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Bone targeted delivery of Salmon calcitonin hydroxyapatite nanoparticles for sublingual osteoporosis therapy (SLOT).

骨靶向递送鲑鱼降钙素羟基磷灰石纳米粒用于舌下骨质疏松治疗 (SLOT)。

  • 影响因子:5.94
  • DOI:10.1016/j.nano.2020.102153
  • 作者列表:"Kotak DJ","Devarajan PV
  • 发表时间:2020-01-24
Abstract

:We present salmon calcitonin (SCT) loaded Hydroxyapatite nanoparticles (HAP-NPs) for sublingual osteoporosis therapy. Surface stabilized HAP-NPs were prepared by aqueous precipitation. SCT was loaded by ionic complexation, as confirmed by FTIR. SCT-HAP-NPs exhibited high loading efficiency (~85%), average size (~100nm), and zeta potential (~-25 mv). Stability of SCT was established by circular dichroism spectroscopy and HPLC analysis. Confocal laser scanning microscopy confirmed deep penetration of SCT-HAP-NPs into the mucosa with >4-fold enhancement in permeability relative to SCT solution. Sublingual SCT-HAP-NPs revealed relative bioavailability of ~15% compared to the subcutaneous injection in rabbits (200iu). Significant and comparable improvement in serum biomarkers with increase in bone mass and mechanical strength and decreased bone erosion compared to subcutaneous SCT was confirmed in ovariectomized (OVX) osteoporosis rat model. Such comparable pharmacodynamic effect at the same dose suggested targeted bone delivery and promise of sublingual SCT-HAP-NPs as a non-invasive alternative to the injection.

摘要

: 我们提出鲑鱼降钙素 (SCT) 负载羟基磷灰石纳米颗粒 (HAP-NPs) 用于舌下骨质疏松治疗。采用水沉淀法制备表面稳定的 HAP-NPs。SCT 通过离子络合加载,经 FTIR 证实。SCT-HAP-NPs 表现出高负载效率 (~ 85%) 、平均尺寸 (~ 100nm) 和 zeta 电位 (~-25 mv)。通过圆二色谱和 HPLC 分析建立 SCT 的稳定性。共聚焦激光扫描显微镜证实 SCT-HAP-NPs 深入黏膜,相对于 SCT 溶液的渗透性增强> 4 倍。与兔皮下注射 (200iu) 相比,舌下 SCT-HAP-NPs 显示相对生物利用度约为 15%。在去卵巢 (OVX) 骨质疏松大鼠模型中证实了与皮下 SCT 相比,血清生物标志物随着骨量和机械强度的增加和骨侵蚀的减少而显著和可比的改善。这种相同剂量的类似药效学作用建议靶向骨递送和舌下 SCT-HAP-NPs 作为注射的非侵入性替代方案的承诺。

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影响因子:4.73
发表时间:2020-01-24
来源期刊:Epigenetics
DOI:10.1080/15592294.2020.1716491
作者列表:["Zhang X","Ehrlich KC","Yu F","Hu X","Meng XH","Deng HW","Shen H","Ehrlich M"]

METHODS::A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

影响因子:3.23
发表时间:2020-01-24
DOI:10.1007/s00432-019-03119-3
作者列表:["Riffel P","Schwaab J","Lutz C","Naumann N","Metzgeroth G","Fabarius A","Schoenberg SO","Hofmann WK","Valent P","Reiter A","Jawhar M"]

METHODS:PURPOSE:Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear. METHODS:BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis. RESULTS:Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). CONCLUSIONS:Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.

影响因子:5.94
发表时间:2020-01-24
DOI:10.1016/j.nano.2020.102153
作者列表:["Kotak DJ","Devarajan PV"]

METHODS::We present salmon calcitonin (SCT) loaded Hydroxyapatite nanoparticles (HAP-NPs) for sublingual osteoporosis therapy. Surface stabilized HAP-NPs were prepared by aqueous precipitation. SCT was loaded by ionic complexation, as confirmed by FTIR. SCT-HAP-NPs exhibited high loading efficiency (~85%), average size (~100nm), and zeta potential (~-25 mv). Stability of SCT was established by circular dichroism spectroscopy and HPLC analysis. Confocal laser scanning microscopy confirmed deep penetration of SCT-HAP-NPs into the mucosa with >4-fold enhancement in permeability relative to SCT solution. Sublingual SCT-HAP-NPs revealed relative bioavailability of ~15% compared to the subcutaneous injection in rabbits (200iu). Significant and comparable improvement in serum biomarkers with increase in bone mass and mechanical strength and decreased bone erosion compared to subcutaneous SCT was confirmed in ovariectomized (OVX) osteoporosis rat model. Such comparable pharmacodynamic effect at the same dose suggested targeted bone delivery and promise of sublingual SCT-HAP-NPs as a non-invasive alternative to the injection.

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