe2O3, APTS-Fe2O3, and GLU-Fe2O3) on smooth muscle cells (SMCs). Cellular uptake of nanoparticles by SMC displays the dose, the incubation time and surface property dependent patterns. Through the thin section TEM images, we observe that DMSA-Fe2O3is incorporated into the lysosome of SMCs. The magnetic nanoparticles have no inflammation impact, but decrease the viability of SMCs. The other questions about metabolism and other impacts will be the next subject of further studies.