Freely-migrating-defect production during irradiation at elevated temperatures.
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Coronary myointimal hyperplasia in freshwater Lake Michigan salmon (genus Oncorhynchus). Evidence for lipoprotein-related atherosclerosis.
The relationship between plasma lipoprotein concentration and histologic myointimal proliferative lesions in the coronary vessels was examined in 37 freshwater Chinook salmon (Oncorhynchus tshawytscha). The fish were obtained during the migrating, schooling, and spawning periods of the fourth year of life. Plasma apoB polypeptides were maximally elevated in the migrating fish in correlation with a high degree of coronary vascular disease. Both the relative incidence and the severity of lesions were greater in migrating salmon as compared with spawning fish. In contrast, plasma apoA polypeptides were maximally elevated in association with reduced levels of plasma apoB in spawning fish in which coronary lesions were reduced in severity and incidence. Simultaneous observations confirmed the relative decrease in circulating thyroid hormone and increase in adrenal cortical hormones characteristic of the maturation process. These data in the mature freshwater Lake Michigan Chinook salmon provide direct support for the hypothesis that coronary proliferative atherogenesis proceeds in parallel with excessive exposure to apoB-containing lipoproteins and that reversal is associated with excessive exposure to apoA-containing lipoproteins. The temporal relationship to altered hormone status is described, but the pathophysiologic significance for atherogenesis cannot be determined from these data.
Adrenal Cortex Hormones↗
Leucocyte migration inhibition response to tissue antigens in asymptomatic individuals infected with Trypanosoma cruzi.
The direct leucocyte migration inhibition test was used to study 31 asymptomatic humans chronically infected with Trypanosoma cruzi and 23 normal uninfected controls. The antigenic preparations used were made from mouse and guinea-pig heart, skeletal muscle, kidney, liver and brain. Positive responses were found in the parasite-infected individuals to kidney, liver and brain antigen but not to antigen prepared from heart of skeletal muscle tissue. No correlation was found between T. cruzi antibody titres and migration index values to these various antigens. On the other hand, a positive correlation was only noted between the titres of tissue-reacting immunoglobulins and the migration indices induced by brain antigens: when titres of tissue-reacting immunoglobulins were elevated, less leucocyte migration inhibition was detected.
Adult↗
Integrating stress physiology, environmental change, and behavior in free-living sparrows.
As weather deteriorates, breeding animals have a diverse array of options to ensure survival. Because of their mobility, birds can easily abandon territories to seek out benign conditions away from the breeding site. The timing of abandonment, however, may have repercussions for territory size, mate quality, reproductive success, and survival. There is a large body of evidence indicating that the adrenocortical response to stress plays a role in mediating the onset and maintenance of this behavioral switch. Here we develop a model describing the interactions of weather, food availability, body condition, and stress physiology in initiating departure from the breeding site. We tested the model using a population of white-crowned sparrows breeding at high elevation in the Sierra Nevada, where severe weather at the beginning of the breeding season often induces temporary abandonment of breeding territories and facultative altitudinal migration to lower elevation refugia. The data show that (1). during inclement weather, exogenous corticosterone delays return to the breeding site after territory abandonment; (2). during good weather, exogenous corticosterone alone does not induce territory abandonment, but does increase activity range around the breeding site; and (3). the magnitude of the corticosteroid response to stress is inversely related to body condition of the sparrow.
Adipose Tissue↗
Heterogeneity amongst fibroblasts in the production of migration stimulating factor (MSF): implications for cancer pathogenesis.
Fetal skin fibroblasts migrate into 3D collagen gels to a significantly greater extent than do adult cells. This enhanced motility of fetal fibroblasts appears to result from the production of a "migration stimulating factor" (MSF) which is not made by their normal adult counterparts. Adult skin fibroblasts retain responsiveness to MSF and cells exposed to this factor achieve the elevated levels of migration characteristic of fetal cells. MSF has been purified to homogeneity, has an apparent molecular mass of 70 kD and has been further characterized in terms of a number of biochemical parameters. Studies concerned with the mechanism of action of MSF indicate that it stimulates the production of a high molecular weight class of hyaluronic acid (HA). Concurrent exposure of cells to Streptomyces hyaluronidase blocks the stimulation of adult fibroblast migration by MSF. In a related series of experiments, we have shown that TGF-beta inhibits the effects of MSF on both cell migration and HA production. Taken together, these data suggest that the stimulation of fibroblast migration by MSF is dependent upon (and may directly result from) a primary induction of HA synthesis. We have previously reported that skin fibroblasts obtained from patients with sporadic and familial breast cancer, as well as the unaffected first-degree relatives of familial breast cancer patients, commonly display a fetal-like migratory phenotype. Subsequent work has indicated that (a) these fetal-like cells also produce MSF, and (b) detectable levels of MSF are present in the serum of sporadic breast cancer patients both prior to and following surgical resection of the primary tumor mass. On the basis of these and related observations, we have put forward an hypothesis suggesting that the disruption in normal epithelial-mesenchymal interactions caused by the persistent production of MSF by fibroblasts in the adult may contribute directly to the pathogenesis of an epithelial cancer. The demonstration of aberrant fibroblasts in sporadic cancer patients (both in our own and independent studies) is not consistent with the "germ-line genetic lesion" model commonly invoked to account for the presence of such cells in patients with hereditary cancer syndromes.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Glial cells: modulators of neuronal environment.
Studies of glial cells in neural tissue culture systems suggest that glial cells subserve different functions during development and aging of the central nervous system and that they may help modulate the neuronal environment by virtue of their responsiveness to hormones and other intrinsic factors. There is a marked proliferation of glial cells during early stages of brain development, probably reflecting the involvement of glial cells in myelination and other growth processes. Studies in culture suggest that proliferation of glial cells can be induced by steroid hormones. The migration rate of glial cells from cerebellar explants of embryonic chick brain grown in organotypic culture was measured in control and hormone-treated explants. Treatment with cortisol, corticosterone, estradiol, and progesterone significantly elevated glial cell migration from the tissue explants. The influence of steroid hormones on glial cells may be mediated via a steroid intracellular mechanism. In C-6 glioma cells and in chick embryo dissociated brain cell cultures consisting predominantly of glial cells, 3H-corticosterone was shown to accumulate by a saturable but non-specific retention mechanism. In contrast, the accumulation of 3H-corticosterone by predominantly neuronal cultures was both saturable and specific. Glial cells in culture exhibit certain age-related changes, including changes in resting membrane potentials and in cellular responses to hormone treatment, as measured by changes in incorporation of 3H-leucine into protein and incorporation of 3H-uridine into RNA. The possibility that glial cells in vivo may likewise exhibit differential responses to hormones throughout the lifespan suggests that hormones may markedly influence cellular aging.
Aging↗
LDL induces intracellular signalling and cell migration via atypical LDL-binding protein T-cadherin.
Cadherins are a superfamily of adhesion molecules that mediate Ca(2+)-dependent cell-cell adhesion. T-cadherin (T-cad), a unique glycosylphosphatidylinositol-anchored member of the cadherin superfamily, was initially identified by immunoblotting of vascular cell membranes as an atypical low affinity low density lipoprotein (LDL)-binding protein. It is not known whether this heterophilic interaction is physiologically relevant. Expression of T-cadherin is upregulated in vascular cells during atherosclerosis, restenosis and tumour angiogenesis, conditions characterized by enhanced cell migration and growth. Elevated levels of serum low density lipoproteins (LDL), which result in cholesterol accumulation in vascular wall, is a widely accepted risk factor in atherosclerosis development. Additionally to its metabolic effects, LDL can produce hormone-like effects in a number of cell types. This study has utilized HEK293 cells and L929 cells stably transfected with T-cadherin cDNA to investigate T-cad-dependent responses to LDL. Stable expression of T-cad in both HEK293 and L929 cells results in significantly (p < 0.05) elevated specific surface binding of [I125]-LDL. Compared with mock-transfectants, cells expressing T-cad exhibit significantly (p < 0.01) enhanced LDL-induced mobilization of intracellular Ca(2+)-stores and a significantly (p < 0.01) increased migration toward an LDL gradient (0.1% BSA + 60 microg/ml LDL) in Boyden chamber migration assay. Thus LDL-binding to T-cad is capable of activating physiologically relevant intracellular signaling and functional responses.
Animals↗
Pairing of homologous DNA sequences by proteins: evidence for three-stranded DNA.
We show that recombinases form joint molecules over very short regions of homology. When these molecules are deproteinized the three strands are in a structure that is surprisingly resistant to dissociation by branch migration, even at elevated temperatures. The joint molecules dissociate at temperatures comparable to those required to melt DNA duplexes of the same length and sequence. We also show that nonenzymatically formed structures of the same length and sequence, which have a free third strand ready to branch migrate, dissociate at much lower temperatures. These results provide compelling evidence that the three DNA strands in the region of pairing are hydrogen bonded to each other. Our observations suggest that such a novel three-stranded DNA molecule, or a structure very similar to it, may be the intermediate in general recombination that is used in the recognition of sequence homology. We discuss some of the structural features implicit in this molecule containing any base sequence and compare them with those manifest in true DNA triple helices containing special sequence motifs.
Animals↗
Foetal and cancer patient fibroblasts produce an autocrine migration-stimulating factor not made by normal adult cells.
We have previously reported that (1) the migration of foetal and adult fibroblasts into three-dimensional collagen matrices is differentially affected by cell density, and (2) skin fibroblasts from cancer patients commonly display a foetal-like mode of migratory behaviour. Data presented here indicate that differences in the migration of these cell types are particularly apparent in cultures plated at high density (i.e. at cell confluence); under these conditions, foetal fibroblasts and the foetal-like fibroblasts of cancer patients migrate into the three-dimensional collagen matrix to a significantly greater extent than do normal adult cells. In this initial study concerned with the biochemical basis of these observations, we report that medium conditioned by either foetal or cancer patient fibroblasts stimulates the migration of confluent adult cells. This stimulation of migration is specific to confluent cells, as the migration of subconfluent adult fibroblasts is unaffected by these conditioned media. Gel filtration chromatography of foetal fibroblast-conditioned medium indicates that migration-stimulating activity is recovered in a single peak with an apparent molecular mass in the range of 50-60 (X 10(3]. The active migration stimulating factor (MSF) in both foetal and cancer patient fibroblast-conditioned media appears to be a protein stable at acid pH, but inactivated by heat, alkaline pH and reductive alkylation. MSF produced by foetal and cancer patient fibroblasts is presumably responsible for the characteristically elevated levels of migration displayed by these cells in confluent culture, thereby suggesting an autocrine mode of action for this factor.(ABSTRACT TRUNCATED AT 250 WORDS)
Cell Movement↗
Differential and synergistic effects of platelet-derived growth factor-BB and transforming growth factor-beta1 on activated pancreatic stellate cells.
OBJECTIVE: The cytokines platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta1 are major factors influencing the transformation from the quiescent to the activated phenotype of pancreatic stellate cells (PSC), a process involved in the pathogenesis of chronic pancreatitis. Albeit much effort has been made to study the effects of PDGF and TGF-beta1 on PSCs, their interaction is still unclear, because these cytokines show both differential and synergistic effects as outlined by this study. METHODS: Culture-activated PSCs of rats were treated with PDGF-BB and TGF-beta1. Subsequent changes of cell proliferation and migration were determined by cell counting, (+)-bromo-2'-deoxyuridine enzyme-linked immunosarbant assay (ELISA), and migration assay. Gene expression, synthesis of proteins, and activation of kinases were further studied by reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, ELISA, and Western blot. RESULTS: PDGF-BB increased PSC proliferation and migration, accompanied by elevated expression of matrix metalloproteinases (MMP)-13 and MMP-3. The mRNA amount of procollagen alpha2(I), alpha-smooth muscle actin (alpha-SMA), tissue inhibitor of metalloproteinase (TIMP)-1, and TGF-beta1 was also increased by PDGF-BB. In contrast, PDGF-BB reduced collagen type I in culture medium and synthesis of alpha-SMA. Treatment of PSC with TGF-beta1 decreased proliferation, had no significant effect on migration and MMP expression, but increased expression and synthesis of procollagen alpha2(I) and alpha-SMA. Both cytokines induced phosphorylation of extracellular signal regulated kinase (ERK)-1/2 and p38, but only PDGF-BB activated the protein kinase B signaling pathway. CONCLUSION: PDGF-BB augments effects of TGF-beta1 on the mRNA level presumably because of up-regulation of TGF-beta1 synthesis and common signaling pathways of the 2 cytokines. However, at the protein level, PDGF-BB impairs typical TGF-beta1 effects such as increased synthesis of collagen (type I) and alpha-SMA. Moreover, PDGF-BB facilitates degradation of extracellular matrix proteins by enhancement of MMP synthesis, but MMP activity was probably limited because of elevated tissue inhibitor of metalloproteinase 1 expression.
Actins↗
Effect of the interferon inducer tilorone in inbred CBA mice.
Tilorone hydrochloride (200 mg/kg) was administered intragastrically to inbred CBA mice. After 5, 18 and 48 hr the number of circulating leucocytes and peritoneal cells as well as the migration of unstimulated peritoneal cells, the blood corticosteroid level and interferon production were investigated. In spite of the considerable decrease of the number of mononuclear cells in the blood and polynuclear ones in the peritoneal exudate, the drug induced production of circulating interferon and stimulated its synthesis by peritoneal cells. The blood corticosteroid level and the mast cell count in the peritoneal cavity were significantly elevated, but the migration of peritoneal cells in antigen-free medium decreased.
Administration, Oral↗
Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration.
FAK localizes to sites of transmembrane integrin receptor clustering and facilitates intracellular signaling events. FAK-null (FAK-) fibroblasts exhibit a rounded morphology, defects in cell migration, and an elevated number of cell-substratum contact sites. Here we show that stable re-expression of epitope-tagged FAK reversed the morphological defects of the FAK- cells through the dynamic regulation of actin structures and focal contact sites in fibronectin (FN) stimulated cells. FAK re-expressing fibroblasts (clones DA2 and DP3) exhibit a characteristic fibrillar shape and display indistinguishable FN receptor-stimulated migration properties compared to normal fibroblasts. Expression of various FAK mutants in the FAK- cells showed that FAK kinase activity, the Tyr-397/SH2 domain binding site, and the first proline-rich SH3 binding region in the FAK C-terminal domain were individually needed to promote full FAK-mediated FAK- cell migration to FN whereas direct paxillin binding to FAK was not required. Expression of the FAK Phe-397 mutant did not promote FAK- cell migration and overexpression of p50(csk) in DA2 cells inhibited migration to FN suggesting that Src-family PTKs play important roles in FAK-mediated motility events. Expression of the FAK C-terminal domain, FRNK, promoted FAK dephosphorylation at Tyr-397 and potently blocked FAK-mediated cell migration. This dominant-negative effect of FRNK was reversed by a point mutation (Leu-1034 to Ser) which prevented FRNK localization to focal contact sites. Our results show that FAK functions as a key regulator of fibronectin receptor stimulated cell migration events through the recruitment of both SH2 and SH3 domain-containing signaling proteins to sites of integrin receptor clustering.
Actins↗
Hepatoma cell migration through a mesothelial cell monolayer is inhibited by cyclic AMP-elevating agents via a Rho-dependent pathway.
1-Oleoyl lysophosphatidic acid (LPA) induces transmonolayer migration (in vitro invasion) of rat ascites hepatoma MM1 cells and their morphological changes leading to the migration. We have previously shown that an LPA analog, palmitoyl cyclic phosphatidic acid (Pal-cPA), suppresses transmonolayer migration of MM1 cells by rapidly increasing the intracellular cyclic AMP (cAMP) concentration. We report here that various cAMP-elevating agents, including dibutyryl cAMP, forskolin, cholera toxin and 3-isobutyl-1-methylxanthine, consistently inhibited LPA-induced transmonolayer migration of MM1 cells. Moreover, pull-down assays for GTP-bound, active RhoA demonstrated that the blockage by cAMP-elevating agents of morphological changes leading to the migration was probably mediated through inhibiting RhoA activation.
Animals↗
Morphogenesis of the human external male genitalia.
The morphogenesis of the external genitalia of human fetuses (16-250 mm crown-rump [CR] length, 6-26 weeks of gestation) obtained after medical termination of pregnancy were studied. Differential development (male/female) started after 50 mm CR length (9 weeks). At that time the external genitalia consisted of a cylindrical genital tubercle 2 mm in length with a visible coronary sulcus and glans and genital swellings on either side. A groove on the ventral aspect of the genital tubercle extended to the coronary sulcus; the lateral boundaries of this groove separated to form the urethral folds. In male fetuses the free edges of the urethral folds fused, starting from the proximal end, to form a tunnel over the ventral aspect of the phallus. The pelvic urethra opened into this tunnel, slightly distal to its origin. The mesodermal tissue forming the genital swellings migrated ventrally and then medially. As medial migration started, the skin in the midline between the genital swellings was raised up as a skin fold, which subsequently, as the genital swellings migrated further, became elevated. The proximal part of the tunnel formed by fusion of the urethral folds (proximal to the point of entry of the pelvic urethra) also was compressed and pushed out as the genital swellings fused in the midline over the root of the phallus. These changes took place at between 80 and 110 mm CR length (12-13 weeks' gestation); at this stage the phallus appeared short and was bent ventrally. With further growth and caudal migration of the scrotum, the phallus lost its ventral curvature. The appearance of the external genitalia at different gestational ages bore a close resemblance to that in children with hypospadias. We therefore conclude that hypospadias can be explained on the basis of an embryological arrest due to the absence of the required stimulus for male phenotypic development at the appropriate time.
Crown-Rump Length↗
Altered PDGF-BB-induced p38 MAP kinase activation in diabetic vascular smooth muscle cells: roles of protein kinase C-delta.
OBJECTIVE: We investigated the regulation of p38 mitogen-activated protein kinase (MAPK) by platelet-derived growth factor (PDGF)-BB and its biological effects in cultured normal and diabetic rat vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: VSMC growth from diabetic rats was faster than that from normal rats. The expression of the PDGF beta-receptor in diabetic VSMCs was significantly elevated compared with that in normal cells, and PDGF-BB-induced p38 phosphorylation in diabetic cells was more enhanced via MAPK kinase (MKK) 3/6. The level of PKC activity in diabetic cells increased more than that in normal cells with or without PDGF-BB. Although protein kinase C (PKC)-betaII and PKC-delta were activated by diabetes, PDGF-BB could further enhance the level of PKC-delta alone. PDGF-BB-induced cell migration was more elevated in diabetic VSMCs, and the increase was significantly inhibited by SB-203580, rottlerin, and antisense oligodeoxynucleotides for PKC-delta. PDGF-BB-induced p38 phosphorylation also regulated cell growth, cyclooxygenase-2 levels, and arachidonic acid release, but not apoptosis. These levels were more elevated in diabetic cells, which were inhibited by SB-203580. CONCLUSIONS: Our study established that PDGF-BB phosphorylated p38 via PKC-delta and the subsequent MKK 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetic VSMCs.
Animals↗
Spatial and temporal variation in lead levels related to body condition in the Mississippi Valley population of Canada geese.
Concern over lead poisoning led to progressive prohibition of toxic shot to harvest waterfowl in the 1980's. Nevertheless, waterfowl remain susceptible to ingestion of lead shot because illegal use continues and spent shot persists in soil and wetland substrates. While mortality due to lead toxicosis has subsided, sublethal effects may still affect survival and reproduction. We measured liver lead levels and body condition in 732 Canada geese (Branta canadensis interior) during July 1984 to April 1989 in southern Illinois (USA), east-central Wisconsin (USA), and northern Ontario (Canada). Although we sampled only individuals that were visibly healthy, 55 of 732 (7.5%) geese had elevated liver lead levels (> 2 ppm). Lead levels of 46 (6.3%) geese indicated subclinical poisoning (2-6 ppm) and 9 (1.2%) geese had lead levels indicative of clinical poisoning (> 6 ppm). A greater proportion of juveniles (14.3%) had elevated lead levels than did adults (6.0%), but there was no difference between genders. Lead levels were highest in autumn and winter in southern Illinois, but were low during nesting and summer, despite legal use of lead shot in northern Ontario during our study. Lead poisoning (> or = 5% of the population) was still evident during all seasons in juveniles, and during autumn and winter in adults, 5 to 10 yr after toxic shot was banned from areas where we collected geese during migration and winter. Elevated lead levels did not affect total body mass, lipid reserves, or mineral levels of geese we collected. Protein levels also were unaffected below 10 ppm, but there was evidence of decline at higher concentrations. Thus, it seems unlikely that lead exposure currently affects survival or reproduction of Mississippi Valley Population (MVP) geese via body condition, although other sublethal effects cannot be discounted.
Age Factors↗
Free fatty acids and type 2 diabetes mellitus.
Acute elevation of plasma free fatty acids (FFAs) is necessary for insulin secretion. Sustained elevation, however, leads to apoptosis of pancreatic beta-cells and is a major risk factor for cardiovascular disease and sudden death in patients with insulin resistance or a family history of diabetes mellitus, as well as in individuals with normal glucose tolerance. Data suggest that reduction of FFA plasma levels may reduce the incidence of cardiovascular disease in these at-risk patients. Thiazolidinediones have been shown not only to improve insulin sensitivity but also to reduce FFA plasma levels. Consequently, endothelial function is maintained, vascular smooth muscle cell proliferation and migration are minimized, elevated blood pressure and microalbuminuria are reduced, and high-density lipoprotein and low-density lipoprotein cholesterol particle sizes are improved.
Adipocytes↗
Alteration of the chemotactic response of human skin fibroblasts to PDGF by growth factors.
Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for fibroblastic cells. In the early stage of wound healing. PDGF is released from aggregated platelets and it is believed that its chemotactic activity may play a key role in the influx of connective tissue cells into wound sites. Using the Boyden chamber assay, we investigated factors that alter the migratory response of human skin fibroblasts to PDGF. The response was related to the growth state of cells; that is, growing cells at low cell density exhibited a greater migratory response to PDGF than density-arrested quiescent cells. The level of random migration was also elevated in growing cells, compared to quiescent cells. The chemotactic response after 3-h exposure to serum was markedly decreased (> 50%). Three-hour preincubation of the cells with transforming growth factor-beta (TGF-beta) or with epidermal growth factor reduced the migratory response to approximately half that in the nonstimulated control. In contrast, cells treated with TGF-beta or basic fibroblast growth factor for 24 h exhibited a two- to threefold greater chemotactic response to PDGF than control cells. This stimulatory effect of TGF-beta on the fibroblast migration induced by PDGF suggests that TGF-beta acts synergistically with PDGF on the influx of connective tissue cells into human wound sites and may explain the potent wound healing activity of TGF-beta in vivo.
Adult↗