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PubMed1994

Growth regulation in primary culture of rabbit arterial smooth muscle cells by platelet-derived growth factor, insulin-like growth factor-I, and epidermal growth factor.

Many studies have linked the proliferation of smooth muscle cells (SMC) to the development of atherosclerotic lesions. We examined the effects of platelet-derived growth factor (PDGF), insulin-like growth factor-I (IGF-I), and epidermal growth factor (EGF) on the regulation of SMC grown on type I collagen-coated dishes in serum-free primary culture. When added alone, PDGF (10 ng/ml), IGF-I (20 ng/ml), and EGF (10 ng/ml) produced minimal effects on BrdU (5-bromo-2'-deoxyuridine) incorporation into cellular DNA and on cell growth. However, simultaneous addition of PDGF and IGF-I significantly stimulated DNA synthesis and cell growth. The combination of PDGF, IGF-I, and EGF synergistically stimulated DNA synthesis and cell proliferation. Flow cytometric analysis indicated that type I collagen alone promoted the phenotypic modulation and progression of the cells from the G0 (contractile phenotype) to the G1A phase (intermediate phenotype), PDGF and IGF-I, together, stimulated the rate of cell transition from the G1A to the G1B and S phases (synthetic phenotype), and PDGF, IGF-I, and EGF together stimulated the rate of cell transition into the S and G2+ M phases. In contrast, in quiescent secondary cultured SMC (G1B phase), PDGF alone was able to initiate DNA synthesis, although IGF-I and EGF were required to complete DNA synthesis. These results reveal that PDGF and IGF-I stimulate the cells to complete the G1A phase and proceed to the G1B phase and that EGF regulates the rate of entry into the S phase in rabbit SMC in primary culture. Furthermore, differences in the responsiveness to these growth factors between primary and secondary cultures reflected the varying phenotypic properties of vascular SMC.

Animals↗

PubMed1991

The calpain-calpastatin system in vascular smooth muscle.

Vascular smooth muscle contains large amounts of the Ca(2+)-dependent protease calpain II. In this study, we compared bovine aortic muscle (muscle phenotype) to cultured bovine aortic cells of smooth muscle origin (modulated phenotype) with respect to major constituents of the calpain-calpastatin system. Bovine aortic muscle contained only calpain II by activity measurements, Western blot of tissue extracts and Northern blot of poly(A)+ RNA. On the other hand, using the same methodologies, both calpains I and II as well as the 110 kDa inhibitor protein, calpastatin, were identified in cultured bovine aortic cells of smooth muscle origin. We conclude that the phenotypic state of smooth muscle cells is associated with differential expression of major components of the calpain-calpastatin system. Moreover, bovine aortic muscle is the only tissue identified to date that contains calpain II exclusively.

Animals↗

PubMed2001

Injury induces dedifferentiation of smooth muscle cells and increased matrix-degrading metalloproteinase activity in human saphenous vein.

Long-term patency of human saphenous vein bypass grafts is low because of intimal thickening and superimposed atherosclerosis. Matrix-degrading metalloproteinases (MMPs) and changes in vascular smooth muscle cell (VSMC) phenotype are thought to be essential for the VSMC migration that contributes to intimal thickening. We examined VSMC phenotype and MMP activity in saphenous veins obtained before and after surgical manipulation. Surgical preparation of the veins significantly increased pro-MMP-1 expression by 2-fold and significantly reduced tissue inhibitor of MMPs (TIMP)-2 expression, whereas MMP-3 and TIMP-1 were unaffected. Furthermore, caseinolytic and gelatinolytic activities measured by in situ zymography were dramatically elevated by injury. The expression of desmin and smoothelin was significantly decreased by injury, whereas vimentin expression was significantly increased. In addition, these changes in phenotype and MMP activity were localized to a subpopulation of VSMCs, the circumferential medial VSMCs. Our data show that surgical preparative injury induces phenotypic modulation of a subpopulation of medial VSMCs to a synthetic phenotype and increases MMP activity. This may favor matrix degradation, VSMC migration, and the subsequent intimal thickening that leads to graft failure.

Caseins↗

PubMed1998

Characterization of the polymorphonuclear leukocyte-induced vasoconstriction in isolated human umbilical veins.

We investigated the contractile effects of both activated and unactivated polymorphonuclear leukocytes (PMNs) on human vascular tissue to characterize the influence of human PMNs on vascular tone. PMNs were added either unactivated or after f-met-leu-phe (fMLP) activation (10(-8) M), into tissue chambers containing human umbilical vein segments under either control or cytokine-treated conditions. The activation state of different PMN preparations was measured by immunofluorescence staining of the adhesion glycoproteins Mac-1 and L-selectin. Both unactivated and activated PMNs induced a cell number-dependent (1.5 x 10(5) to 2 x 10(6) cells/ml) vasoconstriction in human umbilical vein segments. This PMN-induced response was not inhibited by treatment with indomethacin (10(-5) M), superoxide dismutase (2 x 10(-7) M) or L-nitro-monomethyl arginine (10(-4) M). However, treatment of PMNs with the leukotriene biosynthesis inhibitor BIRM-270 partially inhibited (-61 +/- 19%, P <.05) the contraction induced only by unactivated PMNs. Moreover, the supernatant from unactivated, but not that from activated, PMNs elicited a contractile response comparable to that from the addition of cells. We observed a significant correlation between the Mac-1/L-selectin ratio of activated PMNs and the contractile response they generated (r = 0.77, P <.05). The activated PMN response had an endothelium-dependent component, whereas the unactivated PMN response was endothelium-independent. These results suggest that human PMNs of varying activation states have the capacity to modulate vascular smooth muscle tone via distinct mechanisms. Unactivated PMNs appear to modulate tone via a secreted product, whereas the more activated phenotype modulates vascular tone via a cognate interaction with the endothelium.

Flow Cytometry↗

PubMed2006

Cranial modularity shifts during mammalian evolution.

The mammalian skull has been studied as several separate functional components for decades, but the study of modularity is a more recent, integrative approach toward quantitative examination of independent subsets of highly correlated traits, or modules. Although most studies of modularity focus on developmental and genetic systems, phenotypic modules have been noted in many diverse morphological structures. However, few studies have provided empirical data for comparing modules across higher taxonomic levels, limiting the ability to assess the broader evolutionary significance of modularity. This study uses 18-32 three-dimensional cranial landmarks to analyze phenotypic modularity in 106 mammalian species and demonstrates that cranial modularity is generally conserved in the evolution of therian mammals (marsupials and placentals) but differs between therians and monotremes, the two extant subclasses of Mammalia. Within therians, cluster analyses identify six distinct modules, but only three modules display significant integration in all species. Monotremes display only two highly integrated modules. Specific hypotheses of functional and developmental influences on cranial bones were tested. Theoretical correlation matrices for bones were constructed on the basis of shared function, tissue origin, or mode of ossification, and all three of these models are significantly correlated with observed correlation matrices for the mammalian cranium.

Animals↗

PubMed2001

Contacts with fibrils containing collagen I, but not collagens II, IX, and XI, can destabilize the cartilage phenotype of chondrocytes.

OBJECTIVE: Cell-matrix interactions are important regulators of cellular functions, including matrix synthesis, proliferation and differentiation. This is well exemplified by the characteristically labile phenotype of chondrocytes that is lost in monolayer culture but is stabilized in suspension under appropriate conditions. We were interested in the role of collagen suprastructures in maintaining or destabilizing the cartilage phenotype of chondrocytes. DESIGN: Primary sternal chondrocytes from 17-day-old chick embryos were cultured in gels of fibrils reconstituted from soluble collagen I from various sources. The culture media either contained or lacked FBS. Cells were cultured for up to 28 days and the evolution of the phenotype of the cells was assessed by their collagen expression (collagens II and X for differentiated chondrocytes and hypertrophic chodrocytes, repectively; collagen I for phenotypically modulated cells), or by their secretion of alkaline phosphatase (hypertrophic cartilage phenotype). RESULTS: The cells often retained their differentiated phenotype only if cultured with serum. Under serum-free conditions, cartilage characteristics were lost. The cells acquired a fibroblast-like shape and, later, synthesized collagen I instead of cartilage collagens. Shape changes were influenced by beta1-integrin-activity, whereas other matrix receptors were important for alterations of collagen patterns. Heterotypic fibrils reconstituted from collagens II, IX, and XI did not provoke this phenotypic instability. CONCLUSIONS: Chondrocytes sensitively recognize the suprastructures of collagen fibrils in their environment. Cellular interactions with fibrils with appropriate molecular organizations, such as that in cartilage fibrils, result in the maintenance of the differentiated cartilage phenotype. However, other suprastructures, e.g. in reconstituted fibrils mainly containing collagen I, lead to cell-matrix interactions incompatible with the cartilage phenotype. The maintenance of the differentiated traits of chondrocytes is pivotal for the normal function of, e.g., articular cartilage. If pathologically altered matrix suprastructures lead to a dysregulation of collagen production also in vivo compromised cartilage functions inevitably will be propagated further.

Alkaline Phosphatase↗

PubMed2001

Expression of interleukin 8 and its receptors in human colon carcinoma cells with different metastatic potentials.

PURPOSE: In the present study, we examined the expression of a multifunctional cytokine, interleukin 8 (IL-8), and its receptors, CXCR1 and CXCR2, in human colon carcinoma cells with different metastatic potentials and determined their role in modulating phenotypes associated with metastasis. EXPERIMENTAL DESIGN: IL-8, CXCR1, and CXCR2 protein and mRNA expression were examined using ELISA, immunocytochemistry, and reverse transcription-PCR in human colon carcinoma cells with different metastatic potentials. IL-8-mediated proliferation, migration, and tumor-endothelial cell interaction were analyzed. RESULTS: IL-8 mRNA and protein expression was very low in Caco2 cells but elevated in KM12C cells and very high in KM12L4 cells, suggesting an association between the IL-8 production and metastatic potential. Similarly, CXCR1 and CXCR2 expression was lower in Caco2 cells than in low and high metastatic KM12C and KM12L4 cells. The recombinant human IL-8 enhanced the proliferation of colon carcinoma cells. Furthermore, proliferation of low and high metastatic cells expressing different levels of IL-8 was inhibited by neutralizing antibodies to IL-8, CXCR1, and CXCR2. We observed significant differences in the invasive potential of colon carcinoma cells expressing different levels of IL-8. In addition, we observed that IL-8 modulates adhesion of tumor cells to endothelial cells in an autocrine and paracrine manner. CONCLUSION: Our present data suggest an association between constitutive expression of IL-8 and aggressiveness in human colon carcinoma cells and the possible role of IL-8 in modulating different metastatic phenotypes associated with progression and metastasis.

Animals↗

PubMed1995

Identification of a 38-kDa heparin-binding glycoprotein (gp38k) in differentiating vascular smooth muscle cells as a member of a group of proteins associated with tissue remodeling.

Cultured aortic smooth muscle cells (SMC) exhibit morphological and phenotypic modulation characterized by a change from a substrate attached monolayer culture to a multilayered nodular cell culture in which SMC are imbedded into the extracellular matrix. Associated with nodule formation is a change in the pattern of SMC gene expression including increased expression of a well characterized marker of smooth muscle cell differentiation, SM alpha-actin, and a 38-kDa glycoprotein (gp38k). gp38k has sequence homology with proteins reported to be correlated with tissue remodeling. To characterize the gp38k mRNA we designed degenerate oligonucleotides based on partial polypeptide sequencing to select a cDNA encoding the full-length gp38k. Southern analysis indicates that porcine gp38k is present as a single copy gene. Northern analysis indicates that the increase in gp38k is correlated with an increase in the steady state level of gp38k mRNA; and is present in cultures that have initiated the formation of multilayered foci and nodules. The correlation between SMC differentiation and gp38k expression is further established by using culture conditions that facilitate SMC differentiation. Cultures seeded onto reconstituted extracellular matrix show rapid formation of nodules and increased expression of gp38k mRNA. Comparison of the gp38k and cDNA sequences with nucleotide and protein sequences available through GenBank and SwissProt data banks revealed that molecules homologous to gp38k were present in human, mouse, bovine, and Drosophila tissues, suggesting that the gp38k may be a member of a gene family. Although a function for gp38k has not been identified, this report represents the first report of its correlation with a specific process important in phenotypic and morphological modulation of vascular SMC.

Adipokines↗

PubMed2005

Ethnicity and obstructive sleep apnoea.

There is a scarcity of adult prevalence studies of OSA outside the Caucasian populations of North America, Europe and Australia, and comparisons have been complicated by methodological differences in sleep study settings, respiratory events definition, measured risk factors and clinical outcomes, and the lack of objective parameters for the measurement of ethnicity itself. Comparing studies with the same methodological design and respiratory events definition, recent large-scale prevalence studies from Hong Kong, Korea and India show similar OSA rates to populations of mainly Caucasian composition. OSA is a very complex disorder determined by several phenotypes such as obesity, craniofacial structure and abnormalities in neuromuscular and ventilatory control. Genetics may partially explain some of the ethnic clustering of these phenotypes, modulated by cultural and environmental factors. The exact contribution of these component phenotypes to overall OSA risk will be determined by their varying prevalence and relative risk conferred across ethnic groups. For lesser degrees of obesity, Asians are at risk for a more severe degree of illness compared with Caucasians. Inter-ethnic studies suggests that African-American ethnicity may also be a significant risk factor for OSA. The increased prevalences of OSA among American Indians and Hispanic adults, and increased severity among Pacific Islanders and Maoris, were mainly explained by increased obesity parameters. Most cephalometric studies have largely been conducted without specific regard to ethnicity and comparisons of findings across studies have been mainly limited by differences in sampling methods and the varying selection and definition of measured cephalometric variables. The limited number of studies with inter-ethnic comparative data suggest cephalometric variables and their degree of contribution to OSA vary across ethnic groups.

Adult↗

PubMed2006

Susceptibility of human metabolic phenotypes to dietary modulation.

Dietary composition has been shown to influence metabolism and to impact on the prevalence and risk for certain diseases, but hitherto, there have been no systematic studies on the effects of dietary modulation of human metabolic phenotype (metabotype). Here, we have applied 1H NMR spectroscopy in combination with multivariate statistical analysis to characterize the effects of three diets: "vegetarian", "low meat", and "high meat" on the metabotype signature of human participants. Twelve healthy male participants (age range of 25-74 years) consumed each of these diets, in a randomized order, for continuous 15-day-periods with an intervening washout period between each diet of 7 days duration. Each participant provided three consecutive 24-hour urine collections on days 13, 14, and 15 of each dietary period, and 1H NMR spectra were acquired on all samples. Pattern recognition analysis allowed differentiation of the characteristic metabolic signatures of the diets with creatine, carnitine, acetylcarnitine, and trimethylamine-N-oxide (TMAO) being elevated in the high-meat consumption period. Application of orthogonal projection to latent structure discriminant analysis (O-PLS-DA) allowed the low-meat diet and vegetarian diet signatures to be characterized, and p-hydroxyphenylacetate (a microbial mammalian cometabolite) was higher in the vegetarian than meat diet samples, signaling an alteration of the bacterial composition or metabolism in response to diet. This work shows the potential for the routine use of metabonomics in nutritional and epidemiological studies, in characterizing and predicting the metabolic effects and the influence of diet on human metabotypes.

Acetylcarnitine↗

PubMed2000

ICAM-1 expression by vascular smooth muscle cells is phenotype-dependent.

Atherosclerosis is an inflammatory disease characterised by increased expression of adhesion molecules for leukocytes on both the surface of dysfunctional endothelium and on smooth muscle cells (SMC) within the lesion. It is also characterised by altered SMC phenotypic expression, indicated by a decreased volume fraction of myofilaments (V(v)myo) [1,2] and changes in gene expression [3]. The present study used an in vitro model to investigate, by immunofluorescence staining and flow cytometry, the influence of phenotype on vascular SMC expression of the adhesion molecule for leukocytes, intracellular adhesion molecule-1 (ICAM-1), and the regulatory mechanisms involved in this process. Smooth muscle cells with a high V(v)myo, freshly isolated from rat aortic media, expressed little or no ICAM-1 and this could not be induced by interleukin-1beta (IL-1beta). As SMC modulated phenotype, indicated by decreasing V(v)myo over the first 5 days of culture, there was a concomitant increase in ICAM-1 expression. At day 9 of primary culture, when SMC cultures had returned to the high V(v)myo phenotype, ICAM-1 expression was markedly lower. However, these cells retained the capacity to express ICAM-1 in response to IL-1beta. After several passages in culture, cells (with a low V(v)myo) constitutively expressed ICAM-1, with levels further up-regulated in response to IL-1beta. These changes in ICAM-1 expression were not related to proliferative state, since similar results were obtained with growth arrested SMC. Investigation of signalling pathways involved in regulating ICAM-1 expression by primary vascular SMC suggested a complex regulatory mechanism. Activation of adenyl cyclase (with forskolin) caused a significant increase in cells expressing ICAM-1. Treatment with inhibitors of protein kinase C (chelerythrine chloride), protein tyrosine kinase (genistein), or the transcription factor NF-kappaB (PDTC) had no significant effect on IL-1-induced ICAM-1 expression. However, in the presence of serum, both genistein and PDTC caused a significant increase in basal expression. The results indicate that ICAM-1 expression by SMC is phenotype-dependent, with expression evident only after cells have modulated to a low V(v)myo phenotype. They also indicate the existence of complex regulatory mechanisms, possibly involving the SMC cytoskeleton.

Analysis of Variance↗

PubMed2006

Orosomucoid (alpha1-acid glycoprotein) plasma concentration and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation.

BACKGROUND AND OBJECTIVE: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug. METHODS: Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined. RESULTS: Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics. CONCLUSION: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Adult↗

PubMed1999

Modulation of surface transferrin receptors in lymphoid cells de novo infected with human immunodeficiency virus type-1.

To investigate whether transferrin receptor (CD71) expression is affected by acute HIV-1 infection, three different lymphoid cell lines (MT-4, SUPT-1, H9) were infected with HIV-1 and tested for surface CD71 expression after different incubation periods depending on cell survival after infection. We found that expression of surface CD71 was lower in cells infected with HIV-1 than in uninfected controls: the timing and extent of this down-modulation depended apparently on the different susceptibility of the cell lines to HIV-1 infection and cytopathogenicity. Citrate, a molecule capable of chelating iron, dose-dependently prevented down-modulation of surface CD71 in HIV-1 infected cells as well as viral cytopathic effects. We conclude that (i) expression of surface transferrin receptors is down-modulated by acute HIV-1 infection in T lymphoid cells, that (ii) this cell phenotypic modulation is associated with the cytopathic effects of the virus, and that (iii) these phenomena are modulated by iron chelation. These results support the view that iron metabolism may be an important area for interaction between HIV-1 and human cells.

ADP-ribosyl Cyclase↗

PubMed2002

Fibronectin promotes cell cycle entry in smooth muscle cells in primary culture.

Smooth muscle cell proliferation after arterial injury is regulated by growth factors and components of the extracellular matrix. We have previously demonstrated that fibronectin promotes a phenotypic modulation of freshly isolated rat smooth muscle cells from a contractile to a synthetic phenotype in primary culture and supports the ability of the cells to respond to growth factors. Here, we analyzed if fibronectin promotes cell cycle entry in freshly isolated rat aortic smooth muscle cells during primary culture. Cell cycle analysis showed that cells seeded on fibronectin remained in the G(0)/G(1) phase of the cell cycle during the first 6 days of culture. During this period, there was an increased expression of cyclin D1 and p27(KIP1) in the absence of exogenous growth factors. Addition of serum was followed by enhanced cyclin D1 expression, decreased p27(KIP1) levels, hyperphosphorylation of Rb protein, induction of cyclin A and cyclin D3 expression, and cell cycle progression into S phase. The results indicate that fibronectin initiates cell cycle entry in freshly isolated smooth muscle cells by promoting the induction of cyclin D1 and thereby facilitates further cell cycle progression together with growth factors.

Animals↗

PubMed1999

Immunological and molecular characterization of an aggressive murine lymphoma variant: modulation in vitro and in vivo.

The highly metastatic murine ESb-L lymphoma was analyzed with respect to its possible origin and phenotype modulation. By determining the methylation status of the CD8 gene an early thymic origin of the ESb-L lymphoma cells is suggested. It revealed that the precursors of ESb-L cells had at least one CD8 allele expressed during their development. ESb-L tumor cells were found to express ICAM-1, ICAM-2, VLA-4 and Mel14 as adhesion molecules and homing receptors and CD25, CD69 and CD124 (HSA) as T-cell related activation markers. PCR analysis revealed that ESb-L tumor cells express a Th2-like cytokine pattern with mRNAs for IL-4, IL-5, IL-6, IL-10 and IL-13, but not for IL-2 and IFNgamma. In addition mRNA for TNFalpha, LT, IFNalpha and the chemokines MIP1alpha and MIP1beta was found. The expression of the adhesion molecules ICAM-1, ICAM-2, VLA-4 and of the T-cell activation marker CD25 on ESb-L tumor cells could be upregulated by incubating the cells with 10 ng/ml TNFalpha. For CD25 this effect was confirmed also at the mRNA level. Using the lacZ transduced T-cell lymphoma ESb-L-CI we were able to re-isolate live tumor cells from the primary site or from a metastasized liver and to investigate their phenotype ex vivo. MIP1alpha mRNA expression was strongly reduced in ex vivo isolated tumor cells as compared to in vitro grown cells indicating the modulatory role of the tumor microenvironment. The presented data suggest possible roles of TNFalpha and/or other microenvironmental factors modulating the expression of molecules involved in cell migration and adhesion thereby influencing cancer metastasis.

Animals↗

PubMed2001

The genetic basis of modularity in the development and evolution of the vertebrate dentition.

The construction of organisms from units that develop under semi-autonomous genetic control (modules) has been proposed to be an important component of their ability to undergo adaptive phenotypic evolution. The organization of the vertebrate dentition as a system of repeated parts provides an opportunity to study the extent to which phenotypic modules, identified by their evolutionary independence from other such units, are related to modularity in the genetic control of development. The evolutionary history of vertebrates provides numerous examples of both correlated and independent evolution of groups of teeth. The dentition itself appears to be a module of the dermal exoskeleton, from which it has long been under independent genetic control. Region-specific tooth loss has been a common trend in vertebrate evolution. Novel deployment of teeth and reacquisition of lost teeth have also occurred, although less frequently. Tooth shape differences within the dentition may be discontinuous (referred to as heterodonty) or graded. The occurrence of homeotic changes in tooth shape provides evidence for the decoupling of tooth shape and location in the course of evolution. Potential mechanisms for region-specific evolutionary tooth loss are suggested by a number of mouse gene knockouts and human genetic dental anomalies, as well as a comparison between fully-developed and rudimentary teeth in the dentition of rodents. These mechanisms include loss of a tooth-type-specific initiation signal, alterations of the relative strength of inductive and inhibitory signals acting at the time of tooth initiation and the overall reduction in levels of proteins required for the development of all teeth. Ectopic expression of tooth initiation signals provides a potential mechanism for the novel deployment or reacquisition of teeth; a single instance is known of a gene whose ectopic expression in transgenic mice can lead to ectopic teeth. Differences in shape between incisor and molar teeth in the mouse have been proposed to be controlled by the region-specific expression of signalling molecules in the oral epithelium. These molecules induce the expression of transcription factors in the underlying jaw mesenchyme that may act as selectors of tooth type. It is speculated that shifts in the expression domains of the epithelial signalling molecules might be responsible for homeotic changes in tooth shape. The observation that these molecules are regionally restricted in the chicken, whose ancestors were not heterodont, suggests that mammalian heterodonty may have evolved through the use of patterning mechanisms already acting on skeletal elements of the jaws. In general, genetic and morphological approaches identify similar types of modules in the dentition, but the data are not yet sufficient to identify exact correspondences. It is speculated that modularity may be achieved by gene expression differences between teeth or by differences in the time of their development, causing mutations to have cumulative effects on later-developing teeth. The mammalian dentition, for which virtually all of the available developmental genetic data have been collected, represents a small subset of the dental diversity present in vertebrates as a whole. In particular, teleost fishes may have a much more extensive dentition. Extension of research on the genetic control of tooth development to this and other vertebrate groups has great potential to further the understanding of modularity in the dentition.

Animals↗

PubMed2005

Trimers of N-alkylglycines are potent modulators of the multidrug resistance phenotype.

The multidrug resistance (MDR) phenotype is considered a major cause of the failure of cancer chemotherapy. The acquisition of MDR is usually mediated by the overexpression of drug efflux pumps such as glycoprotein P (P-gp) or multidrug resistance-related protein 1 (MRP1). Thus, the identification, validation, and development of compounds that mitigate the MDR phenotype by modulating the activity of these transport proteins is an important yet elusive target. Here, we have addressed this issue and screened an N-trialkylglycine-based combinatorial library composed of 5120 compounds to search for modulators of the MDR phenotype. The screening identified 20 trimers of N-alkylglycine that increased the intracellular accumulation of daunomycin (DNM) in drug-resistant L1210R tumor cells that overexpressed the P-gp. These compounds seem to act as P-gp antagonists, as evidenced by the augmentation of DNM accumulation in the L1210(P-gp) cell line, a drug-sensitive L1210 cell stably expressing the murine P-gp protein. Similarly, several of the active N-trialkylglycines also produced an increment in DNM uptake in human HL60R cells, which primarily express the MRP1 protein. Trialkylglycines notably sensitized L1210R and HL60R tumor cells to DNM with a potency that rivaled that of verapamil. These findings provide new molecular scaffolds for the development of effective chemosensitizers against the MDR phenotype that, in due turn, could be used as adjuvant drugs in cancer chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Serum deprivation induces a unique hypercontractile phenotype of cultured smooth muscle cells.

Chronic asthma is characterized by hypertrophy and hyperplasia of airway smooth muscle cells (SMC) that limit airflow by a geometric effect. Whether contractility of airway SMC is altered is not clear. Cultured cells were used as a model of hyperplasia. Phenotypic changes seen indicated conversion to a synthetic, weakly contractile type. At confluence, although limited reversal of protein changes was seen, no restoration in contractility occurred. Phenotypic modulation of postconfluent cultured airway SMC under prolonged serum deprivation (arrested cells) is reported here. Two phenotypically distinct groups of cells were identified in primary airway SMC cultures: 1) elongated spindle-shaped cells, which expressed large amounts of smooth muscle contractile and regulatory proteins, and 2) flat and stellate cells, which expressed very little. The first group showed a surprising shortening capacity and a velocity that was even greater than that of the freshly isolated cells, whereas the second group became spherical and noncontractile. Even more surprising was that the myosin heavy chain (MHC) isoform (SM-B) generally said to be associated with the higher shortening velocity disappeared from the cell, while the content of the key rate-limiting regulating enzyme, myosin light chain kinase (MLCK), increased 30-fold. We conclude that a functional, contractile phenotype of airway SMC can be obtained by prolonged serum deprivation. We speculate that the increased contractility could be the result of increased phosphorylation of the 20-kDa myosin light chain resulting from increased content of smooth muscle MLCK rather than any increase in endogenous MHC ATPase activity. This model may be useful for study of SMC differentiation and contraction.

Actins↗