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PubMedDate not supplied

IL-6 promoter polymorphism at position -174 modulates the phenotypic expression of polymyalgia rheumatica in biopsy-proven giant cell arteritis.

OBJECTIVES: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are related diseases in which diverse genetic and environmental factors are implicated. Both GCA and PMR are characterized by an intense acute phase reaction. In these sYndromes the increased production of IL-6 has been observed. To investigate further the genetic influence of IL-6 in GCA and PMR we have examined the IL-6 promoter polymorphism (G to C) at position -174 in the 5' region in a series of patients from Northwest Spain diagnosed with GCA and/or PMR. METHODS: Sixtxy-two biopsy-proven GCA patients (30 of them with associated PMR) and 84 patients with isolated PMR were studied. Patients and ethnically matched controls (n = 124) were from the Lugo region (Galicia, Northwest Spain). Patients and controls were genotyped for HLA-DRB1 and IL-6 polymorphism at position -174 by molecular methods. RESULTS: IL-6-174 allele C was marginally increased infrequency in GCA patients with PMR manifestations compared with isolated GCA (Pcorr 0.06; OR = 2.3). The increase in the frequency of the CC genotype in GCA patients with PMR versus those with isolated GCA was statistically significant (Pcorr 0.02). The increased frequency of allele C in GCA patients with PMR was more commonly observed in HLA-DRBI *04 negative patients. However, this polymorphism was not associated with a higher risk of ischemic events in GCA or with relapses in PMR. CONCLUSION: Allele C at position -174 in the 5' promoter region of the IL-6 gene may be associated with PMR in biopsy-proven GCA patients not carrying HLA-DRBI *04 alleles.

Alleles↗
PubMed1989

Properties of lymph-borne (veiled) dendritic cells in culture. I. Modulation of phenotype, survival and function: partial dependence on GM-CSF.

Lymph-borne dendritic cells (L-DC) collected from the thoracic duct of rats following mesenteric lymphadenectomy are derived from the small intestine. We have cultured these cells in vitro and examined their survival and phenotypic and functional changes. L-DC survive poorly in culture in normal media (less than 50% overnight) but survival can be markedly increased by supplementation with Con A-stimulated spleen cell supernatant or recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) but not by recombinant IL-1, IL-2, IFN-gamma or by an IL-3-rich supernatant. The effects of GM-CSF are blocked by a specific antiserum. L-DC display heterogeneity for some surface markers, cytoplasmic inclusions and enzyme reactivity. After 16-48 hr culture the pattern of expression is markedly different. The numbers of Thy-1-positive L-DC and the amount of Thy-1 expressed increases, as do the numbers of L-DC expressing OX48 antigen. All L-DC remain Ia positive, but the proportion expressing the iC'3b receptor, non-specific esterase or cytoplasmic DNA inclusions decreases to almost zero. In contrast to Langerhans' cells, fresh L-DC are potent stimulators of an allogeneic mixed leucocyte reaction (MLR) but their potency is considerably increased after 16 hr culture. Also in contrast to Langerhans' cells, the increase in potency is not affected by culture with CAS and is thus unlikely to be dependent on GM-CSF. The changes described in L-DC properties could be related to their role as antigen-presenting cells.

Animals↗
PubMed1985

The calcium antagonist nifedipine inhibits arterial smooth muscle cell proliferation.

Migration of smooth muscle cells from the media to the intima of the arterial wall and proliferation of intimal smooth muscle are major early events in the formation of an atherosclerotic lesion. The start of proliferation requires that the cells have passed through a modulation from contractile to synthetic phenotype and that they are stimulated with growth factors. Here, we have examined the effects of the calcium antagonist nifedipine on phenotypic modulation and growth of isolated rat arterial smooth muscle cells cultivated in vitro. The results indicate that micromolar concentrations of nifedipine slow down the rate of transformation of the cells from a contractile to a synthetic phenotype and inhibit initiation of DNA synthesis as well as cellular proliferation. The inhibitory effect on DNA synthesis was seen both in cells stimulated with whole blood serum and with purified platelet-derived growth factor. The results raise the possibility that nifedipine may be used to prevent atherogenesis and to inhibit progression of fibromuscular lesions by interfering with the proliferation of arterial smooth muscle cells.

Actins↗
PubMed2003

Effect of bladder outlet obstruction on detrusor smooth muscle cell: an in vitro study.

BACKGROUND: Although relieving obstruction is generally curative on bladder outlet obstruction (BOO), bladder dysfunction persists in some patients. Repetitive stretch and relaxation applied to cultured bladder smooth muscle (SM) cells in vitro have been used to mimic increases in urodynamic load experienced by the detrusor muscle under conditions of BOO. We first clarified the relationship between phenotype transformation and biomechanical properties of detrusor smooth muscle cell (DSMC) subjected to the cyclic mechanical stretch. MATERIALS AND METHODS: Cultured rat DSMC were grown on collagen-coated silicone membranes and subjected to continuous cycles of stretch-relaxation. All experiments were performed on cells between passages 2 and 4. Each cycle consists of 5 seconds of stretch and 5 seconds of relaxation. The computer controlled vacuum induced 10% (1), 20% (2), and 30% (3) maximum elongation of the plate membrane at different designed pressures. The deoxyribonucleic acid synthesis rate was assessed by performing tritiated thymidine incorporation assay. The expression of SM-alpha-actin and proliferation of DSMC were analyzed by immunofluorescent assay and flow cytometry. The image analysis and micropipet aspiration systems were used to investigate the single cell contraction and viscoelasticity. Using the 3-element standard linear solid model, the elastic modulus K(1), K(2), and viscoelastic coefficient mu were determined, which show the passive deformation ability of detrusor cells. RESULTS: As the basic structural changes to mechanical stretch, DSMC undergo phenotypic modulation from their normal contractile phenotype to a "synthetic" phenotype: the DSMC become more proliferative and the actin less organized along the cell's long axis. The cell proliferation index of control and stretched group (10%, 20%, 30% elongation) are 0.24, 0.43, 0.58, and 0.65, respectively. The actin filaments in unstimulated cells were evident and orientated along the major axis of the cell. After mechanical stretch, the well-spread filaments changed their orientation. The function, such as contraction, and viscoelasticity of a single DSMC subjected to stretch both decreased significantly compared with control. The maximum contractile velocity and maximum cell length shortening rate of group 3 (30% elongation) showed significant decreases compared with unstretched control (P < 0.01). K(1) and K(2) were decreased with the increase of mechanical overload. However, there was no statistic difference between groups 2 and 3. CONCLUSIONS: Functional abnormalitie of BOO have the structural basis: phenotype transformation (i.e., remodeling) of the detrusor cells. Cyclic stretch and relaxation applied to DSMC in vitro can be used to model increases in urodynamic load experienced by the bladder detrusor muscle under conditions of BOO. Phenotype transformation is the structural basis of functional changes of DSMC subjected to periodic overload mechanical stretch.

Actins↗
PubMed2006

Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival.

In response to biological and mechanical injury, or in vitro culturing, vascular smooth muscle cells (VSMCs) undergo phenotypic modulation from a differentiated "contractile" phenotype to a dedifferentiated "synthetic" one. This results in the capacity to proliferate, migrate, and produce extracellular matrix proteins, thus contributing to neointimal formation. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP or cGMP, are critical in the homeostasis of cyclic nucleotides that regulate VSMC growth. Here, we demonstrate that PDE1A, a Ca2+-calmodulin-stimulated PDE preferentially hydrolyzing cGMP, is predominantly cytoplasmic in medial "contractile" VSMCs but is nuclear in neointimal "synthetic" VSMCs. Using primary VSMCs, we show that cytoplasmic and nuclear PDE1A were associated with a contractile marker (SM-calponin) and a growth marker (Ki-67), respectively. This suggests that cytoplasmic PDE1A is associated with the "contractile" phenotype, whereas nuclear PDE1A is with the "synthetic" phenotype. To determine the role of nuclear PDE1A, we examined the effects loss-of-PDE1A function on subcultured VSMC growth and survival using PDE1A RNA interference and pharmacological inhibition. Reducing PDE1A function significantly attenuated VSMC growth by decreasing proliferation via G1 arrest and inducing apoptosis. Inhibiting PDE1A also led to intracellular cGMP elevation, p27Kip1 upregulation, cyclin D1 downregulation, and p53 activation. We further demonstrated that in subcultured VSMCs redifferentiated by growth on collagen gels, cytoplasmic PDE1A regulates myosin light chain phosphorylation with little effect on apoptosis, whereas inhibiting nuclear PDE1A has the opposite effects. These suggest that nuclear PDE1A is important in VSMC growth and survival and may contribute to the neointima formation in atherosclerosis and restenosis.

Animals↗
PubMed2000

Characterization of cultured smooth muscle cells obtained from the palmar digital arteries of horses.

OBJECTIVE: To develop methods to isolate, culture, and characterize smooth muscle cells (SMC) from equine palmar digital arteries. SAMPLE POPULATION: Segments of the medial or lateral palmar digital arteries from the forelimbs of 6 horses. PROCEDURE: To obtain smooth muscle explants, arterial segments were incised longitudinally. The tunica intima was gently scraped from the underlying tunica media, and explants were obtained from the tunica media. Approximately 18 to 24 explants were obtained from each palmar digital arterial segment. A substrate-attached technique was used to initiate primary culture of SMCCultured cells were identified as SMC, using light microscopy, electron microscopy, reverse transcriptase-polymerase chain reaction (RT-PCR), and northern blot analysis. The replication index and serum dependence of equine SMC in culture was characterized by use of bromodeoxyuridine. RESULTS: The SMC of equine palmar digital arteries were successfully cultured, as confirmed by RT-PCR and northern blot analysis techniques for smooth muscle alpha-actin and detection of SMC-specific organelles during electron microscopy. When characterized by light and electron microscopy, SMC were found to have undergone phenotypic modulation to a more synthetic phenotype in culture while retaining characteristics of SMC. CONCLUSIONS AND CLINICAL RELEVANCE: Culture of SMC from equine palmar digital arteries via an explant protocol is a viable technique for studying vascular biological mechanisms in horses. In vitro studies of SMC may aid investigators in determining cellular mechanisms involved in disease processes such as laminitis.

Actins↗
PubMed2003

[The relationship between phenotype transformation and biomechanical properties of detrusor smooth muscle cell subjected to the cyclic mechanical stretch].

OBJECTIVE: To investigate the relationship between phenotype transformation and biomechanical properties of detrusor smooth muscle cell (DSMC) subjected to the cyclic mechanical stretch. METHODS: Cultured rat DSMCS were grown on collagen-coated silicone membranes and subjected to continuous cycles of stretch-relaxation. All experiments were made on cells between passage 2 and 4. Each cycle consists of 5-second stretch and 5-second relaxation. The computer controlled vacuum induced 10% (I), 20% (II) and 30% (III) maximum elongation of the plate membrane at different designed pressures. We assessed DNA synthesis rate using tritiated thymidine incorporation assay. Using immunofluorescent assay and flow cytometer, we analysed the expression of SM-alpha-actin and proliferation of DSMC. The image analysis and micropipette aspiration systems were employed to investigate the single cell contraction and viscoelasticity. The elastic modulus K(1), K(2) and viscoelastic coefficient micro were determined using the three-element standard linear solid model, thus demonstrating the passive deformation ability of detrusor cells. RESULTS: As the basic structural changes to mechanical stretch, DSMCs underwent phenotypic modulation from their normal contractile phenotype to a "synthetic" phenotype: the DSMCs became more proliferative and the actin less organized along the cell's long axis. The cell proliferation index (CPI) of control and stretched group (10%, 20%, 30% elongation) were 0.24, 0.43, 0.58 and 0.65 respectively. After mechanical stretch, the well-spread filaments changed their orientation. Contraction and viscoelasticity of single DSMC subjected to stretch both decreased significantly compared to control. The Vmax and. DeltaLmax of group III (30% elongation) saw significant decreases compared with unstretched control (P < 0.01). K(1) and K(2) decreased with the increasing of mechanical overload, however, there was no statistic difference between groups II and group III. CONCLUSIONS: Structure determines function. Conversely, dysfunction implies the structural transformation. Functional abnormalities of BOO have the structural basis: phenotype transformation of detrusor cells. Cyclic stretch and relaxation applied to DSMCs in vitro can be used to model the increases in urodynamic load experienced by the bladder detrusor muscle under the conditions of bladder outlet obstruction. Phenotypic transformation is the structural basis of functional changes of DSMC subjected to periodic overload mechanical stretch.

Animals↗
PubMed2003

The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation.

Vascular smooth muscle cells (VSMC) in mature, normal blood vessels exhibit a differentiated, quiescent, contractile morphology, but injury induces a phenotypic modulation toward a proliferative, dedifferentiated, migratory phenotype with upregulated extracellular matrix protein synthesis (synthetic phenotype), which contributes to intimal hyperplasia. The mTOR (the mammalian target of rapamycin) pathway inhibitor rapamycin inhibits intimal hyperplasia in animal models and in human clinical trials. We report that rapamycin treatment induces differentiation in cultured synthetic phenotype VSMC from multiple species. VSMC treated with rapamycin assumed a contractile morphology, quantitatively reflected by a 67% decrease in cell area. Total protein and collagen synthesis were also inhibited by rapamycin. Rapamycin induced expression of the VSMC differentiation marker contractile proteins smooth muscle (SM) alpha-actin, calponin, and SM myosin heavy chain (SM-MHC), as observed by immunoblotting and immunohistochemistry. Notably, we detected a striking rapamycin induction of calponin and SM-MHC mRNA, suggesting a role for mTOR in transcriptional control of VSMC gene expression. Rapamycin also induced expression of the cyclin-dependent kinase inhibitors p21(cip) and p27(kip), consistent with cell cycle withdrawal. Rapamycin inhibits mTOR, a signaling protein that regulates protein synthesis effectors, including p70 S6K1. Overexpression of p70 S6K1 inhibited rapamycin-induced contractile protein and p21(cip) expression, suggesting that this kinase opposes VSMC differentiation. In conclusion, we report that regulation of VSMC differentiation is a novel function of the rapamycin-sensitive mTOR signaling pathway.

Animals↗
PubMed2004

Id family of transcription factors and vascular lesion formation.

Vascular smooth muscle cell (VSMC) modulation to a de-differentiated phenotype and proliferation are key components of vascular lesion formation. Understanding how these processes are regulated is essential to understanding the progression of vascular diseases such as atherosclerosis and in-stent restenosis. The Id family of helix-loop-helix (HLH) transcription factors has emerged as important regulators of cellular growth and differentiation. Recent published findings have implicated the Id proteins as important regulators of growth and phenotypic modulation in VSMC and in the vascular response to injury. In this review, we summarize what is known regarding how the Id proteins function to control cellular growth and differentiation and their role in vascular lesion formation.

Animals↗
PubMed2001

The endocrine system, vertigo and balance.

Steroid, amine and peptide hormones affect the peripheral vestibular system. Vasopressin hypersensitivity of the endolymphatic sac may be implicated in the pathogenesis of Meniere's disease. Specific vasopressin antagonists will help define the role of vasopressin in Meniere's disease. The modulation of central vestibular pathways by neuroactive steroids may involve effects on gamma-aminobutyric acid-ergic and glutaminergic pathways. The vestibular nuclei also express enzymes that are important in the synthesis of steroids and the modulation of their activity. Steroids mediate both facilitatory and deleterious effects of stress on vestibular compensation. The quality and quantity of stressor that determines the pattern of hormonal output, may be important. Clinical observation suggests that episodic ataxia type 2, a P/Q calcium channelopathy, may be phenotypically modulated by endocrine fluctuations. Steroid hormones may affect the episodic ataxia type 2 phenotype by modulation of voltage-gated calcium channel activity via second messenger systems and ion channel subunit expression. Despite evidence to support the link, the role of the endocrine system in vestibular function and disease is as yet virtually unexplored.

Animals↗
PubMed1995

In situ behavior of human Langerhans cells in skin organ culture.

BACKGROUND: Epidermal Langerhans cells (ELC) play a critical role in the initiation of cutaneous immune responses. ELC are characterized by the expression of major histocompatibility complex (MHC) class II Ag and a number of adhesion/costimulatory molecules. Evidence suggests that cytokines induced within the epidermis regulate the functions of ELC, including their phenotypic expression. In the human system, no information is available regarding the behavior of the ELC in situ: their changes in morphology, expression of functional molecules or migration within the microenvironment. In the present study, using an ex vivo human skin organ culture model, we addressed the above questions and also examined the phenotypic modulation of ELC in situ by cytokines. EXPERIMENTAL DESIGN: Skin explants were cultured either in a Trowell-type method or free in the medium. Skin explants were cultured with and without cytokines and were processed for light and electron microscopy and for immunohistochemical definition of ELC phenotypes. RESULTS: In the Trowell-type skin organ culture, morphologic integrity of ELC, CD1a molecule, and Birbeck granules could be preserved intact up to 3 to 4 days in culture. During the first 3 days of culture, the intensity of MHC-II (HLA-DR, DP, and DQ) and CD1a expression on ELC increased sharply, and the dendritic appearance of ELC became more prominent at Day 3. Adhesion molecules, ICAM-1, LFA-3, HECA-452, sLx, and B7/BB1 were also spontaneously acquired in varying amounts by CD1a+ ELC after 3 days in culture. Significant increase of CD1a and ICAM-1 expression on ELC was observed within 12 hours, when skin explants were cultured free in the medium with GM-CSF and TNF-alpha, respectively. Further, we demonstrated spontaneous migration of ELC within the epidermis and then to the dermis during the Trowell-type skin culture. We also showed the migration of ELC out of the human skin when skin explants were cultured directly in the medium. CONCLUSIONS: Human ELC showed significant phenotypic changes within the epidermis and acquired migratory capacity during the skin organ culture. ELC in skin organ culture appear to undergo a phenotypic maturation within the epidermis. ELC in situ rapidly respond to GM-CSF and TNF-alpha by increasing the expression of CD1a and ICAM-1 molecules, respectively. These results suggest the modulation of phenotypic characteristics of ELC and their migration in response to the changes of epidermal microenvironment and cytokines and implicate the potential use of skin organ culture model to elucidate the role of human ELC in the immunopathology of skin diseases.

Antigens, CD1↗
PubMed1997

Immunohistochemical and ultrastructural examination of smooth muscle cells in aortocoronary saphenous vein grafts.

In this study, phenotypic modulation and remodulation of smooth muscle cells and associated intermediate filament expression were demonstrated by means of immunohistochemistry and ultrastructure to understand the development of intimal hyperplasia in aortocoronary saphenous vein grafts. In nongrafted saphenous veins, all smooth muscle cells expressed vimentin and desmin and were of a contractile form. In saphenous vein grafts showing stenotic intimal hyperplasia (luminal stenosis < 75%), expression of desmin was notably lower, whereas that of vimentin was higher. The cells were shown to be of a synthetic phenotype, suggesting modulation from the original contractile form. In saphenous vein grafts showing occlusive intimal hyperplasia (luminal stenosis > 76%), desmin expression in smooth muscle cells was increased again, and such cells were of a contractile form, suggesting remodulation from the synthetic phenotype. Some of the smooth muscle cells of the synthetic phenotype were positive for an antibody against proliferation cell nuclear antigen. Smooth muscle cells of the contractile form were negative for this antibody. The study suggests that smooth muscle cells of synthetic phenotype are highly responsible for "growing" intimal hyperplasia of aortocoronary saphenous vein grafts.

Actins↗
PubMed2005

Deficient innervation characterizes intestinal strictures in a rat model of colitis.

Intestinal strictures are a common complication of Crohn's disease leading to serious consequences. With unknown etiology and cellular composition, strictures can be neither prevented nor reversed by current therapeutic strategies, and research has been limited by the lack of a well-developed animal model. We observed the sporadic occurrence of intestinal strictures at Day 35 in the TNBS rat model of colitis, which persisted beyond Day 90. Strictured tissue showed fusion, thickening, and disorganization of the smooth muscle layers. Immunocytochemistry revealed that all strictures were characterized by deficient innervation with a complete loss of intrinsic neurons, and a 92% loss of total axons per area. The number of alpha-smooth muscle actin-positive smooth muscle cells (SMC) increased in strictures, but immunolabeling showed phenotypic modulation of these cells, with the SMC phenotype (desmin-positive, vimentin-negative) entirely replaced by a myofibroblast phenotype (desmin-negative, vimentin-positive). Although cellular structure still predominated in the strictured regions, histochemistry showed increased extracellular matrix collagen, from 6 +/- 0.9% to 22 +/- 4% of total area. With previous evidence for neural loss in colitis, and in vitro studies showing neural regulation of smooth muscle cell (SMC) growth, we conclude that the regional loss of innervation may initiate tissue re-modeling that is characteristic of stricture formation.

Animals↗
PubMed1988

Differentiation of phase I and variant strains of Bordetella pertussis on Congo red media.

The addition of Congo red, Trypan blue or haemin to the growth medium allowed the differentiation of phase-I and variant strains of Bordetella pertussis. Phase-I strains produced red (CR+), blue or dark brown colonies on a modified cyclodextrin solid medium containing Congo red, Trypan blue or haemin, respectively, whereas variant (Vir- and phase IV) strains grew as pale (CR-) colonies. Spontaneous CR- variants were isolated and characterised and had a phenotype like that of Vir- or phenotypically modulated, C-mode strains in that they did not produce the haemolysin, haemagglutinin(s), histamine-sensitising factor (pertussis toxin), heat-labile toxin and two major envelope polypeptides associated with phase-I strains. Two such variants had reduced virulence for mice. CR+ strains, when grown on a high nicotinic acid medium to induce modulation, gave CR- colonies. Thus the CR+ phenotype is a characteristic of phase-I B. pertussis and its expression appears to be controlled in a manner similar to that of other phase I-related factors. CR- variants of B. parapertussis and B. bronchiseptica were also deficient in these factors. Four isolates of B. avium were CR-.

Bordetella pertussis↗
PubMedDate not supplied

Characterization of a mammalian smooth muscle cell line that has retained transcriptional and posttranscriptional potencies.

Unlike skeletal and cardiac muscle cells that differentiate irreversibly, smooth muscle cells (SMCs) retain a high degree of plasticity. During the so-called phenotypic modulation, SMCs can undergo transition between a contractile phenotype and a highly proliferative synthetic phenotype, as apparent from the extinction of numerous smooth muscle (SM) markers when they are passaged in culture. It would be very useful to have an SMC line that can be indefinitely propagated for the cellular and molecular analysis of the mechanisms that underlie the control of SM differentiation. This report describes an immortalized rabbit aorta SMC-derived cell line (U8A4) that has conserved differentiated properties through multiple subcultures. U8A4 cells can grow in the absence of serum and express the SMC markers studied, including SM alpha-actin, SM calponin, SM22alpha, SM alpha-tropomyosin (alpha-TM), SM myosin heavy chain (SM-MHC), and myocardin. U8A4 cells can activate SMC-restricted promoters like those of SM22alpha, SM calponin, and SM-MHC genes as efficiently as described previously for rat SMC lines (PAC1, A7r5, and A10). These cells can also process exogenous alpha-TM transcripts according to an SM-specific pattern. These results demonstrate that the U8A4 cell line constitutes a good alternative model to existing SMC lines that could facilitate the study of the transcriptional and posttranscriptional regulatory mechanisms underlying SMC differentiation.

Actins↗
PubMed1987

Temporal sequence of morphological alterations in artery walls during experimental atherogenesis--occurrence of leukocytes.

In rabbit carotid arteries arteriosclerotic lesions were induced by repeated local transmural electrical stimulations. The sequence of early morphological alterations in the vessel wall and especially the kinetics of leukocytes were examined by transmission electron microscopy. After a stimulation period of only 1 day monocytes and heterophilic granulocytes adhered to the endothelial surface. In the subendothelium mainly beneath the anode, focal amorphous insudates were present together with mononuclear and granulocytic cells. Thereby, the endothelium was maintained as a continuous lining as shown by surface staining with silver nitrate. However, both pattern and size of the endothelial cells were altered in comparison to the controls. Some of the endothelial cells displayed a heavy cytoplasmic silver salt deposition. After 2 days of the electrical stimulation schedule, the first myocytes occurred in the subendothelial space. The mediamyocytes sending pseudopods through the internal elastic lamina still appeared to be in a contractile phenotype. In the 7-day-old proliferative lesion modulated smooth muscle cells were the predominant cell type; only 10%-20% of the subendothelial cells were identified as macrophages and heterophils. This proportion decreased further, and after a stimulation period of 28 days the granulocytes disappeared completely. At this stage of plaque development, the intimal myocyte population mainly consisted of contractile smooth muscle cells and intermediary states between the contractile and modulated phenotype. The insudation, immigration of white blood cells, and subsequent migration and proliferation of myocytes reinforces the view that the initial phases of arteriosclerotic lesions may represent a special form of an inflammatory response.

Animals↗
PubMed1990

Inhibition of induced melanogenesis in Cloudman melanoma cells by four phenotypic modifiers.

Retinoic acid, hexamethylene bisacetamide, sodium butyrate, and dimethylsulfoxide, four compounds which modulate phenotypic expression in a variety of neoplastic cell lines, all inhibited the induction of tyrosinase activity and melanogenesis by the combination of melanocyte-stimulating hormone and isobutylmethyxanthine in Cloudman S91 melanoma cells. Results were the same in assays of whole cells or in extracts made from them. Only retinoic acid, however, was effective at inhibiting the activation of dopachrome isomerase, another regulatory enzyme in melanogenesis. Despite inhibiting the effects of melanocyte-stimulating hormone (MSH) and isobutylmethylxanthine on tyrosinase activity, all of the agents tested increased the binding of MSH to intact cells. Ultrastructural analysis of treated cells following DOPA cytochemistry revealed that both retinoic acid and hexamethylene bisacetamide arrested melanosomal maturation at stage I-II. Retinoic acid resulted in a derangement of melanosomal structure. The specificity of these agents for preventing the induction of melanogenesis makes them powerful tools for the dissection of this complex cellular process.

1-Methyl-3-isobutylxanthine↗