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Results for “Phenotypic modulation”

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PubMed1991

Cyclosporine A inhibits induction of DNA synthesis by PDGF and other peptide mitogens in cultured rat aortic smooth muscle cells and dermal fibroblasts.

The immunosuppressive drug cyclosporine A was recently shown to inhibit smooth muscle proliferation in the vascular response to injury. To examine if this may be due to a direct effect of the drug on the smooth muscle cells (SMCs), we have studied its influence on the phenotypic modulation of rat aortic SMCs in primary cultures and on the induction of DNA synthesis by peptide mitogens in serum-starved subcultures. The results demonstrate that cyclosporine A does not interfere with the transition of the SMCs from a contractile to a synthetic phenotype, an early step in the preparation for cell division. On the other hand, it inhibits induction of DNA synthesis by recombinant platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and insulin-like growth factor-I (IGF-I). Maximum effect was obtained at a concentration of 1-3 micrograms/ml and the drug could be added 4-6 h after the growth factors with full inhibitory effect. No distinct effect on the stimulation of overall RNA and protein synthesis by PDGF-BB was observed, indicating that the drug was not of general cytotoxicity at the concentrations used. Throughout this part of the investigation, similar results were obtained with rat dermal fibroblasts. The findings indicate that cyclosporine A inhibits induction of DNA synthesis by peptide mitogens, and suggest that the inhibitory effect of cyclosporine A on smooth muscle proliferation in vivo at least in part may be due to a direct action on these cells.

Animals↗

PubMed2003

Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias.

We have recently demonstrated that in an autosomal dominant porphyria, erythropoietic protoporphyria (EPP), the coinheritance of a ferrochelatase (FECH) gene defect and of a wild-type low-expressed FECH allele is generally involved in the clinical expression of EPP. This mechanism may provide a model for phenotype modulation by minor variations in the expression of the wild-type allele in the other three autosomal dominant porphyrias that exhibit incomplete penetrance: acute intermittent porphyria (AIP), variegata porphyria (VP) and hereditary coproporphyria (HC), which are caused by partial deficiencies of hydroxy-methyl bilane synthase (HMBS), protoporphyrinogen oxidase (PPOX) and coproporphyrinogen oxidase (CPO), respectively. Given the dominant mode of inheritance of EPP, VP, AIP and HC, we first confirmed that the 200 overtly porphyric subjects (55 EPP, 58 AIP, 56 VP; 31 HC) presented a single mutation restricted to one allele (20 novel mutations and 162 known mutations). We then analysed the available single-nucleotide polymorphisms (SNPs) present at high frequencies in the general population and spreading throughout the FECH, HMBS, PPOX and the CPO genes in four case-control association studies. Finally, we explored the functional consequences of polymorphisms on the abundance of wild-type RNA, and used relative allelic mRNA determinations to find out whether low-expressed HMBS, PPOX and the CPO alleles occur in the general population. We confirm that the wild-type low-expressed allele phenomenon is usually operative in the mechanism of variable penetrance in EPP, but conclude that this is not the case in AIP and VP. For HC, the CPO mRNA determinations strongly suggest that normal CPO alleles with low-expression are present, but whether this low-expression of the wild-type allele could modulate the penetrance of a CPO gene defect in HC families remains to be ascertained.

Acute Disease↗

PubMed2026

Athero-oncology: Vascular smooth muscle cell tumor-like transformation in atherosclerosis and therapeutic opportunities.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, and its pathogenesis and treatment strategies remain major challenges. Recent advances in single-cell RNA sequencing and lineage tracing have revealed that vascular smooth muscle cells (VSMCs) are not merely passive structural components of atherosclerotic plaques, but highly plastic participants that undergo clonal expansion, phenotypic modulation, and transdifferentiation into functionally diverse cell states. These findings have prompted the emergence of an "athero-oncology" framework, which explores selected tumor-like cellular programs in VSMCs during AS without equating atherosclerosis with cancer. In this review, we summarize the evidence supporting VSMC-derived clonal expansion and phenotypic diversification in atherosclerotic lesions and discuss key mechanisms involved in this process, including proliferative expansion and survival programs, metabolic reprogramming, epigenetic regulation, DNA damage and genomic stress, VSMC senescence, pathological angiogenesis, and remodeling of the inflammatory and immune microenvironment. We further highlight shared signaling pathways between VSMC-driven plaque remodeling and tumor biology, while emphasizing fundamental differences between AS and malignant disease in growth limitation, mutational burden, metastatic potential, and clinical behavior. Finally, we discuss oncology-inspired therapeutic opportunities and boundaries, including pathway-level targeting of proliferative, metabolic, epigenetic, and inflammatory programs, as well as the risks of directly repurposing anticancer therapies for chronic vascular disease. This framework may provide new insights into vascular biology and therapeutic development.

atherosclerosis↗

PubMed2006

Serum deprivation results in redifferentiation of human umbilical vascular smooth muscle cells.

Phenotypic change of vascular smooth muscle cells (VSMCs) from a differentiated to a dedifferentiated state accompanies the early stage of atherosclerosis and restenosis. Although much progress has been made in determining the molecular mechanisms involved in VSMC dedifferentiation, research on VSMC redifferentiation is hindered by the lack of an appropriate complete redifferentiation model. We established an in vitro model of redifferentiation by using postconfluent VSMCs from human umbilical artery. We demonstrated that serum-deprived VSMCs are capable of complete redifferentiation. After serum deprivation, postconfluent cultured human umbilical VSMCs became elongated and spindle shaped, with elevation of myofilament density, and reacquired contraction. Expressions of VSMC-specific contractile proteins, such as smooth muscle (SM) alpha-actin, SM-myosin heavy chain, calponin, and SM 22alpha, were increased and reached the levels in differentiated cells after serum deprivation. To determine the molecular mechanism of the phenotypic reversion, the levels of expression, phosphorylation, and binding activity of serum response factor (SRF), a key phenotypic modulator for VSMCs, were measured. The results showed that SRF binding activity with CArG motif was significantly increased after serum deprivation, whereas no changes were found in SRF expression and phosphorylation. The increased SRF binding activity was accompanied by an increase in expression of its coactivators such as myocardin. Furthermore, the phenotypic reversion was markedly inhibited by decoy double-strand oligodeoxynucleotides containing SM alpha-actin CArG motif, which was able to competitively bind to SRF. The results suggested that serum deprivation results in redifferentiation of human umbilical VSMCs. This novel model of VSMC phenotypic reversion should be valuable for research on vascular disease.

Cell Differentiation↗

PubMed1999

TGFbeta isoforms and decorin gene expression are modified in fibroblasts obtained from non-syndromic cleft lip and palate subjects.

Interaction between extracellular matrix (ECM) and cytokines is thought to be crucial for palatal development. The localization of transforming growth factors (TGFalpha and TGFbeta isoforms) in craniofacial tissues suggests that they carry out multiple functions during development. In the present report, we studied TGFalpha, TGFbeta1, and TGFbeta3 expressions and their effects on ECM macromolecule production of normal and cleft palatal fibroblasts in vitro, to investigate the mechanisms by which the phenotypic modulation of fibroblasts occurs during the cleft palate process. The results indicated that, while TGFalpha mRNA was not evidenced in CLP or normal fibroblasts, a reduced TGFbeta1 hybridization signal was detected in CLP fibroblasts. In addition, these secreted more active TGFbeta3 than TGFbeta1, as evaluated in a biological assay. The CLP phenotype, which differed from the normal one because of its higher PG decorin expression and greater production of GAG and collagen, was further modified by the addition of growth factors. In fact, in CLP fibroblasts, TGFalpha and TGFbeta1 down-regulated PG decorin transcript, TGFbeta1 increased collagen and GAG in both cellular and extracellular compartments, and TGFbeta3 promoted secretory processes of cells. In conclusion, the data represent the first report in a human model in vitro that TGFbeta1 and beta3 are differently expressed and are correlated to the CLP phenotype. Thus, strength is given to the hypothesis that TGFbeta isoforms are the potential inducers of phenotypic expression in palatal fibroblasts during development and that an autocrine growth factor production mechanism may be responsible for the phenotypic modifications.

Analysis of Variance↗

PubMed1997

A novel tetrodotoxin-sensitive Na+ current in cultured human coronary myocytes.

Voltage-gated Na+ currents (INaS) are usually not found in arterial smooth muscle. We enzymatically isolated myocytes from the media of left coronary arteries of heart transplant patients with ischemic cardiopathy. Using the whole-cell voltage-clamp technique (20 degrees C to 22 degrees C), we detected no INa in any of the freshly isolated myocytes. In contrast, when the cells were grown in culture, we could record a large INa. This INa was characterized by a biexponential decay comprising a fast inactivating and sustained components that could not be separated by their electrophysiological and pharmacological properties. INa activated at depolarizations positive to -50 mV, was maximal at 0 mV, and was available from relatively low resting membrane potentials (half-inactivation at -46 mV). INa was modulated by several ligands known to bind selectively at different sites of Na+ channels. It was blocked with high affinity by tetrodotoxin (IC50, approximately 10 nmol/L) and local anesthetics (bupivacaine and lidocaine; IC50, approximately 100 nmol/L) and by Cd2+ (IC50, approximately 300 mumol/L). INa was modulated by Na+ channel agonists such as toxin AsV from Anemonia sulcata and veratridine, which slowed current kinetics dramatically. In conclusion, human coronary myocytes in culture can express an atypical tetrodotoxin-sensitive INa with a large sustained component, which is expected to contribute to massive Na+ influx into these cells. Phenotypic modulation of the expression of this INa may be related to cell dedifferentiation and proliferation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1999

Clusterin (Apo J) regulates vascular smooth muscle cell differentiation in vitro.

Previously we reported a significant and substantial increase in the synthesis and secretion of clusterin in cultured porcine vascular smooth muscle cells (VSMC) during the time when the VSMC culture modulates from a proliferating monolayer morphology to a nodular cell culture morphology. That in vitro process appears to recapitulate some aspects of in vivo vascular remodeling in response to injury and is facilitated by the presence of a well-developed extracellular matrix. To directly test the hypothesis that clusterin regulates VSMC phenotypic modulation, cultured VSMC were stably transfected with an expression plasmid containing the full-length murine clusterin sequence in antisense orientation. Twenty-four clones were selected on the basis of neomycin resistance and characterized for clusterin expression and culture morphology. In contrast to clone SM-CLU18AS, which expresses a high level of clusterin and forms multicellular nodules, clone SM-CLU13AS expresses a low level of clusterin and does not form nodules even in the presence of a preformed collagen gel. Importantly, clusterin-negative SM-CLU13AS retains the ability to form nodules in an environment containing exogenous clusterin. SM-CLU13AS forms nodules when cultured in Matrigel (which contains clusterin) and in the presence of clusterin-containing conditioned media prepared from nodular SMC cultures or SM-CLU18AS cultures. These results demonstrate that clusterin is required for VSMC nodule formation and suggest that it may play a role in smooth muscle cell reorganization in the vascular wall.

Animals↗

PubMed1997

Different hematological phenotypes caused by the interaction of triplicated alpha-globin genes and heterozygous beta-thalassemia.

The pathophysiology and clinical severity of beta-thalassemia are related to the degree of alpha/non-alpha-chain imbalance. A triplicated alpha-globin gene locus can exacerbate effects of excess alpha-chains caused by a defective beta-globin gene, although this is not observed in all cases. Extensive studies on this condition are lacking. We report a group of 17 patients who are heterozygous for both the alpha alpha alpha(anti-3.7) allele and a mutation in the beta-globin gene cluster. Their clinical phenotypes varied: six had mild anemia with microcytosis and hypochromia, while 11 had more severe anemia with splenomegaly requiring splenectomy (three cases) and blood transfusions (four cases). Different phenotypes were also evident in the presence of the same beta-thalassemia mutation: in one family, two individuals had the same alpha- and beta-globin genotypes but presented with different hematologic phenotypes. In addition, the complex interaction involving a triplicated alpha-globin gene, beta39- and delta+27-thalassemia mutations is studied in a family with two siblings presenting with hemolytic anemia, normal Hb A2 and increased Hb F. Analysis of this series of patients suggests that additional genetic determinants play a role in modulating phenotypic expression in individuals with identical alpha- and beta-globin genotypes. Interaction with a triplicated alpha-gene can play a role in the clinical presentation of patients with defective beta-globin gene expression and should be considered in the diagnosis of atypical cases.

Adult↗

PubMedDate not supplied

Generation of monocyte-derived dendritic cells from patients with renal cell cancer: modulation of their functional properties after therapy with biological response modifiers (IFN-alpha plus IL-2 and IL-12).

The combination of interferon-alpha (IFN-alpha) plus interleukin (IL-2) has been accepted in the treatment of metastatic renal cell carcinoma (MRCC), whereas vaccines based on IL-12 or dendritic cells (DCs) are still being investigated. Here the authors analyzed 1) the feasibility to generate functional monocyte-derived DCs (MDDCs) from patients treated with biological response modifiers (BRMs) who have MRCC, 2) the phenotypic modulations of these MDDCs during BRM treatment. Eight and 13 MRCC patients received IL-2 plus IFN-alpha or IL-12 immunotherapy, respectively. The adherent fraction of mononuclear cells from patients' blood drawn before, during, and after immunotherapy was incubated in clinically approved culture medium supplemented with 5% autologous serum, rhu granulocyte macrophage colony-stimulating factor, and rhuIL-4 for a week. At day 7 or 8 of culture, floating cells were examined in flow cytometric and functional assays (alloreactivity, proliferation assays in the presence of tetanus toxoid or tumor peptides, IL-12 secretion). In all patients except two, MDDCs could be generated but at a lower rate compared with healthy volunteers. Morphologic and phenotypical analyses revealed immature DCs with low levels of CD1a or CD83 expression throughout therapy with BRMs. Capacities in mixed leukocyte reactions were similar to those of healthy volunteers and stable during immunotherapy, whereas presentation of major histocompatibility complex class II tetanus toxoid peptide complexes was slightly enhanced during and after IL-12 therapy. IL-12 expression levels under IFN-gamma and CD40L stimulation were significantly lower in MDDC cultures from patients with MRCC compared with healthy volunteers. Overall, peripheral blood mononuclear cells from a cohort of 21 patients with metastatic disease who were treated with BRMs maintained their ability to differentiate into functional MDDCs with no selective quantitative or qualitative advantage.

Antibodies, Monoclonal↗

PubMed2000

[Molecular structure and function of mechanosensor mechanisms: an alternative prospect for the development of new drugs].

Mechanical stress to cells induces various physiological cellular responses and pathophysiological changes in many cell types. However, the molecular mechanisms remain unclear. Clarification of the mechanosensor mechanisms on the molecular level may provide an alternative approach for the development of new drugs. In the 73rd Annual Meeting of The Japanese Pharmacological Society, the latest studies performed by the following five departments were reported and discussed: 1) Expression of putative stretch sensitive nonselective cation channels of mammal, by M. Suzuki et al. (Department of Pharmacology, Jichi Medical School); 2) Mechanosensitive ATP release in aortic endothelial cells, by M. Oike et al. (Department of Pharmacology, Graduate School of Medical Science, Kyushu University); 3) Lysophosphatidic acid acts as an endogenous modulator on mechanotransduction, by H. Ohata et al. (Department of Pharmacology, School of Pharmaceutical Sciences, Showa University); 4) Stretch-induced myosin light chain phosphorylation without force development in canine basilar artery, by K. Obara et al. (Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka); and 5) Transcriptional regulation of smooth muscle phenotypic modulation, by R. Nagai (Department of Cardiovascular Medicine, University of Tokyo). This article reviews these reports.

Adenosine Triphosphate↗

PubMed1998

Isolation and characterization of the 5'-flanking regulatory region of the human natriuretic peptide receptor C gene.

Phenotypic modulation of vascular smooth muscle cells (SMCs) plays a central role in the pathogenesis of atherosclerosis. Natriuretic peptide receptor-C (NPR-C) is highly expressed in vascular SMCs in the experimental arteriosclerotic neointimal area as well as in cultured SMCs, suggesting that increased expression of the NPR-C gene is related to the phenotypic alteration of vascular SMCs. To elucidate the molecular mechanisms and to identify the essential DNA sequences in NPR-C gene expression, a genomic clone containing over 8 kilobases of the 5'-flanking region of the human NPR-C gene has been isolated. Sequence analysis revealed that a number of putative regulatory elements including unusual tandem repeated AP-2-like sequences were observed in the 5'-flanking region. Primer extension and ribonuclease protection analyses revealed that transcription of the human NPR-C gene starts from two major regions. Promoter analysis using deletion constructs in human cells, highly producing NPR-C transcripts, showing that the region (from - 33 to + 13 relative to the transcription start point) had a potential promoter activity suggested that the region from -33 to + 13, containing a pyrimidine-rich stretch composed of four CTTTTT-repeated sequences, is sufficient for the proximal promoter activity. Moreover, three distinct DNA sequences surrounding the transcription start site (P1, from -60 to -33; P2, from + 14 to +40; P3, from +41 to +66) were revealed to be functional as a cis-acting positive enhancer, and a nuclear protein(s) from the human cells was demonstrated to specifically bind to the sequences, respectively. However, promoter analysis has shown that the P2 and P3 sequences could not activate the human NPR-C promoter in a synergistic manner. On the basis of deoxyribonuclease I footprinting analysis showing that a DNA element from +48 to +60 within the P3 sequence is preferentially protected, the P3 sequence appears to contain a potential regulatory element involved in NPR-C gene expression. The present study demonstrated the structure of the 5'-regulatory region of the human NPR-C gene and multiple cis-acting positive sequences closely located around the transcription start points with an important role in regulation of human NPR-C gene expression.

Amino Acid Sequence↗

PubMed1996

Radiological and histological variants of thanatophoric dysplasia are associated with common mutations in FGFR-3.

We describe two fetuses of the 21st week of gestation that share some macroscopic, radiologic, and histologic findings of thanatophoric dysplasia (TD), but also show distinct differences from the usual subtypes of TD. These differences mainly comprise the lack of facial abnormality, only mild reduction of chondrocyte proliferation and hypertrophy, and the lack of fibrous tissue interposition between cartilage and periosteal bone. Thus, these two cases may represent a distinct variant of thanatophoric dysplasia. The molecular analysis of the FGF-R-3 gene demonstrated in both cases mutations which were not significantly different from those of other cases of TD. Thus, the phenotypic modulation within the subtypes of TD may be influenced by additional and yet unknown factors.

Adult↗

PubMed1998

A multifunctional transcription factor (A1p145) regulates the smooth muscle phenotype in mesangial cells.

A1p145, a novel DNA binding protein for type IV collagen gene (COL4), has multiple functions including DNA replication factor C and DNA binding for several other genes. To elucidate the mechanisms underlying the differentiation process of mesangial cells (MCs), we investigated the effects of A1p145 on rat MCs. Cells in the early passages showed a smooth muscle-like phenotype such as low cell turnover, high levels of expression for COL4, and smooth muscle alpha-actin (SMA). Cells in the late passages lost their phenotype. The amount of binding activity to COL4 promoter was inversely correlated with the level of COL4 mRNA. Introduction of antisense for A1p145 into late passage cells enhanced the levels of mRNA for COL4 and SMA. The levels of proliferating cell nuclear antigen mRNA were also suppressed. These results suggest that A1p145 is a negative transcription factor for COL4 and may be a phenotypic modulator.

Actins↗

PubMed1986

Culture and characterization of murine dendritic Thy-1+ epidermal cells.

Although numerous advances have been made in characterizing the phenotype, ontogeny, ultrastructure, and cytochemistry of the murine Thy-1+ dendritic epidermal cell (Thy-1+ EC), elucidation of its functional qualities has been hampered by the difficulty in preparing pure populations of these cells. We therefore sought to obtain expanded, purified populations of Thy-1+ EC using culture techniques. Since Thy-1+ EC are bone marrow-derived, density gradient enriched populations of freshly harvested epidermal cells (FH-EC) were placed in culture under conditions known or suspected to promote mitogenesis among leukocyte subsets. FH-EC prepared from truncal skin of C3H/HeN mice (Thy-1.2+) were cultured at 37 degrees C in 5% CO2 in complete medium (CM) of Eagle's Hanks' amino acid with 10% fetal calf serum, nutrients, and antibiotics at 10(6) FH-EC/well in 24-well culture plates. CM was supplemented with one or more of the following: concanavalin A (Con-A), interleukin-1/epidermal cell-derived thymocyte-activating factor (IL-1/ETAF), IL-2, IL-3, gamma interferon, indomethacin (IM), and anti-Thy-1.2 antibody. Media with appropriate supplements were changed every 2-3 days. Freshly isolated, enriched FH-EC contained 7-20% Thy-1+ EC (defined as brightly fluorescing cells readily distinguishable from weakly fluorescing keratinocytes), which also stained with antibodies directed against asialo GM1, Ly 5.1, and vimentin but did not stain with antibodies to other T cell-, B cell- or macrophage phenotypic markers. Analysis of 10 separate cultures revealed a 3- to 10-fold expansion of nonkeratinocyte Thy-1+ cells after 21 +/- 4 days in culture in CM supplemented with Con-A and IM, and 70-100% of viable cells after expansion were Thy-1+. Phenotypic analysis of expanded cells revealed the emergence in 10 separate cultures of one of two mutually exclusive distinct populations: one Thy-1+, asialo GM1+, L3T4- (natural killer phenotype) and the other Thy-1+, asialo GM1-, L3T4+ (T helper phenotype). Experiments designed to explain the emergence of an L3T4+ population suggest that phenotypic modulation occurred in vitro.

Animals↗

PubMed2005

Contribution of Kv channels to phenotypic remodeling of human uterine artery smooth muscle cells.

Vascular smooth muscle cells (VSMCs) perform diverse functions that can be classified into contractile and synthetic (or proliferating). All of these functions can be fulfilled by the same cell because of its capacity of phenotypic modulation in response to environmental changes. The resting membrane potential is a key determinant for both contractile and proliferating functions. Here, we have explored the expression of voltage-dependent K+ (Kv) channels in contractile (freshly dissociated) and proliferating (cultured) VSMCs obtained from human uterine arteries to establish their contribution to the functional properties of the cells and their possible participation in the phenotypic switch. We have studied the expression pattern (both at the mRNA and at the protein level) of Kvalpha subunits in both preparations as well as their functional contribution to the K+ currents of VSMCs. Our results indicate that phenotypic remodeling associates with a change in the expression and distribution of Kv channels. Whereas Kv currents in contractile VSMCs are mainly performed by Kv1 channels, Kv3.4 is the principal contributor to K+ currents in cultured VSMCs. Furthermore, selective blockade of Kv3.4 channels resulted in a reduced proliferation rate, suggesting a link between Kv channels expression and phenotypic remodeling.

Cell Proliferation↗

PubMed1999

Changes in the balance of phosphoinositide 3-kinase/protein kinase B (Akt) and the mitogen-activated protein kinases (ERK/p38MAPK) determine a phenotype of visceral and vascular smooth muscle cells.

The molecular mechanisms behind phenotypic modulation of smooth muscle cells (SMCs) remain unclear. In our recent paper, we reported the establishment of novel culture system of gizzard SMCs (Hayashi, K., H. Saga, Y. Chimori, K. Kimura, Y. Yamanaka, and K. Sobue. 1998. J. Biol. Chem. 273: 28860-28867), in which insulin-like growth factor-I (IGF-I) was the most potent for maintaining the differentiated SMC phenotype, and IGF-I triggered the phosphoinositide 3-kinase (PI3-K) and protein kinase B (PKB(Akt)) pathway. Here, we investigated the signaling pathways involved in de-differentiation of gizzard SMCs induced by PDGF-BB, bFGF, and EGF. In contrast to the IGF-I-triggered pathway, PDGF-BB, bFGF, and EGF coordinately activated ERK and p38MAPK pathways. Further, the forced expression of active forms of MEK1 and MKK6, which are the upstream kinases of ERK and p38MAPK, respectively, induced de-differentiation even when SMCs were stimulated with IGF-I. Among three growth factors, PDGF-BB only triggered the PI3-K/PKB(Akt) pathway in addition to the ERK and p38MAPK pathways. When the ERK and p38MAPK pathways were simultaneously blocked by their specific inhibitors or an active form of either PI3-K or PKB(Akt) was transfected, PDGF-BB in turn initiated to maintain the differentiated SMC phenotype. We applied these findings to vascular SMCs, and demonstrated the possibility that the same signaling pathways might be involved in regulating the vascular SMC phenotype. These results suggest that changes in the balance between the PI3-K/PKB(Akt) pathway and the ERK and p38MAPK pathways would determine phenotypes of visceral and vascular SMCs. We further reported that SMCs cotransfected with active forms of MEK1 and MKK6 secreted a nondialyzable, heat-labile protein factor(s) which induced de-differentiation of surrounding normal SMCs.

Animals↗

PubMed1981

Modulation of glycosaminoglycan biosynthesis by retinoids.

In conclusion, retinoids modulate phenotypic changes such as morphology, adhesion, and growth rate. These changes also result in specific alterations of glycosaminoglycans. We have observed increases in the degree of sulfation in fibroblast matrix heparan sulfate and, a change in the ratio of sulfamido to ester sulfate in matrix heparan sulfate in 407 cell surface. Matrix glycosaminoglycans have been functionally implicated in cellular interactions, and have a specific role in adhesion and growth rates. Our results are consistent with the proposed role for heparan sulfate. It is possible that some of the modulation in cellular behavior resulting from retinoid treatment may be mediated by cell surface and cellular changes in heparan sulfate and other glycosaminoglycans.

Acitretin↗

PubMed2002

Detection of biofilm-forming strains of Staphylococcus epidermidis and S. aureus.

The formation of biofilm represents an important virulence factor of certain strains of Staphylococcus epidermidis and S. aureus. The ability of bacteria to aggregate, forming biofilms, is strictly related to the capacity of producing an extracellular mucoid substance often referred to as slime, whose main component is of polysaccharidic nature and consists of glycosaminoglycans. In recent years, new molecular techniques based on PCR have come alongside more traditional methods for identification of virulent biofilm-forming strains. The detection of the genes governing the production of such extracellular polysaccharide and, in particular, the icaA, the icaC and the icaD genes, provides us with a rapid and accurate technique for strain characterization. However, well-established methods, such as the Congo red agar test are still needed in order to confirm the phenotypic expression in the case of possible phase-variant strains. In future, the complete knowledge of the genetic mechanisms of phenotype modulation, comprehending all regulatory genes, could permit the characterization of the isolates just by molecular means in a single step.

Bacterial Adhesion↗