ABSTRACT
Activating mutations in the FGFR3 receptor tyrosine kinase lead to most prevalent form of genetic dwarfism in humans, the achondroplasia. Many features of the complex function of FGFR3 in growing skeleton were characterized, which facilitated identification of therapy targets, and drove progress toward treatment. In August 2021, the vosoritide was approved for treatment of achondroplasia, which is based on a stable variant of the C-natriuretic peptide. Other drugs may soon follow, as several conceptually different inhibitors of FGFR3 signaling progress through clinical trials. Here, we review the current achondroplasia therapeutics, describe their mechanisms, and illuminate motivations leading to their development. We also discuss perspectives of curing achondroplasia, and options for repurposing achondroplasia drugs for dwarfing conditions unrelated to FGFR3.
Subject(s)
Achondroplasia , Achondroplasia/drug therapy , Achondroplasia/therapy , Humans , Mutation , Receptor, Fibroblast Growth Factor, Type 3/genetics , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Signal TransductionABSTRACT
Primary cilium is a solitary organelle that emanates from the surface of most postmitotic mammalian cells and serves as a sensory organelle, transmitting the mechanical and chemical cues to the cell. Primary cilia are key coordinators of various signaling pathways during development and maintenance of tissue homeostasis. The emerging evidence implicates primary cilia function in tooth development. Primary cilia are located in the dental epithelium and mesenchyme at early stages of tooth development and later during cell differentiation and production of hard tissues. The cilia are present when interactions between both the epithelium and mesenchyme are required for normal morphogenesis. As the primary cilium coordinates several signaling pathways essential for odontogenesis, ciliary defects can interrupt the latter process. Genetic or experimental alterations of cilia function lead to various developmental defects, including supernumerary or missing teeth, enamel and dentin hypoplasia, or teeth crowding. Moreover, dental phenotypes are observed in ciliopathies, including Bardet-Biedl syndrome, Ellis-van Creveld syndrome, Weyers acrofacial dysostosis, cranioectodermal dysplasia, and oral-facial-digital syndrome, altogether demonstrating that primary cilia play a critical role in regulation of both the early odontogenesis and later differentiation of hard tissue-producing cells. Here, we summarize the current evidence for the localization of primary cilia in dental tissues and the impact of disrupted cilia signaling on tooth development in ciliopathies.
Subject(s)
Cilia/physiology , Odontogenesis/physiology , Animals , Cell Differentiation/physiology , Humans , Maxillofacial Development/physiology , Signal Transduction/physiologyABSTRACT
OBJECTIVE: Statins are widely used drugs for cholesterol lowering, which were recently found to counteract the effects of aberrant fibroblast growth factor receptor (FGFR3) signaling in cell and animal models of FGFR3-related chondrodysplasia. This opened an intriguing therapeutic possibility for human dwarfing conditions caused by gain-of-function mutations in FGFR3, although the mechanism of statin action on FGFR3 remains unclear. Here, we determine the effect of statins on FGFR signaling in chondrocytes. DESIGN: Cultured chondrocyte cell lines, mouse embryonic tibia cultures and limb bud micromasses were treated with FGF2 to activate FGFR signaling. The effects of atorvastatin, fluvastatin, lovastatin and pravastatin on FGFR3 protein stability and on FGFR-mediated chondrocyte growth-arrest, loss of extracellular matrix (ECM), induction of premature senescence and hypertrophic differentiation were evaluated. RESULTS: Statins did not alter the level of FGFR3 protein expression nor produce any effect on FGFR-mediated inhibition of chondrocyte proliferation and hypertrophic differentiation in cultured chondrocyte cell lines, mouse tibia cultures or limb bud micromasses. CONCLUSION: We conclude that statins do not inhibit the FGFR signaling in chondrocytes. Therefore the statin-mediated rescue of FGFR3-related chondrodysplasia, described before, is likely not intrinsic to the growth plate cartilage.
Subject(s)
Chondrocytes/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors , Animals , Cell Differentiation/drug effects , Cell Line , Cells, Cultured , Chondrocytes/metabolism , Chondrogenesis/drug effects , Humans , Limb Buds/drug effects , Limb Buds/metabolism , Mice , Rats , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Signal Transduction/drug effects , Tibia/drug effects , Tibia/embryology , Tibia/growth & development , Tissue Culture TechniquesABSTRACT
We show that for a certain class of dynamics at the nodes the response of a network of any topology to arbitrary inputs is defined in a simple way by its response to a monotone input. The nodes may have either a discrete or continuous set of states and there is no limit on the complexity of the network. The results provide both an efficient numerical method and the potential for accurate analytic approximation of the dynamics on such networks. As illustrative applications, we introduce a quasistatic mechanical model with objects interacting via frictional forces and a financial market model with avalanches and critical behavior that are generated by momentum trading strategies.
Subject(s)
Financial Management , Friction , Models, Theoretical , Plastics , Computer Simulation , ElasticityABSTRACT
Marinesco-Sjögren syndrome (MSS; MIM 248800) is an autosomal recessive disorder characterized by congenital cerebellar ataxia, early cataracts, developmental delay, myopathy and short stature. Alterations in the gene SIL1 cause MSS in some patients with typical findings. In this study, molecular investigations including sequencing of the SIL1 gene, western blotting and microscopic investigations in fibroblast cultures were carried out in a cohort of 15 patients from 14 unrelated families, including the large, inbred family reported by Superneau et al., having the clinical features of MSS to provide insights into the pathophysiology of the disorder. A total of seven different mutations were found in eight of the patients from seven families. The mutations caused loss of the BIP-associated protein (BAP) protein in four patients by western blot. Novel clinical features such as dental abnormalities, iris coloboma, eczema and hormonal abnormalities were noticed in some patients, but there was no clear way to distinguish those with and without SIL1 mutations. Cultured fibroblasts contained numerous cytoplasmic inclusion bodies, similar to those identified in the brain of the whoozy mouse in five unrelated patients, three with and two without SIL1 mutations, suggesting some SIL1 negative patients share a common cellular pathogenesis with those who are SIL1 positive.
Subject(s)
Guanine Nucleotide Exchange Factors/genetics , Phenotype , Spinocerebellar Degenerations/genetics , Spinocerebellar Degenerations/physiopathology , Base Sequence , Blotting, Western , Child, Preschool , DNA Primers/genetics , Female , Genotype , Humans , Infant , Male , Microscopy, Electron, Transmission , Molecular Sequence Data , Mutation/genetics , Sequence Analysis, DNAABSTRACT
AIM: In this study, we analysed the post-translational modification of receptor tyrosine kinase-like orphan receptor (Ror1). Ror1 is highly upregulated in B cells of patients with chronic lymphocytic leukaemia (CLL). Molecularly, Ror1 acts as the Wnt receptor in the non-canonical Wnt pathway. METHODS: The level of Ror1 glycosylation in HEK293 cells and in primary human CLL cells was analysed by treatment of inhibitors interfering with different steps of glycosylation process and by direct treatment of cell lysates with N-glycosidase. Ror1 ubiquitination was determined by ubiquitination assay. Functional consequences of post-translational modifications were analysed by immunohistochemistry and by analysis of cell surface proteins. Differences in Ror1 glycosylation were confirmed by analysis of 14 samples of B cells from CLL patients. RESULTS: We demonstrate that Ror1 is extensively modified by N-linked glycosylation. Glycosylation produces several variants of Ror1 with electrophoretic migration of approx. 100, 115 and 130 kDa. Inhibition of glycosylation interferes with cell surface localization of the 130-kDa variant of Ror1 and prevents Ror1-induced formation of filopodia. Moreover, we show that 130-kDa Ror1 is mono-ubiquitinated. Furthermore, individual CLL patients show striking differences in the electrophoretic migration of Ror1, which correspond to the level of glycosylation. CONCLUSION: Our data show that Ror1 undergoes complex post-translational modifications by glycosylation and mono-ubiquitination. These modifications regulate Ror1 localization and signalling, and are highly variable among individual CLL patients. These may suggest that Ror1 signals only in a subset of CLL patients despite Ror1 levels are ubiquitously high in all CLL patients.
Subject(s)
B-Lymphocytes/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Protein Processing, Post-Translational , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Signal Transduction , Animals , Blotting, Western , CHO Cells , Cricetinae , Cricetulus , Electrophoresis, Polyacrylamide Gel , Flow Cytometry , Glycosylation , HEK293 Cells , Humans , Immunohistochemistry , Microscopy, Confocal , Molecular Weight , Protein Processing, Post-Translational/drug effects , Protein Transport , Pseudopodia/metabolism , Receptor Tyrosine Kinase-like Orphan Receptors/chemistry , Receptor Tyrosine Kinase-like Orphan Receptors/genetics , Signal Transduction/drug effects , Transfection , UbiquitinationABSTRACT
IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138(+) cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and in vivo. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.
Subject(s)
Janus Kinase 2/antagonists & inhibitors , Multiple Myeloma/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects , Animals , Apoptosis/drug effects , Bone Marrow Cells/physiology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclin D2/physiology , Humans , Interleukin-6/pharmacology , MAP Kinase Signaling System/drug effects , Mice , Multiple Myeloma/pathologyABSTRACT
Fibroblast growth factor 2 (FGF2) is one of the most studied growth factors to date. Most attention has been dedicated to the smallest, 18 kDa FGF2 variant that is released by cells and acts through activation of cell-surface FGF-receptor tyrosine kinases. There are, however, several higher molecular weight (HMW) variants of FGF2 that rarely leave their producing cells, are retained in the nucleus and act independently of FGF-receptors (FGFR). Despite significant evidence documenting the expression and intracellular trafficking of HMW FGF2, many important questions remain about the physiological roles and mechanisms of action of HMW FGF2. In this review, we summarize the current knowledge about the biology of HMW FGF2, its role in disease and areas for future investigation.
Subject(s)
Protein Isoforms/chemistry , Protein Isoforms/metabolism , Receptors, Fibroblast Growth Factor/chemistry , Receptors, Fibroblast Growth Factor/metabolism , Animals , Fibroblast Growth Factor 2/genetics , Fibroblast Growth Factor 2/metabolism , Gene Expression Regulation , Humans , Molecular Weight , Phenotype , Protein Isoforms/genetics , Receptors, Fibroblast Growth Factor/genetics , Ribonucleoprotein, U2 Small Nuclear/metabolism , Ribosomal Proteins/metabolism , SMN Complex Proteins/metabolismSubject(s)
Fibroblast Growth Factors/genetics , Multiple Myeloma/genetics , Receptor, Fibroblast Growth Factor, Type 3/genetics , Cell Line, Tumor , Fibroblast Growth Factors/metabolism , Genetic Variation , Humans , Ligands , Multiple Myeloma/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Signal Transduction , Up-RegulationSubject(s)
Fibroblast Growth Factor 2/biosynthesis , Leukemia/metabolism , Lymphoma/metabolism , Neoplasm Proteins/biosynthesis , Apoptosis , Apoptosis Regulatory Proteins , Autocrine Communication , Cell Division , Culture Media, Conditioned/chemistry , Fibroblast Growth Factor 2/genetics , Fibroblast Growth Factor 2/metabolism , Fibroblast Growth Factor 2/pharmacology , Gene Expression Regulation, Neoplastic , Humans , Leukemia/genetics , Leukemia/pathology , Lymphoma/genetics , Lymphoma/pathology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Receptors, Fibroblast Growth Factor/biosynthesis , Receptors, Fibroblast Growth Factor/genetics , Signal Transduction , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolismABSTRACT
Fibroblast growth factor receptors (FGFR1-4) are implicated in various cellular events, including cell growth and transformation. Here, we showed that patients suffering from chronic myeloid leukaemia (CML) express high levels of FGFR3 mRNA in white blood cells (WBCs). After stem cell transplantation and reconstitution of haematopoiesis, the expression of FGFR3 decreased and was maintained at low levels that are typical of healthy individuals. However, FGFR3 expression became upregulated again in those patients that had accelerated BCR/ABL rearrangement and underwent relapse of leukaemia. Our findings suggest that, in CML, the changing levels of FGFR3 transcripts in WBCs may have prognostic significance.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/surgery , Leukocytes/metabolism , Protein-Tyrosine Kinases , RNA, Messenger/metabolism , Receptors, Fibroblast Growth Factor/genetics , Gene Expression , Genetic Markers , Humans , RNA, Messenger/analysis , Receptor, Fibroblast Growth Factor, Type 3 , Recurrence , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, HomologousABSTRACT
Differentiating myeloid cells may become resistant to various apoptotic stimuli. In the present study, dimethyl sulfoxide (DMSO) and all-trans retinoic acid (ATRA) were found to modulate the sensitivity of HL-60 cells to death receptor-mediated apoptosis in a time-dependent manner. During the early stages of differentiation, DMSO treatment increased the response of HL-60 cells to tumor necrosis factor alpha; (TNF-alpha), but enhanced responsiveness was lost during later differentiation stages. In contrast, ATRA treatment induced resistance to TNF-alpha-induced apoptosis. HL-60 cells were resistant to Fas-mediated apoptosis but were sensitized by culturing in serum-free conditions. Similar to its effect on TNF-alpha sensitivity, DMSO pretreatment augmented the response to Fas-mediated signaling, which coincided with increased expression of Fas on DMSO-pretreated cells. However, during the later stages of DMSO-induced differentiation, sensitivity to anti-Fas antibody-induced apoptosis declined significantly, although Fas expression was still elevated. The reduced sensitivity to anti-Fas treatment partially correlated with increased Fas-associated phosphatase-1 mRNA expression. Thus, regardless of either Fas up-regulation or potentiation of TNF-alpha-mediated apoptosis during early DMSO-induced differentiation, a slow increase in resistance to apoptosis mediated through these death receptors occurs during DMSO-induced differentiation, which contrasts with the rapid induction of resistance following treatment with ATRA.
Subject(s)
Apoptosis , Carrier Proteins/metabolism , Protein Tyrosine Phosphatases/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Antibodies, Monoclonal/metabolism , Antigens, CD/biosynthesis , Carrier Proteins/genetics , Cell Differentiation , Culture Media, Serum-Free , Dimethyl Sulfoxide/pharmacology , HL-60 Cells , Humans , Kinetics , Leukemia, Myeloid , Protein Phosphatase 1 , Protein Tyrosine Phosphatase, Non-Receptor Type 13 , Protein Tyrosine Phosphatases/genetics , Proto-Oncogene Proteins c-bcl-2/biosynthesis , RNA, Messenger , Receptors, Tumor Necrosis Factor/biosynthesis , Receptors, Tumor Necrosis Factor, Type II , Tretinoin/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Up-Regulation , fas Receptor/metabolismABSTRACT
An elevated level of fibroblast growth factor-2 (FGF-2) in peripheral blood is considered to play a role in regulating the growth of leukemia cells. Here, we show that the level of plasma FGF-2 is increased in 54% of B cell chronic lymphocytic leukemias (B-CLL) and in 44% of chronic myeloid leukemias (CML). Notably, white blood cells (WBCs) from B-CLL patients contain 18, 22 and 24 kDa isoforms of FGF-2 whereas WBCs from CML patients contain only the 24 kDa isoform. Furthermore, as cultured B-CLL WBCs release 18 kDa FGF-2 into the medium, they constitute a potential source of FGF-2 in the blood. In a receptor binding assay, 125I-FGF-2 binds weakly to B-CLL WBCs, whereas the ligand binds more strongly to CML WBCs. Correspondingly, FGF-2 is unable to activate mitogen-activated protein kinase kinase (MEK) and its substrate, extracellular signal-regulated kinase (ERK), in B-CLL cells, whereas phosphorylation of both these cell growth-related kinases increases following treatment of CML WBCs. We conclude that B-CLL WBCs secrete FGF-2 with no apparent autocrine actions. In contrast, WBCs in CML bind FGF-2 provided by other FGF-2-hyperproducing cells and activate the MEK/ERK kinase cascade, possibly to modulate cell growth.
Subject(s)
Fibroblast Growth Factor 2/blood , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Adult , Aged , Aged, 80 and over , Base Sequence , Culture Media, Conditioned , DNA Primers , Female , Fibroblast Growth Factor 2/chemistry , Humans , Male , Middle Aged , Molecular Weight , RNA, Messenger/genetics , Receptors, Fibroblast Growth Factor/geneticsABSTRACT
Effects of infusions of neuropeptide Y (NPY) into 3rd ventricle of growing sheep fed on diets containing restricted (R) or elevated (E) levels of protein on the immunoreactive (ir) somatostatin neurones, ir somatotrophs, growth hormone (GH) concentration in the blood plasma were studied. The long-term restriction of protein in the diet elicited: enhancing irSS content in periventricular perikarya; diminishing irSS stores in the median eminence and elevating the number ir somatotrophs and content of irGH. NPY infusions enhanced the content of irSS in perikarya in sheep fed on E diet and diminished the number of ir somatotrophs and content of irGH of sheep fed on R diet. The R diet as well as NPY infusions caused an increase in GH mean concentrations in the blood plasma. Obtained results suggest that stimulatory effect of restricted feeding and/or NPY action on GH secretion can be due to attenuated SS output. Since dietary restrictions and exogenous NPY have similar influence on the activation of GH secretion, we suggest that NPY could be a neuromodulatory link between nutritional cues and somatotropic axis in sheep.
Subject(s)
Dietary Proteins/pharmacology , Growth Hormone/blood , Hypothalamo-Hypophyseal System/drug effects , Neuropeptide Y/pharmacology , Animals , Body Weight , Diet, Protein-Restricted , Female , Growth Hormone/analysis , Hypothalamo-Hypophyseal System/chemistry , Injections, Intraventricular , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor I/metabolism , Median Eminence/chemistry , Median Eminence/drug effects , Paraventricular Hypothalamic Nucleus/chemistry , Paraventricular Hypothalamic Nucleus/drug effects , Pituitary Gland, Anterior/chemistry , Pituitary Gland, Anterior/drug effects , Protein-Energy Malnutrition/blood , Protein-Energy Malnutrition/physiopathology , Sheep , Somatostatin/analysis , Somatostatin/metabolismABSTRACT
During development, fibroblast growth factors (FGFs) serve highly specific functions that are mediated through high-affinity transmembrane receptors and modulated by membrane-bound proteoglycans. Proteoglycans, in an embryonic environment called embryoglycans, contain numerous carbohydrate ectodomains, the structure of which undergoes rearrangement. Since they can be lost from the cell surface, they are sometimes found in extracellular space where they may also serve some regulatory function. Here we address the potential roles of three naturally occurring isoforms of Lewis X (LeX) in FGF-2-mediated proliferation of embryonic stem (ES) cells. We have found that the addition of sulfated LeX to ES cells at a concentration of 17 nM promotes FGF-2 mitogenic activity while a 10-fold higher concentration leads to a reduction of FGF-2-mediated proliferation. Notably, this dose-dependent modulation operated only for sulfated LeX. Other fucosylated motifs, basic LeX trisaccharide and sialylated LeX, also affected ES cell proliferation but the mechanism cannot be clearly correlated with the presence or absence of FGF-2. The suppression of biosynthesis of O-linked carbohydrates including LeX reduced basal proliferation of ES cells and interfered with the mitogenic effect of FGF-2. However, in inhibitor-treated cells, the stimulatory activity of FGF-2 can be reestablished to its original level by exogenous LeX oligosaccharides. Our results show that (A) O-linked LeX oligosaccharides can regulate mitogenic activity of FGF-2 in embryonic cells, (B) and this ability varies with subtle modifications in their structure. Importantly, our data represent the first insight into the mechanism of how growth factor activities might be modulated by shedded embryoglycan ectodomains.
Subject(s)
Embryo, Mammalian/metabolism , Fibroblast Growth Factor 2/metabolism , Lewis X Antigen/metabolism , Proteoglycans/metabolism , Animals , Cell Division/physiology , Cells, Cultured , Embryo, Mammalian/cytology , Female , Immunoblotting , Mice , Mice, Inbred Strains , Pregnancy , Proteoglycans/biosynthesis , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, Fibroblast Growth Factor, Type 1 , Receptor, Fibroblast Growth Factor, Type 2 , Receptors, Fibroblast Growth Factor/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/metabolism , Uterus/metabolismABSTRACT
It has been established that sows up- or down-regulate their milk production as the frequency of nursings is changed. The amount of udder massage by piglets might also influence milk production. To investigate whether these effects are associated with changes in prolactin or insulin levels, we enforced five sows each to nurse either every 35 min (MIN35) or every 70 min (MIN70) over a 26- to 28-hr period. Milk production was measured during the first 24 hr of this period. During the last three to four nursings, blood was collected every 5 min. Plasma prolactin levels increased after milk ejection (P < 0.05), whereas insulin levels increased only briefly in MIN70 sows. Sows nursing every 35 min had lower basal (P < 0.001) and maximal (P < 0.05) concentrations of insulin than MIN70 sows. There were no differences between the two groups in prolactin levels. Nursings with a postejection udder massage longer than 90 s tended to induce a higher increase in prolactin (P < 0.1) than nursings with a shorter massage. When the effects of imposed nursing frequency were removed, there was an across-sows positive residual correlation between average prolactin levels (P < 0.05) and the duration of post-ejection udder massage during the preceding 24 hr. We conclude that when milk production of a sow is changed by altering the nursing frequency within natural limits, the necessary alteration in catabolic state of energy metabolism may be associated with altered insulin levels. The duration of udder massage in a single nursing might have only a slight immediate impact on prolactin levels, but may influence prolactin levels more substantially if increased for a period of 24 hr.
Subject(s)
Insulin/blood , Lactation , Prolactin/blood , Swine/blood , Animals , Animals, Suckling , Female , Maternal Behavior , Time Factors , Weight GainABSTRACT
Three-month old Polish Lowland female lambs were fed isocaloric diets containing 14.2% (standard) or 8.1% of proteins for twenty weeks. Changes in body weight were characteristic for normal growth performance in all animals, but daily body gain calculated for the whole experimental period was significantly lower in lambs fed a low protein diet (87.9 +/- 13.5 and 158 +/- 13.8 g/day, respectively). Two series of blood collections (4 hrs with 15 min interval) were performed at age of 21 and 26 weeks in order to analyze the growth hormone (GH) concentration in the peripheral blood. The results obtained by radioimmunoassay showed that at both ages the mean concentration of GH was significantly higher in the group fed a low protein diet (4.84 +/- 2.23 and 3.68 +/- 1.86 vs 1.46 +/- 0.72 and 1.48 +/- 0.44 ng/ml, respectively) and this difference was associated with significant elevation of the pulse amplitude (3.83 +/- 4.23 and 4.54 +/- 3.06 vs 1.48 +/- 1.11 and 1.31 +/- 0.68 ng/ml, respectively). Using immunocytochemistry, the somatostatin in the hypothalamus and the GH in the pituitary cells were analyzed in all animals slaughtered at age of 8 months. Lowering the content of dietary proteins diminished markedly the content of immunoreactive somatostatin in the median eminence (ME) and augmented the concentrations of the immunoproduct in the somatostatin perikarya. In the pituitary gland, a marked increase of the number of GH-producing cells was observed. The results obtained indicate that chronic restriction of dietary proteins, irrespective of sufficient energy supply, augment the secretion of GH via a decrease in the hypothalamic somatostatin output due to the suppression of its axonal transport.
Subject(s)
Aging/physiology , Diet, Protein-Restricted , Growth Hormone/metabolism , Hypothalamus/physiology , Neurons/physiology , Pituitary Gland, Anterior/physiology , Protein-Energy Malnutrition/physiopathology , Animals , Body Weight , Female , Growth Hormone/analysis , Growth Hormone/blood , Hypothalamus/cytology , Hypothalamus/physiopathology , Neurons/cytology , Pituitary Gland, Anterior/cytology , Pituitary Gland, Anterior/physiopathology , Reference Values , SheepABSTRACT
An inherited basis for sleep-disordered breathing (SDB) has been suggested by reports of families with multiple affected members and by a previous study of the familial aggregation of symptoms of SDB. In this study, we quantify and characterize the aggregation of SDB and assess the degree to which familial similarities may be independent of obesity. This was a genetic-epidemiologic study that assessed the distribution of SDB in families identified through a proband with diagnosed sleep apnea and among families in the same community with no relative with known sleep apnea. SDB was assessed with overnight in-home monitoring of airflow, oxygen saturation, chest wall impedance, heart rate, and body movement. Standardized questionnaires were used to assess symptoms, and weight, height, and neck circumference were measured directly. Intergenerational and intragenerational correlation coefficients and pairwise odds ratios (ORs) were calculated with adjustment for proband sampling. In toto, 561 members of 91 families were studied: (1) 47 subjects with laboratory-confirmed SDB (index probands), (2) 44 community control subjects, and (3) the spouses and relatives of 1 and 2. Of all 91 families, 32 (35%) had two or more members with SDB, 30 (33%) had one affected member, and 29 had no affected members. SDB was more prevalent in the relatives of index probands (21%) than among neighborhood control subjects (12%) (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Sleep Apnea Syndromes/epidemiology , Sleep Apnea Syndromes/genetics , Adult , Body Mass Index , Female , Humans , Logistic Models , Male , Middle Aged , Neck/anatomy & histology , Obesity/epidemiology , Obesity/genetics , Odds Ratio , Polysomnography , Prevalence , Risk FactorsABSTRACT
Milk production, plasma bovine somatotropin (bST) and insulin-like growth factor I (IGF-I) were measured in dairy cows following a single subcutaneous injection of a slowly released preparation of either recombinant enterokinase linker bST (somidobove: 640 mg) or recombinant methionyl bST (sometribove: 500 mg). There was a 3-7-fold increase in plasma bST concentrations during the first three postinjection hours in cows treated with both sometribove (from 3.4 +/- 0.8 to 11.2 +/- 3.0 ng ml-1) or somidobove (from 2.3 +/- 0.3 to 17.5 +/- 2.6 ng ml-1). In the next 8 days the bST concentration in the bST-treated cows varied, but was still significantly increased above the controls. In the following days, the concentrations of bST did not differ from the controls. Plasma concentrations of IGF-I increased nearly 2-fold as early as 24 h following recombinant bST administration and then continued to rise so that by 48 h postinjection they were nearly four times higher (control 16.2, bST-treated 61.7 ng ml-1). From 48 h after sometribove injection, IGF-I concentrations remained at a plateau (varying between 60.4 and 85.7 ng ml-1) till day 11. Then it decreased slowly, but still remained higher on day 14 than those in placebo-treated cows (44.4 +/- 17.8 ng ml-1 in bST-treated animals; 12.2 +/- 7.5 ng ml-1 in the controls). Although IGF-I level was increasing in all bST-treated animals, the absolute IGF-I increase was not related to the increase in milk production.
Subject(s)
Growth Hormone/blood , Insulin-Like Growth Factor I/metabolism , Animals , Cattle , Delayed-Action Preparations , Female , Growth Hormone/administration & dosage , Growth Hormone/pharmacokinetics , Lactation/drug effects , Milk/physiology , Recombinant Proteins/administration & dosage , Recombinant Proteins/blood , Recombinant Proteins/pharmacokineticsABSTRACT
Bioptic samples from the vastus lateralis muscle were analyzed in a group of Czechoslovak representatives in the Nordic combination (ski-jumping and 15 km cross-country skiing). The distribution of individual muscle fibre types (FG, FOG and SO) was detected and correlated with values obtained by motor and functional performance tests. Histochemical analysis of the bioptic samples revealed a considerably heterogeneous distribution of muscle fibre types in the group studied. No typical profilation for this sport discipline was found. Weak correlation between the proportion of fast muscle fibres and explosive strength parameters was ascertained. The correlation between the proportion of slow muscle fibres and the capacity of O2 utilization (VO2max) was statistically significant. Strong correlation between the proportion of fast twitch fibres and relative maximal strength of knee extensors (N/kg) was disclosed. A non-linear relation between the area of fast twitch fibres and vigour of take-off was found.