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Praziquantel and Moxidectin pharmacokinetics in dogs after Helmimax administration

The purpose of the research is to study Praziquantel and Moxidectin pharmacokinetics in dogs after Helmimax administration.Materials and methods. Helmimax pharmacokinetics was studied on 8 adult male dogs of different breeds aged 2 to 5 years and weighing 15–35 kg. Helmimax was administered orally in the fasted state with a small amount of feed at a dose of 5 mg/kg for Praziquantel and 0.25 mg/kg for Moxidectin at the rate of 1 tablet per 10 kg of body weight. Blood was sampled at various periods after the administration. The collected blood underwent sample processing: formed element and protein precipitation, solid-phase extraction, and microfiltration. The active components were analyzed and detected by the HPLC-MS/MS. Active substances in the blood plasma were determined according to the developed technique which had been validated. The device was calibrated before the measurement.Results and discussion. As a result of the studies, the Praziquantel and Moxidectin pharmacokinetic parameters were calculated. The maximum concentration was 0.240 and 0.130 μg/mL, the time-to-peak concentration was 2.15 and 1.48 hours, and the elimination half-life was 8.41 and 3.61 hours for Moxidectin and Praziquantel, respectively

Altered developmental programs and oriented cell divisions lead to bulky bones during salamander limb regeneration

There are major differences in duration and scale at which limb development and regeneration proceed, raising the question to what extent regeneration is a recapitulation of development. We address this by analyzing skeletal elements using a combination of micro-CT imaging, molecular profiling and clonal cell tracing. We find that, in contrast to development, regenerative skeletal growth is accomplished based entirely on cartilage expansion prior to ossification, not limiting the transversal cartilage expansion and resulting in bulkier skeletal parts. The oriented extension of salamander cartilage and bone appear similar to the development of basicranial synchondroses in mammals, as we found no evidence for cartilage stem cell niches or growth plate-like structures during neither development nor regeneration. Both regenerative and developmental ossification in salamanders start from the cortical bone and proceeds inwards, showing the diversity of schemes for the synchrony of cortical and endochondral ossification among vertebrates

Ablation of the Pro-Apoptotic Protein Bax Protects Mice from Glucocorticoid-Induced Bone Growth Impairment

Dexamethasone (Dexa) is a widely used glucocorticoid to treat inflammatory diseases; however, a multitude of undesired effects have been reported to arise from this treatment including osteoporosis, obesity, and in children decreased longitudinal bone growth. We and others have previously shown that glucocorticoids induce apoptosis in growth plate chondrocytes. Here, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family, plays a key role in Dexa-induced chondrocyte apoptosis and bone growth impairment. Indeed, experiments in the human HCS-2/8 chondrocytic cell line demonstrated that silencing of Bax expression using small-interfering (si) RNA efficiently blocked Dexa-induced apoptosis. Furthermore, ablation of Bax in female mice protected against Dexa-induced bone growth impairment. Finally, Bax activation by Dexa was confirmed in human growth plate cartilage specimens cultured ex vivo. Our findings could therefore open the door for new therapeutic approaches to prevent glucocorticoid-induced bone growth impairment through specific targeting of Bax

Analysis of neural crest-derived clones reveals novel aspects of facial development

Cranial neural crest cells populate the future facial region and produce ectomesenchyme-derived tissues, such as cartilage, bone, dermis, smooth muscle, adipocytes, and many others. However, the contribution of individual neural crest cells to certain facial locations and the general spatial clonal organization of the ectomesenchyme have not been determined. We investigated how neural crest cells give rise to clonally organized ectomesenchyme and how this early ectomesenchyme behaves during the developmental processes that shape the face. Using a combination of mouse and zebrafish models, we analyzed individual migration, cell crowd movement, oriented cell division, clonal spatial overlapping, and multilineage differentiation. The early face appears to be built from multiple spatially defined overlapping ectomesenchymal clones. During early face development, these clones remain oligopotent and generate various tissues in a given location. By combining clonal analysis, computer simulations, mouse mutants, and live imaging, we show that facial shaping results from an array of local cellular activities in the ectomesenchyme. These activities mostly involve oriented divisions and crowd movements of cells during morphogenetic events. Cellular behavior that can be recognized as individual cell migration is very limited and short-ranged and likely results from cellular mixing due to the proliferation activity of the tissue. These cellular mechanisms resemble the strategy behind limb bud morphogenesis, suggesting the possibility of common principles and deep homology between facial and limb outgrowth

Фармакокинетика празиквантела и моксидектина в организме собак после применения гельмимакса

The purpose of the research is to study Praziquantel and Moxidectin pharmacokinetics in dogs after Helmimax administration.Materials and methods. Helmimax pharmacokinetics was studied on 8 adult male dogs of different breeds aged 2 to 5 years and weighing 15–35 kg. Helmimax was administered orally in the fasted state with a small amount of feed at a dose of 5 mg/kg for Praziquantel and 0.25 mg/kg for Moxidectin at the rate of 1 tablet per 10 kg of body weight. Blood was sampled at various periods after the administration. The collected blood underwent sample processing: formed element and protein precipitation, solid-phase extraction, and microfiltration. The active components were analyzed and detected by the HPLC-MS/MS. Active substances in the blood plasma were determined according to the developed technique which had been validated. The device was calibrated before the measurement.Results and discussion. As a result of the studies, the Praziquantel and Moxidectin pharmacokinetic parameters were calculated. The maximum concentration was 0.240 and 0.130 μg/mL, the time-to-peak concentration was 2.15 and 1.48 hours, and the elimination half-life was 8.41 and 3.61 hours for Moxidectin and Praziquantel, respectively.Цель исследований – изучение фармакокинетики празиквантела и моксидектина в организме собак после применения гельмимакса.Материалы и методы. Исследования фармакокинетики гельмимакса проводили на 8 взрослых собаках самцах массой тела 15–35 кг разных пород в возрасте от 2 до 5 лет. Гельмимакс вводили перорально натощак с небольшим количеством корма в дозе 5 мг/кг по празиквантелу и 0,25 мг/кг по моксидектину из расчета 1 таблетка на 10 кг массы тела. Отбор крови проводили через различные временные интервалы после введения. Отобранную кровь подвергали пробоподготовке: осаждение форменных элементов, белков, твердофазная экстракция, микрофильтрация. Анализ и детектирование действующих компонентов проводили методом ВЭЖХ МС/МС. Определение действующих веществ в плазме крови проводили по разработанной методике, которая прошла валидацию. Перед измерением осуществляли калибровку прибора.Результаты и обсуждение. В результате проведенных исследований были рассчитаны фармакокинетические показатели празиквантела и моксидектина. Максимальная концентрация составила 0,240 и 0,130 мкг/мл, время достижения максимальной концентрации 2,15 и 1,48 ч, период полувыведения 8,41 и 3,61 ч для моксидектина и празиквантела соответственно

Estrogen/Estrogen Receptor Alpha Signaling in Mouse Posterofrontal Cranial Suture Fusion

BACKGROUND: While premature suture fusion, or craniosynostosis, is a relatively common condition, the cause is often unknown. Estrogens are associated with growth plate fusion of endochondral bones. In the following study, we explore the previously unknown significance of estrogen/estrogen receptor signaling in cranial suture biology. METHODOLOGY/PRINCIPAL FINDINGS: Firstly, estrogen receptor (ER) expression was examined in physiologically fusing (posterofrontal) and patent (sagittal) mouse cranial sutures by quantitative RT-PCR. Next, the cranial suture phenotype of ER alpha and ER beta knockout (alphaERKO, betaERKO) mice was studied. Subsequently, mouse suture-derived mesenchymal cells (SMCs) were isolated; the effects of 17-beta estradiol or the estrogen antagonist Fulvestrant on gene expression, osteogenic and chondrogenic differentiation were examined in vitro. Finally, in vivo experiments were performed in which Fulvestrant was administered subcutaneously to the mouse calvaria. Results showed that increased ERalpha but not ERbeta transcript abundance temporally coincided with posterofrontal suture fusion. The alphaERKO but not betaERKO mouse exhibited delayed posterofrontal suture fusion. In vitro, addition of 17-beta estradiol enhanced both osteogenic and chondrogenic differentiation in suture-derived mesenchymal cells, effects reversible by Fulvestrant. Finally, in vivo application of Fulvestrant significantly diminished calvarial osteogenesis, inhibiting suture fusion. CONCLUSIONS/SIGNIFICANCE: Estrogen signaling through ERalpha but not ERbeta is associated with and necessary for normal mouse posterofrontal suture fusion. In vitro studies suggest that estrogens may play a role in osteoblast and/or chondrocyte differentiation within the cranial suture complex

Identification of DHX9 as a cell cycle regulated nucleolar recruitment factor for CIZ1

CIP1-interacting zinc finger protein 1 (CIZ1) is a nuclear matrix associated protein that facilitates a number of nuclear functions including initiation of DNA replication, epigenetic maintenance and associates with the inactive X-chromosome. Here, to gain more insight into the protein networks that underpin this diverse functionality, molecular panning and mass spectrometry are used to identify protein interaction partners of CIZ1, and CIZ1 replication domain (CIZ1-RD). STRING analysis of CIZ1 interaction partners identified 2 functional clusters: ribosomal subunits and nucleolar proteins including the DEAD box helicases, DHX9, DDX5 and DDX17. DHX9 shares common functions with CIZ1, including interaction with XIST long-non-coding RNA, epigenetic maintenance and regulation of DNA replication. Functional characterisation of the CIZ1-DHX9 complex showed that CIZ1-DHX9 interact in vitro and dynamically colocalise within the nucleolus from early to mid S-phase. CIZ1-DHX9 nucleolar colocalisation is dependent upon RNA polymerase I activity and is abolished by depletion of DHX9. In addition, depletion of DHX9 reduced cell cycle progression from G1 to S-phase in mouse fibroblasts. The data suggest that DHX9-CIZ1 are required for efficient cell cycle progression at the G1/S transition and that nucleolar recruitment is integral to their mechanism of action

Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage.

Cartilaginous structures are at the core of embryo growth and shaping before the bone forms. Here we report a novel principle of vertebrate cartilage growth that is based on introducing transversally-oriented clones into pre-existing cartilage. This mechanism of growth uncouples the lateral expansion of curved cartilaginous sheets from the control of cartilage thickness, a process which might be the evolutionary mechanism underlying adaptations of facial shape. In rod-shaped cartilage structures (Meckel, ribs and skeletal elements in developing limbs), the transverse integration of clonal columns determines the well-defined diameter and resulting rod-like morphology. We were able to alter cartilage shape by experimentally manipulating clonal geometries. Using in silico modeling, we discovered that anisotropic proliferation might explain cartilage bending and groove formation at the macro-scale

Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage

Cartilaginous structures are at the core of embryo growth and shaping before the bone forms. Here we report a novel principle of vertebrate cartilage growth that is based on introducing transversally-oriented clones into pre-existing cartilage. This mechanism of growth uncouples the lateral expansion of curved cartilaginous sheets from the control of cartilage thickness, a process which might be the evolutionary mechanism underlying adaptations of facial shape. In rod-shaped cartilage structures (Meckel, ribs and skeletal elements in developing limbs), the transverse integration of clonal columns determines the well-defined diameter and resulting rod-like morphology. We were able to alter cartilage shape by experimentally manipulating clonal geometries. Using in silico modeling, we discovered that anisotropic proliferation might explain cartilage bending and groove formation at the macro-scale