Vasopressin receptors: structural functional relationships and role in neural and endocrine regulation.
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Amino Acid Sequence↗
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Growth hormone. A paracrine growth factor?
A number of tissues, including the brain, pituitary, immune system, placenta, mammary gland, and testis, may be self-contained units of GH regulation, production, and action. The production of GH and GH-releasing factors outside the hypothalamo-pituitary axis complements, rather than replaces, the traditional endocrine interactions between GH-releasing factors, GH, and its target tissues.
Animals↗
GnRH receptors in human breast cancer and its contiguous not-involved breast tissue.
The present study was undertaken to evaluate the presence of GnRH receptors (GnRH-R) in breast cancer and not-involved breast tissue, and the relationships between GnRH-R and receptors for estrogen (ER) and progesterone (PgR) in the same tissues. Utilizing a tritiated natural GnRH in order to assay the native receptor binding we analyzed the level of binding sites for GnRH in membranes derived from 90 breast tumors and in 40 cases from neighboring, not-involved breast tissue. GnRH-R was found both in cancer and normal tissues. The prevalence for GnRH-R was higher in tumor than in not-tumor tissue (45% vs 39%, respectively), but the overall levels were not significantly different (15.9+/-24 fmol/mg protein vs 18.2+/-39 fmol/mg protein, respectively). The only statistically different content of GnRH-R we found concerned PgR negative vs PgR positive tumor tissues (mean content: 23 vs 11 fmol/mg protein, respectively in PgR- and PgR+ tumors, p=0.03 by t test); furthermore the proportion of GnRH-R positive cases in the tumor resulted significantly higher in premenopausal patients vs postmenopausal (56% vs 32%, by Chi square test, p<0.05). The GnRH receptors status of primary tumor and contiguous not-involved breast tissue resulted associated (overall agreement: 63%, p<0.05) but no specific steroid patterns for GnRH-R positivity was observed.
Binding Sites↗
Paracrine and endocrine roles of insulin-like factor 3.
Insulin-like factor 3 (INSL3) is expressed in Leydig cells of the testis and theca cells of the ovary. This peptide affects testicular descent by acting on gubernaculum via its specific receptor leucine-rich repeat-containing G protein-coupled receptor 8 (LGR8). From initial animal data showing the cryptorchid phenotype of Insl3/Lgr8 mutants, an extensive search for mutations in INSL3 and LGR8 genes was undertaken in human patients with cryptorchidism, and a frequency of mutation of 4-5% has been detected. However, definitive proofs of a causative role for some of these mutations are still lacking. More recent data suggest additional paracrine (in the testis and ovary) and endocrine actions of INSL3 in adults. INSL3 circulates at high concentrations in serum of adult males and its production is dependent on the differentiation effect of LH. Therefore, INSL3 is increasingly used as a specific marker of Leydig cell differentiation and function.
Animals↗
Effects of radiation therapy on chondrocytes in vitro.
The negative irradiation complications of growth loss leading to limb length asymmetry and pathological fracture incurred following radiation therapy in pediatric patients has led to a renewed interest in understanding the specific effects of irradiation on the growth plate and the surrounding bone. In the present report, we examined the radiation therapy effects on primary rat growth cartilage chondrocytes in order to determine the chondrocyte radiosensitivity relative to other bone cell constituents and tumor cells, the postirradiation temporal progression of radiation-induced alterations in chondrocyte function, and the time course for the functional restoration of chondrocyte pathways that drive the eventual recovery in growth function. We employed an in vitro primary rat costochondral growth cartilage cell culture model system to evaluate the radiation therapy effects on proliferative chondrocytes using serial radiation doses (0-20 Gy) that are well within the clinically relevant range. Following irradiation, all of the following occurred in a dose-dependent manner: proliferation decreased, cytotoxicity increased, several markers of apoptosis increased, markers of radiation-induced cellular differentiation increased, and cell synthetic activity was disturbed. Alterations in proliferation, cell death, and induction of apoptosis are likely due to a transient radiation-induced derangement of the parathyroid hormone-related protein-Indian hedgehog proliferation-maturation pathway. Alterations in cellular differentiation and cell synthetic activity are novel observations for chondrocytes. Further, these results correspond very well to our previous work in an in vivo Sprague-Dawley rat model, making this model particularly relevant to researching the radiation therapy effects on longitudinal growth.
Alkaline Phosphatase↗
GABA and glutamate specifically induce contractions in the sponge Tethya wilhelma.
Sponges (Porifera) are nerve- and muscleless. Nevertheless, they react to external stimuli in a coordinated way, by body contraction, oscule closure or stopping pumping activity. The underlying mechanisms are still unknown, but evidence has been found for chemical messenger-based systems. We used the sponge Tethya wilhelma to test the effect of gamma-aminobutyric acid (GABA) and glutamate (L: -Glu) on its contraction behaviour. Minimal activating concentrations were found to be 0.5 microM (GABA) and 50 microM (L: -Glu), respectively. Taking maximum relative contraction speed and minimal relative projected body area as a measure of the sponge's response, a comparison of the dose-response curves indicated a higher sensitivity of the contractile tissue for GABA than for L: -Glu. The concentrations eliciting the same contractile response differ by about 100-fold more than the entire concentration range tested. In addition, desensitising effects and spasm-like reactions were observed. Presumably, a GABA/L: -Glu metabotropic receptor-based system is involved in the regulation of contraction in T. wilhelma. We discuss a coordination system for sponges based on hypothetical chemical messenger pathways.
Analysis of Variance↗
Involvement of insulin-like growth factor-I in psoriasis as a paracrine growth factor: dermal fibroblasts play a regulatory role in developing psoriatic lesions.
To investigate the contribution of dermal fibroblasts to the development of psoriasis, we examined the expression of mRNA for insulin-like growth factor-I (IGF-I) and its regulator IGF-I binding proteins (IGFBPs) in psoriatic fibroblasts by RT-PCR. We also studied the effect of inflammatory cytokines including interferon gamma (IFN-gamma), tumor necrosis factor alfa (TNF-alpha), and IFN-alpha on the expression of IGF-I and IGFBPs in the fibroblasts. Semiquantitative analysis revealed that IGF-I mRNA expression in psoriatic fibroblasts (PF) was significantly higher than in control fibroblasts (CF). However, no significant difference in IGF-I mRNA was shown between nonlesional psoriatic fibroblasts (NF) and CF. Treatment with IFN-alpha in vitro upregulated IGF-I mRNA in PF and in CF. TNF-alpha appeared to downregulate IGF-I mRNA in PF but had no effect on CF. IFN-gamma did not show a significant effect on IGF-I mRNA levels in any type of fibroblast. IGFBP-3 mRNA was expressed equally in PF and CF, and was not affected by cytokines. The expression of IGFBP-5 mRNA in PF was downregulated by IFN-gamma and TNF-alpha. Taken together, these results indicate that dermal fibroblasts may contribute to the epidermal hyperplasia of psoriasis by promoting keratinocyte proliferation through IGF-I, whose secretion could be modulated by inflammatory cytokines.
Adolescent↗
Paracrine role of soluble guanylate cyclase and type III nitric oxide synthase in ovine fetal pulmonary circulation: a double labeling immunohistochemical study.
Endothelial nitric oxide synthase (eNOS) or NOS-III in the endothelium catalyzes production of nitric oxide (NO). Nitric oxide diffuses freely into vascular smooth muscle, where it activates soluble guanylate cyclase (sGC) to produce guanosine 3',5'-cyclic monophosphate (cGMP) and causes vasorelaxation. The NO/cGMP pathway is an important signaling pathway in the control of perinatal pulmonary circulation. An exact colocalization of NOS-III in the pulmonary endothelium and sGC in the vascular smooth muscle was demonstrated using a double immunolabeling technique. The sGC immunoreactivity was higher in resistant pulmonary vessels and veins than in conduit arteries, whereas NOS-III immunoreactivity was higher in conduit arteries than in veins. These results demonstrated anatomically in situ a paracrine role of NOS-III and sGC in the regulation of fetal pulmonary circulation and suggested a heterogeneous distribution of NOS-III and sGC within fetal ovine pulmonary vasculature. Our results provided an anatomic basis that supported previous functional studies on perinatal control of pulmonary circulation.
Animals↗
Immunohistochemical study of NGF and its receptors in the synovial membrane of the ankle joint of adjuvant-induced arthritic rats.
To study the role of nerve growth factor (NGF) in local inflammation, we investigated the expression of NGF and its receptors, trkA and p75, in the ankle joints of adjuvant-induced arthritic rats. Infiltrated mononuclear cells revealed a positive immunoreactivity for NGF and trkA; they were also positive for immunostaining for W3/25 and ED1, which mainly stain T cells and macrophages, respectively. Changes in the ratios of NGF-positive cells to mononuclear cells showed a relatively similar pattern for trkA-positive cells, which peaked at weeks 2 to 3 after the adjuvant injection. In double-immunofluorescence staining, 80% and 65% of NGF-positive cells stained for W3/25 and ED1, respectively. Similarly, 67% and 80% of trkA-positive cells also corresponded to W3/25- and ED1-positive cells, respectively. However, p75 immunoreactivity localized on the nerve fibers but not on the cells of the ankle joints. Dense meshworks of p75-positive nerve fibers with numerous terminal varicosities were observed at weeks 2 to 4. The present findings suggest that infiltrated mononuclear cells may secrete NGF in an autocrine or paracrine manner in the inflamed synovium. An upregulation of NGF in these mononuclear cells and an increase in density of the synovial nerve fibers may be involved in the development of adjuvant arthritis in rats.
Animals↗
Gastrin: old hormone, new functions.
It is exactly a century since the gastric hormone gastrin was first described as a blood-borne regulator of gastric acid secretion. The identities of the main active forms of the hormone (the "classical gastrins") and their cellular and molecular sites of action in regulating acid secretion have all attracted sustained attention. However, recent work on peptides derived from the gastrin precursor that do not stimulate acid secretion ("non-classical gastrins"), together with studies on mice over-expressing the gene, or in which the gastrin gene has been deleted, suggest hitherto unsuspected roles in regulating cell proliferation, migration, and differentiation. Moreover, microarray and proteomic studies have identified previously unsuspected target genes of the classical gastrins. Some of the newer actions have implications for our understanding of the progression to cancer in oesophagus, stomach, pancreas and colon, all of which have recently been linked in one way or another to dysfunctional signalling involving products of the gastrin gene. The present review focuses on recent progress in understanding the biology of both classical and non-classical gastrins.
Animals↗
Rapid gene transcription induced by stretch in cardiac myocytes and fibroblasts and their paracrine influence on stationary myocytes and fibroblasts.
Functional adaptation of cardiac cells in response to haemodynamic load requires dynamic alteration of gene expression. In this study, we examined early changes in gene expression following stretch in myocytes and fibroblasts isolated from neonatal rat hearts. In the first hour of biaxially applied static stretch, the changes in expression of immediate-early genes, such as c-fos, c-jun and fra-1, were quantified. The expression of the atrial natriuretic peptide (ANP) gene in myocytes was measured as an indication of the hypertrophic response. In stretched myocytes, expression of c-fos and ANP increased transiently to 227% and 176% respectively after 30 min stretch, whereas c-jun and fra-1 expression decreased in the 1st hour of stretch. In stretched fibroblasts the expression of c-fos and fra-1 increased transiently to maxima of 145% and 146% respectively after 30 min stretch, whereas c-jun expression did not change significantly. To study the indirect effects of stretch, as an indication of cross-talk between cardiac cells, stationary myocytes and fibroblasts were incubated with stretch-conditioned medium (CM) from stretched (0-60 min) myocytes and fibroblasts. CM from stretched myocytes reduced c-fos and induced c-jun expression in myocytes and fibroblasts, reduced fra-1 expression in myocytes but induced fra-1 expression in fibroblasts. CM from stretched fibroblasts induced c-fos expression and had little effect on c-jun expression in myocytes and fibroblasts, induced the fra-1 expression in myocytes but had little effect on fra-1 expression in fibroblasts. CM from myocytes and CM from fibroblasts induced ANP expression in myocytes to 206% and 120% respectively after 45 min stretch. Static stretch of myocytes and fibroblasts appears to stimulate, within 1 h, secretion of cell type-specific factors that participate in the regulation of proto-oncogene and ANP expression of stationary myocytes and fibroblasts. These early changes in gene transcription suggest that stretch of the myocardium initiates intracellular gene expression as well as cross-talk between the cell types.
Animals↗
Growth hormone as an early embryonic growth and differentiation factor.
In this review we consider the evidence that growth hormone (GH) acts in the embryo as a local growth, differentiation, and cell survival factor. Because both GH and its receptors are present in the early embryo before the functional differentiation of pituitary somatotrophs and before the establishment of a functioning circulatory system, the conditions are such that GH may be a member of the large battery of autocrine/paracrine growth factors that control embryonic development. It has been clearly established that GH is able to exert direct effects, independent of insulin-like growth factor-I (IGF-I), on the differentiation, proliferation, and survival of cells in a wide variety of tissues in the embryo, fetus, and adult. The signaling pathways behind these effects of GH are now beginning to be determined, establishing early extrapituitary GH as a bona fide developmental growth factor.
Animals↗
Inhibitory activity of anti-interleukin-4 and anti-interleukin-10 antibodies on Toxoplasma gondii proliferation in mouse peritoneal macrophages cocultured with splenocytes from infected mice.
Cocultures of splenocytes from Toxoplasma gondii-immunized mice or from naive mice, separated by a transwell membrane from naive macrophage layers, induced a decrease in T. gondii proliferation in macrophages in comparison with cultures without splenocytes or cocultures with splenocytes from infected mice. Interleukin 4 (IL-4) and IL-10 levels increased in cocultures of splenocytes from infected mice with naive macrophages. In contrast, the levels of these cytokines decreased in cocultures with splenocytes from immunized mice. No correlation was found between the release of interferon-gamma (IFN-gamma) and the inhibition of parasite multiplication. Cocultures with splenocytes from immunized mice induced an increase in tumor necrosis factor-alpha (TNF-alpha) levels. In contrast, in cocultures with splenocytes from infected mice, TNF-alpha production decreased. In cocultures with splenocytes from infected mice, T. gondii proliferation in macrophages was neutralized by anti-IL4 or anti-IL10 antibodies and was associated with increased TNF-alpha production. Moreover, this study demonstrates the significant combined effect of IL-4 and IL-10 on the down-regulation of macrophage-effector functions. A soluble positive signal was given by splenocytes to induce the production of TNF-alpha by macrophages. This signal was inhibited by IL4 and IL10. This process is biologically relevant in the regulation of T. gondii proliferation.
Animals↗
Immunocytochemical evidence for a paracrine interaction between GIP and GLP-1-producing cells in canine small intestine.
Glucagon-like-peptide 1 (GLP-1) released from the intestine is considered to be an important incretin. We have recently demonstrated that glucose-dependent insulinotropic peptide (GIP) stimulated GLP-1 secretion from canine ileal L cells in culture. To investigate further the interplay between GLP-1- and GIP-secreting cells, we set out to determine the exact location and abundance of both cell types throughout the canine intestine. Canine small intestine was subdivided into 15-20 segments and investigated by immunocytochemistry with computer-assisted imaging. The abundance of GIP-, GLP-1- and somatostatin-immunoreactive cells was determined. GIP-secreting K cells were equally distributed in duodenum and jejunum, with the GLP-1-secreting L cells concentrated in the jejunum (5% duodenum, 73% jejunum and 22% ileum). These results indicated that the middle section of the small intestine containing 69% of the K cells also contained 51% of the L cells. Double immunostaining confirmed this overlap and furthermore over 30% of the L cells in this region were found adjacent to K cells. These results suggest the existence of a paracrine interaction between the K and L cells and indicate the importance of the jejunum in the regulation of insulin release by enteric-derived incretins.
Animals↗
Immunolocalization of vascular endothelial growth factor in the GH3 cell line.
The question of whether vascular endothelial growth factor (VEGF) is expressed in the GH3 cell line was investigated using immunocytochemistry, immunoelectron microscopy, and Western blotting. Using immunocytochemistry, VEGF was demonstrated in approximately 90% of the cells. Immunopositivity was localized mainly in the paranuclear Golgi region. In a small minority of cells, diffuse cytoplasmic immunostaining was also noted. By immunoelectron microscopy VEGF was evident in the secretory granules, cytoplasmic vesicles, rough endoplasmic reticulum, and the Golgi apparatus. Western blotting confirmed the results of the morphologic studies. It can be concluded that VEGF, which is know to induce angiogenesis and to increase vascular permeability, is produced in the prolactin- and growth hormone (GH)-secreting GH3 cell line. The functional role of VEGF in the GH3 cells is unknown. It is possible that this growth factor affects endocrine activity of GH3 cells by a paracrine mechanism.
Animals↗
Changes in therapy for solid tumors: potential for overcoming drug resistance in vivo with molecular targeting agents.
Recent advances in molecular biology have led to the development of selective molecular targeting agents for genes involved in cell proliferation, apoptosis, and angiogenesis in cancer cells. The current success of molecular targeting therapy is shown by: imatinib mesylate (STI571, Gleevec), targeted to the Bcr/Abl fusion protein derived from a translocation between chromosomes 9 and 22 in chronic myelogenous leukemia; rituximab (Rituxan), a monoclonal antibody to CD20 used in non-Hodgkin's lymphoma; trastuzumab (Herceptin), a chimeric monoclonal antibody to HER-2 used in breast cancer; and gefinitib (ZD1839, Irresa), a tyrosine kinase inhibitor of the epidermal growth factor receptor used in non-small cell lung cancer. The superior therapeutic efficacy of these molecular targeting agents over traditional chemotherapy has been shown by the survival benefit achieved for patients with advanced or recurrent cancers. Although the precise molecular mechanisms by which these agents produce or enhance an antitumor effect, alone or in combination with anticancer drugs, are not known, the specific inhibition of target genes critically involved in tumor progression and metastasis by the agent is clear. However, further studies to determine which patient groups and anticancer drugs are appropriate for combination therapy with these molecular targeting agents are needed. Herein, we discuss the current status and potential for overcoming drug resistance in solid tumors and focus on the differential features of the tumor microenvironment in solid and hematologic malignancies.
Animals↗
Electroacupuncture and moxibustion promote neutrophil apoptosis and improve ulcerative colitis in rats.
The purpose of this study was to investigate the effect of electroacupuncture (EA) and moxibustion on promoting neutrophil apoptosis. A rat model of ulcerative colitis was established by immunological methods using human colonic mucosa as antigen. All rats were randomly assigned to the model control (MC) group, EA group, or herbs-partition moxibustion (HPM) group. Normal rats were used as the normal control (NC) group. Peripheral blood mononuclear cells (PBMCs) from all rats and circular neutrophils from NC rats were isolated and cultured. Circular neutrophils were incubated with cultured supernatants of PBMCs from the MC, NC, EA, and HPM groups, respectively. Neutrophil apoptosis and concentration of IL-1beta, IL-6, and TNF-alpha from induced cultured supernatants were detected by cell cytometry and ELISA, respectively. Compared with MC, HPM, and EA rats, mucosal inflammatory lesions abated remarkably. No hyperemia or edema was seen in the lamina propria, inflammatory cell infiltration decreased, neutrophil infiltration disappeared, and epithelial and crypt cells proliferated and repaired the ulceration of the mucosa. Neutrophil apoptosis was promoted. Concentrations of IL-1beta, IL-6, and TNF-alpha were decreased, respectively. We conclude that EA and HPM therapy can improve ulcerative colitis rats histologically, which may be due to promoting neutrophil apoptosis and down-regulating monocyte cytokines. EA and moxibustion are effective for treating ulcerative colitis.
Animals↗
Endothelins mediate neutrophil activation, ProMMP-9 release and endothelial cell detachment.
Neutrophils isolated from human peripheral blood added to a monolayer of human endothelial cells (ECV-304 cell line) stimulated with LPS (100 ng ml(-1)) resulted in: (a) neutrophil activation, measured by spreading and release of leukotriene B(4) (LTB(4)); (b) neutrophil degranulation, measured by release of matrix pro-metalloproteinase-9 (proMMP-9) and (c) loss of the monolayer integrity due to detachment of the endothelial cells. Stimulation of endothelial cells with tumor necrosis factor-alpha (TNF-alpha 10 ng ml(-1)) or interleukin-1 (IL-1; 10 ng ml(-1)) induced a similar dose-dependent increase in the neutrophil activation and endothelial cell detachment. Pre-treatment of LPS-activated ECV-304 cells with [Phe22]BigET-1(19-37) (10(-9) M; an inhibitor of endothelin converting enzyme (ECE)) or addition of BQ-123 (10(-6) M; a selective endothelin A (ET(A)) receptor antagonist) to the co-cultures, significantly reduced neutrophil spreading (50-70% inhibition) as well as the levels of LTB(4) (70-100% inhibition) and proMMP-9 (40-50% inhibition) in the co-culture supernatants. In addition, the detachment of endothelial cells was also reduced (60-75% inhibition). Moreover, the exogenous addition of ET-1 (10(-9) M) to neutrophil suspensions induced neutrophil spreading and release of LTB(4) and proMMP-9. Taken together, these findings indicate that neutrophils added to stimulated endothelial cells in the co-culture system employed in this study, get activated by products of these cells and degranulate. In parallel, the detachment of endothelial cell monolayer from the culture plates, possibly by the action of neutrophil granule-derived gelatinases, is observed. Endothelins (ETs) produced by the endothelial cells are suggested to play an essential role in these phenomena.
Aspartic Acid Endopeptidases↗