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1

Keratinocyte Growth Factor2 Accelerates Wound Healing in Incisional Wounds  

Microsoft Academic Search

Background.Keratinocyte growth factor-2 (KGF-2) also described as fibroblast growth factor-10 (FGF-10) is a newly identified member of the fibroblast growth factor family. KGF-2 is 96% identical to the recently identified rat FGF-10 and specifically stimulates growth of normal human epidermal keratinocytes. The present study was undertaken to examine the effects of topically applied KGF-2 in an incisional wound healing model.

Pablo A. Jimenez; Mark A. Rampy

1999-01-01

2

Arsenic induces overexpression of growth factors in human keratinocytes  

Microsoft Academic Search

Although epidemiological studies have shown that inorganicarsenicals are human skin carcinogens and induce hyperproliferation and hyperkeratosis, there is currently no known mechanism for their action or an established animal model for its study. We observed increased mRNA transcripts and secretion of keratinocyte growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and transforming growth factor-? (TGF?) and the proinflammatory cytokine tumor

Dori R. Germolec; Takahiko Yoshida; Kevin Gaido; James L. Wilmer; Petia P. Simeonova; Fujio Kayama; Florence Burleson; Wumin Dong; Robert W. Lange; Michael I. Luster

1996-01-01

3

Expression of keratinocyte growth factor in periapical lesions.  

PubMed

The epithelial proliferation associated with inflammatory periapical lesions and with periapical cyst formation represents an interesting but poorly understood pathological change. Keratinocyte growth factor (KGF) is a recently identified growth factor that is produced by stromal fibroblasts and acts specifically to stimulate epithelial growth and differentiation. To investigate its possible role in the activation of the normally quiescent rests of Malassez, we examined the expression of KGF by in situ hybridization of sections of normal periodontal ligament (PDL) and of 12 periapical granulomas or cysts. Normal PDL and periapical granulomas with scant inflammatory infiltration showed few cells expressing message for KGF. However, KGF-expressing cells were found in the connective tissue stroma close to dense foci of inflammatory cells and to proliferating epithelial elements and cystic epithelial linings. Examination of tissues by the reverse-transcription polymerase chain reaction (RT-PCR) showed KGF expression in 4 specimens of periapical lesions but low or undetectable levels in normal PDL. These observations suggest that the induction of KGF expression in the stromal cells of periapical lesions may play an important role in stimulating the epithelial proliferation associated with cyst formation. PMID:8952618

Gao, Z; Flaitz, C M; Mackenzie, I C

1996-09-01

4

Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes  

Microsoft Academic Search

To survive and proliferate in pure culture, human melanocytes require basic fibroblast growth factor (bFGF) and cAMP. Without these factors, even in the presence of serum, the cells die. Melanocytes cultured in the presence of keratinocytes, however, sur- vive for weeks without added bFGF and cAMP. We show here that the growth factor for melanocytes pro- duced by human keratinocytes

R. Halaban; R. Langdon; N. Birchall; C. Cuono; A. Baird; G. Scott; G. Moellmann; J. McGuire

1988-01-01

5

Keratinocyte growth factor is highly overexpressed in inflammatory bowel disease.  

PubMed Central

Recently we demonstrated an important function of keratinocyte growth factor (KGF) in wound re-epithelialization. As KGF is mitogenic for various epithelial cells, we speculated about a role of KGF in epithelial repair processes of other organs as seen in a variety of inflammatory diseases. Here we demonstrate a strikingly increased expression of KGF in surgical specimens from patients suffering from Crohn's disease and ulcerative colitis. The levels of KGF expression strongly correlated with the degree of inflammation as assessed by histological analysis of adjacent tissue and expression analysis of the pro-inflammatory cytokine interleukin-1 beta. The highest levels of KGF mRNA and protein were found in mesenchymal cells of the lamina propria, particularly in highly inflamed areas. As the KGF receptor is expressed in intestinal epithelial cells, KGF seems to act in a paracrine manner to stimulate proliferation of these cells. These data suggest a crucial role of KGF in epithelial repair after injury caused by inflammatory processes. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8701991

Brauchle, M.; Madlener, M.; Wagner, A. D.; Angermeyer, K.; Lauer, U.; Hofschneider, P. H.; Gregor, M.; Werner, S.

1996-01-01

6

Keratinocyte Growth Factor Stimulates Macrophage Inflammatory Protein 3? and Keratinocyte-derived Chemokine Secretion by Mouse Uterine Epithelial Cells  

PubMed Central

Problem Communication between uterine epithelial cells and the underlying stromal fibroblasts is critical for proper endometrial function. Stromal fibroblast-derived growth factors have been shown to regulate epithelial immune functions. The purpose of this study was to determine whether keratinocyte growth factor (KGF) regulates uterine epithelial cell chemokine and antimicrobial secretion. Method of study Uterine epithelial cells were isolated from Balb/c mice and cultured in either 96-well plates or transwell inserts. Epithelial cells were treated with KGF, epidermal growth factor (EGF), or hepatocyte growth factor (HGF). Macrophage inflammatory protein 3? (MIP3?) and keratinocyte-derived chemokine (KC) levels were measured by ELISA. Results Keratinocyte growth factor stimulated the secretion of MIP3? and KC. The effects on MIP3? by KGF were specific because EGF and HGF had no effect. In contrast, KGF, EGF, and HGF had similar effects on KC. Furthermore, KGF administered to the apical side of epithelial cells had no effect on MIP3? or KC secretion, indicating that the KGF receptor is located on the basolateral surface of uterine epithelial cells. Conclusion We demonstrate that KGF plays a role in uterine epithelial cell secretion of MIP3? and KC, key immune mediators involved in the protection of mucosal surfaces in the female reproductive tract. PMID:20455876

Haddad, Severina N.; Wira, Charles R.

2013-01-01

7

Keratinocyte Growth Factor Enhances Maturation of Fetal Rat Lung Type II Cells  

Microsoft Academic Search

Keratinocyte growth factor (KGF) or fibroblast growth factor (FGF)-7, a peptide produced by stromal cells and in particular by lung mesenchyme, has recently been shown to influence early lung morphogenesis and to be a mitogen for fetal and adult alveolar type II cells. Although contradictory findings have been re- ported regarding its effects on surfactant protein expression, its effects on

Nadia Chelly; Oumel-Banine Mouhieddine-Gueddiche; Anne-Marie Barlier-Mur; Bernadette Chailley-Heu; Jacques R. Bourbon

1999-01-01

8

Large Induction of Keratinocyte Growth Factor Expression in the Dermis During Wound Healing  

Microsoft Academic Search

Recent studies have shown that application of basic fibroblast growth factor (basic FGF) to a wound has a beneficial effect. However, it has not been assessed whether endogenous FGF also plays a role in tissue repair. In this study we found a 160-fold induction of mRNA encoding keratinocyte growth factor (KGF) 1 day after skin injury. This large induction was

Sabine Werner; Kevin G. Peters; Michael T. Longaker; Frances Fuller-Pace; Michael J. Banda; Lewis T. Williams

1992-01-01

9

Altered expression of keratinocyte growth factor and its receptor in psoriasis.  

PubMed

One of the biological characteristics of psoriasis is excessive flaking of the skin. This is directly related to the marked hyperplasia of epidermal keratinocytes and to incomplete epidermal differentiation. Keratinocyte growth factor (KGF), a potent mitogen for human keratinocytes, is expressed by stromal cells. Alterations in the KGF signaling pathway might account for the epidermal hyperplasia associated with psoriasis. To test this hypothesis, we investigated the expression of KGF and its receptor (KGFR) in psoriasis tissue. KGF and KGFR mRNA levels were found to be frequently elevated in psoriatic skin specimens as compared with normal skin. Increased KGF transcript expression was localized to the dermal layer of the involved skin specimen using in situ hybridization. In contrast, KGFR transcript and protein expression was localized to the basal layer of keratinocytes in normal skin and to the basal and suprabasal layers of the psoriatic epidermis, coincident with the expanded proliferative keratinocyte pool. To identify molecules that might regulate KGFR expression we investigated the effects of various pharmacological agents and cytokines on KGFR synthesis by keratinocytes. Phorbol ester, interleukin-6, interferon-gamma, and ultraviolet B (UVB) treatment all led to substantial down-regulation of KGFR expression. The down-regulation of KGFR synthesis by UVB suggests a possible mechanism for the antiproliferative action of this agent in the treatment of psoriasis. Taken together, these results suggest that increased KGFR-mediated signaling in keratinocytes in the lesional epidermis might account in part for the epidermal hyperplasia in psoriasis. PMID:9403712

Finch, P W; Murphy, F; Cardinale, I; Krueger, J G

1997-12-01

10

Effect of nerve growth factor and keratinocyte growth factor on wound healing of the sinus mucosa.  

PubMed

The healing of the sinuses after sinus surgery is often compromised by the development of adhesions. The aim of this study was to determine whether nerve growth factor (NGF) and keratinocyte growth factor (KGF) aid epithelial and fibroblast wound healing after surgery. Two in vitro models were used to compare their effect on wound closure rates and expression of cell adhesion (E-cadherin), tight junction formation (zona occludens-1), cell proliferation (proliferative cell nuclear antigen and Ki67), and ciliogenesis (Foxj1 and beta tubulin IVb) genes by real-time reverse transcription polymerase chain reaction. Epithelial cells from sinonasal tissue were seeded in collagen-coated Transwells, creating an air-liquid interface, and a submergent model was used for fibroblasts. In epithelial cells, NGF (20-50 ng/mL) significantly decreased wound areas to <40% compared with controls that were still 70% of their original sizes by 24 hours (p<0.05). E-cadherin and zona occludens-1 expression were up-regulated by 20- and 2.5-fold, respectively, relative to controls. KGF (5-100 ng/mL) slowed fibroblast proliferation by reducing (0.8-fold) and Ki67 (0.25-fold) expression. NGF (10 ng/mL) slowed Ki67 expression by 0.5-fold. NGF accelerated in vitro epithelial wound closure while NGF and KGF reduced fibroblast proliferation. PMID:18086292

Tan, Lorwai; Hatzirodos, Nick; Wormald, Peter-John

2008-01-01

11

Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors  

Microsoft Academic Search

Although numerous epidemiological studies have shown that inorganic arsenicals are human skin carcinogens, there is currently no accepted mechanism for its action or an established animal model for its study. We observed increased mRNA transcripts and secretion of keratinocyte growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and transforming growth factor-? (TGF-?) and the proinflammatory cytokine tumor necrosis factor-? (TNF-?)

Dori R Germolec; Judson Spalding; Gary A Boorman; James L Wilmer; Takahiko Yoshida; Petia P Simeonova; Alessandra Bruccoleri; Fujio Kayama; Kevin Gaido; Raymond Tennant; Florence Burleson; Wumin Dong; Robert W Lang; Michael I Luster

1997-01-01

12

Keratinocyte Growth Factor Protects Mice from Chemotherapy and Radiation induced Gastrointestinal Injury and Mortality1  

Microsoft Academic Search

Keratinocyte growth factor (KGF) stimulates the proliferation and differentiation of epithelial cells including those of the gastrointestinal tract. Although chemotherapeutics and radiation exposure kill rapidly proliferating tumor cells, rapidly dividing normal cells of the host's gas trointestinal tract are also frequently damaged, leading to the clinical condition broadly termed \\

Catherine L. Farrell; James V. Bready; Karen L. Rex; Jennifer N. Chen; Christopher R. DiPalma; Songmei Yin; David C. Hill; Bernadette Wiemann; Charlie O. Starnes; Andrew M. IInvilÃ; Sharon L. Aukerman; Glenn F. Pierce; Arlen Thomason; Christopher S. Potten; Thomas R. Ulich; David L. Lacey

13

Keratinocyte growth factor signalling: a mathematical model of dermalepidermal interaction in epidermal wound healing  

E-print Network

in epidermal wound healing Helen J. Wearing *, Jonathan A. Sherratt Centre for Theoretical Modelling of their therapeutic value is essential to achieve improved wound healing. Keratinocyte growth factor (KGF) seems tissue. In this paper, we are concerned with part of the second stage: epidermal wound healing

Rohani, Pejman

14

Keratinocyte response to immobilized growth factors for enhanced dermal wound healing  

NASA Astrophysics Data System (ADS)

Chronic wounds cost billions of dollars per year to treat and wound care is limited to ineffective and/or expensive options. Chronic wounds are characterized by a failure to reepithelialize, as well as deficiencies in growth factors, such as epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1), normally present during wound healing. Our system described herein begins to tackle the problems associated with designing bioactive materials for chronic wound healing applications. We show that we can induce accelerated keratinocyte migration with photo-immobilized EGF and further control migration speed through the culture of cells on different types of gradient patterns of EGF. We also successfully immobilized IGF-1 while retaining its bioactivity, and further showed it induces directed keratinocyte migration, although not as potently as immobilized EGF. Potential synergy between co-immobilized IGF-1 and EGF was also investigated, although EGF continued to dominate the cellular response, and no significant increase in cell migration was achieved via the addition of IGF-1 to the system. To further understand cellular response to our immobilized growth factors, we investigated keratinocyte signaling and function in response to changes in EGF presentation. It was found that immobilized and soluble EGF can play different, yet complementary, roles in regulating keratinocyte function. Specifically, keratinocytes responded to immobilized EGF with high EGF receptor (EGFR) activation, accompanied by low proliferation and high migratory activity. In contrast, keratinocytes treated with soluble EGF displayed a highly proliferative, rather than migratory, phenotype. We then transitioned our photo-immobilization techniques to materials that may be more suitable as a wound dressing, such as silk fibroin films. Silk fibroin is a natural fiber with many desirable qualities for a biomaterial including high strength and elasticity, biocompatibility, a beta-keratin structure which closely mimics human keratin, and ease of fabrication and modification. These silk films can also provide topographical cues via simple cast molding of any feature on the micron scale. This system allowed simultaneous presentation of topographic cues, inhibitory and/or synergistic, with our chemotactic cues. Our preliminary data suggest keratinocytes remain viable on silk fibroin films, and that these films can be patterned with immobilized EGF to induce keratinocyte migration.

Stefonek-Puccinelli, Tracy Jane

15

[Expression of transforming growth factor beta 1 in keratinocytes of oral submucous fibrosis tissue].  

PubMed

To explore significance of transforming growth factor beta 1 (TGF beta 1) in the pathogenesis of oral submucous fibrosis (OSF), TGF beta 1 mRNAs in keratinocytes of the paraffin embeded tissues of 25 OSF cases, 5 normals (NOR) and 10 oral lichen planus (OLP) were determined by the in situ hybridization technique. The result showed that there was an expression of TGF beta 1 mRNA in keratinocytes of 15 OSFs (60%). The positive expression of TGF beta 1 mRNA was mainly in kerationcytes of early and middle stage OSF. There was no expression in that of 5 NORs and 10 OLPs. The study suggests that keratinocytes of OSF tissue may synthesize and release TGF beta 1 which may play an important role in the pathogenesis of OSF and participate as a mediator in the pathogenetic process of OSF. PMID:10680515

Gao, Y; Ling, T; Wu, H

1997-07-01

16

Altered expression of keratinocyte growth factor and its receptor in psoriasis.  

PubMed Central

One of the biological characteristics of psoriasis is excessive flaking of the skin. This is directly related to the marked hyperplasia of epidermal keratinocytes and to incomplete epidermal differentiation. Keratinocyte growth factor (KGF), a potent mitogen for human keratinocytes, is expressed by stromal cells. Alterations in the KGF signaling pathway might account for the epidermal hyperplasia associated with psoriasis. To test this hypothesis, we investigated the expression of KGF and its receptor (KGFR) in psoriasis tissue. KGF and KGFR mRNA levels were found to be frequently elevated in psoriatic skin specimens as compared with normal skin. Increased KGF transcript expression was localized to the dermal layer of the involved skin specimen using in situ hybridization. In contrast, KGFR transcript and protein expression was localized to the basal layer of keratinocytes in normal skin and to the basal and suprabasal layers of the psoriatic epidermis, coincident with the expanded proliferative keratinocyte pool. To identify molecules that might regulate KGFR expression we investigated the effects of various pharmacological agents and cytokines on KGFR synthesis by keratinocytes. Phorbol ester, interleukin-6, interferon-gamma, and ultraviolet B (UVB) treatment all led to substantial down-regulation of KGFR expression. The down-regulation of KGFR synthesis by UVB suggests a possible mechanism for the antiproliferative action of this agent in the treatment of psoriasis. Taken together, these results suggest that increased KGFR-mediated signaling in keratinocytes in the lesional epidermis might account in part for the epidermal hyperplasia in psoriasis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:9403712

Finch, P. W.; Murphy, F.; Cardinale, I.; Krueger, J. G.

1997-01-01

17

Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor.  

PubMed

Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFN?, IL-1?, IL-4, IL-6, IL-17A, IL-22 or TNF?. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFN?, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD. PMID:25617811

Bae, Ok-Nam; Ahn, Seyeon; Jin, Sun Hee; Hong, Soo Hyun; Lee, Jinyoung; Kim, Eun-Sun; Jeong, Tae Cheon; Chun, Young-Jin; Lee, Ai-Young; Noh, Minsoo

2015-03-01

18

Fibroblast Growth Factor-Peptide Improves Barrier Function and Proliferation in Human Keratinocytes After Radiation  

SciTech Connect

Purpose: Epidermal keratinocytes, which can be severely damaged after ionizing radiation (IR), are rapid turnover cells that function as a barrier, protecting the host from pathogenic invasion and fluid loss. We tested fibroblast growth factor-peptide (FGF-P), a small peptide derived from the receptor-binding domain of FGF-2, as a potential mitigator of radiation effects via proliferation and the barrier function of keratinocytes. Methods and Materials: Keratinocytes isolated from neonatal foreskin were grown on transwells. After being exposed to 0, 5, or 10 Gy IR, the cells were treated with a vehicle or FGF-P. The permeability of IR cells was assessed by using transepithelial electrical resistance (TEER) and a paracellular tracer flux of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) with Ussing chambers. The cell proliferation was measured with yellow tetrazolium salt (MTT) and tritiated thymidine ([{sup 3}H]-TdR) assays. The phosphorylation of extracellular signal-regulated kinases (ERK) was measured in an enzyme-linked immunosorbent (ELISA)-like assay, and the proteins related to tight junctions (TJ) and adherens junctions (AJ) were examined with Western blotting. We used a mouse model to assess the ability of FGF-P to promote the healing of skin {beta} burns created with a strontium applicator. Results: We found (1) FGF-P reduced the permeability of irradiated keratinocytes, as evidenced by increased TEER and decreased diffusion of FITC-BSA, both associated with the regulation of different proteins and levels of TJ and AJ; and (2) FGF-P enhanced the proliferation of irradiated keratinocytes, as evidenced by increased MTT activity and [{sup 3}H]-TdR incorporation, which was associated with activation of the ERK pathway; and (3) FGF-P promoted the healing of skin {beta} burns. Conclusions: FGF-P enhances the barrier function, including up-regulation of TJ proteins, increases proliferation of human keratinocytes, and accelerates the healing of skin {beta} burns. FGF-P is a promising mitigator that improves the proliferation and barrier function of keratinocytes after IR.

Zhang Kunzhong [Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York 14642 (United States); Tian Yeping [Second Military Medical College, Shanghai, P.R. China 200433 (China); Yin Liangjie; Zhang Mei [Department of Radiation Oncology, University of Florida, Gainesville Florida 32610 (United States); Beck, Lisa A. [Department of Dermatology, University of Rochester Medical Center, Rochester, New York 14642 (United States); Zhang, Bingrong; Okunieff, Paul [Department of Radiation Oncology, University of Florida, Gainesville Florida 32610 (United States); Zhang Lurong, E-mail: lurongzhang@ufl.edu [Department of Radiation Oncology, University of Florida, Gainesville Florida 32610 (United States); Vidyasagar, Sadasivan, E-mail: vidyasagar@ufl.edu [Department of Radiation Oncology, University of Florida, Gainesville Florida 32610 (United States)

2011-09-01

19

ARSENITE AND INSULIN EXHIBIT OPPOSING EFFECTS ON EPIDERMAL GROWTH FACTOR RECEPTOR AND KERATINOCYTE PROLIFERATIVE POTENTIAL  

PubMed Central

Previous work has suggested that arsenic exposure contributes to skin carcinogenesis by preserving the proliferative potential of human epidermal keratinocytes, thereby slowing the exit of putative target stem cells into the differentiation pathway. To find a molecular basis for this action, present work has explored the influence of arsenite on keratinocyte responses to epidermal growth factor (EGF). The ability of cultured keratinocytes to found colonies upon passaging several days after confluence was preserved by arsenite and EGF in an additive fashion, but neither was effective when the receptor tyrosine kinase activity was inhibited. Arsenite prevented the loss of EGF receptor protein and phosphorylation of tyrosine 1173, preserving its capability to signal. The level of nuclear ?-catenin was higher in cells treated with arsenite and EGF in parallel to elevated colony forming ability, and expression of a dominant negative ?-catenin suppressed the increase in both colony forming ability and yield of putative stem cells induced by arsenite and EGF. As judged by expression of three genes regulated by ?-catenin, this transcription factor had substantially higher activity in the arsenite/EGF-treated cells. Trivalent antimony exhibited the same effects as arsenite. A novel finding is that insulin in the medium induced the loss of EGF receptor protein, which was largely prevented by arsenite exposure. PMID:17400267

Patterson, Timothy J.; Rice, Robert H.

2007-01-01

20

Keratinocytic vascular endothelial growth factor as a novel biomarker for pathological skin condition.  

PubMed

Skin is an emerging target tissue in pharmaceutical and cosmetic science. Safety assessment for dermal toxicity is a critical step for development of topically applicable pharmaceutical agents and ingredients in cosmetics. Urgent needs exist to set up toxicity testing methods for dermal safety, and identification of novel biomarkers for pathological cutaneous alteration is highly required. Here we will discuss if vascular endothelial growth factor (VEGF) has a potential as a biomarker for dermal impairment. Experimental and clinical evidences for induction of keratinocytic VEGF under pathological conditions will be reviewed. PMID:25593638

Bae, Ok-Nam; Noh, Minsoo; Chun, Young-Jin; Jeong, Tae Cheon

2015-01-01

21

Keratinocytic Vascular Endothelial Growth Factor as a Novel Biomarker for Pathological Skin Condition  

PubMed Central

Skin is an emerging target tissue in pharmaceutical and cosmetic science. Safety assessment for dermal toxicity is a critical step for development of topically applicable pharmaceutical agents and ingredients in cosmetics. Urgent needs exist to set up toxicity testing methods for dermal safety, and identification of novel biomarkers for pathological cutaneous alteration is highly required. Here we will discuss if vascular endothelial growth factor (VEGF) has a potential as a biomarker for dermal impairment. Experimental and clinical evidences for induction of keratinocytic VEGF under pathological conditions will be reviewed. PMID:25593638

Bae, Ok-Nam; Noh, Minsoo; Chun, Young-Jin; Jeong, Tae Cheon

2015-01-01

22

Keratinocyte Growth Regulation in Defined Organotypic Cultures Through IL1Induced Keratinocyte Growth Factor Expression in Resting Fibroblasts  

Microsoft Academic Search

Balanced keratinocyte proliferation and differentiation resulting in regular tissue organization strictly depend on dermal support. Organotypic cultures represent biologically relevant in vitro models to study the molecular mechanism of the underlying dermal–epidermal interactions. To mimic the state of resting fibroblasts in the dermis, postmitotic (irradiated) fibroblasts were incorporated in the collagen matrix, where they typically support epidermal proliferation and tissue

Nicole Maas-Szabowski; Hans-Jürgen Stark; Norbert E. Fusenig

2000-01-01

23

Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium.  

PubMed Central

Epithelial-mesenchymal interactions mediate aspects of normal lung growth and development and are important in the restoration of normal alveolar architecture after lung injury. To determine if fibroblasts are a source of soluble growth factors for alveolar type II cells, we investigated the effect of fibroblast-conditioned medium (CM) on alveolar type II cell DNA synthesis. Serum-free CM from confluent adult human lung fibroblasts was concentrated fivefold by lyophilization. Type II cells were isolated from adult rats by elastase dissociation and incubated with [3H]thymidine and varying dilutions of concentrated CM and serum from day 1 to 3 of culture. Stimulation of type II cell DNA synthesis by fibroblast-CM was maximal after 48 h of conditioning and required the presence of serum. The activity of the CM was eliminated by boiling and by treatment with trypsin, pepsin, or dithiothreitol and was additive with saturating concentrations of acidic fibroblast growth factor, epidermal growth factor, and insulin. The growth factor activity bound to heparin-Sepharose and was eluted with 0.6 and 1.0 M NaCl. Neutralizing antibody studies demonstrated that the primary mitogens isolated in the 0.6 and 1.0 M NaCl fractions were keratinocyte growth factor (KGF, fibroblast growth factor 7) and hepatocyte growth factor/scatter factor (HGF/SF), respectively. HGF/SF was demonstrated in the crude CM and KGF was detected in the 0.6 M NaCl eluent by immunoblotting. Northern blot analysis confirmed that the lung fibroblasts expressed both KGF and HGF/SF transcripts. Human recombinant KGF and HGF/SF induced a concentration- and serum-dependent increase in rat alveolar type II cell DNA synthesis. We conclude that adult human lung fibroblasts produce at least two soluble heparin-binding growth factors, KGF and HGF/SF, which promote DNA synthesis and proliferation of rat alveolar type II cells in primary culture. KGF and HGF/SF may be important stimuli for alveolar type II cell proliferation during lung growth and after lung injury. Images PMID:7688769

Panos, R J; Rubin, J S; Csaky, K G; Aaronson, S A; Mason, R J

1993-01-01

24

Effects of transforming growth factor beta-1 on growth-regulatory genes in tumour-derived human oral keratinocytes.  

PubMed Central

This study examined the effect of transforming growth factor beta-1 (TGF-beta 1) on c-myc, RB1, junB and p53 expression together with pRb phosphorylation, in carcinoma-derived and normal human oral keratinocytes with a range of inhibitory responses to this ligand. Amplification of c-myc was observed in eight of eight tumour-derived cell lines and resulted in corresponding mRNA expression. The down-regulation of c-myc expression by TGF-beta 1 predominantly reflected growth inhibition by TGF-beta 1, but in two of eight tumour-derived cell lines which were partially responsive to TGF-beta 1 c-myc expression was unaltered by this ligand. While RB1 mRNA levels were unaltered by TGF-beta 1, the ligand caused the accumulation of the underphosphorylated form of the Rb protein in all cells irrespective of TGF-beta 1-induced growth arrest. junB expression was up-regulated by TGF-beta 1 in cells with a range of growth inhibitory responses. All cells contained mutant p53. TGF-beta 1 did not affect p53 mRNA expression in both tumour-derived and normal keratinocytes and there was no alteration in p53 protein levels in keratinocytes expressing stable p53 protein following TGF-beta 1 treatment. The data indicate that TGF-beta-induced growth control can exist independently of the presence of mutant p53 and the control of Rb phosphorylation and c-myc down-regulation. It may be that TGF-beta growth inhibition occurs via multiple mechanisms and that the loss of one pathway during tumour progression does not necessarily result in the abrogation of TGF-beta-induced growth control. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:7547241

Paterson, I. C.; Patel, V.; Sandy, J. R.; Prime, S. S.; Yeudall, W. A.

1995-01-01

25

Polarized endocytosis of the keratinocyte growth factor receptor in migrating cells: role of SRC-signaling and cortactin.  

PubMed

Cell migration is a physiological process that requires endocytic trafficking and polarization of adhesion molecules and receptor tyrosine kinases (RTKs) to the leading edge. Many growth factors are able to induce motility by binding to specific RTK on target cells. Among them, keratinocyte growth factor (KGF or FGF7) and fibroblast growth factor 10 (FGF10), members of the FGF family, are motogenic for keratinocytes, and exert their action by binding to the keratinocyte growth factor receptor (KGFR), a splicing variant of FGFR2, exclusively expressed on epithelial cells. Here we analyzed the possible role of cortactin, an F-actin binding protein which is tyrosine phosphorylated by Src and is involved in KGFR-mediated cell migration, in the KGFR endocytosis and polarization to the leading edge of migrating cells upon ligand-induced stimulation. Biochemical phosphorylation study revealed that both KGF and FGF10 were able to induce tyrosine phosphorylation of Src and in turn of cortactin, as demonstrated by using the specific pharmacological Src-inhibitor SU6656, although FGF10 effect was delayed with respect to that promoted by KGF. Immunofluorescence analysis demonstrated the polarized localization of KGFR upon ligand stimulation to the leading edge of migrating keratinocytes, process that was regulated by Src. Moreover, we showed that the colocalization of cortactin with KGFR at the plasma membrane protrusions and on early endosomes after KGF and FGF10 treatment was Src-dependent. Further, by using a RNA interference approach through microinjection, we showed that cortactin is required for KGFR endocytosis and that the clathrin-dependent internalization of the receptor is a critical event for its polarization. Finally, KGFR expression and polarization enhanced cell migration in a scratch assay. Our results indicate that both Src and cortactin play a key role in the KGFR endocytosis and polarization at the leading edge of migrating keratinocytes, supporting the crucial involvement of RTK trafficking in cell motility. PMID:22195012

Belleudi, Francesca; Scrofani, Cristina; Torrisi, Maria Rosaria; Mancini, Patrizia

2011-01-01

26

Polarized Endocytosis of the Keratinocyte Growth Factor Receptor in Migrating Cells: Role of Src-Signaling and Cortactin  

PubMed Central

Cell migration is a physiological process that requires endocytic trafficking and polarization of adhesion molecules and receptor tyrosine kinases (RTKs) to the leading edge. Many growth factors are able to induce motility by binding to specific RTK on target cells. Among them, keratinocyte growth factor (KGF or FGF7) and fibroblast growth factor 10 (FGF10), members of the FGF family, are motogenic for keratinocytes, and exert their action by binding to the keratinocyte growth factor receptor (KGFR), a splicing variant of FGFR2, exclusively expressed on epithelial cells. Here we analyzed the possible role of cortactin, an F-actin binding protein which is tyrosine phosphorylated by Src and is involved in KGFR-mediated cell migration, in the KGFR endocytosis and polarization to the leading edge of migrating cells upon ligand-induced stimulation. Biochemical phosphorylation study revealed that both KGF and FGF10 were able to induce tyrosine phosphorylation of Src and in turn of cortactin, as demonstrated by using the specific pharmacological Src-inhibitor SU6656, although FGF10 effect was delayed with respect to that promoted by KGF. Immunofluorescence analysis demonstrated the polarized localization of KGFR upon ligand stimulation to the leading edge of migrating keratinocytes, process that was regulated by Src. Moreover, we showed that the colocalization of cortactin with KGFR at the plasma membrane protrusions and on early endosomes after KGF and FGF10 treatment was Src-dependent. Further, by using a RNA interference approach through microinjection, we showed that cortactin is required for KGFR endocytosis and that the clathrin-dependent internalization of the receptor is a critical event for its polarization. Finally, KGFR expression and polarization enhanced cell migration in a scratch assay. Our results indicate that both Src and cortactin play a key role in the KGFR endocytosis and polarization at the leading edge of migrating keratinocytes, supporting the crucial involvement of RTK trafficking in cell motility. PMID:22195012

Belleudi, Francesca; Scrofani, Cristina; Torrisi, Maria Rosaria; Mancini, Patrizia

2011-01-01

27

Human keratinocytes are a major source of cutaneous platelet-derived growth factor.  

PubMed Central

PDGF has been implicated as one of the principal mitogens involved in cutaneous wound healing. While it has been previously reported that both platelets and monocytes are a source of PDGF in human dermal wound repair, the production of PDGF by human keratinocytes has not yet been described. In this manuscript, we report the production of PDGF by cultured human keratinocytes. Both PDGF A and B chain mRNA can be detected in cultured cells. While only PDGF-AA polypeptide is found in significant levels in keratinocyte-conditioned culture media, all three PDGF isoforms (AA, AB, and BB) are present in detergent-solubilized cell extracts. No evidence of PDGF receptor expression was observed in cultured keratinocytes when analyzed for either mRNA levels or polypeptide expression, suggesting that PDGF does not play an autocrine role in keratinocyte growth. Analysis of cryosections of human cutaneous wounds by immunostaining for PDGF showed that both PDGF A and B chain is constitutively expressed in normal epidermis, as well as in newly reconstituted wound epidermis. No evidence for PDGF receptor polypeptide expression in the epidermis was detected by immunostaining of cryosections. Images PMID:8349805

Ansel, J C; Tiesman, J P; Olerud, J E; Krueger, J G; Krane, J F; Tara, D C; Shipley, G D; Gilbertson, D; Usui, M L; Hart, C E

1993-01-01

28

The role of chronic inflammation in cutaneous fibrosis: fibroblast growth factor receptor deficiency in keratinocytes as an example.  

PubMed

Fibrosis is associated with a variety of skin diseases and causes severe aesthetic and functional impairments. Functional studies in rodents, together with clinical observations, strongly suggest a crucial role of chronic injury and inflammation in the pathogenesis of fibrotic diseases. The phenotype of mice lacking fibroblast growth factor (FGF) receptors 1 and 2 in keratinocytes supports this concept. In these mice, a defect in keratinocytes alone initiated an inflammatory response, which in turn caused keratinocyte hyperproliferation and dermal fibrosis. As the mechanism underlying this phenotype, we identified a loss of FGF-induced expression of claudins and occludin, which caused abnormalities in tight junctions with concomitant deficits in epidermal barrier function. This resulted in severe transepidermal water loss and skin dryness. In turn, activation of keratinocytes and epidermal ?? T cells occurred, which produced IL-1 family member 8 and S100A8 and S100A9. These cytokines attracted immune cells and activated fibroblasts, resulting in a double paracrine loop through production of keratinocyte mitogens by dermal cells. In addition, a profibrotic response was induced in fibroblasts. Our results highlight the importance of an intact epidermal barrier for the prevention of inflammation and fibrosis and the role of chronic inflammation in the pathogenesis of fibrotic diseases. PMID:22076327

Meyer, Michael; Müller, Anna-Katharina; Yang, Jingxuan; ?ulcová, Jitka; Werner, Sabine

2011-12-01

29

Correlation between the 1.6 A crystal structure and mutational analysis of keratinocyte growth factor.  

PubMed Central

A comprehensive deletion, mutational, and structural analysis of the native recombinant keratinocyte growth factor (KGF) polypeptide has resulted in the identification of the amino acids responsible for its biological activity. One of these KGF mutants (delta23KGF-R144Q) has biological activity comparable to the native protein, and its crystal structure was determined by the multiple isomorphous replacement plus anomalous scattering method (MIRAS). The structure of KGF reveals that it folds into a beta-trefoil motif similar to other members of fibroblast growth factor (FGF) family whose structures have been resolved. This fold consists of 12 anti-parallel beta-strands in which three pairs of the strands form a six-stranded beta-barrel structure and the other three pairs of beta-strands cap the barrel with hairpin triplets forming a triangular array. KGF has 10 well-defined beta strands, which form five double-stranded anti-parallel beta-sheets. A sixth poorly defined beta-strand pair is in the loop between residues 133 and 144, and is defined by only a single hydrogen bond between the two strands. The KGF mutant has 10 additional ordered amino terminus residues (24-33) compared to the other FGF structures, which are important for biological activity. Based on mutagenesis, thermal stability, and structural data we postulate that residues TRP125, THR126, and His127 predominantly confer receptor binding specificity to KGF. Additionally, residues GLN152, GLN138, and THR42 are implicated in heparin binding. The increased thermal stability of delta23KGF-R144Q can structurally be explained by the additional formation of hydrogen bonds between the GLN side chain and a main-chain carbonyl on an adjoining loop. The correlation of the structure and biochemistry of KGF provides a framework for a rational design of this potentially important human therapeutic. PMID:10082365

Osslund, T. D.; Syed, R.; Singer, E.; Hsu, E. W.; Nybo, R.; Chen, B. L.; Harvey, T.; Arakawa, T.; Narhi, L. O.; Chirino, A.; Morris, C. F.

1998-01-01

30

Keratinocyte Growth Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury  

PubMed Central

Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown. Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS. Methods: Volunteers were randomized to intravenous KGF (60 ?g/kg) or placebo for 3 days, before inhaling 50 ?g LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury. Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony–stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor. Conclusions: KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895. PMID:24716610

Shyamsundar, Murali; McAuley, Daniel F.; Ingram, Rebecca J.; Gibson, David S.; McKeown, Scott T.; Edwards, Alex; Taggart, Cliff; Elborn, Joseph S.; Calfee, Carolyn S.; Matthay, Michael A.

2014-01-01

31

Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats.  

PubMed Central

Alveolar type II cell proliferation occurs after many forms of lung injury and is thought to play a critical role in alveolar epithelial repair. Keratinocyte growth factor/fibroblast growth factor 7 (KGF) has been shown to promote alveolar type II cell growth in primary culture and alveolar epithelial hyperplasia in vivo. In this study, we used immunohistochemical analysis to determine the intrapulmonary distribution and cellular localization of recombinant human KGF (rhKGF) instilled into the trachea of rats. 6 h after administration, immunoreactive KGF was observed within the lung parenchyma and along alveolar epithelial cell membranes. By 18-24 h, KGF was detected intracellularly in alveolar epithelial cells and intraalveolar macrophages. Immunoreactive KGF was not demonstrable 48 h after delivery or in lung sections from PBS-treated animals. Intratracheal instillation of 5 mg/kg rhKGF stimulated a marked, time-dependent increase in the alveolar type II cell specific labeling index to a maximum level of 33 +/- 3% 48 h after rhKGF administration compared with 1.3 +/- 0.3% after PBS instillation. In addition, this increase in type II cell proliferation in vivo was documented by flow cytometric analysis of isolated type II cells which revealed a nearly fivefold increase in the proportion of cells traversing through the S and G2/M phases of the cell cycle. To test the hypothesis that KGFs effects on type II cells in vivo might affect the response to lung injury, rats were treated with rhKGF and exposed to hyperoxia. Animals that received 1 or 5 mg/kg rhKGF exhibited dramatically reduced mortality (P < 0.001, for both doses). Survival for animals treated with 0.1 mg/kg rhKGF was not significantly different from either untreated rats or animals treated with heat-denatured rhKGF. The lungs of rhKGF-treated animals that survived hyperoxia exposure had minimal hemorrhage and no exudate within the intraalveolar space. These experiments established that intratracheal administration of rhKGF stimulated alveolar type II cell proliferation in vivo and reduced hyperoxia-induced lung injury in rats. Directed delivery of KGF to the lungs may provide a therapeutic strategy to preserve or restore the alveolar epithelium during exposure to hyperoxia or other injurious agents. Images PMID:7560096

Panos, R J; Bak, P M; Simonet, W S; Rubin, J S; Smith, L J

1995-01-01

32

Efficacy of keratinocyte growth factor (palifermin) for the treatment of caustic esophageal burns  

PubMed Central

Current treatment strategies against the development of corrosive esophageal strictures remain unsatisfactory. Thus, the aim of the present study was to investigate the efficacy of keratinocyte growth factor, in the form of palifermin, for the prevention of stricture development following esophageal caustic injuries in a rat model. A total of 32 female Wistar albino rats were divided into four groups, which included the control (C), burn (B), steroid (S) and steroid plus palifermin (S/P) groups. An experimental corrosive esophageal burn model was established in the B, S and S/P groups. Weight gain was recorded and histopathological evaluation was performed for each group. Weight gain in the S and B groups was compared with the control group and statistically significant differences were observed. In addition, statistically significant differences in weight gain were observed between the S/P group and the B group. Histopathologically, statistically significant differences were identified with regard to submucosal collagen deposition, muscularis mucosa and tunica muscularis damage when comparing the B group with the C group. In addition, statistically significant differences were observed when comparing the S and S/P groups with the B group. Furthermore, significant submucosal collagen deposition and tunica muscularis damage were observed in the S group when compared with the S/P group. The stenosis indexes in the C and S groups were significantly lower compared with the B group. In addition, the stenosis index in the S/P group was significantly lower compared with the S group. To the best of our knowledge, the present study is the first to investigate the effect of palifermin on corrosive esophageal burns. The addition of palifermin to the corrosive esophageal burn standard treatment regimen was found to reduce the degree of fibrosis and ameliorate histopathological damage in an experimental model of corrosive esophagitis in rats. PMID:25187801

NUMANO?LU, KEMAL VARIM; TATLI, DUYGU; BEKTA?, SIBEL; ER, EBUBEKIR

2014-01-01

33

Efficacy of keratinocyte growth factor (palifermin) for the treatment of caustic esophageal burns.  

PubMed

Current treatment strategies against the development of corrosive esophageal strictures remain unsatisfactory. Thus, the aim of the present study was to investigate the efficacy of keratinocyte growth factor, in the form of palifermin, for the prevention of stricture development following esophageal caustic injuries in a rat model. A total of 32 female Wistar albino rats were divided into four groups, which included the control (C), burn (B), steroid (S) and steroid plus palifermin (S/P) groups. An experimental corrosive esophageal burn model was established in the B, S and S/P groups. Weight gain was recorded and histopathological evaluation was performed for each group. Weight gain in the S and B groups was compared with the control group and statistically significant differences were observed. In addition, statistically significant differences in weight gain were observed between the S/P group and the B group. Histopathologically, statistically significant differences were identified with regard to submucosal collagen deposition, muscularis mucosa and tunica muscularis damage when comparing the B group with the C group. In addition, statistically significant differences were observed when comparing the S and S/P groups with the B group. Furthermore, significant submucosal collagen deposition and tunica muscularis damage were observed in the S group when compared with the S/P group. The stenosis indexes in the C and S groups were significantly lower compared with the B group. In addition, the stenosis index in the S/P group was significantly lower compared with the S group. To the best of our knowledge, the present study is the first to investigate the effect of palifermin on corrosive esophageal burns. The addition of palifermin to the corrosive esophageal burn standard treatment regimen was found to reduce the degree of fibrosis and ameliorate histopathological damage in an experimental model of corrosive esophagitis in rats. PMID:25187801

Numano?lu, Kemal Varim; Tatli, Duygu; Bekta?, Sibel; Er, Ebubekir

2014-10-01

34

Inhibition of growth of normal and human papillomavirus-transformed keratinocytes in monolayer and organotypic cultures by interferon-gamma and tumor necrosis factor-alpha.  

PubMed Central

The growth response of normal and human papillomavirus (HPV)-transformed cervical keratinocytes to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha was investigated in monolayer and organotypic raft cultures. The proliferation rates of monolayer cultures were assessed by [3H]TdR incorporation and fluorimetric DNA titration. The growth of keratinocytes in organotypic cultures was estimated by their ability to stratify on collagen rafts and by immunohistochemistry for Ki67 antigen expression. IFN-gamma reduced the DNA synthesis of normal and HPV-transformed keratinocytes in monolayer cultures and exerted a marked growth inhibitory effect in organotypic raft cultures. In control raft cultures, normal keratinocytes produced an epithelial sheet of approximately 10 cells in thickness that closely resembled normal cervical epithelium and was characterized by sparse Ki67 antigen-positive cells whereas HPV-transformed keratinocytes produced up to 15 poorly differentiated epithelial layers that were reminiscent of high grade cervical lesions seen in vivo and exhibited a full thickness Ki67 antigen expression. When normal and HPV-transformed keratinocytes were maintained in the presence of IFN-gamma, the epithelial sheet was reduced to a few cells in thickness and the density of Ki67 antigen-positive cells was decreased. A more pronounced growth inhibitory effect in monolayer and organotypic cultures was observed when IFN-gamma was associated with tumor necrosis factor-alpha Tumor necrosis factor-alpha alone reduced the DNA synthesis of normal keratinocytes but was significantly less effective than IFN-gamma to inhibit the growth of HPV-transformed keratinocytes. These results suggest that similar responses in vivo to regulatory molecules may play a role in the development of HPV-related lesions. Images Figure 1 PMID:7887441

Delvenne, P.; al-Saleh, W.; Gilles, C.; Thiry, A.; Boniver, J.

1995-01-01

35

Angiopoietin-related growth factor (AGF) supports adhesion, spreading, and migration of keratinocytes, fibroblasts, and endothelial cells through interaction with RGD-binding integrins  

SciTech Connect

Angiopoietin-related growth factor (AGF) is a newly identified member of angiopoietin-related proteins (ARPs)/angiopoietin-like proteins (Angptls). AGF has been considered as a novel growth factor in accelerating cutaneous wound healing, as it is capable of stimulating keratinocytes proliferation as well as angiogenesis. But in our paper, we demonstrate that AGF stimulates keratinocytes proliferation only at high protein concentration, however, it can potently promote adhesion, spreading, and migration of keratinocytes, fibroblasts, and endothelial cells. Furthermore, we confirm that the adhesion and migration cellular events are mediated by RGD-binding integrins, most possibly the {alpha}{sub v}-containing integrins, by in vitro inhibition assays using synthetic competitive peptides. Our results strongly suggest that AGF is an integrin ligand as well as a mitogenic growth factor and theoretically participates in cutaneous wound healing in a more complex mechanism.

Zhang Yueqing [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China); Hu Xiaobo [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China); Tian Ruiyang [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China); Wei Wangui [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China); Hu Wei [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China); Chen Xia [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China); Han Wei [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China); Chen Huayou [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China); Gong Yi [Shanghai Institute for Biological Sciences, Graduate school of Chinese Academy of Sciences, 500 Cao Bao Road, Shanghai 200233 (China)]. E-mail: ygong@sibs.ac.cn

2006-08-18

36

The Effects of Adenoviral Transfection of the Keratinocyte Growth Factor Gene on Epidermal Stem Cells: an In Vitro Study  

PubMed Central

Epidermal stem cells (ESCs) are characterized as slow-cycling, multi-potent, and self-renewing cells that not only maintain somatic homeostasis but also participate in tissue regeneration and repair. To examine the feasibility of adenoviral vector-mediated keratinocyte growth factor (KGF) gene transfer into in vitro-expanded ESCs, ESCs were isolated from samples of human skin, cultured in vitro, and then transfected with recombinant adenovirus (Ad) carrying the human KGF gene (AdKGF) or green fluorescent protein gene (AdGFP). The effects of KGF gene transfer on cell proliferation, cell cycle arrest, cell surface antigen phenotype, and ?-catenin expression were investigated. Compared to ESCs transfected with AdGFP, AdKGF-transfected ESCs grew well, maintained a high proliferative capacity in keratinocyte serum-free medium, and expressed high levels of ?-catenin. AdKGF infection increased the number of ESCs in the G0/G1 phase and promoted ESCs entry into the G2/M phase, but had no effect on cell surface antigen phenotype (CD49f+/CD71?). The results suggest that KGF gene transfer can stimulate ESCs to grow and undergo cell division, which can be applied to enhance cutaneous wound healing. PMID:24170090

Li, Xinping; Liang, Ling; Zhao, Pin; Uchida, Kenzo; Baba, Hisatoshi; Huang, Hong; Bai, Wenfang; Bai, Liming; Zhang, Mingsheng

2013-01-01

37

Transcription factor PEA3 participates in the induction of urokinase plasminogen activator transcription in murine keratinocytes stimulated with epidermal growth factor or phorbol-ester.  

PubMed Central

Keratinocytes in culture represent cells which exhibit continued and controlled growth in the organism. We have investigated the synthesis of urokinase plasminogen activator mRNA in exponentially growing cultures of primary murine keratinocytes and the keratinocyte cell line BALB/MK. The tumor promotor 12-O-tetradecanoyl phorbol-13-acetate (TPA) and epidermal growth factor (EGF) induced urokinase mRNA synthesis. We made a series of progressive 5' deletions as well as internal deletions in the region upstream of the murine uPA gene. These were joined to the cat reporter gene, and used to map the TPA and EGF responsive regions of the promoter. We found both responsive sequences within a 90 base pair Hae III fragment, located 2.4 kb. upstream of the mRNA cap site. This DNA fragment conferred TPA inducibility on reporter gene expression independent of its distance and orientation to the transcription initiation site. Footprinting and gel retardation studies identified the responsible sequence to be a binding site for PEA3 juxtaposed to an octameric TRE-element. Transfections with point mutants showed that these target sequences were necessary for TPA and EGF induction of transcription. Images PMID:2119494

Rørth, P; Nerlov, C; Blasi, F; Johnsen, M

1990-01-01

38

Ispaghula (Plantago ovata) seed husk polysaccharides promote proliferation of human epithelial cells (skin keratinocytes and fibroblasts) via enhanced growth factor receptors and energy production.  

PubMed

Endogenous carbohydrates, especially oligo- and polysaccharides, participate in the regulation of a broad range of biological activities, e. g., signal transduction, inflammation, fertilisation, cell-cell-adhesion and act as in vivo markers for the determination of cell types. In the present study, water-soluble (WS) and gel-forming polysaccharides (GF) of ispaghula seed husk (Plantago ovata Forsskal, Plantaginaceae) were characterised as neutral and acidic arabinoxylans and tested under in vitro conditions for regulating activities on cell physiology of human keratinocytes and human primary fibroblasts. Only water-soluble polysaccharides exhibited strong and significant effects on cell physiology of keratinocytes and fibroblasts. Proliferation of cells of the spontaneously immortalised keratinocyte cell line HaCaT was significantly up-regulated in a dose-independent manner. Analysis of activated signal pathways by RNA analysis proved an effect of the acidic arabinoxylan on the expression of keratinocyte growth factor (KGF) in HaCaT cells. Differentiation behaviour of normal human keratinocytes (NHK) determined by involucrin was slightly influenced, due to the enhanced cell proliferation, leading to a cell-cell-mediated indirect induction of early differentiation. WS did not influence late differentiation, as determined by keratin K1 and K10 titres. PMID:15678371

Deters, A M; Schröder, K R; Smiatek, T; Hensel, Andreas

2005-01-01

39

Infection of Keratinocytes with Trichophytum rubrum Induces Epidermal Growth Factor-Dependent RNase 7 and Human Beta-Defensin-3 Expression  

PubMed Central

Human keratinocytes are able to express various antimicrobial peptides (AMP) to protect the skin from exaggerated microbial colonization and infection. Recently, in vitro growth-inhibiting activity of the skin-derived AMP psoriasin, RNase 7 and human beta-defensin (hBD)-2 against dermatophytes such as Trichophyton (T.) rubrum have been reported. To evaluate whether keratinocytes are able to respond to T. rubrum infection by an induced expression of AMP we exposed primary keratinocytes to living conidia of T. rubrum. This led to conidia germination and mycelial growth which was paralleled by a strong gene induction of the skin-derived AMP RNase 7 and hBD-3. Gene expression of the AMP psoriasin (S100A7) and hBD-2 were only slightly induced. The T. rubrum-mediated RNase 7 gene induction was accompanied by increased secretion of RNase 7. Parallel treatment of the keratinocytes with T. rubrum and the cytokine combination IL-17A/IFN-? resulted in synergistic induction of RNase 7 and hBD-3 expression. Since patients receiving therapy by inhibition of the epidermal growth factor receptor (EGFR) more often suffer from dermatophytoses we investigated whether EGFR may be involved in the T. rubrum-mediated RNase 7 and hBD-3 induction. Primary keratinocytes incubated with an EGFR blocking antibody as well as with the EGFR antagonist AG1478 showed a significantly diminished RNase 7 and hBD-3 induction upon exposure of the keratinocytes to T. rubrum indicating that EGFR is involved in the T. rubrum-mediated induction of RNase 7 and hBD-3. The growth of T. rubrum in vitro was inhibited by hBD-3 in a dose-dependent manner suggesting that hBD-3 may contribute to cutaneous innate defense against T. rubrum. Taken together our data indicate that keratinocytes are able to initiate a fast defense response towards T. rubrum by the increased expression of AMP active against T. rubrum. A dysregulation of AMP may contribute to chronic and recurring dermatophytoses. PMID:24747887

Rademacher, Franziska; Schröder, Lena; Brasch, Jochen; Harder, Jürgen

2014-01-01

40

Pemphigus Vulgaris IgG Cause Loss of Desmoglein-Mediated Adhesion and Keratinocyte Dissociation Independent of Epidermal Growth Factor Receptor  

PubMed Central

Autoantibody-induced cellular signaling mechanisms contribute to the pathogenesis of autoimmune blistering skin disease pemphigus vulgaris (PV). Recently, it was proposed that epidermal growth factor receptor (EGFR) might be involved in PV signaling pathways. In this study, we investigated the role of EGFR by comparing the effects of epidermal growth factor (EGF) and PV-IgG on the immortalized human keratinocyte cell line HaCaT, and primary normal human keratinocytes. In contrast to EGF treatment, PV-IgG neither caused the canonical activation of EGFR via phosphorylation at tyrosine (Y)1173 followed by internalization of EGFR nor the phosphorylation of the EGFR at the c-Src-dependent site Y845. Nevertheless, both PV-IgG and EGF led to cell dissociation and cytokeratin retraction in keratinocyte monolayers. Moreover, the effects of EGF were blocked by inhibition of EGFR and c-Src whereas the effects of PV-IgG were independent of both signaling pathways. Similarly, laser tweezer experiments revealed that impaired bead binding of epidermal cadherins desmoglein (Dsg) 3 and Dsg 1 in response to PV-IgG was not affected by inhibition of either EGFR or c-Src. In contrast, EGF treatment did not interfere with Dsg bead binding. Taken together, our study indicates that the loss of Dsg-mediated adhesion and keratinocyte dissociation in pemphigus is independent of EGFR. Moreover, the mechanisms by which both EGF and PV-IgG lead to keratinocyte dissociation and cytokeratin retraction appear to be different. PMID:19147829

Heupel, Wolfgang-Moritz; Engerer, Peter; Schmidt, Enno; Waschke, Jens

2009-01-01

41

Epidermal growth factor receptor/beta-catenin/T-cell factor 4/matrix metalloproteinase 1: a new pathway for regulating keratinocyte invasiveness after UVA irradiation.  

PubMed

Previous studies have established that UV irradiation results in epidermal growth factor receptor (EGFR) activation in keratinocytes. However, the signaling pathways and cellular effects related to this process remain incompletely elucidated. Herein, we describe for the first time that UVA-mediated EGFR activation results in beta-catenin tyrosine phosphorylation at the Y654 residue responsible for the dissociation of E-cadherin/alpha-catenin/beta-catenin complexes. Moreover, UVA induces an EGFR-dependent, but Wnt-independent, beta-catenin relocalization from the membrane to the nucleus followed by its association with T-cell factor 4 (TCF4). This newly formed beta-catenin/TCF4 complex binds to a specific site on matrix metalloproteinase 1 (MMP1) promoter and governs MMP1 gene and protein expression, as well as cell migration in collagen and gelatin. Altogether, these results suggest that UVA stimulates keratinocyte invasiveness through two coordinated EGFR-dependent processes: loss of cell-to-cell contact due to beta-catenin/E-cadherin/alpha-catenin dissociation and increased cell migration through extracellular matrix component degradation due to beta-catenin/TCF4-dependent MMP1 regulation. These events may represent an important step in epidermis repair following UVA injury and their abnormal regulation could contribute to photoaging and photocarcinogenesis. PMID:19336574

Jean, Christine; Blanc, Amandine; Prade-Houdellier, Naïs; Ysebaert, Loïc; Hernandez-Pigeon, Hélène; Al Saati, Talal; Haure, Marie-José; Coluccia, Addolorata-Maria-Luce; Charveron, Marie; Delabesse, Eric; Laurent, Guy

2009-04-15

42

Cooperative effects in vitro on fibroblast and keratinocyte functions related to wound healing by transforming growth factor-beta and a low molecular weight fraction from hemolyzed blood.  

PubMed

Blood or its constituents, respectively, contain a.o. substances such as TGF-beta (transforming growth factor-beta), PDGF (platelet-derived growth factor) and other factors, which beneficially influence wound healing. Patients with perivascular disturbances and consequently with inadequate supply of the affected tissue cells often suffer from poor healing of dermal wounds. Here, various cellular functions in situations of poor supply and related to wound healing, such as proliferation, colony formation, and migration of fibroblasts, and of monolayer formation by keratinocytes were emulated in vitro by supplementing cultures with reduced amounts of serum. Computer-aided image analysis allowed to quantify the cellular reactions under normal and serum-deprived medium conditions and under the influence of a low molecular weight fraction manufactured by dialysis of hemolyzed calf blood (HD, Solcoseryl) and of TGF-beta. Both preparations are in use for the treatment of poorly healing wounds. While HD preferentially normalized the reduced viability of fibroblasts, the keratinocyte activity was enhanced by TGF-beta. Restoration of fibroblast and keratinocyte functions proved most effective when combining HD with TGF-beta. PMID:7945526

Miltenburger, H G; Baschong, W; Hörner, V; Marx, G

1994-07-01

43

Estradiol Protects Dermal Hyaluronan/Versican Matrix during Photoaging by Release of Epidermal Growth Factor from Keratinocytes*  

PubMed Central

Hyaluronan (HA) and versican are key components of the dermis and are responsive to ultraviolet (UV)B-induced remodeling. The aim of this study was to explore the molecular mechanisms mediating the effects of estrogen (E2) on HA-rich extracellular matrix during photoaging. Hairless skh-1 mice were irradiated with UVB (three times, 1 minimal erythema dose (80 mJ/cm2), weekly) for 10 weeks, and endogenous sex hormone production was abrogated by ovariectomy. Subcutaneous substitution of E2 by means of controlled-release pellets caused a strong increase in the dermal HA content in both irradiated and nonirradiated skin. The increase in dermal HA correlated with induction of HA synthase HAS3 by E2. Expression of splice variant 2 of the HA-binding proteoglycan versican was also increased by E2. In search of candidate mediators of these effects, it was found that E2 strongly induced the expression of epidermal growth factor (EGF) in UVB-irradiated epidermis in vivo and in keratinocytes in vitro. EGF in turn up-regulated the expression of HAS3 and versican V2 in dermal fibroblasts. HAS3 knockdown by shRNA caused inhibition of fibroblast proliferation. Furthermore, HAS3 and versican V2 induction by E2 correlated positively with proliferation in vivo. In addition, the accumulation of inflammatory macrophages, expression of inducible cyclooxygenase 2, as well as proinflammatory monocyte chemotactic protein 1 were decreased in response to E2 in the dermis. Collectively, these data suggest that E2 treatment increases the amount of dermal HA and versican V2 via paracrine release of EGF, which may be implicated in the pro-proliferative and anti-inflammatory effects of E2 during photoaging. PMID:22493503

Röck, Katharina; Meusch, Michael; Fuchs, Nikola; Tigges, Julia; Zipper, Petra; Fritsche, Ellen; Krutmann, Jean; Homey, Bernhard; Reifenberger, Julia; Fischer, Jens W.

2012-01-01

44

Keratinocyte growth factor-2 and autologous serum potentiate the regenerative effect of mesenchymal stem cells in cornea damage in rats  

PubMed Central

AIM To investigate the healing process after severe corneal epithelial damage in rats treated with mesenchymal stem cells (MSCs) cultured with or without keratinocyte growth factor (KGF-2) and autologous serum (AS) on amniotic membrane (AM). Many patients are blind and devastated by severe ocular surface diseases due to limbal stem cell deficiency. Bone marrow-derived MSCs are potential sources for cell-based tissue engineering to repair or replace the corneal tissue, having the potential to differentiate to epithelial cells. METHODS The study included 5 groups each including 10 female “Sprague Dawley” rats in addition to 20 male rats used as bone marrow donors. Group I rats received AM+MSCs, Group II rats AM+MSCs cultured with KGF-2, Group III rats AM+MSCs cultured with KGF-2+AS, Group IV rats only AM and Group V rats, none. AS was derived from blood drawn from male rats and bone marrow was obtained from the femur and tibia bones of the same animals. Therapeutic effect was evaluated with clinical, histopathological and immunohistochemical assessment. MSC engraftment was demonstrated via detection of donor genotype (Y+) in the recipient tissue (X) with polymerase chain reaction. RESULTS Corneal healing was significantly better in Groups I-III rats treated with MSC transplantation compared to Group IV and Group V rats with supportive treatment only. The best results were obtained in Group III rats with 90% transparency, 70% lack of neovascularization, and 100% epithelium damage limited to less than 1/4 of cornea. CONCLUSION We suggest that culture of MSCs with KGF-2 and AS on AM is effective in corneal repair in case of irreversible damage to limbal stem cells. PMID:24790860

P?narl?, Ferda Alpaslan; Ökten, Gülsen; Beden, Ümit; F??g?n, Tunç; Kefeli, Mehmet; Kara, Nurten; Duru, Feride; Tomak, Leman

2014-01-01

45

The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats  

SciTech Connect

Purpose: Radiation-induced lung toxicity is a significant dose-limiting side effect of radiotherapy for thoracic tumors. Recombinant human keratinocyte growth factor (rHuKGF) has been shown to be a mitogen for type II pneumocytes. The purpose of this study was to determine whether rHuKGF prevents or ameliorates the severity of late lung damage from fractionated irradiation in a rat model. Methods and materials: Female Fisher 344 rats were irradiated to the right hemithorax with a dose of 40 Gy/5 fractions/5 days. rHuKGF at dose of 5 mg/kg or 15 mg/kg was given via a single intravenous injection 10 min after the last fraction of irradiation. Animals were followed for 6 months after irradiation. Results: The breathing rate increased beginning at 6 weeks and reached a peak at 14 weeks after irradiation. The average breathing frequencies in the irradiated groups with rHuKGF (5 mg/kg and 15 mg/kg) treatment were significantly lower than that in the group receiving radiation without rHuKGF (116.5 {+-} 1.0 and 115.2 {+-} 0.8 vs 123.5 {+-} 1.2 breaths/min, p < 0.01). The severity of lung fibrosis and the level of immunoreactivity of integrin {alpha}v{beta}6, TGF{beta}1, type II TGF{beta} receptor, Smad3, and phosphorylated Smad2/3 were significantly decreased only in the group receiving irradiation plus high-dose rHuKGF treatment compared with irradiation plus vehicle group, suggesting a dose response for the effect of rHuKGF. Conclusions: This study is the first to demonstrate that rHuKGF treatment immediately after irradiation protects against late radiation-induced pulmonary toxicity. These results suggest that restoration of the integrity of the pulmonary epithelium via rHuKGF stimulation may downregulate the TGF-{beta}-mediated fibrosis pathway. These data also support the use of rHuKGF in a clinical trial designed to prevent radiation-induced lung injury.

Chen Liguang [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Brizel, David M. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Rabbani, Zahid N. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Samulski, Thaddeus V. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Farrell, Catherine L. [Amgen, Inc., Thousand Oaks, CA (United States); Larrier, Nicole [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Anscher, Mitchell S. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Vujaskovic, Zeljko [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)]. E-mail: vujas@radonc.duke.edu

2004-12-01

46

Insulin-like growth factor-binding protein-7 (IGFBP7) transcript: A-to-I editing events in normal and cancerous human keratinocytes.  

PubMed

Non-melanoma skin cancers (NMSC) are the most common malignancies in caucasians worldwide. Insulin-like growth factor-binding protein-7 (IGFBP7) was suggested to function as a tumor suppressor gene in several cancers, and to play a role in the proliferation of keratinocytes. A-to-I RNA editing is a post-transcriptional mechanism frequently used to expand and diversify transcriptome and proteome repertoire in eukaryotic cells. A-to-I RNA editing can alter codons, substitute amino acids and affect protein sequence, structure, and function. Two editing sites were identified within the IGFBP7 transcript. To evaluate the expression and editing of IGFBP7 mRNA in NMSC compared to normal epidermis. We examined the expression and mRNA editing level of IGFBP7 in 22 basal cell carcinoma (BCC), 15 squamous cell carcinoma (SCC), and 18 normal epidermis samples that were surgically removed from patients by the Mohs Micrographic Surgery procedure. We studied the effect of IGFBP7 editing on an immortalized HaCaT keratinocyte cell model. IGFBP7 mRNA is over expressed in BCC and SCC compared to normal epidermis. Moreover, the IGFBP7 transcript is highly edited in normal epidermis, but its editing is significantly reduced in BCC and SCC. The edited form of IGFBP7 can inhibit proliferation and induce senescence in cultured keratinocytes. This study describes for the first time A-to-I editing in the coding sequence of a tumor suppressor gene in humans, and suggests that IGFBP7 editing serves as a fine-tuning mechanism to maintain the equilibrium between proliferation and senescence in normal skin. PMID:23543219

Hochberg, Malka; Gilead, Leon; Markel, Gal; Nemlich, Yael; Feiler, Yulia; Enk, Claes David; Denichenko, Polina; Karni, Rotem; Ingber, Arieh

2013-08-01

47

Epidermal Growth Factor Receptor Transactivation Is Required for Mitogen-Activated Protein Kinase Activation by Muscarinic Acetylcholine Receptors in HaCaT Keratinocytes  

PubMed Central

Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are expressed, but M1 and M3 are the subtypes involved in mitogenic signaling. Stimulation with the cholinergic agonist carbachol leads to activation of the MAP kinase extracellular signal regulated kinase, together with the protein kinase Akt. The activation is fully dependent on the transactivation of the epidermal growth factor receptor (EGFR), which even appears to be the sole pathway for the muscarinic receptors to facilitate MAP kinase activation in HaCaT cells. The transactivation pathway involves a triple-membrane-passing process, based on activation of matrix metalloproteases, and extracellular ligand release; whereas phosphatidylinositol 3-kinase, Src family kinases or protein kinase C do not appear to be involved in MAP kinase activation. Furthermore, phosphorylation, ubiquitination and endocytosis of the EGF receptor after cholinergic transactivation are different from that induced by a direct stimulation with EGF, suggesting that ligands other than EGF itself mediate the cholinergic transactivation. PMID:25421240

Ockenga, Wymke; Kühne, Sina; Bocksberger, Simone; Banning, Antje; Tikkanen, Ritva

2014-01-01

48

Epidermal growth factor receptor transactivation is required for mitogen-activated protein kinase activation by muscarinic acetylcholine receptors in HaCaT keratinocytes.  

PubMed

Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are expressed, but M1 and M3 are the subtypes involved in mitogenic signaling. Stimulation with the cholinergic agonist carbachol leads to activation of the MAP kinase extracellular signal regulated kinase, together with the protein kinase Akt. The activation is fully dependent on the transactivation of the epidermal growth factor receptor (EGFR), which even appears to be the sole pathway for the muscarinic receptors to facilitate MAP kinase activation in HaCaT cells. The transactivation pathway involves a triple-membrane-passing process, based on activation of matrix metalloproteases, and extracellular ligand release; whereas phosphatidylinositol 3-kinase, Src family kinases or protein kinase C do not appear to be involved in MAP kinase activation. Furthermore, phosphorylation, ubiquitination and endocytosis of the EGF receptor after cholinergic transactivation are different from that induced by a direct stimulation with EGF, suggesting that ligands other than EGF itself mediate the cholinergic transactivation. PMID:25421240

Ockenga, Wymke; Kühne, Sina; Bocksberger, Simone; Banning, Antje; Tikkanen, Ritva

2014-01-01

49

Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System  

PubMed Central

Abstract Aims: To evaluate mechanisms underlying modulation of inflammatory chemokines in primary human keratinocytes (normal human epidermal keratinocytes) and repair-related processes in wound models by plant polyphenols (PPs) with antioxidant and superoxide scavenging properties (verbascoside [Vb], resveratrol [Rv], polydatin [Pd], quercetin [Qr], and rutin). Results: Epidermal growth factor receptor (EGFR)-controlled chemokines CXCL8/interleukin 8 (IL-8), CCL2/monocyte chemotactic protein-1 (MCP-1), and CXCL10/interferon gamma-produced protein of 10?kDa (IP-10) were modulated by transforming growth factor alpha (TGF-?) and by the tumor necrosis factor alpha/interferon gamma combination (T/I). EGFR phosphorylation, nuclear translocation, and downstream cytoplasmic signaling pathways (extracellular regulation kinase [ERK]1/2, p38, STAT3, and PI-3K) were studied. All PPs did not affect TGF-?-induced STAT3 phosphorylation, whereas they suppressed T/I-activated NFkappaB and constitutive and T/I-induced but not TGF-?-induced ERK1/2 phosphorylation. Vb and Qr suppressed total EGFR phosphorylation, but they synergized with TGF-? to enhance nuclear accumulation of phosphorylated EGFR. Vb strongly inhibited TGF-?-induced p38 phosphorylation and T/I-induced NFkappaB and activator protein-1 (AP-1) binding to DNA. Vb was an effective inhibitor of T/I-stimulated chemokine synthesis, and it accelerated scratch wound healing in vitro. Anti-inflammatory and wound healing activities of Vb were confirmed in vivo in the full-thickness excision wound. Although Pd and Rv did not affect EGFR activation/translocation, they and Qr synergized with TGF-? and T/I in the induction of IL-8 transcription/synthesis while opposing enhanced MCP-1 and IP-10 transcription/synthesis connected with pharmacologically impaired EGFR functioning. Innovation: PPs perturb the EGFR system in human keratinocytes, and this effect may be implicated in the regulation of inflammatory and repair-related processes in the skin. Conclusion: Anti-inflammatory and wound healing effects of PPs depend on their interaction with EGFR-controlled cytoplasmic and nuclear pathways rather than on their direct redox properties. Antioxid. Redox Signal. 16, 314–328. PMID:21967610

Pastore, Saveria; Lulli, Daniela; Fidanza, Paolo; Potapovich, Alla I.; Kostyuk, Vladimir A.; De Luca, Chiara; Mikhal'Chik, Elena

2012-01-01

50

A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: Activation of proteinase-activated receptor 1 and epidermal growth factor receptor  

SciTech Connect

Biological functions of tissue kallikrein (TK, KLK1) are mainly mediated by kinin generation and subsequent kinin B2 receptor activation. In this study, we investigated the potential role of TK and its signaling pathways in cultured human keratinocyte migration and in a rat skin wound healing model. Herein, we show that TK promoted cell migration and proliferation in a concentration- and time-dependent manner. Inactive TK or kinin had no significant effect on cell migration. Interestingly, cell migration induced by active TK was not blocked by icatibant or L-NAME, indicating an event independent of kinin B2 receptor and nitric oxide formation. TK's stimulatory effect on cell migration was inhibited by small interfering RNA for proteinase-activated receptor 1 (PAR{sub 1}), and by PAR{sub 1} inhibitor. TK-induced migration was associated with increased phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK), which was blocked by inhibition of protein kinase C (PKC), Src, EGFR and ERK. TK-induced cell migration and EGFR phosphorylation were blocked by metalloproteinase (MMP) inhibitor, heparin, and antibodies against EGFR external domain, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR). Local application of TK promoted skin wound healing in rats, whereas icatibant and EGFR inhibitor blocked TK's effect. Skin wound healing was further delayed by aprotinin and neutralizing TK antibody. This study demonstrates a novel role of TK in skin wound healing and uncovers new signaling pathways mediated by TK in promoting keratinocyte migration through activation of the PAR{sub 1}-PKC-Src-MMP pathway and HB-EGF/AR shedding-dependent EGFR transactivation.

Gao, Lin; Chao, Lee [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)] [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States); Chao, Julie, E-mail: chaoj@musc.edu [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)] [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)

2010-02-01

51

Heparin and Its Non-Anticoagulant Analogues Inhibit Human Keratinocyte Growth Without Inducing Differentiation  

Microsoft Academic Search

In addition to its anti-coagulant effect, heparin inhibits the growth of several types of cells. Recent studies suggest that heparin inhibition of proliferation of cultured human keratinocytes results primarily from interaction with keratinocyte-generated, heparin-binding autocrine growth factors. In this study, we evaluated whether non-anticoagulant heparin analogs, and oligosaccharide fragments of heparin, retain the growth-inhibitory properties of whole heparin on human

Sreekumar Pillai; Lisa Gilliam; H. Edward Conrad; Walter M. Holleran

1994-01-01

52

Human growth factor (huGRO), interleukin-8 (IL8) and interferon-?-inducible protein (?-IP-10) gene expression in cultured normal human keratinocytes  

Microsoft Academic Search

HuGRO, IL-8 and ?-IP-10 belong to a recently described superfamily of genes encoding a group of cytokines with inflammatory, growth regulating and\\/or leukocyte chemotactic properties (chemokines). We studied huGRO, IL-8 and ?-IP-10 gene expression in unstimulated and stimulated (TNF?, INF?, TNF? + IFN?, IL-1?, PMA and LPS) normal human keratinocytes by Northern blot analysis. The mRNA for none of the

Dick M. Boorsma; Peter de Haan; Rein Willemze; Tom J. Stoof

1994-01-01

53

Keratinocyte growth factor in inflammatory bowel disease. Increased mRNA transcripts in ulcerative colitis compared with Crohn's disease in biopsies and isolated mucosal myofibroblasts.  

PubMed Central

Inflammation in the gastrointestinal tract is associated with increased epithelial cell proliferation. Keratinocyte growth factor (KGF) is an epithelial cell mitogen widely expressed by mesenchymal cells subjacent to the epithelial cells. In this study, we have investigated the expression and distribution of KGF in normal and diseased (Crohn's disease and ulcerative colitis(UC)) intestine by quantitative competitive reverse-transcriptase polymerase chain reaction in whole biopsies and purified lamina propria myofibroblasts and by in situ hybridization. Analysis of whole mucosal biopsies reveals significantly higher numbers of KGF mRNA transcripts in UC compared with Crohn's colitis and control colon (P < 0.001). KGF transcripts were also elevated in Crohn's ileitis compared with normal ileum. In situ hybridization showed a marked increase in cells expressing KGF mRNA throughout the lamina propria in both UC and Crohn's tissue. In Crohn's disease, positively hybridizing cells were only rarely seen in the submucosa but were abundant around the bases of the crypts and were not associated with lymphoid aggregates. In purified mucosal myofibroblasts, increased (15- to 20-fold) KGF mRNA expression was seen in UC compared with control and Crohn's tissue. These results confirm and extend earlier studies showing that KGF transcripts are elevated in inflammatory bowel disease, but they show for the first time that transcripts are higher in UC than Crohn's disease because of increased production by mucosal mesenchymal cells. Images Figure 2 Figure 3 PMID:9358773

Bajaj-Elliott, M.; Breese, E.; Poulsom, R.; Fairclough, P. D.; MacDonald, T. T.

1997-01-01

54

Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation  

PubMed Central

Myeloablative conditioning before bone marrow transplantation (BMT) results in thymic epithelial cell (TEC) injury, T-cell immune deficiency, and susceptibility to opportunistic infections. Conditioning regimen–induced TEC damage directly contributes to slow thymopoietic recovery after BMT. Keratinocyte growth factor (KGF) is a TEC mitogen that stimulates proliferation and, when given before conditioning, reduces TEC injury. Some TEC subsets are refractory to KGF and functional T-cell responses are not fully restored in KGF-treated BM transplant recipients. Therefore, we investigated whether the addition of a pharmacologic inhibitor, PFT-?, to transiently inhibit p53 during radiotherapy could spare TECs from radiation-induced damage in congenic and allogeneic BMTs. Combined before BMT KGF + PFT-? administration additively restored numbers of cortical and medullary TECs and improved thymic function after BMT, resulting in higher numbers of donor-derived, naive peripheral CD4+ and CD8+ T cells. Radiation conditioning caused a loss of T-cell zone fibroblastic reticular cells (FRCs) and CCL21 expression in lymphoid stroma. KGF + PFT-? treatment restored both FRC and CCL21 expression, findings that correlated with improved T-cell reconstitution and an enhanced immune response against Listeria monocytogenes infection. Thus, transient p53 inhibition combined with KGF represents a novel and potentially translatable approach to promote rapid and durable thymic and peripheral T-cell recovery after BMT. PMID:19965631

Kelly, Ryan M.; Goren, Emily M.; Taylor, Patricia A.; Mueller, Scott N.; Stefanski, Heather E.; Osborn, Mark J.; Scott, Hamish S.; Komarova, Elena A.; Gudkov, Andrei V.; Holländer, Georg A.

2010-01-01

55

AMPK regulation of the growth of cultured human keratinocytes  

SciTech Connect

AMP kinase (AMPK) is a fuel sensing enzyme that responds to cellular energy depletion by increasing processes that generate ATP and inhibiting others that require ATP but are not acutely necessary for survival. In the present study, we examined the relationship between AMPK activation and the growth (proliferation) of cultured human keratinocytes and assessed whether the inhibition of keratinocyte growth by vitamin D involves AMPK activation. In addition, we explored whether the inhibition of keratinocyte proliferation as they approach confluence could be AMPK-related. Keratinocytes were incubated for 12 h with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside (AICAR). At concentrations of 10{sup -4} and 10{sup -3} M, AICAR inhibited keratinocyte growth by 50% and 95%, respectively, based on measurements of thymidine incorporation into DNA. It also increased AMPK and acetyl CoA carboxylase phosphorylation (P-AMPK and P-ACC) and decreased the concentration of malonyl CoA confirming that AMPK activation had occurred. Incubation with the thiazolidinedione, troglitazone (10{sup -6} M) caused similar alterations in P-AMPK, P-ACC, and cell growth. In contrast, the well known inhibition of keratinocyte growth by 1,25-dihydroxyvitamin D{sub 3} (10{sup -7} and 10{sup -6} M) was not associated with changes in P-AMPK or P-ACC. Like most cells, the growth of keratinocytes diminished as they approached confluence. Thus, it was of note that we found a progressive increase in P-AMPK (1.5- to 2-fold, p < 0.05) as keratinocytes grown in control medium went from 25% to 100% confluence. In conclusion, the data are consistent with the hypothesis that activation of AMPK acts as a signal to diminish the proliferation of cultured keratinocytes as they approach confluence. They also suggest that AMPK activators, such as AICAR and troglitazone, inhibit keratinocyte growth and that the inhibition of cell growth by 1,25-dihydroxyvitamin D{sub 3} is AMPK-independent.

Saha, Asish K. [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States)]. E-mail: aksaha@bu.edu; Persons, Kelly [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States); Safer, Joshua D. [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States); Luo Zhijun [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States); Holick, Michael F. [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States); Ruderman, Neil B. [Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA (United States)

2006-10-20

56

Amphiregulin Carboxy-Terminal Domain Is Required for Autocrine Keratinocyte Growth  

Microsoft Academic Search

The EGFR ligand amphiregulin (AREG) has been implicated as an important autocrine growth factor in several epithelial malignancies and in psoriasis, a hyperproliferative skin disorder. To characterize the mechanisms by which AREG regulates autocrine epithelial cell growth, we transduced human keratinocytes (KCs) with lentiviral constructs expressing tetracycline (TET)-inducible small hairpin RNA (shRNA). TET-induced expression of AREG shRNA markedly reduced autocrine

Stefan W Stoll; Jessica L Johnson; Yong Li; Laure Rittié; James T Elder

2010-01-01

57

Vimentin is necessary for colony growth of human diploid keratinocytes.  

PubMed

The role of vimentin (Vim) in diploid epithelial cells is not well known. To understand its biological function, we cultured human epidermal keratinocytes under conditions that support migration, proliferation, stratification and terminal differentiation. We identified a keratinocyte subpopulation that shows a p63(+)/?5?1(bright) phenotype and displays Vim intermediate filaments (IFs) besides their keratin IF network. These cells were mainly located at the proliferative/migratory rim of the growing colonies; but also, they were scarce and scattered or formed small groups of basal cells in confluent stratified epithelia. Stimulation of cells with EGF and wounding experiments in confluent arrested epithelia increased the number of Vim(+) keratinocytes in an extent higher to the expected for a cell population doubling. BrdU labeling demonstrated that most of the proliferative cells located at the migratory border of the colony have Vim, in contrast with proliferative cells located at the basal layer at the center of big colonies which lacked of Vim IFs, suggesting that Vim expression was not solely linked to proliferation. Therefore, we silenced Vim mRNA in the cultured keratinocytes and observed an inhibition of colony growth. Such results, together with long-term cultivation assays which showed that Vim might be associated to pattern formation in cultured epithelia, suggest that Vim expression is essential for a highly motile phenotype, which is necessary for keratinocyte colony growth and possibly for development and wound healing. Vim(+)/p63(+)/?5?1(bright) epithelial cells may play a significant physiological role in embryonic morphogenetic movements; wound healing and other pathologies such as carcinomas and hyperproliferative diseases. PMID:25142512

Castro-Muñozledo, Federico; Velez-DelValle, Cristina; Marsch-Moreno, Meytha; Hernández-Quintero, Miriam; Kuri-Harcuch, Walid

2015-01-01

58

Nerve growth factor levels in cultured human skin cells: effect of gestation and viral transformation  

Microsoft Academic Search

Extracts of cultured human keratinocytes and fibroblasts were assayed for nerve growth factor-like immunoreactivity (NGF) by a specific enzyme-linked immunoabsorbant assay. NGF levels were higher in primary cultured keratinocytes than in freshly isolated keratinocytes or culture through multiple passages. Viral transformation of keratinocytes with the human papilloma virus (HPV 16) significantly increased NGF levels, whilst transformation with the simian virus

P. Anand; P. Foley; H. A. Navsaria; D. Sinicropi; R. E. Williams-Chestnut; I. M. Leigh

1995-01-01

59

Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing  

PubMed Central

The molecular mechanism underlying the promotion of wound healing by TGF-beta 1 is incompletely understood. We report that TGF-beta 1 regulates the regenerative/migratory phenotype of normal human keratinocytes by modulating their integrin receptor repertoire. In growing keratinocyte colonies but not in fully stratified cultured epidermis, TGF-beta 1: (a) strongly upregulates the expression of the fibronectin receptor alpha 5 beta 1, the vitronectin receptor alpha v beta 5, and the collagen receptor alpha 2 beta 1 by differentially modulating the synthesis of their alpha and beta subunits; (b) downregulates the multifunctional alpha 3 beta 1 heterodimer; (c) induces the de novo expression and surface exposure of the alpha v beta 6 fibronectin receptor; (d) stimulates keratinocyte migration toward fibronectin and vitronectin; (e) induces a marked perturbation of the general mechanism of polarized domain sorting of both beta 1 and beta 4 dimers; and (f) causes a pericellular redistribution of alpha v beta 5. These data suggest that alpha 5 beta 1, alpha v beta 6, and alpha v beta 5, not routinely used by keratinocytes resting on an intact basement membrane, act as "emergency" receptors, and uncover at least one of the molecular mechanisms responsible for the peculiar integrin expression in healing human wounds. Indeed, TGF-beta 1 reproduces the integrin expression pattern of keratinocytes located at the injury site, particularly of cells in the migrating epithelial tongue at the leading edge of the wound. Since these keratinocytes are inhibited in their proliferative capacity, these data might account for the apparent paradox of a TGF-beta 1-dependent stimulation of epidermal wound healing associated with a growth inhibitory effect on epithelial cells. PMID:7537276

1995-01-01

60

Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth.  

PubMed

Interleukin-6 (IL-6) is one of the major inflammatory interleukins that has been linked to cancer progression. In our model for human skin squamous cell carcinoma (SCC), IL-6 expression is strongly upregulated upon progression from benign tumors to highly malignant, metastasizing SCCs. We now demonstrate that IL-6 promotes malignant and invasive tumor growth in human skin SCCs by inducing cell type specific cytokine profiles in tumor keratinocytes and stromal fibroblasts, activating the latter towards a tumor associated fibroblast (TAF) phenotype. In three-dimensional organotypic cocultures in vitro invasive growth of IL-6 overexpressing tumor keratinocytes, is associated with increased expression of matrix metalloproteinase-2 (MMP-2), MMP-14 and tissue inhibitor of metalloproteinases-2, and clearly depends on IL-6 activated fibroblasts. IL-6-induced secretion of monocyte chemotactic protein-1 (MCP-1) in tumor keratinocytes and of hepatocyte growth factor in fibroblasts is crucial for regulating expression and activation of MMP-2. This functional role of IL-6 is confirmed in vivo. Here MMP-14 and MMP-2 expression occur exclusively in surface transplants of IL-6 overexpressing keratinocytes and fibroblasts are identified as important source of MMP-2. Our data indicate that tumor keratinocytes derived IL-6 activates stromal fibroblasts towards a TAF phenotype, promoting tumor invasion via enhanced expression and activation of MMP-2. PMID:23165423

Depner, Sofia; Lederle, Wiltrud; Gutschalk, Claudia; Linde, Nina; Zajonz, Alexandra; Mueller, Margareta M

2014-08-01

61

Human hair follicle dermal sheath and papilla cells support keratinocyte growth in monolayer coculture.  

PubMed

Traditional skin grafting techniques are effective but limited methods of skin replacement. Autologous transplantation of rapidly cultured keratinocytes is successful for epidermal regeneration, but the current gold-standard technique requires mouse fibroblast feeders and serum-rich media, with serum-free systems and dermal fibroblast (DF) feeders performing relatively poorly. Here, we investigated the capacity of human hair follicle dermal cells to act as alternative supports for keratinocyte growth. Dermal papilla (DP) dermal sheath (DS), DF and 3T3 cells were used as inactivated feeder cells for human keratinocyte coculture. Under conditions favouring dermal cells, proliferation of keratinocytes in the presence of either DS or DP cells was significantly enhanced compared with DF cells, at levels comparable to keratinocytes cultured under gold-standard conditions. Secreted protein acidic and rich in cysteine (SPARC) expression increased DS and DP cells relative to DFs; however, further experiments did not demonstrate a role in keratinocyte support. PMID:23489431

Hill, Rebecca P; Gardner, Aaron; Crawford, Heather C; Richer, Rachel; Dodds, Anna; Owens, William A; Lawrence, Clifford; Rao, Sam; Kara, Bo; James, S Elizabeth; Jahoda, Colin A

2013-03-01

62

Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation  

PubMed Central

Myeloablative conditioning results in thymic epithelial cell (TEC) injury, slow T-cell reconstitution, and a high risk of opportunistic infections. Keratinocyte growth factor (KGF) stimulates TEC proliferation and, when given preconditioning, reduces TEC injury. Thymocytes and TECs express androgen receptors, and exposure to androgen inhibits thymopoiesis. In this study, we have investigated whether TEC stimulation via preconditioning treatment with KGF and leuprolide acetate (Lupron), 2 clinically approved agents, given only before conditioning would circumvent the profound TEC and associated T-cell deficiency seen in allogeneic bone marrow transplant (BMT) recipients. Only combined treatment with KGF plus leuprolide acetate normalized TEC subset numbers and thymic architecture. Thymopoiesis and thymic output were supranormal, leading to the accelerated peripheral reconstitution of naive CD4 and CD8 T cells with a broad V? repertoire and decreased homeostatic T-cell proliferation. Combined therapy facilitated T:B cooperativity and enabled a B-cell humoral response to a CD4 T cell–dependent neoantigen challenge soon after BMT. In vivo antigen-specific CD8 T-cell responses and clearance of a live pathogen was superior with combined versus individual agent therapy. Thus, KGF combined with androgen blockade represents a novel approach to restore thymic function and facilitates the rapid recovery of peripheral T-cell function after allogeneic BMT. PMID:18334670

Kelly, Ryan M.; Highfill, Steven L.; Panoskaltsis-Mortari, Angela; Taylor, Patricia A.; Boyd, Richard L.; Holländer, Georg A.

2008-01-01

63

BAG-1 enhances cell-cell adhesion, reduces proliferation and induces chaperone-independent suppression of hepatocyte growth factor-induced epidermal keratinocyte migration  

SciTech Connect

Cell motility is important in maintaining tissue homeostasis, facilitating epithelial wound repair and in tumour formation and progression. The aim of this study was to determine whether BAG-1 isoforms regulate epidermal cell migration in in vitro models of wound healing. In the human epidermal cell line HaCaT, endogenous BAG-1 is primarily nuclear and increases with confluence. Both transient and stable p36-Bag-1 overexpression resulted in increased cellular cohesion. Stable transfection of either of the three human BAG-1 isoforms p36-Bag-1 (BAG-1S), p46-Bag-1 (BAG-1M) and p50-Bag-1 (BAG-1L) inhibited growth and wound closure in serum-containing medium. However, in response to hepatocyte growth factor (HGF) in serum-free medium, BAG-1S/M reduced communal motility and colony scattering, but BAG-1L did not. In the presence of HGF, p36-Bag-1 transfectants retained proliferative response to HGF with no change in ERK1/2 activation. However, the cells retained E-cadherin localisation at cell-cell junctions and exhibited pronounced cortical actin. Point mutations in the BAG domain showed that BAG-1 inhibition of motility is independent of its function as a chaperone regulator. These findings are the first to suggest that BAG-1 plays a role in regulating cell-cell adhesion and suggest an important function in epidermal cohesion.

Hinitt, C.A.M.; Wood, J.; Lee, S.S. [Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY (United Kingdom)] [Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY (United Kingdom); Williams, A.C. [Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, University Walk, Bristol, BS8 1TD (United Kingdom)] [Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, University Walk, Bristol, BS8 1TD (United Kingdom); Howarth, J.L.; Glover, C.P.; Uney, J.B. [The Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY (United Kingdom)] [The Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY (United Kingdom); Hague, A., E-mail: a.hague@bristol.ac.uk [Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY (United Kingdom)

2010-08-01

64

Expression of paired-like homeodomain transcription factor 2c (PITX2c) in epidermal keratinocytes  

SciTech Connect

Paired-like homeodomain transcription factor 2 (PITX2) has been implicated as one of the genes responsible for Rieger syndrome. It has been also shown to play a central role during development. In this study, we investigated the functional role of PITX2 in keratinocyte differentiation. RT-PCR analysis showed that PITX2c isoform was predominantly expressed in a differentiation-dependent manner. Consistent with, immunohistochemical staining showed that PITX2 expression was increased in the upper layer of epidermis. When PITX2c was overexpressed in cultured keratinocytes by a recombinant adenovirus, the differentiation markers such as involucrin and loricrin were significantly increased at both mRNA and protein levels. In addition, PITX2c overexpression led to the decrease of cell growth, concomitantly with the upregulation of cell cycle-related genes p21. To investigate the effect of PITX2c in vivo, we microinjected PITX2c expression vector into zebrafish embryo. Interestingly, overexpression of PITX2c in zebrafish embryo led to the formation of horn-like structure and thickening of epidermis, together with the increase of keratin 8 (K8) expression. These results suggest that PITX2c has a role in proliferation and differentiation of epidermal keratinocytes.

Shi, Ge [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of) [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Department of Dermatology, The First Affiliated Hospital, Guangxi Traditional Chinese Medical University, Guangxi, Nanning, 530023 (China); Sohn, Kyung-Cheol; Choi, Tae-Young; Choi, Dae-Kyoung; Lee, Sang-Sin [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of) [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Ou, Bai-sheng [Department of Dermatology, The First Affiliated Hospital, Guangxi Traditional Chinese Medical University, Guangxi, Nanning, 530023 (China)] [Department of Dermatology, The First Affiliated Hospital, Guangxi Traditional Chinese Medical University, Guangxi, Nanning, 530023 (China); Kim, Sooil; Lee, Young Ho [Department of Anatomy, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of)] [Department of Anatomy, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Yoon, Tae-Jin [Department of Dermatology, School of Medicine, Gyeongsang National University, Jinju, 660-702 (Korea, Republic of) [Department of Dermatology, School of Medicine, Gyeongsang National University, Jinju, 660-702 (Korea, Republic of); Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, 660-702 (Korea, Republic of); Kim, Seong-Jin [Department of Dermatology, Chonnam National University Medical School, Gwangju, 501-757 (Korea, Republic of)] [Department of Dermatology, Chonnam National University Medical School, Gwangju, 501-757 (Korea, Republic of); Lee, Young; Seo, Young-Joon; Lee, Jeung-Hoon [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of) [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Kim, Chang Deok, E-mail: cdkimd@cnu.ac.kr [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of)

2010-11-15

65

MicroRNA let-7a suppresses the growth and invasion of cholesteatoma keratinocytes.  

PubMed

Cholesteatomas are benign epidermally?derived lesions of the temporal bone that are caused by migration of hyperproliferative keratinocytes into the middle ear and mastoid cavity. The molecular mechanisms that regulate the pathogenesis of cholesteatomas are currently not fully understood. The present study demonstrated the antigrowth and anti?invasive effects of let?7a microRNA (miRNA) on cholesteatoma keratinocytes. Let?7a inhibited the growth of cholesteatoma keratinocytes through two different mechanisms: Restriction of the proliferation of keratinocytes by promoting cell cycle arrest in the G0/G1 phase, and the induction of apoptosis of the cells. In addition to its role in the inhibition of cell growth, let?7a suppressed the migration and invasion of cholesteatoma keratinocytes. A mechanistic study showed that let?7a downregulated the expression of miR?21. Considering the function of miR?21 in the regulation of proliferation and apoptosis, let?7a may control cell proliferation and apoptosis by regulating miR?21, and its targets, in cholesteatoma keratinocytes. In conclusion, the present study showed that let?7a downregulates the expression of miR?21, resulting in the suppression of proliferation and induction of apoptosis. The results of the present study reveal the crucial role of let?7a miRNA in the inhibition of growth and invasion of cholesteatoma keratinocytes. PMID:25405753

Zhang, Wenjing; Chen, Xiaohua; Qin, Zhaobing

2015-03-01

66

Procathepsin D secreted by HaCaT keratinocyte cells – A novel regulator of keratinocyte growth  

Microsoft Academic Search

Procathepsin D (pCD), the precursor form of lysosomal aspartic protease, is overexpressed and secreted by various carcinomas. The fact that secreted pCD plays an essential role in progression of cancer has been established. In this study, we describe substantial secretion of pCD by the human keratinocyte cell line HaCaT, under serum-free conditions. Moreover, exogenous addition of purified pCD enhanced the

Aruna Vashishta; Sujata Saraswat Ohri; Jana Vetvickova; Martin Fusek; Jitka Ulrichova; Vaclav Vetvicka

2007-01-01

67

Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2  

PubMed Central

The long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs)—eicosapentaenoic acid (EPA) and its metabolite docosahexaenoic acid (DHA)—inhibit cancer formation in vivo, but their mechanism of action is unclear. Extracellular signal-regulated kinase 1/2 (ERK1/2) activation and inhibition have both been associated with the induction of tumour cell apoptosis by n-3 PUFAs. We show here that low doses of EPA, in particular, inhibited the growth of premalignant and malignant keratinocytes more than the growth of normal counterparts by a combination of cell cycle arrest and apoptosis. The growth inhibition of the oral squamous cell carcinoma (SCC) lines, but not normal keratinocytes, by both n-3 PUFAs was associated with epidermal growth factor receptor (EGFR) autophosphorylation, a sustained phosphorylation of ERK1/2 and its downstream target p90RSK but not with phosphorylation of the PI3 kinase target Akt. Inhibition of EGFR with either the EGFR kinase inhibitor AG1478 or an EGFR-blocking antibody inhibited ERK1/2 phosphorylation, and the blocking antibody partially antagonized growth inhibition by EPA but not by DHA. DHA generated more reactive oxygen species and activated more c-jun N-terminal kinase than EPA, potentially explaining its increased toxicity to normal keratinocytes. Our results show that, in part, EPA specifically inhibits SCC growth and development by creating a sustained signalling imbalance to amplify the EGFR/ERK/p90RSK pathway in neoplastic keratinocytes to a supraoptimal level, supporting the chemopreventive potential of EPA, whose toxicity to normal cells might be reduced further by blocking its metabolism to DHA. Furthermore, ERK1/2 phosphorylation may have potential as a biomarker of n-3 PUFA function in vivo. PMID:23892603

Parkinson, Eric Kenneth

2013-01-01

68

Cultivation, frozen storage, and clonal growth of normal human epidermal keratinocytes in serum-free media  

Microsoft Academic Search

Summary Methods are described for serum-free culture of human epidermal keratinocytes derived from neonatal foreskin tissue. Cultures are initiated, stored frozen, and returned to active growth, all with bovine pituitary extract as the only undefined supplement. Clonal growth assays are then performed in a biochemically defined medium. The degree of stratification and differentiation in the defined medium (and also with

Steven T. Boyce; Richard G. Ham

1985-01-01

69

The effect of different biologic and biosynthetic wound covers on keratinocyte growth, stratification and differentiation in vitro  

PubMed Central

The purpose of this study was to compare, by means of in vitro cultivation technique, five marketed brands of wound covers used in the treatment of burns and other skin defects (Biobrane®, Suprathel®, Veloderm®, Xe-Derma®, and Xenoderm®) for their ability to stimulate the keratinocyte growth, stratification, and differentiation. In three independent experiments, human keratinocytes were grown on the tested covers in organotypic cultures by the 3T3 feeder layer technique. Vertical paraffin sections of the wound covers with keratinocytes were processed using hematoxylin–eosin staining and immunostaining for involucrin. Keratinocyte populations on the dressings were assessed for (1) number of keratinocyte strata (primary variable), (2) quantitative growth, (3) thickness of the keratinocyte layer, and (4) cell differentiation. The Xe-Derma wound cover provided the best support to keratinocyte proliferation and stratification, with the number of keratinocyte strata significantly (p?keratinocyte proliferation and stratification. The distinctive position of Xe-Derma may be related to its composition, where natural dermal fibers form a smooth surface, similar to the basement membrane. Furthermore, the results indicate that in vitro evaluation of effects on epithelial growth may accelerate the development of new bio-engineering-based wound covers. PMID:25383177

Mestak, Ondrej

2014-01-01

70

Keratins and the Keratinocyte Activation Cycle  

Microsoft Academic Search

In wound healing and many pathologic conditions, keratinocytes become activated: they turn into migratory, hyperproliferative cells that produce and secrete extracellular matrix components and signaling polypeptides. At the same time, their cytoskeleton is also altered by the production of specific keratin proteins. These changes are orchestrated by growth factors, chemokines, and cytokines produced by keratinocytes and other cutaneous cell types.

Irwin M Freedberg; Marjana Tomic-Canic; Mayumi Komine; Miroslav Blumenberg; Blumenberg

2001-01-01

71

Notch signaling in the integrated control of keratinocyte growth\\/differentiation and tumor suppression  

Microsoft Academic Search

Oncogenesis is closely linked to abnormalities in cell differentiation. Notch signaling provides an important form of intercellular communication involved in cell fate determination, stem cell potential and differentiation. Here we review the role of this pathway in the integrated growth\\/differentiation control of the keratinocyte cell type, and the maintenance of normal skin homeostasis. In parallel with the pro-differentiation function of

Karine Lefort; G. Paolo Dotto

2004-01-01

72

Clonal growth of human keratinocytes with small amounts of dialyzed serum  

Microsoft Academic Search

Summary  A survey of commercially availabla media revealed that medium F-12 was superior to medium 199 for clonal growth of human epidermal\\u000a keratinocytes (HK) when supplemented with 10 ?g\\/ml hydrocortisone (HC) plus dialyzed fetal bovine serum protein (FBSP), rather\\u000a than the whole serum used in previous studies. Qualitative and quantitative adjustment of the medium composition for optimal\\u000a clonal growth with minimal

Donna M. Peehl; Richard G. Ham

1980-01-01

73

Keratinocyte-Derived Granulocyte?Macrophage Colony Stimulating Factor Accelerates Wound Healing: Stimulation of Keratinocyte Proliferation, Granulation Tissue Formation, and Vascularization  

Microsoft Academic Search

Chronic, nonhealing wounds represent a major clinical challenge to practically all disciplines in modern medicine including dermatology, oncology, surgery, and hematology. In skin wounds, granulocyte?macrophage colony stimulating factor (GM-CSF) is secreted by keratinocytes shortly after injury and mediates epidermal cell proliferation in an autocrine manner. Many other cells involved in wound healing including macrophages, lymphocytes, fibroblasts, endothelial cells, and dendritic

Amrit Mann; Kai Breuhahn; Peter Schirmacher; Manfred Blessing

2001-01-01

74

Lithium Regulates Keratinocyte Proliferation Via Glycogen Synthase Kinase 3 and NFAT2 (Nuclear Factor of Activated T Cells 2)  

PubMed Central

Certain environmental factors including drugs exacerbate or precipitate psoriasis. Lithium is the commonest cause of drug-induced psoriasis but underlying mechanisms are currently unknown. Lithium inhibits glycogen synthase kinase 3 (GSK-3). As lithium does not exacerbate other T-cell-mediated chronic inflammatory diseases, we investigated whether lithium may be acting directly on epidermal keratinocytes by inhibiting GSK-3. We report that lithium-induced keratinocyte proliferation at therapeutically relevant doses (1–2 mM) and increased the proportion of cells in S phase of the cell cycle. Inhibition of GSK-3 in keratinocytes by retroviral transduction of GSK-binding protein (an endogenous inhibitory protein) or through a highly selective pharmacological inhibitor also resulted in increased keratinocyte proliferation. Nuclear factor of activated T cells (NFAT) is an important substrate for GSK-3 and for cyclosporin, an effective treatment for psoriasis that inhibits NFAT activation in keratinocytes as well as in lymphocytes. Both lithium and genetic/pharmacological inhibition of GSK-3 resulted in increased nuclear localization of NFAT2 (NFATc1) and increased NFAT transcriptional activation. Finally, retroviral transduction of NFAT2 increased keratinocyte proliferation whereas siRNA-mediated knockdown of NFAT2 reduced keratinocyte proliferation and decreased epidermal thickness in an organotypic skin equivalent model. Taken together, these data identify GSK-3 and NFAT2 as key regulators of keratinocyte proliferation and as potential molecular targets relevant to lithium-provoked psoriasis. J. Cell. Physiol. 227: 1529–1537, 2012. © 2011 Wiley Periodicals, Inc. PMID:21678407

Hampton, Philip J; Jans, Ralph; Flockhart, Ross J; Parker, Graeme; Reynolds, Nick J

2012-01-01

75

Biocompatibility and growth of human keratinocytes and fibroblasts on biosynthesized cellulose-chitosan film.  

PubMed

Bacterial cellulose (BC)-chitosan (BCC) films made via bio-co-polymerization by Acetobacter xylinum were developed and characterized for physical and biological properties. With the incorporation of chitosan MW 3 x 10(4) and 8 x 10(4) into bacterial cellulose, the modified films (BCC-MW 30,000 and BCC-MW 80,000, respectively) became denser, with a smaller average pore size of 13.1-15.3 nm in dry form. The BCC films have no toxicity against L929 mouse fibroblast cells. Tissue compatibility was then evaluated by growth and spreading of human skin keratinocytes and fibroblasts. The results revealed that the growth of human skin keratinocytes and fibroblasts on the BCC films was comparable to that on the BC film; however, improvement of cell adhesion and spreading on the BCC films was observed in human skin keratinocytes. The results of the biological response experiments showed no significant difference between BCC-MW 30,000 and BCC-MW 80,000. PMID:20507705

Kingkaew, Jeerun; Jatupaiboon, Nirun; Sanchavanakit, Neeracha; Pavasant, Prasit; Phisalaphong, Muenduen

2010-01-01

76

The EP3 receptor stimulates ceramide and diacylglycerol release and inhibits growth of primary keratinocytes.  

PubMed

Primary human keratinocytes (PHKs) are known to express the EP3 subtype of prostaglandin E2 receptor. To better understand the role of EP3 receptors in regulating epidermal function, we characterized their expression, localization, and signaling effects in human skin. Three different splice variants of the EP3 receptor (EP3A1, EP3C, and EP3D) were found to be expressed. Immunohistochemical analysis of human skin demonstrated that EP3 receptors were most prominently expressed in the basal and lower spinous layers of the epidermis. The EP3 receptor agonist sulprostone was then used to examine EP3 receptor-dependent keratinocyte signaling pathways and functional effects. We observed that sulprostone inhibits keratinocyte growth at doses between 0.02 and 2 nM and induces sn-1,2-diacylglycerol (DAG) and ceramide production. Concurrent expression of the cell-cycle inhibitory protein p21WAF1 also occurred. These data suggest that EP3 receptors produce epidermal growth inhibition through the action of DAG and ceramide second messengers. PMID:16274459

Konger, Raymond L; Brouxhon, Sabine; Partillo, Steven; VanBuskirk, JoAnne; Pentland, Alice P

2005-12-01

77

REVIEW ARTICLE Role of Keratinocytes in the Development of Vitiligo  

E-print Network

Vitiligo is an acquired depigmentary disorder of the skin that results from the loss of functioning epidermal melanocytes. Most studies on vitiligo have concentrated on the abnormality of melanocytes rather than the abnormality of keratinocytes; however, epidermal melanocytes form a functional and structural unit with neighboring keratinocytes. In fact, direct cell-to cell contact stimulates in vitro proliferation of melanocytes, and growth factors produced by adjacent keratinocytes regulate the proliferation and differentiation of melanocytes. The potential role of keratinocyte-derived cytokines has also been presented. We focused on the structural changes in vitiliginous keratinocytes, which may result in loss of melanocytes, to examine the pathomechanism of vitiligo. The results of a comparison between depigmented and normally pigmented epidermis in patients with vitiligo showed that the keratinocytes in the depigmented epidermis were more vulnerable to apoptosis. Impaired Phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase (Akt) activation followed by reduced nuclear factor-?B activation under increased tumor necrosis factor? levels was demonstrated as a mechanism for keratinocyte apoptosis. The role of aquaporin 3 in keratinocyte apoptosis was addressed based on the relationship between the PI3K/AKT pathway and the E-cadherin-catenin complex. Apoptotic keratinocytes induced a lower expression of keratinocyte-derived factors, including stem cell factor, in depigmented epidermis, resulting in passive melanocyte

Ai-young Lee, Ph.D.

78

Growth and differentiation of human keratinocytes without a feeder layer or conditioned medium  

Microsoft Academic Search

Summary  An improved procedure has been developed for clonal growth of normal human epidermal keratinocytes (HK) without feeder cells\\u000a or conditioned medium. The use of medium 199, supplemented with 0.4 ?g\\/ml hydrocortisone (HC) and 20% (v\\/v) whole fetal bovine\\u000a serum (wFBS) and conditioned overnight by 3T3 cells, eliminated the need for a feeder layer of lethally irradiated 3T3 cells\\u000a for HK

Donna M. Peehl; Richard G. Ham

1980-01-01

79

Connexin43 Reduces Melanoma Growth within a Keratinocyte Microenvironment and during Tumorigenesis in Vivo*  

PubMed Central

Connexins (Cx) have been identified as tumor suppressors or enhancers, a distinction that appears to be dependent on the type and stage of disease. However, the role of connexins in melanoma tumorigenesis and their status during cancer onset and progression remain controversial and unclear. Here, we show that the aggressive B16-BL6 mouse melanoma cell line expresses low basal levels of Cx26 and Cx43, rendering them gap junctional intercellular communication-deficient as elucidated by immunofluorescence, Western blotting, and dye transfer studies. Following ectopic expression of green fluorescent protein-tagged Cx26 and Cx43 in these connexin-deficient melanomas, punctate gap junction-like plaques were evident at sites of cell-cell apposition, and the incidence of dye transfer was significantly increased similar to connexin-rich keratinocytes. We found that the expression of Cx43, but not Cx26, significantly reduced cellular proliferation and anchorage-independent growth from control melanomas, whereas migration was unaffected. Additionally, melanomas expressing Cx43 displayed significantly reduced growth within the in situ-like microenvironment of keratinocytes, despite a lack of heterocellular gap junctional intercellular communication between the two cell types. Furthermore, when grown in vivo in the chicken chorioallantoic membrane, primary tumors derived from Cx43-expressing melanomas were significantly smaller than controls, whereas Cx26-expressing melanomas produced tumors similar to controls. Collectively, these results suggest that Cx43, and not Cx26, can act as a tumor suppressor during melanoma tumorigenesis. PMID:24297173

Ableser, Mark J.; Penuela, Silvia; Lee, Jack; Shao, Qing; Laird, Dale W.

2014-01-01

80

Growth factors in bone  

Microsoft Academic Search

Summary.  \\u000a Bone contains several growth factors, including bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-?),\\u000a insulin-like growth factors I and II (IGF-I and IGF-II), platelet derived growth factor (PDGF) and basic and acidic fibroblast\\u000a growth factor (bFGF and aFGF). Spatial and temporal variations in the expression and secretion of the various growth factors\\u000a have been demonstrated in osteoblastic cultures

E. Solheim

1998-01-01

81

Targeted delivery of tumor necrosis factor-related apoptosis-inducing ligand to keratinocytes with a pemphigus mAb.  

PubMed

We determined the feasibility of using an anti-desmoglein (Dsg) mAb, Px44, to deliver a biologically active protein to keratinocytes. Recombinantly produced Px44-green fluorescent protein (GFP) injected into mice and skin organ culture delivered GFP to the cell surface of keratinocytes. We replaced GFP with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to produce Px44-TRAIL. We chose TRAIL as a biological model because it inhibits activated lymphocytes and causes apoptosis of hyperproliferative keratinocytes, features of various skin diseases. Px44-TRAIL formed a trimer, the biologically active form of TRAIL. Standard assays of TRAIL activity showed that Px44-TRAIL caused apoptosis of Jurkat cells and inhibited IFN-? production by activated CD4+ T cells. Enzyme-linked immunoassay with Px44-TRAIL showed delivery of TRAIL to Dsg. Immunofluorescence with Px44-TRAIL incubated on skin sections and cultured keratinocytes or injected into mouse skin, human organ culture, or human xenografts detected TRAIL on keratinocytes. Px44-TRAIL caused apoptosis of the hyperproliferative, but not differentiating, cultured keratinocytes through binding to Dsg3. Foldon, a small trimerization domain, cloned into Px44-TRAIL maintained its stability and biological activity at 37°?C for at least 48 hours. These data suggest that such targeted therapy is feasible and may be useful for hyperproliferative and inflamed skin diseases. PMID:23439393

Kouno, Michiyoshi; Lin, Chenyan; Schechter, Norman M; Siegel, Don; Yang, Xiaoping; Seykora, John T; Stanley, John R

2013-09-01

82

The 55-kD tumor necrosis factor receptor on human keratinocytes is regulated by tumor necrosis factor-alpha and by ultraviolet B radiation.  

PubMed Central

In previous studies we showed that cultured human keratinocytes expressed the 55-kD TNF receptor (TNFR) and that its expression the important for TNF alpha-mediated upregulation of intercellular adhesion molecule-1 (ICAM-1) expression on keratinocytes. Because factors that either reduce or enhance TNFR expression are likely to have a major impact on the biological effects of TNF alpha on keratinocytes, these studies were conducted to determine the factors that regulate its expression on keratinocytes. Using reverse transcriptase polymerase chain reaction, human keratinocytes were shown to lack 75-kD TNFR expression, indicating that TNF responsiveness of human keratinocytes critically depended on regulation of 55-kD TNFR expression. Human keratinocyte 55-kD TNFR surface and mRNA expression was found to be regulated in vitro by recombinant human (rh) TNF alpha. Stimulation of keratinocytes with rhTNF alpha initially decreased, but later increased, 55-kD TNFR surface expression. This biphasic modulation of 55-kD TNFR surface expression was associated with concomitant changes in 55-kD TNFR mRNA expression. Ultraviolet B (UVB) radiation, a well-known inducer of synthesis and secretion of TNF alpha by human keratinocytes, was found to mimic TNF alpha-induced modulation of 55-kD TNFR surface and mRNA expression via a TNF alpha-mediated autocrine regulatory mechanism. Production of soluble 55-kD TNFR by human keratinocytes remained unaffected by TNF alpha stimulation or UVB irradiation. These studies provide clear evidence that membrane expression of the human 55-kD TNFR may be regulated in human keratinocytes by the ligand itself: TNF alpha. Since in previous studies UVB irradiation transiently inhibited TNF alpha-induced human keratinocyte ICAM-1 expression, it is proposed that UVB radiation-induced biphasic modulation of human keratinocyte 55-kD TNFR expression may affect the capacity of these cells to respond to TNF alpha. Images PMID:8392091

Trefzer, U; Brockhaus, M; Lötscher, H; Parlow, F; Budnik, A; Grewe, M; Christoph, H; Kapp, A; Schöpf, E; Luger, T A

1993-01-01

83

Correlation of donor age and telomerase activity with in vitro cell growth and replicative potential for dermal fibroblasts and keratinocytes.  

PubMed

Previous studies suggested telomerase activity as a determinant of cell replicative capacity by delaying cell senescence. This study aimed to evaluate the feasibility of adopting telomerase activity as a selection criterion for in vitro expanded skin cells before autologous transplantation. Fibroblasts and keratinoctyes were derived from the same consenting patients aged 9-69 years, and cultured separately in serum-supplemented and serum-free media, respectively. Telomerase activity of fresh and cultured cells were measured and correlated with cell growth rate, donor age and passage number. The results showed that telomerase activity and cell growth were independent of donor age for both cell types. Telomerase was expressed in freshly digested epidermis and dermis and continued expressing in vitro. Keratinocytes consistently showed 3-12 folds greater telomerase activity than fibroblast both in vivo and in vitro. Conversely, growth rate for fibroblast exceeded that of keratinocyte. Telomerase activity decreased markedly at Passage 6 for keratinocytes and ceased by Passage 3 for fibroblasts. The decrease or cessation of telomerase activity coincided with senescence for keratinocyte but not for fibroblast, implying a telomerase-regulated cell senescence for the former and hence a predictor of replicative capacity for this cell type. Relative telomerase activity for fibroblasts from the younger age group was significantly higher than that from the older age group; 69.7% higher for fresh isolates and 31.1% higher at P0 (p<0.05). No detectable telomerase activity was to be found at later subcultures for both age groups. Similarly for keratinocytes, telomerase activity in the younger age group was significantly higher (p<0.05) compared to that in the older age group; 507.7% at P0, 36.8% at P3 and the difference was no longer significant at P6. In conclusion, the study provided evidence that telomerase sustained the proliferation of keratinocytes but not fibroblasts. Telomerase activity is an important criterion for continued survival and replication of keratinocytes, hence its positive detection before transplantation is desirable. Inferring from our results, the use of keratinocytes from Passage 3 or lesser for construction of skin substitute or cell-based therapy is recommended owing to their sustained telomerase expression. PMID:19632116

Ng, M H; Aminuddin, B S; Hamizah, S; Lynette, C; Mazlyzam, A L; Ruszymah, B H I

2009-11-01

84

UV-A-induced decrease in nuclear factor-kappaB activity in human keratinocytes.  

PubMed Central

Previous reports have demonstrated an increase in nuclear factor-kappaB (NF-kappaB) activity in response to UV radiation. These studies have essentially focused on the DNA-damaging fraction of solar UV radiation (UV-B and UV-C). In contrast, the effects of UV-A radiation (320-400 nm) on NF-kappaB are not well known. In this study, we present evidence that UV-A radiation induces a marked decrease in NF-kappaB DNA-binding activity in NCTC 2544 human keratinocytes. In addition, NCTC 2544 keratinocytes pretreated with UV-A fail to respond to NF-kappaB inducers. Moreover, UV-A radiation induces a decrease in NF-kappaB-driven luciferase reporter gene expression in NCTC 2544 keratinocytes. The expression of the gene encoding IkappaBalpha (IkappaB is the NF-kappaB inhibitor), which is closely associated with NF-kappaB activity, is also reduced (3-fold) upon UV-A treatment. Our results indicate that the UV-A-induced decrease in NF-kappaB DNA-binding activity is associated with a decrease in the levels of the p50 and p65 protein subunits. This is the first evidence that an oxidative stress, such as UV-A radiation, may induce a specific decrease in NF-kappaB activity in mammalian cells, probably through degradation of NF-kappaB protein subunits. These findings suggest that UV-A could modulate the NF-kappaB-dependent gene expression. PMID:10051429

Djavaheri-Mergny, M; Gras, M P; Mergny, J L; Dubertret, L

1999-01-01

85

E-cadherin expression in melanoma cells restores keratinocyte-mediated growth control and down-regulates expression of invasion-related adhesion receptors.  

PubMed

In human epidermis, functional symbiosis requires homeostatic balance between keratinocytes and melanocytes. Compelling evidence from co-culture studies demonstrated a sophisticated, multileveled regulation of normal melanocytic phenotype orchestrated by undifferentiated, basal-type keratinocytes. Keratinocytes control cell growth and dendricity, as well as expression of melanoma-associated cell surface molecules of normal melanocytes. In contrast, melanoma cells are refractory to the keratinocyte-mediated regulation. The loss of regulatory dominance by keratinocytes occurs in concert with down-regulation of E-cadherin expression in melanoma cells. To investigate the potential role of E-cadherin in melanoma-keratinocyte interaction, we transduced E-cadherin-negative melanoma cells with full-length E-cadherin cDNA using an adenoviral vector. Our results show that functional E-cadherin expression in melanoma cells leads to cell adhesion to keratinocytes rendering them susceptible for keratinocyte-mediated control. In a skin reconstruction model, ectopic E-cadherin expression inhibits invasion of melanoma cells into dermis by down-regulating invasion-related adhesion receptors, MelCAM/MUC18 and beta3 integrin subunit, and by induction of apoptosis. Thus, disruption of the E-cadherin-mediated, normal regulatory control from keratinocytes may represent one of the mechanisms accounting for melanocyte transformation. PMID:10793063

Hsu, M Y; Meier, F E; Nesbit, M; Hsu, J Y; Van Belle, P; Elder, D E; Herlyn, M

2000-05-01

86

FGF growth factor analogs  

DOEpatents

The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

Zamora, Paul O. (Gaithersburg, MD); Pena, Louis A. (Poquott, NY); Lin, Xinhua (Plainview, NY); Takahashi, Kazuyuki (Germantown, MD)

2012-07-24

87

Growth factors in bone repair  

Microsoft Academic Search

The role of growth factors (GF) in bone repair is widely recognised, particularly for bone morphogenetic proteins (BMPs),\\u000a fibroblast growth factor (FGF), insulin-like growth factors (IGFs), platelet-derived growth factor (PDGF), transforming growth\\u000a factor-? (TGF-?) and vascular endothelial growth factor (VEGF). GF are usually stored in the extracellular matrix (ECM), but\\u000a after injury are actively released by ECM, cells and platelets.

Valentina Devescovi; Elisa Leonardi; Gabriela Ciapetti; Elisabetta Cenni

2008-01-01

88

New microbial growth factor  

NASA Technical Reports Server (NTRS)

A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a previously unknown microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight and has high specific activity. When added to the diets for a meadow-vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain.

Bok, S. H.; Casida, L. E., Jr.

1977-01-01

89

Hepatocyte Growth Factor Establishes Autocrine and Paracrine Feedback Loops for the Protection of Skin Cells after UV Irradiation  

Microsoft Academic Search

Hepatocyte growth factor (HGF) is a multifunctional cytokine, which, among various other activities, acts as a growth factor for melanocytes and has recently been implicated in the pathogenesis of malignant melanoma. In the skin, the main source for HGF is dermal fibroblasts (FB). Here, we have investigated the regulation of HGF production and secretion by cytokines derived from UV-irradiated keratinocytes

Michael Mildner; Veronika Mlitz; Florian Gruber; Johann Wojta; Erwin Tschachler

2007-01-01

90

Role of Growth Factors, Cytokines, and Their Receptors in the Pathogenesis of Psoriasis  

Microsoft Academic Search

Psoriasis is characterized by epidermal hyperplasia, altered epidermal maturation, and local accumulation of acute and chronic inflammatory cells. Keratinocyte hyperplasia in psoriasis may be explained in part by overproduction of growth factors or cytokines which stimulate epidermal proliferation and by altered metabolism of growth-factor receptors in affected skin. Psoriatic epidermis displays overproduction of TGF-alpha and interleukin-6 (IL-6), factors produced by

James G. Krueger; Jeffrey F. Krane; D. Martin Carter; Alice B. Gottlieb

1990-01-01

91

Production of IL-18 (IFN-gamma-inducing factor) messenger RNA and functional protein by murine keratinocytes.  

PubMed

Recently, the novel cytokine IL-18 (IFN-gamma-inducing factor) has been described as a growth and differentiation factor for Th1 cells. Epidermal keratinocytes (KC) are known to direct T cell education by production of cytokines. Therefore, expression of IL-18 was sought in KC. Epidermal RNA was analyzed following stimulation with contact sensitizers or controls for IL-18 mRNA expression by semiquantitative reverse transcription-PCR. Constitutive expression of IL-18 mRNA was low in untreated epidermal cells (EC), but early up-regulation of IL-18 mRNA signals was detected following application of a contact allergen in vivo. The peak strength of IL-18 signals was observed within 4 to 6 h following stimulation with an allergen. Application of an irritant (benzalconiumchloride) or solvents did not result in increased signal strength. To determine the cellular origin of IL-18 mRNA in EC, depletion experiments were performed. IL-18 signals were not affected by depletion with anti-CD3 (T cells) or anti-MHC class II mAb-coupled beads identifying KC as a major source of IL-18. These results were confirmed by analysis of mRNA derived from the KC cell line PAM 212. Strong IL-18 signals could be detected by reverse transcription-PCR. To delineate whether IL-18 protein was produced by EC/KC, a sandwich ELISA was used to assay for IL-18 production. Supernatants from allergen-stimulated EC and KC showed production of IL-18 protein. To confirm that IL-18 protein was functional, EC or KC supernatants were tested for their ability to induce IFN-gamma production. Significant amounts of IFN-gamma were detected in supernatants of allergen-treated cells. In aggregate, our data indicate that murine KC are a source of both IL-18 mRNA and functional protein. PMID:9200466

Stoll, S; Müller, G; Kurimoto, M; Saloga, J; Tanimoto, T; Yamauchi, H; Okamura, H; Knop, J; Enk, A H

1997-07-01

92

Do nerve growth factor-related mechanisms contribute to loss of cutaneous nociception in leprosy?  

Microsoft Academic Search

While sensory loss in leprosy skin is the consequence of invasion by M. leprae of Schwann cells related to unmyelinated fibres, early loss of cutaneous pain sensation, even in the presence of nerve fibres and inflammation, is a hallmark of leprosy, and requires explanation. In normal skin, nerve growth factor (NGF) is produced by basal keratinocytes, and acts via its

Paul Facer; Dawn Mann; Rajeev Mathur; Shubha Pandya; Uma Ladiwala; Bhim Singhal; Jo-Anne Hongo; Dominick V Sinicropi; Giorgio Terenghi; Praveen Anand

2000-01-01

93

Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis.  

PubMed Central

Ultraviolet (UV) radiation is the main physiological stimulus for human skin pigmentation. Within the epidermal-melanin unit, melanocytes synthesize and transfer melanin to the surrounding keratinocytes. Keratinocytes produce paracrine factors that affect melanocyte proliferation, dendricity, and melanin synthesis. In this report, we show that normal human keratinocytes secrete nitric oxide (NO) in response to UVA and UVB radiation, and we demonstrate that the constitutive isoform of keratinocyte NO synthase is involved in this process. Next, we investigate the melanogenic effect of NO produced by keratinocytes in response to UV radiation using melanocyte and keratinocyte cocultures. Conditioned media from UV-exposed keratinocytes stimulate tyrosinase activity of melanocytes. This effect is reversed by NO scavengers, suggesting an important role for NO in UV-induced melanogenesis. Moreover, melanocytes respond to NO-donors by decreased growth, enhanced dendricity, and melanogenesis. The rise in melanogenesis induced by NO-generating compounds is associated with an increased amount of both tyrosinase and tyrosinase-related protein 1. These observations suggest that NO plays an important role in the paracrine mediation of UV-induced melanogenesis. PMID:9045865

Roméro-Graillet, C; Aberdam, E; Clément, M; Ortonne, J P; Ballotti, R

1997-01-01

94

Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts  

Microsoft Academic Search

In skin, fibroblasts of the connective tissue play a decisive role in epidermal homeostasis and repair by contributing to the regulation of keratinocyte proliferation and differentiation. The AP-1 transcription factor subunit JUN plays a crucial role in this mesenchymal-epithelial interplay by regulating the expression of two critical paracrine- acting cytokines, keratinocyte growth factor (KGF) and granulocyte-macrophage colony-stimulating factor (GM- CSF).

Lore Florin; Nicole Maas-Szabowski; Sabine Werner; Axel Szabowski; Peter Angel

2005-01-01

95

Reversal of silver sulfadiazine-impaired wound healing by epidermal growth factor  

Microsoft Academic Search

Silver sulfadiazine (Ag-SD) is a useful antibacterial agent for wound treatment. However, recent findings indicate that the compound delays the wound-healing process. That delay may be reversed by treatment with growth factors. The purpose of this study, was to evaluate the cyto-protective effect of epidermal growth factor (EGF) against Ag-SD treated keratinocytes and to investigate the reversibility of the impaired

Ae-Ri Cho Lee; Hyunju Leem; Jaegwan Lee; Kyung Chan Park

2005-01-01

96

Effect of Wnt3a on Keratinocytes Utilizing in Vitro and Bioinformatics Analysis  

PubMed Central

Wingless-type (Wnt) signaling proteins participate in various cell developmental processes. A suppressive role of Wnt5a on keratinocyte growth has already been observed. However, the role of other Wnt proteins in proliferation and differentiation of keratinocytes remains unknown. Here, we investigated the effects of the Wnt ligand, Wnt3a, on proliferation and differentiation of keratinocytes. Keratinocytes from normal human skin were cultured and treated with recombinant Wnt3a alone or in combination with the inflammatory cytokine, tumor necrosis factor ? (TNF?). Furthermore, using bioinformatics, we analyzed the biochemical parameters, molecular evolution, and protein–protein interaction network for the Wnt family. Application of recombinant Wnt3a showed an anti-proliferative effect on keratinocytes in a dose-dependent manner. After treatment with TNF?, Wnt3a still demonstrated an anti-proliferative effect on human keratinocytes. Exogenous treatment of Wnt3a was unable to alter mRNA expression of differentiation markers of keratinocytes, whereas an altered expression was observed in TNF?-stimulated keratinocytes. In silico phylogenetic, biochemical, and protein–protein interaction analysis showed several close relationships among the family members of the Wnt family. Moreover, a close phylogenetic and biochemical similarity was observed between Wnt3a and Wnt5a. Finally, we proposed a hypothetical mechanism to illustrate how the Wnt3a protein may inhibit the process of proliferation in keratinocytes, which would be useful for future researchers. PMID:24686518

Nam, Ju-Suk; Chakraborty, Chiranjib; Sharma, Ashish Ranjan; Her, Young; Bae, Kee-Jeong; Sharma, Garima; Doss, George Priya; Lee, Sang-Soo; Hong, Myung-Sun; Song, Dong-Keun

2014-01-01

97

The oncogenic GLI transcription factors facilitate keratinocyte survival and transformation upon exposure to genotoxic agents.  

PubMed

Ultraviolet B (UVB) light is the principal aetiological factor associated with non-melanoma skin cancer, the most prevalent group of malignancies in the Caucasian population. Exposure to environmental chemicals has also been shown to promote skin carcinogenesis and, as for UVB, this is associated with the acquisition of genomic DNA damage. Cells respond to DNA damage by inducing cell cycle arrest to facilitate DNA repair, although apoptosis will occur if the damage is excessive. Oncogenes may drive carcinogenesis by disrupting the balanced control of cell cycle progression, DNA repair and apoptosis, allowing for the propagation of cells with damaged DNA. The transcription factors GLI1 and GLI2 have been implicated in both the initiation and progression of several cancers, including basal cell carcinoma. Here we show that GLI1 and an active mutant of GLI2 (?NGLI2) promote apoptotic resistance in N/TERT human keratinocytes upon exposure to UVB and the DNA-alkylating chemicals such as methyl methanesulphonate (MMS) and N-ethyl-N-nitrosurea. Compared with control and untreated N/TERT-GLI1 and -GLI2 cells, those that survived genotoxic insult formed significantly more colonies in soft agar and were significantly more invasive when grown in three-dimensional organotypic collagen gel cultures. Indeed, surviving N/TERT-GLI1 and -GLI2 cells expressed higher levels of the epithelial-to-mesenchymal transition markers Snail and vimentin, and a subpopulation of MMS-treated cells displayed an elongated fibroblast-like morphology with decreased levels of E-cadherin. Finally, whereas Bcl2 was strongly increased in N/TERT-GLI2 cells, the level of induction was weak in N/TERT-GLI1 cells, indicating that GLI1 may activate anti-apoptotic mechanisms(s) independently of Bcl2. In summary, our results show that GLI1 and GLI2 facilitate the propagation of cells with damaged DNA, and thus their expression may be naturally higher in cells that form the earliest precursor tumour lesions. PMID:23792444

Harrison, W; Cochrane, B; Neill, G; Philpott, M

2014-05-01

98

cis-Urocanic acid stimulates primary human keratinocytes independently of serotonin or platelet-activating factor receptors.  

PubMed

Urocanic acid (UCA) is a major epidermal chromophore that undergoes trans to cis isomerization after ultraviolet radiation (UVR). cis-UCA suppresses cell-mediated immunity. Recent studies suggest that cis-UCA binds to serotonin (5-hydroxytryptamine) 2A (5-HT(2A)) receptor and that antagonists of 5-HT(2A) and the platelet-activating factor (PAF) receptor can block cis-UCA-induced immune suppression in mice. Here, we examined the involvement of 5-HT(2A) and PAF receptors in the ability of cis-UCA to stimulate immunomodulatory mediator production in primary human keratinocytes. Using real-time reverse transcription-PCR (RT-PCR), PAF but not 5-HT(2A) receptor mRNA was constitutively expressed in primary human keratinocytes. Treatment with cis-UCA increased prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), and IL-6 secretion, whereas 5-HT only stimulated IL-6 production. Pretreatment with a 5-HT receptor antagonist partially inhibited IL-6 increase by 5-HT, but did not inhibit mediator production by cis-UCA. Similarly, a PAF receptor antagonist did not inhibit cis-UCA-induced increase in PGE(2). Intracellular calcium mobilization studies using a human epithelial cell line stably transfected with PAF receptor also showed little evidence that cis-UCA stimulated PAF receptor and it did not bind to this receptor. Thus, cis-UCA stimulates mediator production by a pathway that is independent of these receptors in human keratinocytes, and these cells may not be the major target for cis-UCA-induced immune suppression. PMID:19474802

Kaneko, Kazuyo; Travers, Jeffrey B; Matsui, Mary S; Young, Antony R; Norval, Mary; Walker, Susan L

2009-11-01

99

Growth and differentiation of normal human melanocytes in a TPA-free, cholera toxin-free, low-serum medium and influence of keratinocytes  

Microsoft Academic Search

Melanocyte cultures were obtained from a modification of the keratinocyte culture system MCDB153. Either promelanocytes or mature melanocytes were selected from epidermal cell primary cultures. Pure subcultures of actively dividing melanocytes of both types were grown in a low-serum medium totally deprived of TPA and cholera toxin called melanocyte growth medium (MGM). Early passaged cells from MGM primary cocultures were

P. Donatien; J. E. Surlève-Bazeille; A. J. Thody; A. TaÏeb

1993-01-01

100

An ideal preparation for dermal regeneration: skin renewal growth factors, the growth factor composites from porcine platelets.  

PubMed

The use of growth factor composites from platelets has been introduced to many areas of clinical applications and studies. With the richest source of growth factors (GFs), beneficial effects have been shown on tissue regeneration and wound healing. However, animal and clinical studies have revealed inconsistent outcomes with the use of platelet-derived growth factors (PDGFs), which were likely due to variations in the presence and concentrations of GFs between various sources. Autologous PDGFs are considered to be safer, but they are limited by the feasibility of large-scale production to be used extensively in the acute phase, greater surface area, or general cosmetic applications. This study employed a simple process to obtain growth factor composites from activated platelets of porcine origin, namely skin renewal growth factors (SRGF). The functions of SRGF were subsequently evaluated on cultured human fibroblasts, keratinocytes, and melanocytes. Our data revealed that SRGF significantly promoted the proliferation of fibroblasts, accompanied by increased expression of collagens (types I, III, IV, and VIII) and proteoglycans. Diminished proliferation and arrested differentiation of keratinocytes were evidenced by the attenuated expression of laminin V and keratin 10. In addition, SRGF also suppressed the growth of melanocytes and reduced the expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and paired box 3 (PAX3), which mediates melanogensis. Our results suggest that SRGF possesses beneficial properties and is a promising and cost-effective composition for the development of a safe cosmetic agent or topical products for skin regeneration. The development of SRGF may also provide an alternative strategy for tissue engineering. PMID:22950429

Wang, Kuo-Hsien; Wu, Yo-Ping Greg; Lo, Wen-Cheng

2012-12-01

101

Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NF{kappa}B and AhR and EGFR-ERK pathway  

SciTech Connect

Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor (TNFalpha) and interferon (IFNgamma) (T/I), UVA + UVB irradiation, and bacterial lipopolysaccharide (LPS) were used. We demonstrated differential modulation of inflammatory responses in keratinocytes at signal transduction, gene transcription, and protein synthesis levels as a function of PP chemical structure, the pro-inflammatory trigger used, and PP interaction with intracellular detoxifying systems. The PPs remarkably inhibited constitutive, LPS- and T/I-induced but not TGFalpha-induced ERK phosphorylation. They also suppressed NFkappaB activation by LPS and T/I. Verbascoside and quercetin invariably impaired EGFR phosphorylation and UV-associated aryl hydrocarbon receptor (AhR)-mediated signaling, while rutin, polydatin and resveratrol did not affect EGFR phosphorylation and further activated AhR machinery in UV-exposed keratinocytes. In general, PPs down-regulated gene expression of pro-inflammatory cytokines/enzymes, except significant up-regulation of IL-8 observed under stimulation with TGFalpha. Both spontaneous and T/I-induced release of IL-8 and IP-10 was suppressed, although 50 {mu}M resveratrol and polydatin up-regulated IL-8. At this concentration, resveratrol activated both gene expression and de novo synthesis of IL-8 and AhR-mediated mechanisms were involved. We conclude that PPs differentially modulate the inflammatory response of human keratinocytes through distinct signal transduction pathways, including AhR and EGFR. - Graphical abstract: Display Omitted Highlights: > Effects of plant polyphenols on inflammatory responses in human keratinocytes. > Inflammatory stimuli used: TGFalpha, TNFalpha+IFNgamma, UVA+UVB, and LPS. > Inflammatory pathways connected with NFB, ERK1/2, EGFR, and AhR were investigated. > Plant polyphenols, flavonoids, stilbenoids, and phenylpropanoids, were studied. > Modulation of inflammation depends on phenolic core structure and glycosylation.

Potapovich, Alla I. [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy); Biology Department, Belarus State University, Skorina Prosp. 10, Minsk 220050 (Belarus); Lulli, Daniela; Fidanza, Paolo [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy); Kostyuk, Vladimir A. [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy); Biology Department, Belarus State University, Skorina Prosp. 10, Minsk 220050 (Belarus); De Luca, Chiara; Pastore, Saveria [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy); Korkina, Liudmila G., E-mail: l.korkina@idi.it [Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy)

2011-09-01

102

Escape from Transforming Growth Factor beta Control and Oncogene Cooperation in Skin Tumor Development  

Microsoft Academic Search

Control of tumor development by surrounding normal cells has been suggested by a number of in vitro studies. In vivo, tumorigenicity of ras-transformed primary keratinocytes can be suppressed by addition of normal dermal fibroblasts. Here, we report that dermal fibroblasts produce a diffusible inhibitory factor belonging to the transforming growth factor beta (TGF-beta) family and possibly corresponding to TGF-beta3. This

Caterina Missero; Santiago Ramon Y. Cajal; G. Paolo Dotto

1991-01-01

103

Human keratinocytes are a source for tumor necrosis factor alpha: Evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light  

Microsoft Academic Search

Tumor necrosis factor alpha (TNF-alpha), in addition to being cytotoxic for certain tumor cells, has turned out as a multifunctional cytokine that is involved in the regulation of immunity and inflammation. Since human keratinocytes have been demonstrated to be a potent source of various cytokines, it was investigated whether epidermal cells synthesize and release TNF-alpha. Supernatants derived from normal human

A. S. Koeck; T. Schwarz; R. Kirnbauer; A. Urbanski; P. Perry; J. C. Ansel; T. A. Luger

1990-01-01

104

Fibroblast growth factor 23.  

PubMed

There is growing interest in the role of fibroblast growth factor 23 (FGF23) in various diseases of disordered mineral metabolism. In chronic kidney disease (CKD), where biochemical evidence of mineral disturbances is especially common, FGF23 measurement has been advocated as an early and sensitive marker for CKD-related bone disease. In this setting, FGF23 analysis may also improve the discrimination of risk of adverse renal and cardiovascular outcomes and aid targeting of those patients that are likely to benefit from interventions. Nonetheless, while the physiological relevance of FGF23 in the control of mineral metabolism is now firmly established, relatively little attention has been paid to important preanalytical and analytical aspects of FGF23 measurement that may impact on its clinical utility. Here we review these issues and discuss the suitability of FGF23 testing strategies for routine clinical practice. The current 'state-of-the-art' enzyme-linked immunosorbent assay methods for FGF23 measurement show poor agreement due to differences in FGF23 fragment detection, antibody specificity and calibration. Such analytical variability does not permit direct comparison of FGF23 measurements made with different assays and is likely to at least in part account for some of the inconsistencies noted between observational studies. From a clinical perspective, the lack of concordance has implications for the development of standardized reference intervals and clinical decision limits. Finally, the inherent assay-dependent biological variability of plasma FGF23 concentration can further complicate the interpretation of results and the design of FGF23-based testing protocols. Currently, it would be premature to consider incorporating FGF23 measurements into standard testing repertoires. PMID:24269946

Smith, Edward R; McMahon, Lawrence P; Holt, Stephen G

2014-03-01

105

An unbiased in vivo screen reveals multiple transcription factors that control HPV E6-regulated hTERT in keratinocytes  

PubMed Central

Activation of telomerase by human papillomavirus 16 (HPV16) E6 is a critical step for cell immortalization and transformation in human foreskin keratinocytes (HFKs). Multiple transcription factors have been identified as being involved in E6-induced hTERT expression. Here, we adapted an unbiased in vivo screen using a LacO-LacI system in human cells to discover hTERT promoter-interacting regulators. This approach allowed us to identify a novel hTERT repressor, Maz, which bound the hTERT promoter. E6 expression reduced Maz binding and correspondingly increased Sp1 binding at the hTERT promoter. Knockdown of Maz further increased histone acetylation, as well as hTERT expression in the presence of E6. Overall, these data indicate the utility of a novel screen for promoter-interacting and transcription-regulating proteins. These data also highlight multiple factors that normally regulate hTERT repression in HFKs, and therefore are targeted by E6 for hTERT expression. PMID:24074563

Xu, Mei; Katzenellenbogen, Rachel A.; Grandori, Carla; Galloway, Denise A.

2013-01-01

106

Modulation of cytokine expression in human keratinocytes and fibroblasts by extracts of scabies mites.  

PubMed

Sarcoptes scabiei lives in the stratum corneum of its mammalian host. Keratinocytes and fibroblasts are among the first cells to encounter the burrowing mite and its products. The aim of this study was to determine if molecules in an extract of S. scabiei modulate the expression of cytokines by keratinocytes and fibroblasts. Human keratinocytes and fibroblasts were exposed to an extract of S. scabiei var. canis in the absence or presence of Escherichia coli lipopolysaccharide. Cytokine expression was measured by an enzyme-linked immunosorbent assay. Components in the S. scabiei extract induced marked increases in secretion of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) and slight increases in production of granulocyte-colony-stimulating factor (G-CSF) by keratinocytes. The scabies extract down-regulated keratinocyte secretion of IL-1 receptor antagonist, but did not influence the production of IL-1alpha or IL-1beta. In comparison, components in the scabies extract induced marked increases in the elaboration of IL-6, IL-8, G-CSF, and VEGF by fibroblasts. Neither cell type produced eotaxin, stem cell factor, or tumor necrosis factor-alpha under any of the conditions tested. This study demonstrates that components in an extract of the mite S. scabiei are able to influence cytokine expression by human keratinocytes and fibroblasts. PMID:14740884

Arlian, Larry G; Morgan, Marjorie S; Neal, Jacqueline S

2003-12-01

107

Interstitial fibrosis and growth factors.  

PubMed Central

Interstitial pulmonary fibrosis (IPF) is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases. The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for this lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy. Our laboratory has focused on the molecular mechanisms through which three selected peptide growth factors could play a role in the development of IPF. Hundreds of growth factors and cytokines could be involved in the complex disease process. We are studying platelet-derived growth factor because it is the most potent mesenchymal cell mitogen yet described, transforming growth factor beta because it is a powerful inducer of extracellular matrix (scar tissue) components by mesenchymal cells, and tumor necrosis factor alpha because it is a pleiotropic cytokine that we and others have shown is essential for the development of IPF in animal models. This review describes some of the evidence from studies in humans, in animal models, and in vitro, that supports the growth factor hypothesis. The use of modern molecular and transgenic technologies could elucidate those targets that will allow effective therapeutic approaches. Images Figure 1 Figure 2 PMID:10931794

Lasky, J A; Brody, A R

2000-01-01

108

Attachment of peptide growth factors to implantable collagen.  

PubMed

Ingrowth of fibrovascular tissue from the woundbed into collagen-based dermal substitutes and survival of cultured epithelium after transplantation may be enhanced by attachment of heparin binding growth factor 2 (HBGF2) and epidermal growth factor (EGF) to collagen. Biotinylation of collagen and the growth factors allows immobilization of HBGF2 and EGF by high affinity binding of tetravalent avidin. Biotinylated HBGF2 and EGF (B-GF) were exposed to complexes of biotinylated collagen (B-COL)-avidin (A) and detected with peroxidase-labeled avidin (AP) followed by chromagen formation on nitrocellulose paper. Binding of biotinylated HBGF2 and EGF was specific (*, P less than 0.05), proportional to the concentration of biotinylated collagen, and resistant to ionic (NaCl) displacement. Data are expressed as mean percentages of maximum binding +/- SEMs: (table; see text) Growth response of cultured human epidermal keratinocytes to HBGF2 (population doubling time, PDT = 0.70 population doublings (PD)/day) confirmed the retention of mitogenic activity after biotinylation (PDT = 0.80 PD/day). Specific binding of biotinylated HBGF2, EGF, or other biologically active molecules (antibiotics, NSAIDs) to implantable collagen may provide a mechanism for positive therapeutic modulation of wound healing, including repair of full-thickness skin wounds with cultured cell-collagen composite grafts. PMID:2469861

Stompro, B E; Hansbrough, J F; Boyce, S T

1989-05-01

109

Role of Melanoma growth stimulatory activity (MGSA\\/gro) on keratinocyte function in wound healing  

Microsoft Academic Search

Melanoma growth stimulatory activity\\/gro? (MGSA), a member of the ?-chemokine family, is produced by a variety of dermal and\\u000a epidermal cells and can act in a paracrine and autocrine fashion. However, little is known about the importance of MGSA in\\u000a wound healing. In this study, we quantified the levels of MGSA protein in burn blister and donor site wound fluids.

Hans-Oliver Rennekampff; John F. Hansbrough; Virgil Woods Jr.; Christine Doré; Verena Kiessig; Jens-Michael Schröder

1997-01-01

110

Effects of cerium oxide nanoparticles on the growth of keratinocytes, fibroblasts and vascular endothelial cells in cutaneous wound healing.  

PubMed

Rapid and effective wound healing requires a coordinated cellular response involving fibroblasts, keratinocytes and vascular endothelial cells (VECs). Impaired wound healing can result in multiple adverse health outcomes and, although antibiotics can forestall infection, treatments that accelerate wound healing are lacking. We now report that topical application of water soluble cerium oxide nanoparticles (Nanoceria) accelerates the healing of full-thickness dermal wounds in mice by a mechanism that involves enhancement of the proliferation and migration of fibroblasts, keratinocytes and VECs. The Nanoceria penetrated into the wound tissue and reduced oxidative damage to cellular membranes and proteins, suggesting a therapeutic potential for topical treatment of wounds with antioxidant nanoparticles. PMID:23266256

Chigurupati, Srinivasulu; Mughal, Mohamed R; Okun, Eitan; Das, Soumen; Kumar, Amit; McCaffery, Michael; Seal, Sudipta; Mattson, Mark P

2013-03-01

111

Thapsigargin induces expression of activating transcription factor 3 in human keratinocytes involving Ca2+ ions and c-Jun N-terminal protein kinase.  

PubMed

Thapsigargin is a specific inhibitor of the sarco/endoplasmic reticulum Ca(2+) ATPase of the endoplasmic reticulum. Here, we show that stimulation of human HaCaT keratinocytes with nanomolar concentrations of thapsigargin triggers expression of activating transcription factor (ATF) 3, a basic-region leucin zipper transcription factor. ATF3 expression was also up-regulated in thapsigargin-stimulated glioma cells, hepatoma cells, retinal pigment epithelial cells, and airway epithelial cells. Thapsigargin-induced up-regulation of ATF3 expression in keratinocytes was attenuated by BAPTA-acetoxymethyl ester or by expression of the Ca(2+)-binding protein parvalbumin in the cytosol of HaCaT cells but not by a panel of pharmacological agents that chelate extracellular Ca(2+) (EGTA) or inhibit either ryanodine receptors (dantrolene) or voltage-gated Ca(2+) channels (nifedipine). Hence, elevated levels of intracellular Ca(2+), released from intracellular stores, are essential for the effect of thapsigargin on the biosynthesis of ATF3. The thapsigargin-induced signaling pathway was blocked by expression of either mitogen-activated protein kinase phosphatase-1 or -5. Experiments involving pharmacological and genetic tools revealed the importance of c-Jun N-terminal protein kinase (JNK) within the signaling cascade, whereas inhibition of extracellular signal-regulated protein kinase or p38 protein kinase did not attenuate thapsigargin-induced expression of ATF3. Functional studies showed that treatment of HaCaT keratinocytes with thapsigargin led to a 2-fold induction of caspase-3/7 activity. The up-regulation of caspase-3/7 activity in thapsigargin-stimulated HaCaT cells was attenuated by inhibition of JNK. Together, these data show that stimulation of HaCaT cells with thapsigargin induces a specific signaling pathway in keratinocytes involving activation of JNK, biosynthesis of ATF3, and up-regulation of caspase-3/7 activity. PMID:20713550

Spohn, Daniel; Rössler, Oliver G; Philipp, Stephan E; Raubuch, Michael; Kitajima, Shigetaka; Griesemer, Désirée; Hoth, Markus; Thiel, Gerald

2010-11-01

112

Growth factors in subglottic stenosis.  

PubMed

We sought to define the role of fibrogenic peptides in subglottic stenosis (SGS). Biopsy specimens were obtained from patients with stenosis following endotracheal intubation (group 1, n = 5, mean age 5), patients without a history of any precedent trauma, ie. idiopathic stenosis (group 2, n = 3, mean age 40), and those without stenosis (group 3, n = 3, mean age 70). Formalin-fixed biopsy specimens were analyzed following immunohistochemical staining to determine if epidermal growth factor (EGF), platelet-derived growth factor-AA and -BB (PDGF-AA/BB), transforming growth factor-beta 1 and -beta 2 (TGF-beta 1, beta 2), or basic fibroblast growth factor (bFGF) was deposited in these tissues. Blinded analysis revealed TGF-beta 2 and PDGF-AA to be present in seven of eight biopsy specimens from SGS and absent in controls. Staining for PDGF-BB was observed in the mucosa and submucosa and occasionally within vessel walls. Staining of individual growth factors appeared to correlate closely with the presence of granulation tissue. Essentially no bFGF or TGF-beta 1 was observed. Differences were found between patients in groups 1 and 2; tissue from group 1 revealed deposition of EGF and PDGF-BB in submucosa, epithelium, and vasculature. In summary, our experimental findings implicate PDGF and TGF-beta 2, perhaps acting in concert, in mediating the pathologic fibrotic process observed in subglottic stenosis. Epidermal growth factor, in conjunction with TGF-beta and PDGF, may also have a role, but further investigation is needed to more precisely define it. PMID:8973279

Scioscia, K A; Miller, F; April, M M; Gruber, B L

1996-12-01

113

Epidermal growth factor induced apoptosis  

Microsoft Academic Search

Apoptosis, or programmed cell death, plays an important role in the pathogenesis of a number of human diseases, including cancers, autoimmune diseases, and neurodegenerative disorders. Recent evidence suggests that EGF induced signal transduction pathways which govern cell proliferation and cell cycle progression also mediate antiproliferative effects leading to increased apoptosis in cells that express high levels of epidermal growth factor

K. B. Reddy

1996-01-01

114

Keratinocytes express the CD146 (Muc18/S-endo) antigen in tissue culture and during inflammatory skin diseases.  

PubMed

The CD146 (or MUC18/MEL-CAM) antigen is a cell adhesion molecule of the immunoglobulin superfamily. Besides in melanoma, expression of CD146 antigen has been demonstrated in breast epithelia and hair follicles. We studied its expression by human keratinocytes in culture as well as in neoplastic and inflammatory skin diseases. Staining of primary cultured keratinocytes revealed expression of CD146 on the cell membrane, preferentially on cell-cell contact sites. Western blot analysis of keratinocytes detected a band of approximately 113 kDa, corresponding to the CD146 protein. In contrast to primary keratinocytes, neither CD146 protein nor mRNA expression was found in the keratinocyte-derived cell lines A431 and HaCaT. Treatment of keratinocytes with the proinflammatory cytokines interleukin-1 and interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, resulted in no change of CD146 expression and incubation with phorbol 12-myristate 13-acetate led to a reduction of CD146 on keratinocytes. By contrast, when culturing keratinocytes in medium devoid of growth supplements, a distinct upregulation was observed as compared with culture in fully supplemented medium. In normal human epidermis expression of the CD146 antigen was not detectable. It was strongly upregulated, however, on suprabasal keratinocytes in psoriasis, in lichen planus, in the epidermis overlying skin neoplasms, and in viral warts. In squamous cell carcinomas and basal cell carcinomas only a minority of tumor cells expressed CD146. Our findings suggest that the CD146 antigen represents an activation marker of keratinocytes and may be involved in cutaneous inflammatory tissue reaction. PMID:10951239

Weninger, W; Rendl, M; Mildner, M; Mayer, C; Ban, J; Geusau, A; Bayer, G; Tanew, A; Majdic, O; Tschachler, E

2000-08-01

115

T-Plastin Expression Downstream to the Calcineurin/NFAT Pathway Is Involved in Keratinocyte Migration  

PubMed Central

Cutaneous wound healing requires keratinocyte proliferation, migration and differentiation to restore the barrier function of the skin. The calcineurin/nuclear factor of activated-T-cell (NFAT) signaling pathway has been recently shown to be involved in keratinocyte growth, differentiation and migration. It is induced by an increased intracellular calcium rate and its inhibition results in decreased capacities of keratinocytes to migrate. Nevertheless, the link between calcineurin activation and keratinocyte migration remains unknown. Recently, Orai1, a pore subunit of a store-operated calcium channel that favors calcium influx, was shown to play a critical role to control proliferation and migration of basal keratinocytes. Of interest, the actin-bundling T-plastin is crucial in cell motility through cross-linking to actin filament and its synthesis was shown to be induced by calcium influx and regulated by the calcineurin/NFAT pathway in tumor Sezary cells. We investigated herein the role of the calcineurin/NFAT pathway-dependent T-plastin in keratinocyte migration, by quantifying T-plastin expression in keratinocytes and by analyzing their migration under calcineurin inhibition or knockdown of NFAT2 or T-plastin. We did confirm the role of the calcineurin/NFAT pathway in keratinocyte migration as shown by their decreased capacities to migrate after FK506 treatment or siNFAT2 transfection in both scratching and Boyden assays. The expression of NFAT2 and T-plastin in keratinocytes was decreased under FK506 treatment, suggesting that T-plastin plays a role in keratinocyte migration downstream to the calcineurin/NFAT pathway. Accordingly, siRNA knockdown of T-plastin expression also decreased their migration capacities. Actin lamellipodia formation as well as FAK and ?6-integrin expression were also significantly decreased after treatment with FK506 or siRNA, reinforcing that NFAT2-dependent T-plastin expression plays a role in keratinocyte migration. These results indicate that T-plastin might be considered as a major actor in the mechanisms underlying calcineurin/NFAT-dependent keratinocyte migration and may explain wound-healing defects observed in patients under calcineurin inhibitor long-term treatment. PMID:25226517

Brun, Cécilia; Demeaux, Agathe; Guaddachi, Frédéric; Jean-Louis, Francette; Oddos, Thierry; Bagot, Martine; Bensussan, Armand; Jauliac, Sébastien; Michel, Laurence

2014-01-01

116

Cyclic stretch induces upregulation of endothelin-1 with keratinocytes in vitro: Possible role in mechanical stress-induced hyperpigmentation  

SciTech Connect

Highlights: {yields} Influence of cyclic stretch on melanogenetic paracrine cytokines was investigated. {yields} Keratinocyte-derived endothelin-1 was upregulated with cyclic stretch. {yields} Degree of upregulation increases dose-dependently. {yields} This upregulation possibly plays a role in the pathogenesis of pigmented disorders. -- Abstract: The aim of this study was to investigate the possible pathological relation between mechanical stress and hyperpigmentation. We did this by investigating the influence of cyclic stretch on the expression of keratinocyte- and fibroblast-derived melanogenetic paracrine cytokines in vitro. Using primary human keratinocytes and fibroblasts, alterations of mRNA expression of melanogenetic paracrine cytokines due to cyclic stretch were investigated using a real-time polymerase chain reaction (PCR). The cytokines included basic fibroblast growth factor (bFGF), stem cell factor (SCF), granulocyte/macrophage colony-stimulating factor, interleukin-1{alpha}, and endothelin-1 (ET-1) for keratinocytes and bFGF, SCF, and hepatocyte growth factor for fibroblasts. The dose dependence of keratinocyte-derived ET-1 upregulation was further investigated using real-time PCR and an enzyme-linked immunosorbent assay. We also investigated the effects of cyclic stretch on the proliferation and differentiation of keratinocytes. Among the melanogenetic paracrine cytokines investigated, keratinocyte-derived ET-1 was consistently upregulated in all four cell lines. The degree of upregulation increased with the degree of the length and frequency of the stretch; in contrast, cell number and differentiation markers showed no obvious alterations with cyclic stretch. Keratinocyte-derived ET-1 upregulation possibly plays a significant role in the pathogenesis of pigmented disorders, such as friction melanosis, caused by mechanical stress.

Kurita, Masakazu, E-mail: masakazukurita@gmail.com [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)] [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan); Okazaki, Mutsumi [Department of Plastic and Reconstructive Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan)] [Department of Plastic and Reconstructive Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 (Japan); Fujino, Takashi [Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)] [Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan); Takushima, Akihiko; Harii, Kiyonori [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)] [Department of Plastic Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611 (Japan)

2011-05-27

117

Growth Factors in Clinical Practice  

Microsoft Academic Search

Growth factors enhance protein synthesis\\u000a and thus reduce the catabolic response to injury. As a result of\\u000a bioengineering and new manufacturing techniques several anabolic agents\\u000a have become available for clinical use and have been evaluated in\\u000a surgical patients with catabolic illness. Data support the anabolic\\u000a effects of growth home in such patients, but its expense and possible\\u000a deleterious effects during

2000-01-01

118

The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes.  

PubMed Central

We have recently shown that (a) human melanocytes express the p75 nerve growth factor (NGF) receptor in vitro; (b) that melanocyte dendricity and migration, among other behaviors, are regulated at least in part by NGF; and (c) that cultured human epidermal keratinocytes produce NGF. We now report that melanocyte stimulation with phorbol 12-tetra decanoate 13-acetate (TPA), previously reported to induce p75 NGF receptor, also induces trk in melanocytes, and TPA effect is further potentiated by the presence of keratinocytes in culture. Moreover, trk in melanocytes becomes phosphorylated within minutes after NGF stimulation. As well, cultures of dermal fibroblasts express neurotrophin-3 (NT-3) mRNA; NT-3 mRNA levels in cultured fibroblasts are modulated by mitogenic stimulation, UV irradiation, and exposure to melanocyte-conditioned medium. Moreover, melanocytes constitutively express low levels of trk-C, and its expression is downregulated after TPA stimulation. NT-3 supplementation to cultured melanocytes maintained in Medium 199 alone prevents cell death. These combined data suggest that melanocyte behavior in human skin may be influenced by neurotrophic factors, possibly of keratinocyte and fibroblast origin, which act through high affinity receptors. Images PMID:7929831

Yaar, M; Eller, M S; DiBenedetto, P; Reenstra, W R; Zhai, S; McQuaid, T; Archambault, M; Gilchrest, B A

1994-01-01

119

Growth factors in orthopedic surgery.  

PubMed

Growth factors have represented an essential issue of interest for the researchers and clinicians in orthopedics and trauma over the last 40 years. In the last 10 to 15 years, the advances registered in this field have permitted the identification of the most active cellular and humoral factors as well as the improvement of their use in the orthopedic and trauma surgery. Their domain of application has been continuously enlarged and the results have been visible from the beginning. The authors present their appreciation on the actual state of this subject as well as their experience with results and related conclusions. PMID:20302195

Zaharia, Comeliu; Niculescu, Marius; Despa, Nicoleta; Simionescu, Maya; Jinga, Victor; Fleseriu, Irina

2010-01-01

120

Effect of TGF-?1 on Re-Epithelialization of Human Keratinocytes In Vitro: An Organotypic Model  

Microsoft Academic Search

Transforming growth factor beta-1 (TGF-?1) has been shown to inhibit keratinocyte proliferation in vitro yet to stimulate wound healing in vivo. To explore this apparent paradox, the effect of TGF-?1 on proliferation and migration was investigated in organotypic cultures after incisional wounding. Organotypic cultures provide a more in vivo – like epidermal tissue and may therefore respond in a different

Jonathan A. Garlick; Lorne B. Taichman

1994-01-01

121

Circulating Vascular Endothelial Growth Factor  

Microsoft Academic Search

Despite significant advances in early detection and treatment, breast cancer still remains the major cause of cancer-related\\u000a death in women. Many studies suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is the\\u000a complex process leading to the formation of new blood vessels from pre-existing vascular network. The VEGF is the most active\\u000a growth factor involved in angiogenesis; more

Roberta Sarmiento; Roberta Franceschini; Sabrina Meo; Massimo Gion; Raffaele Longo; Giampietro Gasparini

122

Vasoactive intestinal polypeptide stimulates cell proliferation and adenylate cyclase activity of cultured human keratinocytes.  

PubMed Central

An increasing body of evidence has suggested trophic effects of peripheral nerves. In this study, the growth stimulatory properties of the sensory neuropeptides vasoactive intestinal polypeptide (VIP), substance P (SP), calcitonin generelated peptide (CGRP), and somatostatin (SOM) on cultured human keratinocytes were investigated. It was shown that VIP, in the presence of lethally treated 3T3 fibroblast feeder cells and epidermal growth factor (EGF), stimulated proliferation of keratinocytes in a dose-dependent manner, whereas SP, CGRP, and SOM were ineffective. VIP stimulated adenylate cyclase activity in membranes obtained from cultured keratinocytes in a dose-dependent manner, indicating an involvement of cAMP as second messenger in this reaction. Furthermore, 125I-labeled VIP was shown to bind to cultured keratinocytes and this binding could be displaced by addition of unlabeled VIP, suggesting the presence of specific receptors. It is therefore possible that VIP, released from sensory nerve endings in the skin, may act as a local mitogenic factor for human keratinocytes by stimulating adenylate cyclase activity via specific VIP receptors. Images PMID:2474824

Haegerstrand, A; Jonzon, B; Dalsgaard, C J; Nilsson, J

1989-01-01

123

Monitoring the cycling activity of cultured human keratinocytes using a CFSE-based dye tracking approach.  

PubMed

The development of methods and tools suitable for functional analysis of keratinocytes placed in an in vitro context is of great importance for characterizing properties associated with their normal state, for detecting abnormalities related to pathological states, or for studying the effects of extrinsic factors. In the present chapter, we describe the use of the intracellular fluorescent dye carboxyfluorescein succinimidyl ester (CFSE) to monitor cell division in mass cultures of normal human keratinocytes. We detail the preparation of CFSE-labeled keratinocyte samples and the identification by flow cytometry of cell subpopulations exhibiting different cycling rates in a mitogenic culture context. In addition, we show that the CFSE-based division-tracking approach enables the monitoring of keratinocyte responsiveness to growth modulators, which is here exemplified by the cell-cycling inhibition mediated by the growth factor TGF-?1. Finally, we show that keratinocyte subpopulations, separated according to their mitotic history using CFSE fluorescence tracking, can be sorted by flow cytometry and used for further functional characterization, including determination of clone-forming efficiency. PMID:23483389

Chadli, Loubna; Cadio, Emmanuelle; Vaigot, Pierre; Martin, Michèle T; Fortunel, Nicolas O

2013-01-01

124

Low electromagnetic field (50 Hz) induces differentiation on primary human oral keratinocytes (HOK).  

PubMed

This work concerns the effect of low frequency electromagnetic fields (ELF) on biochemical properties of human oral keratinocytes (HOK). Cells exposed to a 2 mT, 50 Hz, magnetic field, showed by scanning electron microscopy (SEM) modification in shape and morphology; these modifications were also associated with different actin distribution, revealed by phalloidin fluorescence analysis. Moreover, exposed cells had a smaller clonogenic capacity, and decreased cellular growth. Indirect immunofluorescence with fluorescent antibodies against involucrin and beta-catenin, both differentiation and adhesion markers, revealed an increase in involucrin and beta-catenin expression. The advance in differentiation was confirmed by a decrease of expression of epidermal growth factor (EGF) receptor in exposed cells, supporting the idea that exposure to electromagnetic field carries keratinocytes to higher differentiation level. These observations support the hypothesis that 50 Hz electromagnetic fields may modify cell morphology and interfere in differentiation and cellular adhesion of normal keratinocytes. PMID:14735562

Manni, Vanessa; Lisi, Antonella; Rieti, Sabrina; Serafino, Annalucia; Ledda, Mario; Giuliani, Livio; Sacco, Donatella; D'Emilia, Enrico; Grimaldi, Settimio

2004-02-01

125

Portulaca oleracea L. aids calcipotriol in reversing keratinocyte differentiation and skin barrier dysfunction in psoriasis through inhibition of the nuclear factor ?B signaling pathway  

PubMed Central

Psoriasis affects 2–4% of the population worldwide and its treatment is currently far from satisfactory. Calcipotriol and Portulaca oleracea have been reported to exhibit the capacity to inhibit inflammation in psoriatic patients and improve their clinical condition. However, the efficacy of a combination regimen of these two components remains unknown. The aim of the present study was to explore the therapeutic efficacy of P. oleracea extract combined with calcipotriol on plaque psoriasis and its potential mechanism. Eleven patients with plaque psoriasis were treated with humectant containing the active ingredients of P. oleracea extract, with or without 0.005% calcipotriol ointment in a right-left bilateral lesion self-control study. Differences were evaluated by investigation of the clinical efficacy, adverse effects, skin barrier function, histological structure, expression and proliferation of keratinocytes, differentiation markers (cytokeratin 10, filaggrin and loricrin), inflammatory factors [tumor necrosis factor (TNF)-? and interleukin (IL)-8], as well as the status of the nuclear factor ?B (NF-?B) pathway. The combination of P. oleracea and calcipotriol was revealed to decrease adverse effects, reduce transepidermal water loss, potently reverse keratinocyte differentiation dysfunction, and inhibit the expression of TNF-? and IL-8 and the phosphorylation of the NF-?B inhibitor I?B?. This treatment is therefore anticipated to be suitable for use as a novel adjuvant therapy for psoriatic patients. PMID:25574190

ZHAO, HENGGUANG; LI, SHUANG; LUO, FULING; TAN, QIAN; LI, HUI; ZHOU, WEIKANG

2015-01-01

126

3D co-cultures of keratinocytes and melanocytes and cytoprotective effects on keratinocytes against reactive oxygen species by insect virus-derived protein microcrystals.  

PubMed

Stable protein microcrystals called polyhedra are produced by certain insect viruses. Cytokines, such as fibroblast growth factors (FGFs), can be immobilized within polyhedra. Here, we investigated three-dimensional (3D) co-cultures of keratinocytes and melanocytes on collagen gel containing FGF-2 and FGF-7 polyhedra. Melanocytes were observed to reside at the base of the 3D cell culture and melanin was also typically observed in the lower layer. The 3D cell culture model with FGF-2 and FGF-7 polyhedra was a useful in vitro model of the epidermis due to effective melanogenesis, proliferation and differentiation of keratinocytes. FGF-7 polyhedra showed a potent cytoprotective effect when keratinocytes were treated with menadione, which is a generator of reactive oxygen species. The cytoprotective effect was activated by the inositol triphosphate kinase-Akt pathway leading to upregulation of the antioxidant enzymes superoxide dismutase and peroxiredoxin 6. PMID:25063093

Shimabukuro, Junji; Yamaoka, Ayako; Murata, Ken-Ichi; Kotani, Eiji; Hirano, Tomoko; Nakajima, Yumiko; Matsumoto, Goichi; Mori, Hajime

2014-09-01

127

A comparative study of leukaemia inhibitory factor and interleukin-1alpha intracellular content in a human keratinocyte cell line after exposure to cosmetic fragrances and sodium dodecyl sulphate.  

PubMed

According to European laws animal testing in cosmetic industry will be prohibited in a few years and it will be replaced by alternative methods based on cell and tissue culture. Many ingredients of cosmetic formulations are potentially causes of skin inflammation and sensibilization. Since cytotoxicity is known, among other factors, to trigger irritation, in an alternative model for evaluation of skin irritation, it can be considered also the precocious release of inflammatory mediators, i.e. cytokines, originating mainly from keratinocytes. In this in vitro study we have analysed some parameters directly or indirectly related to irritation/inflammation, in NCTC 2544 human keratinocytes during short-time exposure to some potential irritants cosmetic fragrances, included in the European Laws 2003/15/EEC. IIC50 was extrapolated by MTT and NRU viability indexes after exposure of cell ultures to Geraniol Limonene and Benzylic Alcohol for 1, 3 and 6h. NCTC cells were then exposed to sub-toxic doses of selected compounds and interleukin-1alpha (IL-1alpha) and leukaemia inhibitory factor (LIF) expressions were analysed as early proinflammatory cytokines. To our knowledge our findings demonstrated for the first time that NCTC cells synthesize and modulate LIF after exposure to selected irritating stimuli. Moreover, our results give evidence on LIF role as in vitro precocious endpoint for the assessment of the risk in cosmetic field, because its response under irritation stimuli is very quick and comparable to IL-1alpha. PMID:19878710

Parodi, Alessandro; Sanguineti, Roberta; Catalano, Mariafrancesca; Penco, Susanna; Pronzato, Maria Adelaide; Scanarotti, Chiara; Bassi, Anna Maria

2010-02-01

128

Human papillomavirus causes an angiogenic switch in keratinocytes which is sufficient to alter endothelial cell behavior  

SciTech Connect

One of the requirements for tumor growth is the ability to recruit a blood supply, a process known as angiogenesis. Angiogenesis begins early in the progression of cervical disease from mild to severe dysplasia and on to invasive cancer. We have previously reported that expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7) proteins in primary foreskin keratinocytes (HFKs) decreases expression of two inhibitors and increases expression of two angiogenic inducers [Toussaint-Smith, E., Donner, D.B., Roman, A., 2004. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene 23, 2988-2995]. Here we report that HPV-induced early changes in the keratinocyte phenotype are sufficient to alter endothelial cell behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7 expressing HFKs as well as from human cervical keratinocytes containing the intact HPV16 were able to stimulate proliferation and migration of human microvascular endothelial cells. In addition, introduction of the conditioned media into immunocompetent mice using a Matrigel plug model resulted in a clear angiogenic response. These novel data support the hypothesis that HPV proteins contribute not only to the uncontrolled keratinocyte growth seen following HPV infection but also to the angiogenic response needed for tumor formation.

Chen, W. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States); Li, F.; Mead, L.; White, H. [Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Walker, J. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States); Ingram, D.A. [Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Roman, A. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States)], E-mail: aroman@iupui.edu

2007-10-10

129

Factors affecting growth factor activity in goat milk.  

PubMed

Growth factors that are present in goat milk may be responsible for its beneficial effects on the digestive system as described in ancient Chinese medical texts. To develop a nutraceutical product rich in growth factors for promoting gastrointestinal health, it is essential to collect milk with consistently high growth factor activity. Therefore, we investigated the factors affecting growth factor activity in goat milk. Among the 5 breeds of dairy goats tested, milk from Nubian goats had the highest growth factor activity. Tight-junction leakage induced by a 24-h milking interval did not increase growth factor activity in the milk. Milk collected from pregnant does had a significantly higher growth factor activity than milk collected postpartum. Growth factor activity decreased during the first 8 wk of lactation, fluctuated thereafter, and then increased dramatically after natural mating. During wk 1 to 8, growth factor activity was inversely correlated with milk yield and week of lactation. No correlation was observed during wk 9 to 29. After natural mating of the goats, the growth factor activity in the milk correlated significantly with somatic cell count and conductivity (a measure of membrane permeability), and correlated inversely with milk yield. Based on the above data, goat milk with higher growth factor activity could be selectively collected from Nubian pregnant does. PMID:16702258

Wu, F Y; Tsao, P H; Wang, D C; Lin, S; Wu, J S; Cheng, Y K

2006-06-01

130

Do nerve growth factor-related mechanisms contribute to loss of cutaneous nociception in leprosy?  

PubMed

While sensory loss in leprosy skin is the consequence of invasion by M. leprae of Schwann cells related to unmyelinated fibres, early loss of cutaneous pain sensation, even in the presence of nerve fibres and inflammation, is a hallmark of leprosy, and requires explanation. In normal skin, nerve growth factor (NGF) is produced by basal keratinocytes, and acts via its high affinity receptor (trk A) on nociceptor nerve fibres to increase their sensitivity, particularly in inflammation. We have therefore studied NGF- and trk A-like immunoreactivity in affected skin and mirror-site clinically-unaffected skin from patients with leprosy, and compared these with non-leprosy, control skin, following quantitative sensory testing at each site. Sensory tests were within normal limits in clinically-unaffected leprosy skin, but markedly abnormal in affected skin. Sub-epidermal PGP 9.5- and trk A- positive nerve fibres were reduced only in affected leprosy skin, with fewer fibres contacting keratinocytes. However, NGF-immunoreactivity in basal keratinocytes, and intra-epidermal PGP 9.5-positive nerve fibres, were reduced in both sites compared to non-leprosy controls, as were nerve fibres positive for the sensory neurone specific sodium channel SNS/PN3, which is regulated by NGF, and may mediate inflammation-induced hypersensitivity. Keratinocyte trk A expression (which mediates an autocrine role for NGF) was increased in clinically affected and unaffected skin, suggesting a compensatory mechanism secondary to reduced NGF secretion at both sites. We conclude that decreased NGF- and SNS/PN3-immunoreactivity, and loss of intra-epidermal innervation, may be found without sensory loss on quantitative testing in clinically-unaffected skin in leprosy; this appears to be a sub-clinical change, and may explain the lack of cutaneous pain with inflammation. Sensory loss occurred with reduced sub-epidermal nerve fibres in affected skin, but these still showed trk A-staining, suggesting NGF treatment may restore pain sensation. PMID:10692623

Facer, P; Mann, D; Mathur, R; Pandya, S; Ladiwala, U; Singhal, B; Hongo, J; Sinicropi, D V; Terenghi, G; Anand, P

2000-03-01

131

Role of Dermatopontin in re-epithelialization: Implications on keratinocyte migration and proliferation  

PubMed Central

Re-epithelialization is a key event in wound healing and any impairment in that process is associated with various pathological conditions. Epidermal keratinocyte migration and proliferation during re-epithelialization is largely regulated by the cytokines and growth factors from the provisional matrix and dermis. Extracellular matrix consists of numerous growth factors which mediate cell migration via cell membrane receptors. Dermatopontin (DPT), a non-collagenous matrix protein highly expressed in dermis is known for its striking ability to promote cell adhesion. DPT also enhances the biological activity of transforming growth factor beta 1 which plays a central role in the process of wound healing. This study was designed to envisage the role of DPT in keratinocyte migration and proliferation along with its mRNA and protein expression pattern in epidermis. The results showed that DPT promotes keratinocyte migration in a dose dependant fashion but fail to induce proliferation. Further, PCR and immunodetection studies revealed that the mRNA and protein expression of DPT is considerably negligible in the epidermis in contrast to the dermis. To conclude, DPT has a profound role in wound healing specifically during re-epithelialization by promoting keratinocyte migration via paracrine action from the underlying dermis. PMID:25486882

Krishnaswamy, Venkat Raghavan; Korrapati, Purna Sai

2014-01-01

132

Role of Dermatopontin in re-epithelialization: Implications on keratinocyte migration and proliferation.  

PubMed

Re-epithelialization is a key event in wound healing and any impairment in that process is associated with various pathological conditions. Epidermal keratinocyte migration and proliferation during re-epithelialization is largely regulated by the cytokines and growth factors from the provisional matrix and dermis. Extracellular matrix consists of numerous growth factors which mediate cell migration via cell membrane receptors. Dermatopontin (DPT), a non-collagenous matrix protein highly expressed in dermis is known for its striking ability to promote cell adhesion. DPT also enhances the biological activity of transforming growth factor beta 1 which plays a central role in the process of wound healing. This study was designed to envisage the role of DPT in keratinocyte migration and proliferation along with its mRNA and protein expression pattern in epidermis. The results showed that DPT promotes keratinocyte migration in a dose dependant fashion but fail to induce proliferation. Further, PCR and immunodetection studies revealed that the mRNA and protein expression of DPT is considerably negligible in the epidermis in contrast to the dermis. To conclude, DPT has a profound role in wound healing specifically during re-epithelialization by promoting keratinocyte migration via paracrine action from the underlying dermis. PMID:25486882

Krishnaswamy, Venkat Raghavan; Korrapati, Purna Sai

2014-01-01

133

The essential oils of Chamaecyparis obtusa promote hair growth through the induction of vascular endothelial growth factor gene.  

PubMed

Chamaecyparis obtusa (C. obtusa) is a conifer in the cypress family Cupressaceae, native to northeast Asia. The essential oils of C. obtusa have antibacterial and antifungal effects and several products such as hygienic bands, aromatics, and shampoos contain these oils as a natural source of antimicrobial/antifungal agents. Interestingly, some consumers suffering from baldness and/or other forms of hair loss have reported a hair growth promoting effect of shampoos containing these oils. In the present study, the hair growth promoting effect of C. obtusa oils was elucidated in an animal model. C. obtusa oils promoted the early phase of hair growth in shaved mice. In addition, we examined the molecular effect of C. obtusa oils on the regulation of hair morphogenesis and hair growth using the human keratinocyte cell line HaCaT. In the current study of hair growth regulating genes, the expressions of vascular endothelial growth factor (VEGF), transforming growth factor (TGF beta 1), and keratinocyte growth factor(KGF) have been analyzed by real-time PCR in HaCaT cells. The essential oils of C. obtusa were divided into seven fractions for treatment of HaCaT cells. VEGF transcripts were induced by fractions 6 and 7; however, TGF beta 1 and KGF mRNA levels were unchanged by C. obtusa oils or fractions. Fraction 7 was separated into seven sub-fractions and studied further. Sub-fractions E and D significantly increased VEGF and KGF gene expression without up-regulating the hair growth inhibition factor, TGF beta 1. The components of the two sub-fractions were further analyzed by gas chromatography and mass spectrometry. Cuminol, eucarvone, and calamenene were common to these two sub-fractions, although the effects of these individual components were not determined. Taken together, these results suggest that C. obtusa oils promote hair growth in an animal model and a positive regulator of hair growth, VEGF, was induced by particular components of these oils. PMID:19576968

Lee, Geun-Shik; Hong, Eui-Ju; Gwak, Ki-Seob; Park, Mi-Jin; Choi, Kyung-Chul; Choi, In-Gyu; Jang, Je-Won; Jeung, Eui-Bae

2010-01-01

134

A Modeling Approach to Study the Effect of Cell Polarization on Keratinocyte Migration  

PubMed Central

The skin forms an efficient barrier against the environment, and rapid cutaneous wound healing after injury is therefore essential. Healing of the uppermost layer of the skin, the epidermis, involves collective migration of keratinocytes, which requires coordinated polarization of the cells. To study this process, we developed a model that allows analysis of live-cell images of migrating keratinocytes in culture based on a small number of parameters, including the radius of the cells, their mass and their polarization. This computational approach allowed the analysis of cell migration at the front of the wound and a reliable identification and quantification of the impaired polarization and migration of keratinocytes from mice lacking fibroblast growth factors 1 and 2 – an established model of impaired healing. Therefore, our modeling approach is suitable for large-scale analysis of migration phenotypes of cells with specific genetic defects or upon treatment with different pharmacological agents. PMID:25671585

Fuhr, Matthias Jörg; Meyer, Michael; Fehr, Eric; Ponzio, Gilles

2015-01-01

135

RIP2: A novel player in the regulation of keratinocyte proliferation and cutaneous wound repair?  

SciTech Connect

We could recently demonstrate an important role of receptor interacting protein 4 (RIP4) in the regulation of keratinocyte differentiation. Now, we analyzed a potential role of the RIP4 homolog RIP2 in keratinocytes. Specifically, we demonstrate here that rip2 expression is induced by scratch-wounding and after the induction of differentiation in these cells. Furthermore, serum growth factors and cytokines can induce rip2, with TNF-{alpha}-dependent induction being dependent on p38 MAPK. In addition, we demonstrate that scratch-induced upregulation of rip2 expression is completely blocked by the steroid dexamethasone. Since we also show that RIP2 is an important player in the regulation of keratinocyte proliferation, these data suggest that inhibition of rip2 upregulation after wounding might contribute to the reduced and delayed wound re-epithelialization phenotype seen in glucocorticoid-treated patients.

Adams, Stephanie; Valchanova, Ralitsa S. [Charite-University Medicine Berlin, Institute of Physiology, Arnimallee 22, D-14195 Berlin (Germany)] [Charite-University Medicine Berlin, Institute of Physiology, Arnimallee 22, D-14195 Berlin (Germany); Munz, Barbara, E-mail: barbara.munz@charite.de [Charite-University Medicine Berlin, Institute of Physiology, Arnimallee 22, D-14195 Berlin (Germany)] [Charite-University Medicine Berlin, Institute of Physiology, Arnimallee 22, D-14195 Berlin (Germany)

2010-03-10

136

Growth Factors in Proliferative Diabetic Retinopathy  

PubMed Central

Many growth factors are implicated in the pathogenesis of proliferative diabetic retinopathy. Alteration of growth factors and their receptors in diabetes has been shown in both experimental and clinical studies. Sustained hyperglycemia resulting from long-standing diabetes leads to several biochemical abnormalities that consequently result in retinal hypoxia. Retinal oxygenation state regulates various growth factors that promote angiogenesis in order to meet the oxygen demands of the tissue. However, unregulated expression of these growth factors and induction of complex cascades leading to augmentation of other proangiogenic factors, which may not be regulated by tissue oxygenation, leads to uncontrolled retinal neovascularization and blindness in diabetic patients. PMID:14668050

Khan, Zia Ali

2003-01-01

137

Persea americana Mill. Seed: Fractionation, Characterization, and Effects on Human Keratinocytes and Fibroblasts  

PubMed Central

Methanolic avocado (Persea americana Mill., Lauraceae) seed extracts were separated by preparative HSCCC. Partition and HSCCC fractions were principally characterized by LC-ESI-MS/MS analysis. Their in vitro influence was investigated on proliferation, differentiation, cell viability, and gene expression on HaCaT and normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF). The methanol-water partition (M) from avocado seeds and HSCCC fraction 3 (M.3) were mostly composed of chlorogenic acid and its isomers. Both reduced NHDF but enhanced HaCaT keratinocytes proliferation. HSCCC fraction M.2 composed of quinic acid among chlorogenic acid and its isomers inhibited proliferation and directly induced differentiation of keratinocytes as observed on gene and protein level. Furthermore, M.2 increased NHDF proliferation via upregulation of growth factor receptors. Salidrosides and ABA derivatives present in HSCCC fraction M.6 increased NHDF and keratinocyte proliferation that resulted in differentiation. The residual solvent fraction M.7 contained among low concentrations of ABA derivatives high amounts of proanthocyanidins B1 and B2 as well as an A-type trimer and stimulated proliferation of normal cells and inhibited the proliferation of immortalized HaCaT keratinocytes. PMID:24371457

Ramos-Jerz, Maria del R.; Villanueva, Socorro; Jerz, Gerold; Winterhalter, Peter; Deters, Alexandra M.

2013-01-01

138

Persea americana Mill. Seed: Fractionation, Characterization, and Effects on Human Keratinocytes and Fibroblasts.  

PubMed

Methanolic avocado (Persea americana Mill., Lauraceae) seed extracts were separated by preparative HSCCC. Partition and HSCCC fractions were principally characterized by LC-ESI-MS/MS analysis. Their in vitro influence was investigated on proliferation, differentiation, cell viability, and gene expression on HaCaT and normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF). The methanol-water partition (M) from avocado seeds and HSCCC fraction 3 (M.3) were mostly composed of chlorogenic acid and its isomers. Both reduced NHDF but enhanced HaCaT keratinocytes proliferation. HSCCC fraction M.2 composed of quinic acid among chlorogenic acid and its isomers inhibited proliferation and directly induced differentiation of keratinocytes as observed on gene and protein level. Furthermore, M.2 increased NHDF proliferation via upregulation of growth factor receptors. Salidrosides and ABA derivatives present in HSCCC fraction M.6 increased NHDF and keratinocyte proliferation that resulted in differentiation. The residual solvent fraction M.7 contained among low concentrations of ABA derivatives high amounts of proanthocyanidins B1 and B2 as well as an A-type trimer and stimulated proliferation of normal cells and inhibited the proliferation of immortalized HaCaT keratinocytes. PMID:24371457

Ramos-Jerz, Maria Del R; Villanueva, Socorro; Jerz, Gerold; Winterhalter, Peter; Deters, Alexandra M

2013-01-01

139

Design and Synthesis of Binding Growth Factors  

PubMed Central

Growth factors play important roles in tissue regeneration. However, because of their instability and diffusible nature, improvements in their performance would be desirable for therapeutic applications. Conferring binding affinities would be one way to improve their applicability. Here we review techniques for conjugating growth factors to polypeptides with particular affinities. Conjugation has been designed at the level of gene fusion and of polypeptide ligation. We summarize and discuss the designs and applications of binding growth factors prepared by such conjugation approaches. PMID:22754349

Tada, Seiichi; Kitajima, Takashi; Ito, Yoshihiro

2012-01-01

140

Extracellular matrix and growth factors during heart growth.  

PubMed

The effects of growth factors on tissue remodeling and cell differentiation depend on the nature of the extracellular matrix, the type and organization of integrins, the activation of metalloproteinases and the presence of secreted proteins associated to the matrix. These interactions are actually poorly known in the cardiovascular system. We describe here: 1) the main components of extracellular matrix within the cardiovascular system; 2) the role of integrins in the transmission of growth signals; 3) the shift in the expression of the components of the extracellular matrix (fibronectin and collagens) and the stimulation of the synthesis of metalloproteinases during normal and hypertrophic growth of the myocardium; 4) the effects of growth factors, such as Angiotensin II, Fibroblast Growth Factors (FGF), Transforming Growth Factor-beta (TGF-beta), on the synthesis of proteins of the extracellular matrix in the heart. PMID:16228139

Corda, S; Samuel, J L; Rappaport, L

2000-06-01

141

The importance of both fibroblasts and keratinocytes in a bilayered living cellular construct used in wound healing  

PubMed Central

Cross talk between fibroblasts and keratinocytes, which maintains skin homeostasis, is disrupted in chronic wounds. For venous leg ulcers and diabetic foot ulcers, a bilayered living cellular construct (BLCC), containing both fibroblasts and keratinocytes that participate in cross talk, is a safe and effective product in healing chronic wounds. To show the importance of both cell types in BLCC, constructs were generated containing only fibroblasts or only keratinocytes and compared directly to BLCC via histology, mechanical testing, gene/protein analysis, and angiogenesis assays. BLCC contained a fully differentiated epithelium and showed greater tensile strength compared with one-cell-type constructs, most likely due to formation of intact basement membrane and well-established stratum corneum in BLCC. Furthermore, expression of important wound healing genes, cytokines, and growth factors was modulated by the cells in BLCC compared with constructs containing only one cell type. Finally, conditioned medium from BLCC promoted greater endothelial network formation compared with media from one-cell-type constructs. Overall, this study characterized a commercially available wound healing product and showed that the presence of both fibroblasts and keratinocytes in BLCC contributed to epithelial stratification, greater tensile strength, modulation of cytokine and growth factor expression, and increased angiogenic properties compared with constructs containing fibroblasts or keratinocytes alone. PMID:24635175

Wojtowicz, Abigail M; Oliveira, Steve; Carlson, Mark W; Zawadzka, Agatha; Rousseau, Cecile F; Baksh, Dolores

2014-01-01

142

Roles for Growth Factors in Cancer Progression  

NSDL National Science Digital Library

Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy.

Esther Witsch (Weizmann Institute of Science); Michael Sela (Weizmann Institute of Science); Yosef Yarden (The Weizmann Institute of Science)

2010-04-01

143

Roles for Growth Factors in Cancer Progression  

PubMed Central

Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy. PMID:20430953

Witsch, Esther; Sela, Michael; Yarden, Yosef

2011-01-01

144

Autocrine growth factors and solid tumor malignancy.  

PubMed Central

The ability of malignant cells to escape the constraint that normally regulate cell growth and differentiation has been a primary focus of attention for investigators of cancer cell biology. An outcome of this attention has been the discovery that the protein products of oncogenes play a role in the activation of growth signal pathways. A second outcome, possibly related to abnormal oncogene expression, has been the discovery that malignant cells frequently show an ability to regulate their own growth by the release of autocrine growth modulatory substances. Most important, the growth of certain malignant cell types has been shown to depend on autocrine growth circuits. A malignant tumor whose continued growth depends on the release of an autocrine growth factor may be vulnerable to treatment with specific receptor antagonists or immunoneutralizing antibodies designed to break the autocrine circuit. Information is rapidly emerging concerning autocrine growth factors in selected human solid tissue malignancy. Images PMID:1926844

Walsh, J. H.; Karnes, W. E.; Cuttitta, F.; Walker, A.

1991-01-01

145

Arsenite-Mediated Promotion Of Anchorage-Independent Growth Of HaCat Cells Through Placental Growth Factor.  

PubMed

Various cancers including skin cancer are increasing in 45 million people exposed to arsenic above the World Health Organization's guideline value of 10 ?g/L. However, there is limited information on key molecules regulating arsenic-mediated carcinogenesis. Our fieldwork in Bangladesh demonstrated that levels of placental growth factor (PlGF) in urine samples from residents of cancer-prone areas with arsenic-polluted drinking water were higher than those in urine samples from residents of an area not polluted with arsenic. Our experimental study in human non-tumorigenic HaCaT skin keratinocytes showed that arsenite promoted anchorage-independent growth with increased expression and secretion of PlGF, a ligand of VEGF receptor1 (VEGFR1), and increased VEGFR1/MEK/ERK activities. The arsenite-mediated promotion of anchorage-independent growth was strongly inhibited by PlGF depletion with decreased activities of the PlGF/VEGFR1/MEK/ERK pathway. Moreover, arsenite proteasome-dependently degrades Metal-regulatory transcription factor-1 (MTF-1) protein, resulting in a decreased amount of MTF-1 protein binding to the PlGF promoter. MTF-1 negatively controlled PlGF transcription in HaCaT cells, resulting in increased PlGF transcription. These results suggest that arsenite-mediated MTF-1 degradation enhances activity of PlGF/VEGFR1/MEK/ERK signaling, resulting in promotion of the malignant transformation of keratinocytes. Thus, this study proposed a molecular mechanism for arsenite-mediated development of skin cancer.Journal of Investigative Dermatology accepted article preview online, 10 December 2014. doi:10.1038/jid.2014.514. PMID:25493652

Yajima, Ichiro; Kumasaka, Mayuko Y; Ohnuma, Shoko; Ohgami, Nobutaka; Naito, Hisao; Shekhar, Hossain U; Omata, Yasuhiro; Kato, Masashi

2014-12-10

146

Growth factor involvement in tension-induced skeletal muscle growth  

NASA Technical Reports Server (NTRS)

Long-term manned space travel will require a better understanding of skeletal muscle atrophy which results from microgravity. Astronaut strength and dexterity must be maintained for normal mission operations and for emergency situations. Although exercise in space slows the rate of muscle loss, it does not prevent it. A biochemical understanding of how gravity/tension/exercise help to maintain muscle size by altering protein synthesis and/or degradation rate should ultimately allow pharmacological intervention to prevent muscle atrophy in microgravity. The overall objective is to examine some of the basic biochemical processes involved in tension-induced muscle growth. With an experimental in vitro system, the role of exogenous and endogenous muscle growth factors in mechanically stimulated muscle growth are examined. Differentiated avian skeletal myofibers can be 'exercised' in tissue culture using a newly developed dynamic mechanical cell stimulator device which simulates different muscle activity patterns. Patterns of mechanical activity which significantly affect muscle growth and metabolic characteristics were found. Both exogenous and endogenous growth factors are essential for tension-induced muscle growth. Exogenous growth factors found in serum, such as insulin, insulin-like growth factors, and steroids, are important regulators of muscle protein turnover rates and mechanically-induced muscle growth. Endogenous growth factors are synthesized and released into the culture medium when muscle cells are mechanically stimulated. At least one family of mechanically induced endogenous factors, the prostaglandins, help to regulate the rates of protein turnover in muscle cells. Endogenously synthesized IGF-1 is another. The interaction of muscle mechanical activity and these growth factors in the regulation of muscle protein turnover rates with our in vitro model system is studied.

Vandenburgh, Herman H.

1993-01-01

147

Proliferation and motility of HaCaT keratinocyte derivatives is enhanced by fibroblast nemosis  

SciTech Connect

The role of paracrine tumor-stroma regulation in the progression of cancer is under intense investigation. Activated fibroblasts are key components of the tumor microenvironment providing the soluble factors mediating the regulation. Nemosis is an experimental model to study these parameters: formation of a multicellular spheroid activates fibroblasts and leads to increased production of soluble factors involved in the promotion of growth and motility. Role of nemosis was investigated in the tumorigenesis of HaCaT derivatives representing skin carcinoma progression. Conditioned medium from fibroblast spheroids increased proliferation rate of HaCaT derivatives. Expression of proliferation marker Ki-67 increased significantly in benign A5 and low-grade malignant II-4 cells, but did not further increase in the metastatic RT3 cells. Expression of p63, keratinocyte stem cell marker linked to cancer progression, was augmented by medium from nemotic fibroblasts; this increase was also seen in RT3 cells. Scratch-wound healing of the keratinocytes was enhanced in response to fibroblast nemosis. Neutralizing antibodies against growth factors inhibited wound healing to some extent; the response varied between benign and malignant keratinocytes. Migration and invasion were enhanced by conditioned medium from nemotic fibroblasts in benign and low-grade malignant cells. RT3 keratinocyte migration was further augmented, but invasion was not, indicating their intrinsic capacity to invade. Our data demonstrate that fibroblast nemosis increases proliferation and motility of HaCaT keratinocyte derivatives, and thus nemosis can be used as a model to study the role of soluble factors secreted by fibroblasts in tumor progression.

Raesaenen, Kati, E-mail: kati.rasanen@helsinki.fi [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)] [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland); Vaheri, Antti, E-mail: antti.vaheri@helsinki.fi [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)] [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)

2010-06-10

148

Growth factors from genes to clinical application  

SciTech Connect

The last decade has witnessed an explosion in the identification of growth factors and their receptors. This has been greatly facilitated by recombinant DNA technology, which has provided the tools not only to identify these proteins at the gene level but also to produce recombinant proteins for evaluating their biological activities. With the help of such techniques, we are moving toward an understanding of the biosynthesis of growth factors and their receptors, structure-function relationships, as well as mechanisms for intracellular signal transmission. The possibility of modifying these factors has opened new fields of clinical application. In this paper, four major areas of growth factor research are presented: the characterization of growth factor genes and their protein products, growth factor receptors and signal transduction by the receptors to mediate biological action, the biological actions of the various growth factors, and the role of growth factors in health and disease and their possible clinical application. Some of the topics covered include: structure of the IGFs and their variants; isoforms of PDGF receptor types; tyrosine kinase activation; structure of G-proteins in biological membranes; possible therapeutic application of NGF in the treatment of Parkinson's and Alzheimer's diseases; PDGF's possible role in the development of several fibroproliferative diseases and its therapeutic application in wound healing; and the possible use of angiogenic inhibitors in tumor treatment.

Sara, V.R. (Dept. of Pathology, Karolinska Hospital, Stockholm (SE)); Hall, K.; Low, H. (Dept. of Endocrinology, Karolinska Hospital, Stockholm (SE))

1990-01-01

149

Pathways involved in proliferating, senescent and immortalized keratinocyte cell death mediated by two different TRAIL preparations.  

PubMed

Properly regulated keratinocyte cell death is fundamentally important to maintain structural integrity and homeostatic function of epidermis. Moreover, from an oncological perspective, therapeutic approaches selectively targeting apoptosis of malignant cell types while sparing normal keratinocytes in surrounding skin is desirable. Apo2Ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has been observed to preferentially induce cytopathic effects on transformed/malignant cell types compared with their non-neoplastic counterparts. In this report, two different biologically active preparations of Apo2L/TRAIL, a non-tagged version, NT-Apo2L/TRAIL, and a leucine zipper fusion protein, LZ-Apo2L/TRAIL, were examined for their ability to trigger apoptosis in normal human keratinocytes, and in an immortalized cell line (HaCaT cells). Differences between these preparations were observed, including: NT-Apo2L/TRAIL induced less keratinocyte apoptosis compared with LZ-Apo2L/TRAIL; NT-Apo2L/TRAIL also induced less apoptosis of HaCaT cells compared with LZ-Apo2L/TRAIL; LZ-Apo2L/TRAIL but not NT-Apo2L/TRAIL induced cytotoxic effects when keratinocytes became growth arrested due to undergoing spontaneous replicative senescence--a biological state previously observed to be resistant to UV-light-induced apoptosis. Similarities between preparations included: an enhanced ability for both Apo2L/TRAIL preparations to kill a greater relative percentage of HaCaT cells compared with keratinocytes; enhanced cytotoxicity towards keratinocytes that had their NF-B activity inhibited; a dependence of both Apo2L/TRAIL preparations on FADD and caspase activation; triggering of the same caspase cascades including caspase 8 and 3; and an ability to induce apoptosis even when HaCaT cells and keratinocytes were transduced to overexpress either Bcl-2 or Bcl-x(L) (survival factors that reduce susceptibility to UV-light-induced apoptosis). These results indicate that while both preparations of Apo2L/TRAIL possess biological activity, there are important differences as regards their ability to induce apoptosis in normal and immortalized keratinocytes. Moreover, the death receptor pathway triggered by LZ-Apo2L/TRAIL can overcome the apoptotic resistance normally observed in response to UV-light mediated by Bcl-2/Bcl-x(L), as well as by the state of cellular senescence. Unraveling the molecular basis for these differential biological effects may reveal a new strategic role for these death receptor/ligands linked to apoptosis in maintaining the dynamic balance of keratinocyte proliferation, differentiation, and cell death necessary to achieve a homeostatic thickness and function of normal skin. In addition, it may be possible to utilize these Apo2L/TRAIL preparations for the treatment of various sun-induced skin cancers as they can differentially trigger apoptosis of transformed keratinocytes, or keratinocytes with abnormal NF-kappaB signaling, while sparing adjacent normal keratinocytes. PMID:12473065

Qin, Jian-Zhong; Bacon, Patricia E; Chaturvedi, Vijaya; Bonish, Brian; Nickoloff, Brian J

2002-12-01

150

Wound reepithelialization activates a growth factor- responsive enhancer in migrating keratinocytes  

Microsoft Academic Search

Wound reepithelialization and kerati- nocyte migration require strictly ordered gene ex- pression, which is assumed to be initiated by locally released mitogens and exposure of the cells to dif- ferent matrix components. The mechanisms trigger- ing gene expression specifically during reepitheliali- zation are poorly understood. The far upstream AP-1-driven, FGF-inducible response element (FiRE) of the syndecan-1 gene was activated during

PANU JAAKKOLA; SIRPA KONTUSAARI; TUIRE KAUPPI; ARTO MAATTA; MARKKU JALKANEN

151

Effects of fiber density and plasma modification of nanofibrous membranes on the adhesion and growth of HaCaT keratinocytes.  

PubMed

It may be possible to regulate the cell colonization of biodegradable polymer nanofibrous membranes by plasma treatment and by the density of the fibers. To test this hypothesis, nanofibrous membranes of different fiber densities were treated by oxygen plasma with a range of plasma power and exposure times. Scanning electron microscopy and mechanical tests showed significant modification of nanofibers after plasma treatment. The intensity of the fiber modification increased with plasma power and exposure time. The exposure time seemed to have a stronger effect on modifying the fiber. The mechanical behavior of the membranes was influenced by the plasma treatment, the fiber density, and their dry or wet state. Plasma treatment increased the membrane stiffness; however, the membranes became more brittle. Wet membranes displayed significantly lower stiffness than dry membranes. X-ray photoelectron spectroscopy (XPS) analysis showed a slight increase in oxygen-containing groups on the membrane surface after plasma treatment. Plasma treatment enhanced the adhesion and growth of HaCaT keratinocytes on nanofibrous membranes. The cells adhered and grew preferentially on membranes of lower fiber densities, probably due to the larger area of void spaces between the fibers. PMID:25085812

Bacakova, Marketa; Lopot, Frantisek; Hadraba, Daniel; Varga, Marian; Zaloudkova, Margit; Stranska, Denisa; Suchy, Tomas; Bacakova, Lucie

2015-01-01

152

Opposite effects of EGF on involucrin accumulation of A431 keratinocytes and a variant which is not growth-arrested by EGF  

Microsoft Academic Search

Summary  The A431 cell line is composed of malignant keratinocytes derived from a vulval epidermoïd carcinoma. These cells have the\\u000a peculiarity to stop their proliferation when they are treated with physiological concentrations of EGF, which is a mitogen\\u000a for normal keratinocytes. We reported earlier that EGF induces involucrin accumulation in A431 cells and proposed that the\\u000a arrest of proliferation triggers differentiation

Martin Rosdy; Dow Corning

1988-01-01

153

A Keratinocyte’s Course of Life  

Microsoft Academic Search

An adequate permeability barrier function of the mammalian epidermis is guaranteed by the characteristic architecture of the stratum corneum. This uppermost layer consists of a highly organized extracellular lipid compartment which is tightly joined to the corneocytes. The generation of the extracellular lipid compartment and the transformation of the keratinocytes into corneocytes are the main features of epidermal differentiation. However,

E. Houben; K. De Paepe; V. Rogiers

2007-01-01

154

Priming of mononuclear cells with a combination of growth factors enhances wound healing via high angiogenic and engraftment capabilities.  

PubMed

Recently, we demonstrated that a specific combination of growth factors enhances the survival, adhesion and angiogenic potential of mononuclear cells (MNCs). In this study, we sought to investigate the changes of the angiogenic potential of MNCs after short-time priming with a specific combination of growth factors. MNCs were isolated using density gradient centrifugation and incubated with a priming cocktail containing epidermal growth factor (EGF), insulin-like growth factor (IGF)-1, fibroblast growth factor (FGF)-2, FMS-like tyrosine kinase (Flt)-3L , Angiopoietin (Ang)-1, granulocyte chemotactic protein (GCP)-2 and thrombopoietin (TPO) (all 400 ng/ml) for 15, 30 and 60 min. Wounds in nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice were created by skin excision followed by cell transplantation. We performed a qRT-PCR analysis on the growth factor-primed cells. The angiogenic factors vascular endothelial growth factor (VEGF)-A, FGF-2, hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF) and interleukin (IL)-8 and the anti-apoptotic factors IGF-1 and transforming growth factor-?1 were significantly elevated in the MNCs primed for 30 min. (T30) compared with the non-primed MNCs (T0). The scratch wound assay revealed that T30- conditioned media (CM) significantly increased the rate of fibroblast-mediated wound closure compared with the rates from T0-CM and human umbilical vein endothelial cells (HUVEC)-CM at 20 hrs. In vivo wound healing results revealed that the T30-treated wounds demonstrated accelerated wound healing at days 7 and 14 compared with those treated with T0. The histological analyses demonstrated that the number of engrafted cells and transdifferentiated keratinocytes in the wounds were significantly higher in the T30-transplanted group than in the T0-transplanted group. In conclusion, this study suggests that short-term priming of MNCs with growth factors might be alternative therapeutic option for cell-based therapies. PMID:24118840

Jin, Enze; Kim, Jong-Min; Kim, Sung-Whan

2013-12-01

155

Hepatoma-derived growth factor and its role in keloid pathogenesis.  

PubMed

Hepatoma-derived growth factor (HDGF) is a novel mitogenic growth factor that has been implicated in many different carcinomas. Its role in keloid biology has not yet been investigated. The present study is aimed at examining the role of HDGF in keloid pathogenesis. Immunohistochemical staining and Western blot analyses were used to examine in vivo localization and expression of HDGF in keloid and normal skin tissue. This was followed by the detection of HDGF expression in fibroblasts cultured in vitro and fibroblasts exposed to serum. To investigate the effect of epithelial-mesenchymal interactions, a two-chamber system was employed in which keratinocytes on membrane inserts were co-cultured with the fibroblasts. HDGF expression levels in all cell extracts and conditioned media were assayed through Western blot analysis. In another set of experiments, the effect of exogenous recombinant HDGF on keloid fibroblasts (KF) and normal fibroblasts (NF) was examined. Cell proliferation was assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and by quantifying proliferating cell nuclear antigen (PCNA) expression. Downstream targets of HDGF were identified by detecting their expression through Western blot analysis. Our results indicate that there was an increase in HDGF expression in the dermis of keloid compared with normal skin tissue. The application of serum and epithelial-mesenchymal interactions did not seem to have any effect on intracellular HDGF expression levels. However, co-culturing keloid keratinocytes with KFs resulted in increased HDGF secretion when compared with monoculture or normal controls. Furthermore, treatment with exogenous recombinant HDGF was found to increase the proliferation of KFs, activate the extracellular signal-regulated kinase (ERK) pathway and up-regulate the secretion of vascular endothelial growth factor (VEGF). PMID:19432814

Ooi, B N S; Mukhopadhyay, A; Masilamani, J; Do, D V; Lim, C P; Cao, X M; Lim, I J; Mao, L; Ren, H N; Nakamura, H; Phan, T T

2010-06-01

156

Signaling Mechanism Underlying the Promotion of Keratinocyte Migration by Angiotensin II.  

PubMed

Re-epithelialization begins early during skin wound healing and is regulated by various growth factors and cytokines. Angiotensin II promotes the migration of keratinocytes and thereby contributes to wound healing. We investigated the mechanism by which angiotensin II stimulates human keratinocyte migration. Angiotensin II-induced keratinocyte migration was inhibited by an angiotensin II type 1 receptor (AT1R) antagonist (candesartan) or an angiotensin II type 2 receptor (AT2R) antagonist (PD123319) as well as by depletion of AT1R or AT2R. A biased agonist for AT1R, [Sar(1),Ile(4),Ile(8)]angiotensin II, induced cell migration, whereas depletion of ?-arrestin2 inhibited angiotensin II-induced migration. Angiotensin II-induced migration was blocked by neutralizing antibodies to transforming growth factor-? (TGF-?) as well as by the TGF-? receptor inhibitor SB431542. The amount of TGF-?1 was increased in the culture medium of angiotensin II-treated cells, and this effect was inhibited by candesartan or PD123319. Both angiotensin II- and TGF-?-induced cell migration were inhibited by neutralizing antibodies to the epidermal growth factor (EGF) receptor but not by those to EGF receptor ligands. Angiotensin II-induced phosphorylation of the EGF receptor, and this effect was inhibited by candesartan, PD123319, SB431542, or depletion of ?-arrestin2, but not by neutralizing antibodies to heparin-binding EGF-like growth factor. Our results indicate that ?-arrestin-dependent signaling downstream of AT1R as well as AT2R signaling are necessary for angiotensin II-induced keratinocyte migration, and that such signaling promotes generation of the active form of TGF-?, consequent activation of the TGF-? receptor, and transactivation of the EGF receptor by the TGF-? receptor. PMID:25473119

Sakai, Hiroki; Matsuura, Kenji; Tanaka, Yoshie; Honda, Takeshi; Nishida, Teruo; Inui, Makoto

2015-02-01

157

Release of Stem Cell Factor from a Human Keratinocyte Line, HaCaT, Is Increased in Differentiating versus Proliferating Cells  

Microsoft Academic Search

Stem cell factor, a recently discovered growth factor for hematopoietic stem cells, mast cells, and melanocytes, was initially reported to be produced by fibroblasts. In this study, we investigated the secretion of this factor from human HaCaT cells during in vitro culture and compared it to synthesis by cells in the skin. Release of stem cell factor from freshly cultured

Jürgen Grabbe; Pia Welker; Thomas Rosenbach; Wolf Nürnberg; Sabine Krüger-Krasagakes; Metin Artuc; Edda Fiebiger; Beate M. Henz

1996-01-01

158

New Clue Found to Growth Factor Action.  

ERIC Educational Resources Information Center

Discussed is the discovery which may help to explain epidermal growth factor effects on the cell skeleton. The role of a protein called profilin in the regulation of the microfilament system is described. (CW)

Hoffman, Michelle

1991-01-01

159

Acidic Fibroblast Growth Factor Promotes Vascular Repair  

NASA Astrophysics Data System (ADS)

Intravascular injury to arteries can result in thickening of the intimal smooth muscle layer adjacent to the lumen by migration and proliferation of cells from the underlying medial smooth muscle layer accompanied by deposition of extracellular matrix. This pathological response, which decreases lumen diameter, might, in part, be the result of the access of smooth muscle cells to plasma and platelet-derived growth factors as a consequence of denudation of the overlying confluent monolayer of vascular endothelial cells. Injured rat carotid arteries were treated by i.v. administration of acidic fibroblast growth factor, a heparin-binding protein that is chemotactic and mitogenic for vascular endothelial cells. The growth factor treatment resulted in dose-dependent inhibition of intimal thickening with parallel promotion of endothelial regeneration over the injured area. Therefore, acidic fibroblast growth factor might be efficacious in the prevention of restenosis caused by intimal thickening following angioplasty in humans.

Bjornsson, Thorir D.; Dryjski, Maciej; Tluczek, John; Mennie, Robert; Ronan, John; Mellin, Theodore N.; Thomas, Kenneth A.

1991-10-01

160

Controlled Delivery of Heparin-Binding EGF-Like Growth Factor Yields Fast and Comprehensive Wound Healing  

PubMed Central

Wound healing is a dynamic process that relies on coordinated signaling molecules to succeed. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is proven to accelerate healing, however precise control over its application is necessary to reduce side effects and achieve desired therapeutic benefit. To achieve effective growth factor delivery we designed a bioactive heparin-based coacervate. In vitro, HB-EGF released from the coacervate delivery system displayed enhanced bioactivity and promoted human keratinocyte migration while preserving cell proliferative capability. In a mouse excisional full-thickness wound model, controlled release of HB-EGF within the wound significantly accelerated wound closure more effectively than an equal dosage of free HB-EGF. Healing was induced by rapid re-epithelialization, granulation tissue formation, and accompanied by angiogenesis. Consistent with in vitro results, wounds treated with HB-EGF coacervate exhibited enhanced migration of keratinocytes with retained proliferative potential, forming a confluent layer for regained barrier function within 7 days. Collectively, these results suggest that coacervate-based controlled release of HB-EGF may serve as a new therapy to accelerate healing of cutaneous wounds. PMID:23154193

Johnson, Noah Ray; Wang, Yadong

2014-01-01

161

Growth factor involvement in tension-induced skeletal muscle growth  

NASA Technical Reports Server (NTRS)

Muscle tissue culture techniques were developed to grow skeletal myofibers which differentiate into more adult-like myofibers. Mechanical simulation studies of these muscle cells in a newly developed mechanical cell simulator can now be performed to study growth processes in skeletal muscle. Conditions in the mechanical cell simulator were defined where mechanical activity can either prevent muscle wasting or stimulate muscle growth. The role of endogenous and exogenous growth factors in tension-induced muscle growth is being investigated under the defined conditions of tissue culture.

Vandenburgh, H. H.

1987-01-01

162

Autocrine Growth Factor Signaling in Motility  

Microsoft Academic Search

The objective of this chapter is to summarize our current understanding of the role of growth factor autocrine signaling in\\u000a cell motility. The Epidermal Growth Factor Receptor (EGFR) was chosen as a central example system for motivating autocrine\\u000a operation as important in both normal physiological processes as well as pathological conditions such as cancer. We provide\\u000a specific evidence from research

Elizabeth J. Joslin; Douglas A. Lauffenburger

163

Transforming growth factor ?s and wound healing  

Microsoft Academic Search

The Transforming Growth Factor ? superfamily (TGF?) is one of the most complex groups of cytokines with widespread effects on many aspects of growth and development. The TGF? isoforms and other family members, e.g. Activins and BMPs, have diverse effects in similar physiological situations. TGF? is involved in the wound healing process. The three mammalian isoforms (TGF?1, 2 and 3)

Sharon O'Kane; Mark W. J. Ferguson

1997-01-01

164

Growth factors in cartilage tissue engineering.  

PubMed

Tissue engineering of cartilage consists of two steps. Firstly, the cells from a small biopsy of patient's own tissue have to be multiplied. During this multiplication process they lose their cartilage phenotype. In the second step, these cells have to be stimulated to re-express their cartilage phenotype and produce cartilage matrix. Growth factors can be used to improve cell multiplication, redifferentiation and production of matrix. The choice of growth factors should be made for each phase of the tissue engineering process separately, taking into account cell phenotype and the presence of extracellular matrix. This paper demonstrates some examples of the use of growth factors to increase the amount, the quality and the assembly of the matrix components produced for cartilage tissue engineering. In addition it shows that the "culture history" (e.g., addition of growth factors during cell multiplication or preculture period in a 3-dimensional environment) of the cells influences the effect of growth factor addition. The data demonstrate the potency as well as the limitations of the use of growth factors in cartilage tissue engineering. PMID:12082284

van Osch, Gerjo J V M; Mandl, Erik W; Marijnissen, Willem J C M; van der Veen, Simone W; Verwoerd-Verhoef, Henriette L; Verhaar, Jan A N

2002-01-01

165

Calcium-Regulated Differentiation of Normal Human Epidermal Keratinocytes in Chemically Defined Clonal Culture and Serum-Free Serial Culture  

Microsoft Academic Search

An improved serum-free culture system has been developed for normal human epidermal keratinocytes (HK), Short-term clonal growth and differentiation studies are routinely performed in a defined medium consisting of optimized nutrient medium MCDB 153 supplemented with epidermal growth factor, insulin, hydrocortisone, ethanolamine, and phosphoethanolamine. A small amount of whole bovine pituitary extract (wBPE) is added for initiation of primary cultures,

Steven T. Boyce; Richard G. Ham

1983-01-01

166

Vascular endothelial growth factor (VEGF) in endometriosis  

Microsoft Academic Search

Angiogenesis is likely to be involved in the pathogenesis of endometriosis. According to the transplantation theory, when the exfoliated endometrium is attached to the periton- eal layer, the establishment of a new blood supply is essential for the survival of the endometrial implant and development of endometriosis. From the known angiogenic factors, vascular endothelial growth factor (VEGF) has emerged as

Jacques Donnez; Pierre Smoes; Stephane Gillerot; Francoise Casanas-Roux; Michelle Nisolle

1998-01-01

167

Virus transcript levels and cell growth rates after naturally occurring HPV16 integration events in basal cervical keratinocytes  

PubMed Central

Cervical carcinogenesis is characterized by a clonal selection process in which the high-risk human papillomavirus (HRHPV) genome usually changes from the extra-chromosomal (episomal) state seen in productive infections to DNA that is integrated into host chromosomes. However, it is not clear whether all HRHPV integration events provide cells with a selective growth advantage compared with the episome-containing cells from which they originate. It is also unclear whether selection of cells containing a particular integrant from a mixed population simply reflects the highest levels of virus oncogene expression or has additional determinants. These early events in cervical carcinogenesis cannot readily be addressed by cross-sectional studies of clinical samples. We used the W12 model system to generate a panel of cervical squamous cell clones that were derived from an identical background under non-competitive conditions and differed only by the genomic site of HPV16 integration. Compared with the ‘baseline’ episome-containing cells from which they were isolated, only 9/17 clones (53%) showed significantly greater growth rates and only 7/17 (41%) showed significantly greater expression of the major virus oncogenes E7/E6. There were significant variations in levels of HPV16 transcription per DNA template, changes that were associated with histone modifications in the integrated virus chromatin. Cell growth rates showed only weak and non-significant associations with protein and mRNA levels for E7, E6, and the mean E7/E6 values. We conclude that HPV16 integration in basal cervical cells does not necessarily lead to increased levels of virus oncogenes, or to a competitive growth advantage, when compared with the initiating episome-containing cells. PMID:24752734

Scarpini, Cinzia G; Groves, Ian J; Pett, Mark R; Ward, Dawn; Coleman, Nicholas

2014-01-01

168

Identification of copper/zinc superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation.  

PubMed Central

Recent studies have demonstrated an induction of expression of inducible nitric oxide synthase that is associated with several inflammatory diseases of the skin. To define the mechanisms of action of nitric oxide (NO) in the skin, we attempted to identify genes that are regulated by NO in keratinocytes. Using the human keratinocyte cell line HaCaT as a model system, we identified a Cu/Zn superoxide dismutase (SOD) that was strongly induced by high concentrations (500 microM) of NO-donating agents ¿S-nitrosoglutathione, sodium nitroprusside and (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1,2 -diolate (DETA-NO)¿, but not by serum or by single recombinant growth factors and inflammatory cytokines or by treatment with superoxide anions. Furthermore, endogenously produced NO increased the expression of Cu/Zn SOD mRNA in keratinocytes. Moreover, treatment of HaCaT cells with NO was associated with a biphasic effect on cell proliferation, because low doses (100 microM) of different NO donors (S-nitrosoglutathione and DETA-NO) mediated a proliferative signal to the cells, whereas high concentrations (500 microM) were cytostatic. To determine a possible correlation between the close regulation of Cu/Zn SOD expression and proliferation by NO in keratinocytes, we established a cell line (psp1CZ1N) carrying a human Cu/Zn SOD cDNA under the control of a ponasterone-inducible promoter construct. Ponasterone-induced overexpression of Cu/Zn SOD caused a cytostatic effect in proliferating psp1CZ1N cells. We therefore suggest that the up-regulation of Cu/Zn SOD expression by NO establishes an inhibitory mechanism on keratinocyte proliferation. PMID:10698699

Frank, S; Kämpfer, H; Podda, M; Kaufmann, R; Pfeilschifter, J

2000-01-01

169

Autologous keratinocyte suspension in platelet concentrate accelerates and enhances wound healing – a prospective randomized clinical trial on skin graft donor sites: platelet concentrate and keratinocytes on donor sites  

PubMed Central

Background Wound healing involves complex mechanisms, which, if properly chaperoned, can enhance patient recovery. The abilities of platelets and keratinocytes may be harnessed in order to stimulate wound healing through the formation of platelet clots, the release of several growth factors and cytokines, and cell proliferation. The aim of the study was to test whether autologous keratinocyte suspensions in platelet concentrate would improve wound healing. The study was conducted at the Lausanne University Hospital, Switzerland in 45 patients, randomized to three different topical treatment groups: standard treatment serving as control, autologous platelet concentrate (PC) and keratinocytes suspended in autologous platelet concentrate (PC?+?K). Split thickness skin graft donor sites were chosen on the anterolateral thighs of patients undergoing plastic surgery for a variety of defects. Wound healing was assessed by the duration and quality of the healing process. Pain intensity was evaluated at day five. Results Healing time was reduced from 13.9?±?0.5 days (mean?±?SEM) in the control group to 7.2?±?0.2 days in the PC group (P?keratinocytes in suspension further reduced the healing time to 5.7?±?0.2 days. Pain was reduced in both the PC and PC?+?K groups. Data showed a statistically detectable advantage of using PC?+?K over PC alone (P?keratinocytes in stimulating wound healing and reducing pain. This strikingly simple approach could have a significant impact on patient care, especially critically burned victims for whom time is of the essence. Clinical trial registry information Protocol Record Identification Number: 132/03 Registry URL: http://www.clinicaltrials.gov PMID:23570605

2013-01-01

170

Luteolin Inhibits Human Keratinocyte Activation and Decreases NF-?B Induction That Is Increased in Psoriatic Skin  

PubMed Central

Psoriasis (Ps) is an autoimmune disease characterized by keratinocyte hyperproliferation and chronic inflammation, with increased expression of tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF). Anti-TNF biologic agents are effective in treating Ps, but are associated with increased risk of infections and blood malignancies. Moreover, keratinocyte hyperproliferation and activation have yet to be addressed. Flavonoids, such as luteolin, are natural compounds with potent anti-inflammatory properties, but their actions on keratinocytes remain unknown. We show that TNF (50 ng/mL) triggers significant production of inflammatory mediators interleukin-6, interleukin-8 and VEGF from both human HaCaT and primary keratinocytes. Pretreatment with the flavonoid luteolin (10–100 µM) significantly inhibits mRNA expression and release of all three mediators in a concentration-dependent manner. More importantly, luteolin decreases TNF-induced phosphorylation, nuclear translocation and DNA binding of the nuclear factor-kappa B (NF-?B) typically involved in inflammatory mediator transcription. We also report that luteolin reduces TNF-induced mRNA expression of two genes (NFKB1 and RELA) encoding two NF-?B subunits (NF-?B p50 and NF-?B p65, respectively). Interestingly, we show that gene expression of RELA is increased in human psoriatic skin. Keratinocyte proliferation, which is a characteristic feature of psoriatic skin, is effectively reduced by luteolin in HaCaT cells, but not in primary keratinocytes. Finally, luteolin does not affect intracellular ATP production or viability. Appropriate formulations of luteolin and related flavones may be promising candidates to be developed into local and systemic treatments for Ps and other inflammatory skin diseases. PMID:24587411

Weng, Zuyi; Patel, Arti B.; Vasiadi, Magdalini; Therianou, Anastasia; Theoharides, Theoharis C.

2014-01-01

171

Vascular endothelial growth factor and placenta growth factor concentrations in Down's syndrome and control pregnancies  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) and placenta growth factor (PLGF) are considered to play important roles in angiogenesis and vascular permeability during placental development. Since trisomy 21 placentae show trophoblastic hypoplasia and hypovascularity, we investigated PLGF and VEGF synthesis in Down's syndrome pregnancies. Maternal serum was collected from 102 euploid and 24 trisomy 21 pregnancies between 15 and 20 weeks

F. Debieve; A. Moiset; K. Thomas; S. Pampfer; C. Hubinont

2001-01-01

172

Dysregulated ?Np63? negatively regulates the maspin promoter in keratinocytes via blocking endogenous p73 binding.  

PubMed

While overexpression of the p63 isoform, ?Np63?, has been reported in squamous cell cancers, the contribution of p63 to cancer pathogenesis remains unclear. We previously demonstrated that overexpressed ?Np63? aberrantly maintains proliferation of primary mouse keratinocytes under conditions that normally induce growth arrest and differentiation. To identify genes downstream of dysregulated ?Np63? that may contribute to squamous cancer development and progression, we performed microarray analyses using primary mouse keratinocytes. Herein we report that elevated ?Np63? differentially regulates genes involved in a variety of cellular functions. Of note, multiple protease inhibitor mRNAs were downregulated including: maspin (serpinB5); plasminogen activator inhibitor-2 (PAI-2; serpinB2); and tissue inhibitor of metalloproteinase-3 (TIMP-3). Correspondingly, secreted TIMP-3 and PAI-2 protein declined in the presence of dysregulated ?Np63?, however secreted maspin remained stable. Intracellular maspin protein expression decreased in response to overexpressed ?Np63?, as did PAI-2. In contrast, TIMP-3 protein was not detected intracellularly, supporting a solely extracellular function. Electrophoretic mobility shift assays (EMSAs) using a maspin promoter p53/p63 consensus sequence revealed endogenous transcription factor(s) binding to this sequence in keratinocytes that was disrupted by overexpressed ?Np63?. This was confirmed by ChIP assays. This binding was interrupted by the addition of antibodies recognizing p73, but not p53 or p63, and significantly diminished in EMSA reactions from p73(-/-) keratinocytes, confirming p73 as a constituent. Physical association between p73/?Np63? was observed in control ?-gal overexpressing keratinocytes and was enhanced in the presence of overexpressed ?Np63? These findings underscore the importance of properly balanced p53 homologs for tissue homeostasis. PMID:23475637

King, Kathryn E; Reddi, Deepti Muraleedharan; Ponnamperuma, Roshini M; Gerdes, Michael; Weinberg, Wendy C

2014-09-01

173

UVB light suppresses nitric oxide production by murine keratinocytes and macrophages.  

PubMed

Nitric oxide is an important mediator of excessive cell growth and inflammation associated with many epidermal proliferative disorders. It is a highly reactive oxidant generated in keratinocytes and macrophages via the inducible form of the enzyme nitric oxide synthase (NOS2). In the present studies, we examined the effects of ultraviolet light (UVB, 2.5-25mJ/cm(2)) on interferon-gamma (IFN-gamma)-induced expression of NOS2 in these cells. Transient transfection assays using wild-type and mutant NOS2 promoter/luciferase reporter constructs showed that DNA binding of the transcription factors Stat1 and NF-kappaB was essential for optimal expression of the NOS2 gene. Whereas NF-kappaB was constitutively expressed in both cell types, Stat1 phosphorylation and nuclear binding activity were dependent upon IFN-gamma. UVB light, which is used therapeutically to treat inflammatory dermatosis, was found to suppress IFN-gamma-induced expression of NOS2 mRNA and protein, and nitric oxide production in both keratinocytes and macrophages. In macrophages, this was associated with complete inhibition of NF-kappaB nuclear binding activity and partial (approximately 20-25%) reduction of Stat1 activity. In keratinocytes, both responses were partially reduced at the highest doses of UVB light (15-25mJ/cm(2)). Whereas in macrophages UVB light suppressed NOS2 wild-type promoter-luciferase reporter activity, this activity was stimulated in keratinocytes. These data suggest that UVB light functions to suppress NOS2 gene expression in macrophages by inhibiting the activity of key regulatory transcription factors. In contrast, in keratinocytes, inhibition occurs downstream of NOS2 promoter activity. PMID:12417260

Sur, Runa; Heck, Diane E; Mariano, Thomas M; Jin, Yang; Murphy, William J; Laskin, Jeffrey D

2002-11-15

174

Growth factor parametrization in curved space  

SciTech Connect

The growth rate of matter perturbation and the expansion rate of the Universe can be used to distinguish modified gravity and dark energy models in explaining cosmic acceleration. We explore here the inclusion of spatial curvature into the growth factor. We expand previous results using the approximation {omega}{sub m}{sup {gamma}} and then suggest a new form, f{sub a}={omega}{sub m}{sup {gamma}}+({gamma}-4/7){omega}{sub k}, as an approximation for the growth factor when the curvature {omega}{sub k} is not negligible, and where the growth index {gamma} is usually model dependent. The expression recovers the standard results for the curved and flat {lambda}CDM and Dvali-Gabadadze-Porrati models. Using the best fit values of {omega}{sub m0} and {omega}{sub k0} to the expansion/distance measurements from Type Ia SNe, baryon acoustic oscillation, WMAP5, and H(z) data, we fit the growth index parameter to current growth factor data and obtain {gamma}{sub {lambda}}({omega}{sub k}{ne}0)=0.65{sub -0.15}{sup +0.17} and {gamma}{sub DGP}({omega}{sub k}{ne}0)=0.53{sub -0.12}{sup +0.14}. For the {lambda}CDM model, the 1-{sigma} observational bounds are found consistent with theoretical value, unlike the case for the Dvali-Gabadadze-Porrati model. We also find that the current data we used is not enough to put significant constraints when the 3 parameters in f{sub a} are fit simultaneously. Importantly, we find that, in the presence of curvature, the analytical expression proposed for f{sub a} provides a better fit to the growth factor than other forms and should be useful for future high precision missions and studies.

Gong Yungui; Ishak, Mustapha; Wang Anzhong [College of Mathematics and Physics, Chongqing University of Posts and Telecommunications, Chongqing 400065 (China) and Kavli Institute for Theoretical Physics China, CAS, Beijing 100190 (China); Department of Physics, University of Texas at Dallas, Richardson, Texas 75083 (United States); CASPER, Physics Department, Baylor University, Waco, Texas 76798 (United States)

2009-07-15

175

Periodontal tissue engineering by growth factors  

Microsoft Academic Search

Polypeptide growth factors (GFs) have been shown to modulate the wound healing response in both hard and soft tissues. During the past decade, many investigators have demonstrated the anabolic effects of these wound healing molecules on the promotion of periodontal attachment structures, namely alveolar bone, periodontal ligament and tooth root cementum. The molecular cloning and large sclae purification of GFs

W. V. Giannobile

1996-01-01

176

Distinct Effects of Different Phosphatidylglycerol Species on Mouse Keratinocyte Proliferation  

PubMed Central

We have previously shown that liposomes composed of egg-derived phosphatidylglycerol (PG), with a mixed fatty acid composition (comprising mainly palmitate and oleate), inhibit the proliferation and promote the differentiation of rapidly dividing keratinocytes, and stimulate the growth of slowly proliferating epidermal cells. To determine the species of PG most effective at modulating keratinocyte proliferation, primary mouse keratinocytes were treated with different PG species, and proliferation was measured. PG species containing polyunsaturated fatty acids were effective at inhibiting rapidly proliferating keratinocytes, whereas PG species with monounsaturated fatty acids were effective at promoting proliferation in slowly dividing cells. Thus, palmitoyl-arachidonyl-PG (16?0/20?4), palmitoyl-linoleoyl-PG (16?0/18?2), dilinoleoyl-PG (18?2/18?2) and soy PG (a PG mixture with a large percentage of polyunsaturated fatty acids) were particularly effective at inhibiting proliferation in rapidly dividing keratinocytes. Conversely, palmitoyl-oleoyl-PG (16?0/18?1) and dioleoyl-PG (18?1/18?1) were especially effective proproliferative PG species. This result represents the first demonstration of opposite effects of different species of a single class of phospholipid and suggests that these different PG species may signal to diverse effector enzymes to differentially affect keratinocyte proliferation and normalize keratinocyte proliferation. Thus, different PG species may be useful for treating skin diseases characterized by excessive or insufficient proliferation. PMID:25233484

Xie, Ding; Seremwe, Mutsa; Edwards, John G.; Podolsky, Robert; Bollag, Wendy B.

2014-01-01

177

Nerve Growth Factor and Diabetic Neuropathy  

PubMed Central

Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50–90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium. PMID:14668049

Vinik, Aaron

2003-01-01

178

Structure-activity relationship studies of acridones as potential antipsoriatic agents. 1. Synthesis and antiproliferative activity of simple N-unsubstituted 10H-acridin-9-ones against human keratinocyte growth.  

PubMed

A series of N-unsubstituted hydroxy-10H-acridin-9-ones were synthesized and evaluated for inhibitory action against HaCaT keratinocyte growth, in order to explore their potential as antipsoriatic agents. For structure-activity relationship studies, the number and position of the hydroxyl groups were modified, the oxygen functions substituted or replaced, or additional functional groups were introduced into the acridone scaffold. 1,8-Dihydroxy-10H-acridin-9-one (4), which is an aza-analogue of the antipsoriatic anthralin, was only marginally active. However, 1,3-dihydroxy-substituted 5ee was the most potent acridone within this series and inhibited keratinocyte growth with an IC(50) value comparable to that of anthralin. In contrast to anthralin, nearly all members of the acridone series were devoid of radical generating properties, which were determined by their capability to interact with the free radical 2,2-diphenyl-1-picrylhydrazyl. Structures with a phenolic hydroxyl or an aromatic amine arranged ortho or para to the acridone NH group were exceptions. Also in contrast to anthralin, membrane-damaging effects as documented by the release of lactate dehydrogenase into the culture medium were not observed for acridones. PMID:20452101

Putic, Aleksandar; Stecher, Lambert; Prinz, Helge; Müller, Klaus

2010-08-01

179

Effects of Hepatocyte Growth Factor, Transforming Growth Factor-?1 and Epidermal Growth Factor on Bovine Corneal Epithelial Cells under Epithelial–Keratocyte Interaction in Reconstruction Culture  

Microsoft Academic Search

In the cornea, corneal epithelial cells are in close contact with keratocytes: the epithelial cells organize thickened lamellar structure on a layer of keratocytes embedded in extracellular matrix (ECM). Thus, growth factors are expected to critically regulate corneal component cells under epithelial–keratocyte interaction. The purpose of this study is to clarify effects of hepatocyte growth factor (HGF), transforming growth factor-?1

TOMOHISA NISHIMURA; SHUJI TODA; TAKUYA MITSUMOTO; SHINJI OONO; HAJIME SUGIHARA

1998-01-01

180

Altered (/sup 125/I)epidermal growth factor binding and receptor distribution in psoriasis  

SciTech Connect

Stimulation of growth and differentiation of human epidermis by epidermal growth factor (EGF) is mediated by its binding to specific receptors. Whether EGF receptors primarily mediate cell division or differentiation in hyperproliferative disease such as psoriasis vulgaris is unclear. To study the pathogenesis of psoriasis, 4-mm2 punch biopsy specimens of normal, uninvolved, and involved psoriatic skin were assayed for EGF receptors by autoradiographic, immunohistochemical, and biochemical methods. Using autoradiographic and immunohistochemical methods, basal keratinocytes were found to contain the greatest number of EGF binding sites and immunoreactive receptors as compared to the upper layers of the epidermis in both normal epidermis and psoriatic skin. No EGF receptor differences between normal and psoriatic epidermis were observed in this layer. In the upper layers of the epidermis, a 2-fold increase in EGF binding capacity was observed in psoriatic skin as compared with normal thin or thick skin. Biochemical methods indicated that (/sup 125/I)EGF binding was increased in psoriatic epidermis as compared with similar thickness normal epidermis when measured on a protein basis. Epidermal growth factor was shown to increase phosphorylation of the EGF receptor in skin. EGF receptors retained in the nonmitotic stratum spinosum and parakeratotic stratum corneum may reflect the incomplete, abnormal differentiation that occurs in active psoriatic lesions. Alternatively, retained EGF receptors may play a direct role in inhibiting cellular differentiation in the suprabasal layers.

Nanney, L.B.; Stoscheck, C.M.; Magid, M.; King, L.E. Jr.

1986-03-01

181

PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK)  

SciTech Connect

Polychlorinated biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24 days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism. -- Highlights: ? Human immortal (HaCaT) and primary (NFK) keratinocytes were exposed to PCB153. ? PCB153 significantly reduced telomerase activity and telomere length in HaCaT. ? No effect on telomere length and telomerase activity was found in NFK. ? Increased intracellular superoxide levels and reduced cell growth was seen in both. ? PCB153 may damage telomerase expressing cells like stem cells.

Senthilkumar, P.K. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States)] [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Robertson, L.W. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States) [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA (United States); Ludewig, G., E-mail: Gabriele-ludewig@uiowa.edu [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA (United States)

2012-02-15

182

Connective tissue growth factor in pterygium: simultaneous presence with vascular endothelial growth factor - possible contributing factor to conjunctival scarring  

Microsoft Academic Search

Background. Various growth factors have been detected in pterygium and been associated with its vasculogenesis. The basic pathophysiological mechanisms responsible especially for the fibrotic activity in pterygium are, however, not yet known. Connective tissue growth factor (CTGF) has been shown to be substantially involved in various processes of fibrosis. We report on the presence of CTGF in pterygium and its

Gysbert van Setten; Miltos Aspiotis; Timothy D. Blalock; Gary Grotendorst; Gregory Schultz

2003-01-01

183

Growth factor signalling in endocrine and anti-growth factor resistant breast cancer  

Microsoft Academic Search

Growth factors provide powerful mitogenic and survival signals to breast cancer cells and it is therefore not surprising that\\u000a they are able to subvert inhibitory responses to anti-hormonal drugs. In this review we discuss several mechanisms by which\\u000a this may be achieved and expand our observations to encompass recently emerging anti-growth factor treatments. The information\\u000a presented is underpinned by inhibitor

R. I. Nicholson; I. R. Hutcheson; H. E. Jones; S. E. Hiscox; M. Giles; K. M. Taylor; J. M. W. Gee

2007-01-01

184

Fibroblast Growth Factor Receptor and Platelet-Derived Growth Factor Receptor Abnormalities in Eosinophilic Myeloproliferative Disorders  

Microsoft Academic Search

Rearrangements of the genes encoding the fibroblast growth factor receptor 1 (FGFR1) and platelet-derived growth factor receptors (PDGFR) ? or ? receptor tyrosine kinases are found in a rare but important subset of patients with atypical myeloproliferative disorders that are usually but not always associated with eosinophilia. Chromosomal translocations or other rearrangements at 8p11–12, 4q12 or 5q31–33 give rise to

Nicholas C. P. Cross; Andreas Reiter

2008-01-01

185

Regulation of cell growth and motility by hepatocyte growth factor and receptor expression in various cell species.  

PubMed

Hepatocyte growth factor (HGF), a humoral mediator for regeneration of liver and kidney, possesses multiple biological activities. To investigate target cell specificity and to examine whether multiple actions of HGF are related to properties of the HGF receptor on target cells, we examined the effects of HGF on cell growth and motility and analyzed the HGF receptor in various species of cells. HGF stimulated growth and DNA synthesis of PAM212 (naturally immortalized mouse keratinocytes), Mv1Lu (mink lung epithelia), and A431 (human epidermoid carcinoma) cells, as well as mature hepatocytes, but inhibited those of IM-9 (human B-lymphoblasts). Conversely, HGF had a marked stimulatory effect on cell motility of MDCK (Mardin-Darby canine kidney epithelia) cells, but not on their growth. Also, HGF enhanced the motility of various species of cells, including A431, PAM212, HepG2 (human hepatoma), KB (human epidermoid carcinoma), and J-111 (human monocytes) cells. Scatchard analysis of 125I-HGF binding to hepatocytes indicated that the cells expressed both high- and low-affinity binding sites for HGF with Kd values of 23 and 260 pM, respectively. High-affinity HGF receptor with Kd values of 20-25 pM was detected at 40-720 sites/cell in MDCK, A431, PAM212, Lu99, and IM-9 cells, but not in fibroblasts and hematopoietic cells. In contrast, low-affinity binding sites were detected in all cell lines examined, even in those not responsive to HGF. Northern blots revealed that cells possessing a high-affinity HGF receptor expressed c-MET/HGF receptor mRNA. Therefore, HGF probably regulates both cell growth and motility of various types of epithelial cells and some types of mesenchymal cells. The multiple biological activities of HGF may be exerted through a high-affinity HGF receptor linked to multiple distinct intracellular signaling pathways. PMID:1327854

Tajima, H; Matsumoto, K; Nakamura, T

1992-10-01

186

Epidermal growth factor receptor signaling in tissue  

SciTech Connect

Abstract: A peptide purified from the salivary gland of a mouse was shown few years ago to accelerate incisor eruption and eyelid opening in newborn mice, and was named epidermal growth factor (EGF). The members of this family of peptide growth factors had been identified in numerous physiological and pathological contexts. EGF binds to a cell surface EGF receptor, which induces a biochemical modification (phosphorylation) of the receptor's cytoplasmic tail. There is a growing consensus in the research community that, in addition to cellular and molecular studies, the dynamics of the EGFR network and its operation must be examined in tissues. A key challenge is to integrate the existing molecular and cellular information into a system-level description of the EGFR network at the tissue and organism level. In this paper, the two examples of EGFR signaling in tissues are described, and the recent efforts to model EGFR autocrine loops, which is a predominant mode of EGFR activation in vivo, are summarized.

Shvartsman, Stanislav; Wiley, H. S.; Lauffenburger, Douglas A.

2004-08-01

187

Vascular Endothelial Growth Factor Overexpression Increases Vascularization by Murine But Not Human Endothelial Cells in Cultured Skin Substitutes Grafted to Athymic Mice  

PubMed Central

Cultured skin substitutes (CSS) consisting of fibroblasts, keratinocytes, and biopolymers are an adjunctive treatment for large burns. Because CSS lack a vascular plexus, they vascularize more slowly than split-thickness autografts. Previously, CSS were prepared with dermal microvascular endothelial cells (ECs), which formed vascular analogs at a low frequency but did not contribute to increased vascularization after grafting. The present study addressed whether keratinocytes genetically modified to overexpress vascular endothelial growth factor (VEGF), an endothelial cell mitogen, could improve the persistence and organization of ECs in CSS. CSS were prepared with control or VEGF-modified keratinocytes, with (CSS + ECs) or without added ECs, and were grafted to full-thickness wounds in athymic mice. Elevated VEGF expression was detected in VEGF-modified CSS and CSS + ECs compared with controls, but no significant difference in EC density in vitro was observed. After grafting, VEGF-modified CSS and CSS + ECs showed enhanced vascularization, and organization of human ECs into multicellular structures in CSS + ECs was observed. However, VEGF overexpression did not significantly enhance the proliferation of human ECs, suggesting that other factors may be required. Improved persistence and organization of human ECs in vitro will likely be required for their participation in vascularization of CSS + ECs after grafting. PMID:15247832

Supp, Dorothy M.; Karpinski, Andrea C.; Boyce, Steven T.

2007-01-01

188

Vascular Permeability\\/Vascular Endothelial Growth Factor  

Microsoft Academic Search

The vascular permeability factor (VPF)\\/vascular endothelial growth factor (VEGF) family has more than seven members including\\u000a VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, PlGF, and Trimeresurus flavoviridis (T. f.) svVEGFs. Except for VEGF-E and T.f. svVEGFs, all members are encoded in the mammalian genome and involved in angiogenesis and\\/or lymphangiogenesis. Among these\\u000a five gene products, VEGF-A (also known as VEGF and VPF)

Masabumi Shibuya

189

Epidermal Growth Factor Receptor-Targeted Therapies  

Microsoft Academic Search

\\u000a The epidermal growth factor receptor (EGFR) has been implicated in the progression and maintenance of various solid tumors.\\u000a Efforts in understanding EGFR biology and related signaling cascades have lead to the development of anti-EGFR agents. The\\u000a two main approaches of inhibition that have been ­studied most extensively are monoclonal antibodies and tyrosine kinase inhibitors.\\u000a Despite clear evidence of antitumor activity

Sun M. Ahn; Seungwon Kim; Jennifer R. Grandis

190

Growth Factors and Tension-Induced Skeletal Muscle Growth  

NASA Technical Reports Server (NTRS)

The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we have performed experiments to determine whether mechanical stimulation of cultured avian muscle cells alters their response to anabolic steroids or glucocorticoids. In static cultures, testosterone had no effect on muscle cell growth, but 5alpha-dihydrotestosterone and the synthetic steroid stanozolol increased cell growth by up to 18% and 30%, respectively, after a three day exposure. We completed development of a new IBM-based mechanical cell stimulator system to provide greater flexibility in operating and monitoring our experiments. Our previous long term studies on myofiber growth were designed around a perfusion system of our own design. We have recently changed to performing these studies using a modified CELLCO cartridge bioreactor system Z since it has been certified as the ground-based model for the Shuttle's Space Tissue Loss (STL) F= Cell Culture Module. The current goals of this aspect of the project are three fold: 1) to design a Z cell culture system for studying avian skeletal myofiber atrophy on the Shuttle and Space Station; 0 2) to expand the use of bioreactors to cells which do not grow in either suspension or attached to the hollow fibers; and 3) to combine the bioreactor system with our computerized mechanical cell stimulator to have a better in vitro model to study tension/gravity/stretch regulation of skeletal muscle size. Preliminary studies also reported on involved : (1) how release of tension can induce rapid atrophy of tissues cultured avian skeletal muscle cells, and (2) a mechanism to transfer and maintain avian skeletal muscle organoids in modified cartridges in the Space Tissue Loss Module.

Vandenburgh, Herman H.

1994-01-01

191

Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair  

PubMed Central

Significance: Angiogenesis, the growth of new blood vessels from existing vessels, is an important aspect of the repair process. Restoration of blood flow to damaged tissues provides oxygen and nutrients required to support the growth and function of reparative cells. Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic growth factors in the skin, and the amount of VEGF present in a wound can significantly impact healing. Recent Advances: The activity of VEGF was once considered to be specific for endothelial cells lining the inside of blood vessels, partly because VEGF receptor (VEGFR) expression was believed to be restricted to endothelial cells. It is now known, however, that VEGFRs can be expressed by a variety of other cell types involved in wound repair. For example, keratinocytes and macrophages, which both carry out important functions during wound healing, express VEGFRs and are capable of responding directly to VEGF. Critical Issues: The mechanisms by which VEGF promotes angiogenesis are well established. Recent studies, however, indicate that VEGF can directly affect the activity of several nonendothelial cell types present in the skin. The implications of these extra-angiogenic effects of VEGF on wound repair are not yet known, but they suggest that this growth factor may play a more complex role during wound healing than previously believed. Future Directions: Despite the large number of studies focusing on VEGF and wound healing, it is clear that the current knowledge of how VEGF contributes to the repair of skin wounds is incomplete. Further research is needed to obtain a more comprehensive understanding of VEGF activities during the wound healing process. PMID:25302139

Johnson, Kelly E.; Wilgus, Traci A.

2014-01-01

192

Automatic generation of causal networks linking growth factor stimuli to functional cell state changes.  

PubMed

Despite the increasing number of growth factor-related signalling networks, their lack of logical and causal connection to factual changes in cell states frequently impairs the functional interpretation of microarray data. We present a novel method enabling the automatic inference of causal multi-layer networks from such data, allowing the functional interpretation of growth factor stimulation experiments using pathway databases. Our environment of evaluation was hepatocyte growth factor-stimulated cell migration and proliferation in a keratinocyte-fibroblast co-culture. The network for this system was obtained by applying the steps: (a) automatic integration of the comprehensive set of all known cellular networks from the Pathway Interaction Database into a master structure; (b) retrieval of an active-network from the master structure, where the network edges that connect nodes with an absent mRNA level were excluded; and (c) reduction of the active-network complexity to a causal subnetwork from a set of seed nodes specific for the microarray experiment. The seed nodes comprised the receptors stimulated in the experiment, the consequently differentially expressed genes, and the expected cell states. The resulting network shows how well-known players, in the context of hepatocyte growth factor stimulation, are mechanistically linked in a pathway triggering functional cell state changes. Using BIOQUALI, we checked and validated the consistency of the network with respect to microarray data by computational simulation. The network has properties that can be classified into different functional layers because it not only shows signal processing down to the transcriptional level, but also the modulation of the network structure by the preceeding stimulation. The software for generating computable objects from the Pathway Interaction Database database, as well as the generated networks, are freely available at: http://www.tiga.uni-hd.de/supplements/inferringFromPID.html. PMID:22540519

Guziolowski, Carito; Kittas, Aristotelis; Dittmann, Florian; Grabe, Niels

2012-09-01

193

Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors  

PubMed Central

Purpose of review To summarize recent evidence that IGF1 mediates growth effects of multiple trophic factors and discuss clinical relevance. Recent findings Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogues in short bowel syndrome and Crohn’s disease. This review highlights evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn’s disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that SOCS protein induction by GH or GLP2 in normal or inflamed intestine, may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. Summary IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed. PMID:22241077

Bortvedt, Sarah F.; Lund, P. Kay

2013-01-01

194

The role of connective tissue growth factor in skeletal growth and development  

E-print Network

The role of connective tissue growth factor in skeletal growth and development Reem A. Kanaan1 Gloucestershire Royal Hospital, U.K. Source of support: Self financing Summary Connective tissue growth factor-61, CTGF, NOV family; CTGF ­ connective tissue growth factor; Cyr61/CCN1 ­ cysteine-rich 61; NOV/CCN3

195

The Insulin-Like Growth Factor System  

PubMed Central

The insulin-like growth factor (IGF) system in ubiquitous and plays a role in every tissue of the body. It is comprised of ligands, receptors and binding proteins, each with specific functions. While it plays an essential role in embryonic and post-natal development, the IGF system is also important in normal adult physiology. There are now numerous examples of diseases such as diabetes, cancer, and malnutrition in which the IGF system is a major player and, not surprisingly, there are attempts to affect these disorders by manipulating the system. PMID:14668044

2003-01-01

196

Reduced Expression of Fibroblast Growth Factor Receptor 2IIIb in Hepatocellular Carcinoma Induces a More Aggressive Growth  

PubMed Central

Fibroblast growth factor receptor 2 isoform b (FGFR2-IIIb) is highly expressed in hepatocytes and plays an important role in liver homeostasis and regeneration. Here, we analyzed the expression and function of FGFR2-IIIb in hepatocellular carcinoma (HCC). FGFR2-IIIb expression in HCC tissues and cell lines was lower than in primary human hepatocytes and nontumorous tissue. FGFR2-IIIb-negative HCCs showed a significantly higher Ki-67 labeling index, and loss of FGFR2-IIIb expression correlated significantly with vascular invasion and more advanced tumor stages. A decrease in FGFR-2IIIb expression in HCC cell lines was not related to promoter hypermethylation. However, PCR analysis indicated that chromosomal deletion at 10q accounted for the loss of FGFR2 expression in a subset of HCC cells. FGFR2-IIIb re-expression in stable transfected HCC cell lines induced a higher basal apoptosis rate and a significantly reduced proliferation and migratory potential in vitro. In nude mice, FGFR2-IIIb re-expressing HCC cells grew significantly slower, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay revealed higher apoptosis rates. The antitumorigenic effects of FGFR2-IIIb expression in HCC cells were not affected by keratinocyte growth factor or an inhibitor of FGFR-phosphorylation, indicating that they are independent of tyrosine kinase activation. In conclusion, our data indicate that FGFR2-IIIb inhibits tumorigenicity of HCC cells. Identification of the molecular mechanisms promoting regeneration in normal tissue while suppressing malignancy may lead to novel therapeutic targets of this highly aggressive tumor. PMID:20093481

Amann, Thomas; Bataille, Frauke; Spruss, Thilo; Dettmer, Katja; Wild, Peter; Liedtke, Christian; Mühlbauer, Marcus; Kiefer, Paul; Oefner, Peter J.; Trautwein, Christian; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

2010-01-01

197

Characterization of insulin-like growth factor I and epidermal growth factor receptors in meningioma  

SciTech Connect

Receptors for insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) were localized and characterized in eight samples of human meningioma (four fibrous, two meningothelial, and two angioblastic types), using quantitative autoradiographic techniques. Effects of both growth factors on deoxyribonucleic acid (DNA) synthesis in the cultured meningioma cells were examined. High numbers of specific binding sites for both IGF-I and EGF were homogeneously present in tissue sections derived from fibrous and meningothelial types of meningiomas, whereas binding sites for these growth factors were not detectable in adjacent leptomeninges. While relatively large numbers of IGF-I binding sites were located in the wall of the intratumoral vasculature, the number of binding sites in the stromal component was lower in angioblastic-type meningiomas, including a low number of EGF binding sites detected only in the stromal portion. Scatchard analysis revealed the presence of a single class of high-affinity binding sites for both IGF-I and EGF in the meningiomas examined (dissociation constant (Kd) = 0.6 to 2.9 nM, and the maximum number of binding sites (Bmax) = 16 to 80 fmol/mg for IGF-I; and Kd = 0.6 to 4.0 nM, Bmax = 3 to 39 fmol/mg for EGF). Both growth factors increased the synthesis of DNA, in a dose-dependent manner, as measured by 3H-thymidine incorporation. The combination of IGF-I and EGF synergistically stimulated the synthesis of DNA, and the effects seen with 10% fetal bovine serum could be reproduced at a concentration of 10(-10) M. These observations can be interpreted to mean that both IGF-I and EGF may be involved in the growth modulation of meningiomas, possibly through paracrine or autocrine mechanisms.

Kurihara, M.; Tokunaga, Y.; Tsutsumi, K.; Kawaguchi, T.; Shigematsu, K.; Niwa, M.; Mori, K. (Nagasaki Univ. School of Medicine (Japan))

1989-10-01

198

Growth Factors in Wound Healing: The Present and the Future?  

PubMed

Clinical studies confirm the pivotal role of growth factors in wound healing and their diminished levels in the chronic wound. Results with traditional bolus dosing of a single growth factor have yielded insignificant results, which may be the result of the inherent short half-life of growth factors, hostile microenvironment rich in protease activity, and poor delivery mechanisms. Technologies capable of delivering multiple growth factors in a spatially oriented approach include polymer systems, scaffolds, and hydrogels. With improved delivery systems, treating chronic wounds with growth factors potentially accelerates healing in a manner not previously realized with traditional delivery approaches. PMID:25440422

Dinh, Thanh; Braunagel, Shawn; Rosenblum, Barry I

2015-01-01

199

Scatter factor\\/hepatocyte growth factor is essential for liver development  

Microsoft Academic Search

POLYPEPTIDE growth factors are important effectors of cell growth and differentiation in vitro and are thought to be critical for processes such as specification of cell fate, tissue growth and organogenesis in vivo. Scatter factor1-3\\/hepatocyte growth factor4,5 (SF\\/HGF) is the prototype of an emerging family of growth factors that resemble in their domain structure and mechanism of activation the blood

Claudia Schmidt; Friedhelm Bladt; Stefanie Goedecke; Volker Brinkmann; Wolfgang Zschiesche; Melanie Sharpe; Ermanno Gherardi; Carmen Birchmeler

1995-01-01

200

Explaining Economic Growth: Factor Accumulation, Total Factor Productivity Growth, and Production Efficiency Improvement  

E-print Network

in per capita growth rates. Even after accounting for human capital accumulation, a growing body on the original work of the fixed-factor proportions model of Harrod (1939) and Domar (1946) and the dual of research suggests that something other than capital, labor, and human capital accounts for the bulk

Ahmad, Sajjad

201

Epidermal Expression of Neuropilin 1 Protects Murine keratinocytes from UVB-induced apoptosis  

PubMed Central

Background Neuropilin 1 (NRP1) is expressed on several cell types including neurons and endothelial cells, where it functions as an important regulator in development and during angiogenesis. As a cell surface receptor, NRP1 is able to bind to members of the VEGF family of growth factors and to secreted class 3 semaphorins. Neuropilin 1 is also highly expressed in keratinocytes, but the function of NRP1 in epidermal physiology and pathology is still unclear. Methods and Results To elucidate the role of NRP1 in skin in vivo we generated an epidermis-specific neuropilin 1 knock out mouse model by using the Cre-LoxP-System. Mice were viable and fertile and did not display any obvious skin or hair defects. After challenge with UVB irradiation, we found that deletion of epidermal NRP1 leads to increased rates of apoptosis both in vitro and in vivo. NRP1-deficient primary keratinocytes cultured in vitro showed significantly higher rates of apoptosis 24 hours after UVB. Likewise, there is a significant increase of active caspase 3 positive cells in the epidermis of Keratin 14-Cre-NRP1 (?/?) mice 24 hours after UVB irradiation. By Western Blot analysis we could show that NRP1 influences the cytosolic levels of Bcl-2, a pro-survival member of the Bcl-2 family. After UVB irradiation the amounts of Bcl-2 decrease in both protein extracts from murine epidermis and in NRP1-deficient keratinocytes in vitro, whereas wild type cells retain their Bcl-2 levels. Likewise, levels of phospho-Erk and Rac1 were lower in NRP1-knock out keratinocytes, whereas levels of pro-apoptotic p53 were higher. Conclusion NRP1 expression in keratinocytes is dispensable for normal skin development. Upon UVB challenge, NRP1 contributes to the prevention of keratinocyte apoptosis. This pro-survival function of NRP1 is accompanied by the maintenance of high levels of the antiapoptotic regulator Bcl-2 and by lower levels of pro-apoptotic p53. PMID:23251405

Riese, Anna; Eilert, Yvonne; Meyer, Yvonne; Arin, Meral; Baron, Jens M.; Eming, Sabine; Krieg, Thomas; Kurschat, Peter

2012-01-01

202

Epidermal growth factor signaling in transformed cells.  

PubMed

Members of the epidermal growth factor receptor (EGFR/ErbB) family play a critical role in normal cell growth and development. However, many ErbB family members, especially EGFR, are aberrantly expressed or deregulated in tumors and are thought to play crucial roles in cancer development and metastatic progression. In this chapter, we provide an overview of key mechanisms contributing to aberrant EGFR/ErbB signaling in transformed cells, which results in many phenotypic changes associated with the earliest stages of tumor formation, including several hallmarks of epithelial-mesenchymal transition (EMT). These changes often occur through interaction with other major signaling pathways important to tumor progression, causing a multitude of transcriptional changes that ultimately impact cell morphology, proliferation, and adhesion, all of which are crucial for tumor progression. The resulting mesh of signaling networks will need to be taken into account as new regimens are designed for targeting EGFR for therapeutic intervention. As new insights are gained into the molecular mechanisms of cross talk between EGFR signaling and other signaling pathways, including their roles in therapeutic resistance to anti-EGFR therapies, a continual reassessment of clinical therapeutic regimes and strategies will be required. Understanding the consequences and complexity of EGF signaling and how it relates to tumor progression is critical for the development of clinical compounds and establishing clinical protocols for the treatment of cancer. PMID:25619714

Lindsey, Stephan; Langhans, Sigrid A

2015-01-01

203

The role of the tetraspanin CD151 in primary keratinocyte and fibroblast functions: Implications for wound healing  

SciTech Connect

Previous studies showed that CD151-null mice have a skin wound healing deficit. To gain an understanding of the role of CD151 in re-epithelialisation and dermal contraction, keratinocyte and fibroblast functions were assayed. Primary CD151-null keratinocytes displayed defective migration on Matrigel (a basement membrane equivalent) and laminin-332, the primary adhesion component of basement membranes, but not on collagen-I. Adhesion, spreading and proliferation were also deficient on laminin-332, but not collagen-I. The data suggest that loss of CD151 impairs the function of its primary interaction partners, integrin {alpha}3{beta}1- and/or {alpha}6{beta}4 which bind to laminin-332. Skin fibroblasts also produce CD151 mRNA. CD151-null fibroblasts migrated significantly faster on collagen I than wild type fibroblasts, confirming that they possess functional collagen receptors. However, no significant decrease in the ability of CD151-null fibroblasts to cause contraction in floating collagen gel assays in response to transforming growth factor beta-1 (TGF-{beta}1) or platelet derived growth factor (PDGF-BB) was observed, nor was there an effect on fibroblast adhesion or proliferation on collagen-I. The data implicate CD151 as a facilitator of laminin-332-mediated keratinocyte functions that impact on the re-epithelialisation process intrinsic to wound healing and further suggest a potential novel role for CD151 in fibroblast migration.

Geary, Sean M. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia); Cowin, Allison J. [Child Health Research Institute, North Adelaide, South Australia (Australia); Department of Paediatrics, University of Adelaide, South Australia (Australia); Copeland, Ben; Baleato, Rosa M. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia); Miyazaki, Kaoru [Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Yokohama (Japan); Ashman, Leonie K. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia)], E-mail: leonie.ashman@newcastle.edu.au

2008-07-01

204

Endorsement of Growth Factors in Experiential Training Groups  

ERIC Educational Resources Information Center

The purpose of this study was to identify student growth factors during a semester long Master's level group counseling class. Results indicated that 12 growth factors accounted for 86% of the total number of critical incidents that participants reported as influencing their personal growth and awareness during the group experience. Two other…

Kiweewa, John; Gilbride, Dennis; Luke, Melissa; Seward, Derek

2013-01-01

205

Insulin-like Growth Factor Binding Protein-4 Differentially Inhibits Growth Factor-induced Angiogenesis*  

PubMed Central

An in-depth understanding of the molecular and cellular complexity of angiogenesis continues to advance as new stimulators and inhibitors of blood vessel formation are uncovered. Gaining a more complete understanding of the response of blood vessels to both stimulatory and inhibitory molecules will likely contribute to more effective strategies to control pathological angiogenesis. Here, we provide evidence that endothelial cell interactions with structurally altered collagen type IV may suppress the expression of insulin-like growth factor binding protein-4 (IGFBP-4), a well documented inhibitor of the IGF-1/IGF-1R signaling axis. We report for the first time that IGFBP-4 differentially inhibits angiogenesis induced by distinct growth factor signaling pathways as IGFBP-4 inhibited FGF-2- and IGF-1-stimulated angiogenesis but failed to inhibit VEGF-induced angiogenesis. The resistance of VEGF-stimulated angiogenesis to IGFBP-4 inhibition appears to depend on sustained activation of p38 MAPK as blocking its activity restored the anti-angiogenic effects of IGFBP-4 on VEGF-induced blood vessel growth in vivo. These novel findings provide new insight into how blood vessels respond to endogenous inhibitors during angiogenesis stimulated by distinct growth factor signaling pathways. PMID:22134921

Contois, Liangru W.; Nugent, Desiree P.; Caron, Jennifer M.; Cretu, Alexandra; Tweedie, Eric; Akalu, Abebe; Liebes, Leonard; Friesel, Robert; Rosen, Clifford; Vary, Calvin; Brooks, Peter C.

2012-01-01

206

Connective Tissue Growth Factor: What's in a Name?  

Microsoft Academic Search

Connective tissue growth factor (CTGF) is a member of the recently described CCN gene family which contains CTGF itself, cyr61, nov, elm1, Cop1, and WISP-3. CTGF is transcriptionally activated by several factors although its stimulation by transforming growth factor ? (TGF-?) has attracted considerable attention. CTGF acts to promote fibroblast proliferation, migration, adhesion, and extracellular matrix formation, and its overproduction

Essam El-Din A. Moussad; David R. Brigstock

2000-01-01

207

Interleukin-7 is a growth factor for Sézary lymphoma cells.  

PubMed Central

Sézary syndrome is a cutaneous T cell lymphoma characterized by infiltration of the skin by CD4+ cells. These cells generally respond poorly to mitogens and T cell activators. We have studied the action of IL1 to IL4, IL6, and IL7 on the proliferation of Sézary cells from 12 patients. With the exception of IL2 and IL7, the cytokines studied had no proliferative effect on these cells. Whereas IL2 had only a low proliferative capacity (two- to threefold increase) on peripheral blood mononuclear cells, recombinant IL7 constantly induced a very significant (3-40-fold increase) proliferative response, and was used successfully to generate cell lines in three out of eight cases. Growth of Sézary cell lines was shown to be strictly dependent on IL7, and after 2-5 wk of culture presented a switch to a homogeneous phenotype CD3+4+8-7- (except for one line that remained CD7+), with a typical morphology of Sézary cells. Their tumoral origin was demonstrated by the expression of the same T cell receptor-beta gene rearrangement as the patients' T cells. Importantly, cultured normal epidermal keratinocyte supernatants could support the growth of our Sézary lines. Furthermore, the proliferative activity contained in these supernatants was completely blocked by a monoclonal anti-IL7 antibody. These results suggest that IL7 may, therefore, represent an important cytokine in the physiopathology of cutaneous T cell lymphoma. Images PMID:1381718

Dalloul, A; Laroche, L; Bagot, M; Mossalayi, M D; Fourcade, C; Thacker, D J; Hogge, D E; Merle-Béral, H; Debré, P; Schmitt, C

1992-01-01

208

Pigment-independent cAMP-mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation  

PubMed Central

The epidermis increases pigmentation and epidermal thickness in response to ultraviolet exposure to protect against UV-associated carcinogenesis; however, the contribution of epidermal thickness has been debated. In a humanized skin mouse model that maintains interfollicular epidermal melanocytes, we found that forskolin, a small molecule that directly activates adenylyl cyclase and promotes cAMP generation, up-regulated epidermal eumelanin accumulation in fair-skinned melanocortin-1-receptor (Mc1r)-defective animals. Forskolin-induced pigmentation was associated with a reproducible expansion of epidermal thickness irrespective of melanization or the presence of epidermal melanocytes. Rather, forskolin-enhanced epidermal thickening was mediated through increased keratinocyte proliferation, indirectly through secreted factor(s) from cutaneous fibroblasts. We identified keratinocyte growth factor (Kgf) as a forskolin-induced fibroblast-derived cytokine that promoted keratinocyte proliferation, as forskolin induced Kgf expression both in the skin and in primary fibroblasts. Lastly, we found that even in the absence of pigmentation, forskolin-induced epidermal thickening significantly diminished the amount of UVA and UVB that passed through whole skin and reduced the amount of UVB-associated epidermal sunburn cells. These findings suggest the possibility of pharmacologic-induced epidermal thickening as a novel UV-protective therapeutic intervention, particularly for individuals with defects in pigmentation and adaptive melanization. PMID:23078399

Scott, Timothy L.; Christian, P.A.; Kesler, M.; Donohue, Kevin M.; Shelton, Brent; Wakamatsu, Kazumasa; Ito, Shosuke; D’Orazio, John

2012-01-01

209

Terminal Differentiation of Normal Human Oral Keratinocytes Is Associated with Enhanced Cellular TGF-? and Phospholipase C-?1 Levels and Apoptotic Cell Death  

Microsoft Academic Search

Subculture of primary normal human oral keratinocytes (NHOK) results in terminal differentiation, leading to cell death. To investigate whether the subculture-induced death of NHOK is due to apoptosis, we studied transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, DNA fragmentation, and expression of several apoptosis-associated genes from NHOK with different passage numbers. We also determined the effect of transforming growth factor

Byung-Moo Min; Kyung Mi Woo; Gene Lee; No-Hee Park

1999-01-01

210

Epidermal Growth Factor Receptor Dynamics Influences Response to Epidermal Growth Factor Receptor Targeted Agents  

Microsoft Academic Search

Analysis of gene expression of cancer cell lines exposed to erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR), showed a marked increase in EGFR mRNA in resistant cell lines but not in susceptible ones. Because cetuximab induces EGFR down-regulation, we explored the hypothesis that treatment with cetuximab would interfere with erlotinib-induced EGFR up-regulation and result in

Antonio Jimeno; Maria L. Amador; Nadia Bouraoud; Peter Kulesza; Anirban Maitra; Manuel Hidalgo

2005-01-01

211

Basic fibroblast growth factor induced angiogenesis and prefabricated flap survival.  

PubMed

Prefabrication of a latissimus dorsi myocutaneous flap was performed in adult male Landrace pigs. Gelfoam sponges were used as a delivery system for basic fibroblast growth factor (bFGF) at the muscle-subcutaneous tissue interface. Skin survival and angiogenesis were augmented in the growth-factor-treated animals. These data support the use of basic fibroblast growth factor to enhance flap prefabrication. PMID:11316283

Haws, M J; Erdman, D; Bayati, S; Brown, R E; Russell, R C

2001-01-01

212

Uptake of oligonucleotides by keratinocytes.  

PubMed

Oligonucleotides (ODNs) conjugated to rhodamin (Rh) and 4-[(N-2-chloroethyl-N-methyl)amino] benzylamine were used to investigate ODNs transport into keratinocytes. Affinity labeling of two proteins, 63 and 35 kDa, and the inhibition of the affinity labeling and ODNs uptake by the cells in the presence of nucleic acids, polyanions and trypsin suggest, that the proteins are involved in transport of nucleic acids in keratinocytes. PMID:10474249

Laktionov, P; Dazard, J E; Piette, J; Vives, E; Rykova, E; Vlassov, V; Lebleu, B

1999-01-01

213

Novel Drosophila receptor that binds multiple growth factors  

SciTech Connect

The authors have recently reported the identification of a novel growth factor receptor from Drosophila cell cultures that has dual binding specificity for both insulin and epidermal growth factor (EGF). This 100 kDa protein is also antigenically related to the cytoplasmic region of the mammalian EGF receptor-tyrosine kinase. They now report that this protein binds to mammalian nerve growth factor and human transforming growth factor alpha as well as insulin and EGF with apparent dissociation constants ranging from 10/sup -6/ to 10/sup -8/ M. The 100 kDa protein can be affinity-labeled with these /sup 125/I-labeled growth factors after immunoprecipitation with anti-EGF receptor antiserum. These four growth factors appear to share a common binding site, as evidenced by their ability to block affinity labelling by /sup 125/I-insulin. No significant binding to the 100 kDa protein was observed with platelet-derived growth factor, transforming growth factor beta, or glucagon. The 100 kDa Drosophila protein has a unique ligand-binding spectrum with no direct counterpart in mammalian cells and may represent an evolutionary precursor of the mammalian receptors for these growth factors.

Rosner, M.R.; Thompson, K.L.; Garcia, V.; Decker, S.J.

1986-05-01

214

Effect of gamma-hydroxybutyrate on keratinocytes proliferation: A preliminary prospective controlled study in severe burn patients  

PubMed Central

Background: Hypermetabolism and hyposomatotropism related to severe burns lead to impaired wound healing. Growth hormone (GH) boosts wound healing notably following stimulation of the production of insulin-like growth factor-1 (IGF1), a mitogen factor for keratinocytes. Gamma-hydroxybutyrate (GHB) stimulates endogenous GH secretion. Aim: To assess effects of GHB sedation on keratinocytes proliferation (based on immunohistochemical techniques). Design: Monocentric, prospective, controlled trial. Materials and Methods: Patients (aging 18-65 years, burn surface area >30%, expected to be sedated for at least one month) were alternately allocated, at the 5th day following injury, in three groups according to the intravenous GHB dose administered for 21 days: Evening bolus of 50 mg/kg (Group B), continuous infusion at the rate of 10 mg/kg/h (Group C), or absence of GHB (Group P). They all received local standard cares. Immunohistochemistry (Ki67/MIB-1, Ulex europaeus agglutinin-1 and Mac 387 antibodies) was performed at D21 on adjacent unburned skin sample for assessing any keratinocyte activation. Serum IGF1 levels were measured at initiation and completion of the protocol. Statistical Analysis: Categorical variables were compared with Chi-square test. Comparisons of medians were made using Kruskal-Wallis test. Post hoc analyses were performed using Mann-Whitney test with Bonferroni correction for multiple comparisons. A P < 0.05 was considered to be statistically significant. Results: A total of 14 patients completed the study (Group B: n = 5, Group C: n = 5, Group P: n = 4). Continuous administration of GHB was associated with a significant higher Ki67 immunolabeling at D21 (P = 0.049) and with a significant higher increase in the IGF1 concentrations at D21 (P = 0.024). No adverse effects were disclosed. Conclusions: Our preliminary data support a positive effect of GHB on keratinocyte proliferation and are encouraging enough to warrant large prospective studies. PMID:25024938

Rousseau, Anne-Françoise; Bargues, Laurent; Bever, Hervé Le; Vest, Philippe; Cavalier, Etienne; Ledoux, Didier; Piérard, Gérald E.; Damas, Pierre

2014-01-01

215

[Epidermal growth factor, innovation and safety.  

PubMed

Bioidentical recombinant human epidermal growth factor (rhEGF) is available in concentrations and purity suitable for therapeutic use in long time stable formulations. Beneficial effects in several skin pathologies and lesions have been reported (traumatic and surgical wound healing, laser induced wounds, abnormal scars, keloids, radiation or chemotherapy induced dermatitis, post inflammatory hyperpigmentation or for skin aging damage repairing) and also may be considered for the treatment of several oropharingeal and high gastroesophageal tract mucosa diseases (mouth sores, pharyngeal fistulas, ulcers), and several corneal or conjunctive mucosa lesions. rhEGF has not shown any important side or collateral effects in humans or in laboratory experimentation animals, showing optimal tolerability and safety with continuous use for months. Compounding gives advantages of versatility, individualization, personalization, molecular stability, safety and effectiveness in ideal conditions, showing good tissue penetration, both on intact skin and skin lesions that expose the lower planes to the surface. rhEGF compounds can be considered for prevention or as a treatment of diverse skin and mucosa diseases and conditions through compounding preparations. PMID:25433777

Esquirol Caussa, Jordi; Herrero Vila, Elisabeth

2014-11-26

216

Connective tissue growth factor in tumor pathogenesis  

PubMed Central

Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood. High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors. PMID:23259759

2012-01-01

217

Slow release of ions from internalized silver nanoparticles modifies the epidermal growth factor signaling response.  

PubMed

Due to their distinctive physiochemical properties, including a robust antibacterial activity and plasmonic capability, hundreds of consumer and medical products contain colloidal silver nanoparticles (AgNPs). However, even at sub-toxic dosages, AgNPs are able to disrupt cell functionality, through a yet unknown mechanism. Moreover, internalized AgNPs have the potential to prolong this disruption, even after the removal of excess particles. In the present study, we evaluated the impact, mechanism of action, and continual effects of 50nm AgNP exposure on epidermal growth factor (EGF) signal transduction within a human keratinocyte (HaCaT) cell line. After AgNP expose, EGF signaling was initially obstructed due to the dissolution of particles into silver ions. However, at longer durations, the internalized AgNPs increased EGF signaling activity. This latter behavior correlated to sustained HaCaT stress, believed to be maintained through the continual dissolution of internalized AgNPs. This study raises concerns that even after exposure ceases, the retained nanomaterials are capable of acting as a slow-release mechanism for metallic ions; continually stressing and modifying normal cellular functionality. PMID:25260222

Comfort, Kristen K; Maurer, Elizabeth I; Hussain, Saber M

2014-11-01

218

Expression of transforming growth factor-beta isoforms and their receptors in lepromatous and tuberculoid leprosy.  

PubMed

Leprosy is an infectious disease with two polar forms, tuberculoid leprosy (TT) and lepromatous leprosy (LL), that are characterized by strong cell-mediated immunity (CMI) and CMI anergy, respectively. Transforming growth factor-beta (TGF-beta) belongs to a family of pleiotropic cytokines (TGF-beta1, TGF-beta2 and TGF-beta3) that participate in the control of cell differentiation and proliferation, as well as tissue repair. This cytokine family is unique because it suppresses CMI. In this study, we compared the expression of the three TGF-beta isoforms and their receptors in skin biopsies from LL and TT patients (LL = 20; TT = 20) using immunohistochemistry and automated morphometry. The percentage of cells immunostained for the three TGF-beta isoforms and cells positive for the three TGF-beta receptors in the inflammatory infiltrate located in the papillary dermis, reticular dermis and periadnexal tissue were significantly higher in LL than that in TT, with macrophages being the most common and strongest immunoreactive cells. Some lymphocytes, fibroblasts, keratinocytes and epithelial cells from sweat glands and hair roots were also positive. In situ reverse-transcription polymerase chain reaction corroborated the capacity of these cells to synthesize TGF-beta1 and TGF-beta receptor 2. This high expression of TGF-beta isoforms and their receptors could contribute to CMI anergy and other clinical characteristic features of leprosy, like skin atrophy. PMID:12641657

Kiszewski, C A; Becerril, E; Baquera, J; Aguilar, L D; Hernández-Pando, R

2003-03-01

219

Oncogenic Human Papillomaviruses Activate the Tumor-Associated Lens Epithelial-Derived Growth Factor (LEDGF) Gene  

PubMed Central

The expression of the human papillomavirus (HPV) E6/E7 oncogenes is crucial for HPV-induced malignant cell transformation. The identification of cellular targets attacked by the HPV oncogenes is critical for our understanding of the molecular mechanisms of HPV-associated carcinogenesis and may open novel therapeutic opportunities. Here, we identify the Lens Epithelial-Derived Growth Factor (LEDGF) gene as a novel cellular target gene for the HPV oncogenes. Elevated LEDGF expression has been recently linked to human carcinogenesis and can protect tumor cells towards different forms of cellular stress. We show that intracellular LEDGF mRNA and protein levels in HPV-positive cancer cells are critically dependent on the maintenance of viral oncogene expression. Ectopic E6/E7 expression stimulates LEDGF transcription in primary keratinocytes, at least in part via activation of the LEDGF promoter. Repression of endogenous LEDGF expression by RNA interference results in an increased sensitivity of HPV-positive cancer cells towards genotoxic agents. Immunohistochemical analyses of cervical tissue specimens reveal a highly significant increase of LEDGF protein levels in HPV-positive lesions compared to histologically normal cervical epithelium. Taken together, these results indicate that the E6/E7-dependent maintenance of intracellular LEDGF expression is critical for protecting HPV-positive cancer cells against various forms of cellular stress, including DNA damage. This could support tumor cell survival and contribute to the therapeutic resistance of cervical cancers towards genotoxic treatment strategies in the clinic. PMID:24604027

Leitz, Jenny; Reuschenbach, Miriam; Lohrey, Claudia; Honegger, Anja; Accardi, Rosita; Tommasino, Massimo; Llano, Manuel; von Knebel Doeberitz, Magnus; Hoppe-Seyler, Karin; Hoppe-Seyler, Felix

2014-01-01

220

Growth factor involvement in tension-induced skeletal muscle growth  

NASA Technical Reports Server (NTRS)

New muscle tissue culture techniques were developed to grow embryonic skeletal myofibers which are able to differentiate into more adultlike myofibers. Studies on mechanical simulation of cultured muscle cell growth will now be more directly applicable to mechanically-induced growth in adult muscle, and lead to better models for understanding muscle tissue atrophy caused by disuse in the microgravity of space.

Vandenburgh, Herman W.

1987-01-01

221

Original article Insulin-like growth factorI during growth in bulls  

E-print Network

hormones. Growth hor- mone (GH) and insulin-like growth factorI (IGFi) are of primary importance (Spen- cer- mones, besides other factors (Clemmons and Van Wyk, 1984; Spencer, 1985). In cattle IGF1 is modified by growth hor- mone and by energy intake (Elsasser e t al., 1986; Ronge et al., 1988; Ronge and Blum

Paris-Sud XI, Université de

222

T helper type 1 cytokines and keratinocyte growth factor play a critical role in pseudoepitheliomatous hyperplasia initiation during cutaneous leishmaniasis  

Microsoft Academic Search

Pseudoepitheliomatous hyperplasia (PEH) is an exuberant proliferation of the epidermis. The underlying mechanism(s) that lead\\u000a to PEH have not been completely elucidated. Here, we characterize PEH during the healing stages of cutaneous leishmanial ulcers\\u000a in mice. During experimental cutaneous leishmaniasis (CL) C57BL\\/6 mice produce PEH, and BALB\\/c do not. A series of immunohistochemical\\u000a and immunological studies were performed to identify

Oleg E. Akilov; Michael J. Donovan; Thomas Stepinac; Cristina R. Carter; James P. Whitcomb; Tayyaba Hasan; Mary Ann McDowell

2007-01-01

223

Transient growth - a factor in bypass transition  

Microsoft Academic Search

Transient growth arises through the coupling between slightly damped, highly oblique (nearly streamwise) T-S and Squire modes leading to algebraic growth followed by exponential decay outside the T-S neutral curve. A weak transient growth can also occur for two dimensional or axisymmetric modes since the Orr-Sommerfeld operator and its compressible counterpart are not self-adjoint, therefore their eigenfunctions are not strictly

Eli Reshotko

1999-01-01

224

Transient growth: A factor in bypass transition  

Microsoft Academic Search

Transient growth arises through the coupling between slightly damped, highly oblique (nearly streamwise) T-S and Squire modes leading to algebraic growth followed by exponential decay in a region that is subcritical with respect to the T-S neutral curve. A weak transient growth can also occur for two dimensional or axisymmetric modes since the Orr-Sommerfeld operator and its compressible counterpart are

Eli Reshotko

2001-01-01

225

Rapid Economic Growth: Contributing Factors and Challenges Ahead  

Microsoft Academic Search

The sustained improvement in the underlying conditions for growth for more than two decades has resulted in lifting the Indian economy from the bottom of the growth heap to one of the fastest growing economies in the world. This paper presents the factors that have contributed to the growth acceleration in India over the past 25 years and the challenges

Isher Judge AHLUWALIA

2008-01-01

226

Control of growth factor networks by heparan sulfate proteoglycans.  

PubMed

Growth factor binding to transmembrane protein receptors is generally understood to initiate cell signaling. Receptor binding of heparin-binding growth factors (HB-GFs), such as fibroblast growth factor-2 (FGF-2), is regulated by interactions with heparan sulfate proteoglycans. While there is some specificity for binding to heparan sulfate, overlap in sites for different growth factors may allow for cross regulation. Here we demonstrate, using experiments and computer simulations, that the HB-GFs FGF-2 and heparin-binding EGF-like growth factor (HB-EGF) can cross regulate receptor binding of the other despite having unique receptors. The ability of HSPG to stabilize HB-GF receptor binding is critical for competing growth factors to modulate receptor binding with both enhanced and reduced binding possible depending on this stabilization process. HSPG density and affinity for HB-GF are also critical factors for HB-GF cross regulation. Simulations further reveal that HB-GF can regulate receptor binding of non-HB-GFs such as EGF even when the two proteins share no binding sites when other HB-GF are present within the network. Proliferation studies demonstrate potentiation of HB-EGF-induced growth by FGF-2 indicating that competition networks can alter biological response. Exogenous manipulation of cellular responses to growth factors in complex living systems will require understanding the HSPG-controlled network. PMID:18839312

Forsten-Williams, Kimberly; Chu, Chia Lin; Fannon, Michael; Buczek-Thomas, Jo Ann; Nugent, Matthew A

2008-12-01

227

Control of Growth Factor Networks by Heparan Sulfate Proteoglycans  

PubMed Central

Growth factor binding to transmembrane protein receptors is generally understood to initiate cell signaling. Receptor binding of heparin-binding growth factors (HB-GFs), such as fibroblast growth factor-2 (FGF-2), is regulated by interactions with heparan sulfate proteoglycans. While there is some specificity for binding to heparan sulfate, overlap in sites for different growth factors may allow for cross regulation. Here we demonstrate, using experiments and computer simulations, that the HB-GFs FGF-2 and heparin-binding EGF-like growth factor (HB-EGF) can cross regulate receptor binding of the other despite having unique receptors. The ability of HSPG to stabilize HB-GF receptor binding is critical for competing growth factors to modulate receptor binding with both enhanced and reduced binding possible depending on this stabilization process. HSPG density and affinity for HB-GF are also critical factors for HB-GF cross regulation. Simulations further reveal that HB-GF can regulate receptor binding of non-HB-GFs such as EGF even when the two proteins share no binding sites when other HB-GF are present within the network. Proliferation studies demonstrate potentiation of HB-EGF-induced growth by FGF-2 indicating that competition networks can alter biological response. Exogenous manipulation of cellular responses to growth factors in complex living systems will require understanding the HSPG-controlled network. PMID:18839312

Forsten-Williams, Kimberly; Chu, Chia Lin; Fannon, Michael; Buczek-Thomas, Jo Ann; Nugent, Matthew A.

2008-01-01

228

Molecular cloning and expression of human hepatocyte growth factor  

Microsoft Academic Search

HEPATOCYTE growth factor (HGF) is the most potent mitogen for mature parenchyma! hepatocytes in primary culture, and seems to be a hepatotrophic factor that acts as a trigger for liver regeneration after partial hepatectomy and liver injury. The partial purification and characterization of HGF have been reported1-4. We have demonstrated that pure HGF from rat platelets is a new growth

Toshikazu Nakamura; Tsutomu Nishizawa; Mitchio Hagiya; Tatsuya Seki; Manabu Shimonishi; Atsushi Sugimura; Kosuke Tashiro; Shin Shimizu

1989-01-01

229

GROWTH FACTOR REQUIREMENTS OF SIX FUNGI ASSOCIATED WITH FRUIT DECAY.  

PubMed

Esposito, R. G. (United Fruit Co., Norwood, Mass.), H. Greenwood, and A. M. Fletcher. Growth factor requirements of six fungi associated with fruit decay. J. Bacteriol. 83:-250-255. 1962.-A study of the growth factor requirements of representatives of six genera of fruit-rotting fungi has been made. Gloeosporium musarum, Nigrospora sphaerica, Thielaviopsis paradoxa, and Verticillium theobromae all required biotin for growth. Under certain conditions in nitrate medium, Fusarium roseum appeared to be partially dependent on biotin. T. paradoxa also required thiamine for growth. In addition to biotin, N. sphaerica required an unknown material contained in extracts of yeast. Twenty-one known growth factors were tested and found to be inactive. Thiamine inhibited the growth of F. roseum, apparently by stimulating the formation of ethanol. Biotin reversed the effect of thiamine on growth and ethanol formation. PMID:16561927

Esposito, R G; Greenwood, H; Fletcher, A M

1962-02-01

230

Possible role of transforming growth factor-?1 and vascular endothelial growth factor in Fabry disease nephropathy.  

PubMed

Fabry disease is a lysosomal storage disorder (LSD) caused by deficiency of ?-galactosidase A (?-gal A), resulting in deposition of globotriaosylceramide (Gb3; also known as ceramide trihexoside) in the vascular endothelium of many organs. A gradual accumulation of Gb3 leads to cardiovascular, cerebrovascular and renal dysfunction. Endothelial cell dysfunction leads to renal complications, one of the main symptoms of Fabry disease. However, the pathological mechanisms by which endothelial dysfunction occurs in Fabry disease are poorly characterized. The purpose of this study was to investigate whether the expression of transforming growth factor-?1 (TGF-?1) and vascular endothelial growth factor (VEGF) is associated with the renal pathogenesis of Fabry disease. We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-?1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice. The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice. Activities of cysteine aspartic acid protease (caspase)-6 and caspase-9 were higher in kidneys from Fabry than from the wild-type mice. These results suggest that overexpression of TGF-?1 and VEGF in the Fabry mouse kidney might contribute to Fabry disease nephropathy by inducing apoptosis. To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-?1, VEGFR2, VEGF, FGF-2 and P-p38. The combination of increased expression of TGF-?1 and VEGF caused by Gb3 accumulation may allow upregulation of FGF-2, VEGFR2 and P-p38 expression, and these changes may be associated with Fabry disease nephropathy by inducing apoptosis. PMID:23007467

Lee, Mi Hee; Choi, Eun Nam; Jeon, Yeo Jin; Jung, Sung-Chul

2012-12-01

231

Possible role of transforming growth factor-?1 and vascular endothelial growth factor in Fabry disease nephropathy  

PubMed Central

Fabry disease is a lysosomal storage disorder (LSD) caused by deficiency of ?-galactosidase A (?-gal A), resulting in deposition of globotriaosylceramide (Gb3; also known as ceramide trihexoside) in the vascular endothelium of many organs. A gradual accumulation of Gb3 leads to cardiovascular, cerebrovascular and renal dysfunction. Endothelial cell dysfunction leads to renal complications, one of the main symptoms of Fabry disease. However, the pathological mechanisms by which endothelial dysfunction occurs in Fabry disease are poorly characterized. The purpose of this study was to investigate whether the expression of transforming growth factor-?1 (TGF-?1) and vascular endothelial growth factor (VEGF) is associated with the renal pathogenesis of Fabry disease. We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-?1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice. The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice. Activities of cysteine aspartic acid protease (caspase)-6 and caspase-9 were higher in kidneys from Fabry than from the wild-type mice. These results suggest that overexpression of TGF-?1 and VEGF in the Fabry mouse kidney might contribute to Fabry disease nephropathy by inducing apoptosis. To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-?1, VEGFR2, VEGF, FGF-2 and P-p38. The combination of increased expression of TGF-?1 and VEGF caused by Gb3 accumulation may allow upregulation of FGF-2, VEGFR2 and P-p38 expression, and these changes may be associated with Fabry disease nephropathy by inducing apoptosis. PMID:23007467

LEE, MI HEE; CHOI, EUN NAM; JEON, YEO JIN; JUNG, SUNG-CHUL

2012-01-01

232

Extracellular matrix and growth factors in branching morphogenesis  

NASA Technical Reports Server (NTRS)

The unifying hypothesis of the NSCORT in gravitational biology postulates that the ECM and growth factors are key interrelated components of a macromolecular regulatory system. The ECM is known to be important in growth and branching morphogenesis of embryonic organs. Growth factors have been detected in the developing embryo, and often the pattern of localization is associated with areas undergoing epithelial-mesenchymal interactions. Causal relationships between these components may be of fundamental importance in control of branching morphogenesis.

Hardman, P.; Spooner, B. S.

1993-01-01

233

Augmentation of postresection mucosal hyperplasia by plerocercoid growth factor (PGF)  

Microsoft Academic Search

Postresection villus hyperplasia is a major compensatory mechanism in the short-bowel patient. Substances capable of augmenting postresection mucosal hyperplasia could have therapeutic implications. Human growth hormone (hGH) and human growth hormone releasing factor (hGHRF) stimulate growth of the gastrointestinal tract; however, the diabetogenic actions of growth hormone limit its usefulness in clinical practice. Plerocercoid larvae of the tapewormSpirometra mansonoides produce

Michael H. Hart; C. K. Phares; Steven H. Erdman; Carter J. Grandjean; Jung H. Y. Park; Jon A. Vanderhoof

1987-01-01

234

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer  

Microsoft Academic Search

Solid tumors must induce a vascular stroma to grow beyond a minimal size, and the intensity of the angiogenic response has been correlated with prognosis in breast cancer patients. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a secreted protein that has been implicated in tumor-associated angiogenesis. Vascular permeability factor directly stimulates endothelial cell growth

Lawrence F Brown; Brygida Berse; Robert W Jackman; Kathi Tognazzi; Anthony J Guidi; Harold F Dvorak; Donald R Senger; James L Connolly; Stuart J Schnitt

1995-01-01

235

Transgenic Studies with a Keratin Promoter-Driven Growth Hormone Transgene: Prospects for Gene Therapy  

NASA Astrophysics Data System (ADS)

Keratinocytes are potentially appealing vehicles for the delivery of secreted gene products because they can be transferred to human skin by the relatively simple procedure of grafting. Adult human keratinocytes can be efficiently propagated in culture with sufficient proliferative capacity to produce enough epidermis to cover the body surface of an average adult. However, the feasibility of delivering secreted proteins through skin grafting rests upon (i) the strength of the promoter in keratinocytes and (ii) the efficiency of protein transport through the basement membrane of the stratified epithelium and into the bloodstream. In this paper, we use transgenic technology to demonstrate that the activity of the human keratin 14 promoter remains high in adult skin and that keratinocyte-derived human growth hormone (hGH) can be produced, secreted, and transported to the bloodstream of mice with efficiency that is sufficient to exceed by an order of magnitude the circulating hGH concentration in growing children. Transgenic skin grafts from these adults continue to produce and secrete hGH stably, at ? 1/10 physiological levels in the bloodstream of nontransgenic recipient mice. These studies underscore the utility of the keratin 14 promoter for expressing foreign transgenes in keratinocytes and demonstrate that keratinocytes can be used as effective vehicles for transporting factors to the bloodstream and for eliciting metabolic changes. These findings have important implications for considering the keratinocyte as a possible vehicle for gene therapy.

Wang, Xiaoming; Zinkel, Sandra; Polonsky, Kenneth; Fuchs, Elaine

1997-01-01

236

Cultured human foreskin fibroblasts produce a factor that stimulates their growth with properties similar to basic fibroblast growth factor  

Microsoft Academic Search

Summary  To determine if fibroblasts could be a source of fibroblast growth factor (FGF) in tissue, cells were initiated in culture\\u000a from newborn human foreskin. Cells were studied in Passages 2 to 8. Fibroblast cell lysates promoted radiolabeled thymidine\\u000a uptake by cultured quiescent fibroblasts. Seventy-nine percent of the growth-promoting activity of lysates was recovered from\\u000a heparin-Sepharose. The heparin-binding growth factor reacted

Michael T. Story

1989-01-01

237

Growth factor activation of MAP kinase requires cell adhesion.  

PubMed Central

The MAP kinase pathway is a major regulator of both normal and oncogenic growth. We report that activation of the MAP kinase ERK2 by serum or purified growth factors is strongly dependent on cell adhesion to extracellular matrix proteins. This effect is specific to soluble growth factors, since suspended cells still activate ERK2 in response to plating on fibronectin, and is reversible. Analysis of endogenous Ras and Raf show that these proteins are still activated by serum in suspended cells, whereas MEK activity is inhibited. Conversely, activation of ERK2 by activated mutants of Ras and Raf is still adhesion-dependent but activation by MEK is not. Consistent with these results, activated MEK enhances growth of ras-transformed cells in suspension but not when adherent. These results identify a novel synergism between cell adhesion- and growth factor-regulated pathways, and explain how oncogenic activation of MAP kinases induces both serum- and anchorage-independent growth. PMID:9312018

Renshaw, M W; Ren, X D; Schwartz, M A

1997-01-01

238

PAI-1 mediates the TGF-beta1+EGF-induced "scatter" response in transformed human keratinocytes.  

PubMed

Cooperative interactions between growth factor signaling pathways are important elements in carcinoma progression. A model system combining transforming growth factor-beta1 (TGF-beta1) and EGF was developed to investigate mechanisms underlying induced epithelial-to-mesenchymal transition (EMT) in ras-transformed human (HaCaT II-4) keratinocytes. Dual stimulation with TGF-beta1+EGF resulted in keratinocyte "plasticity" and pronounced colony dispersal. The most highly expressed transcript, identified by mRNA profiling, encoded plasminogen activator inhibitor-1 (PAI-1; SERPINE1). PAI-1 negatively regulates plasmin-dependent matrix degradation, preserving a stromal scaffold permissive for keratinocyte motility. Mitogen-activated extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) and p38 signaling were required for maximal PAI-1 upregulation and TGF-beta1+EGF-stimulated cell locomotion, as pharmacologic disruption of MEK/p38 activity ablated both responses. Moreover, PAI-1 knockdown alone effectively inhibited TGF-beta1+EGF-dependent cell scattering, indicating a functional role for this SERPIN in the dual-growth factor model of induced motility. Moreover, EGFR signaling blockade or EGFR knockdown attenuated TGF-beta1-induced PAI-1 expression, implicating EGFR transactivation in TGF-beta1-stimulated PAI-1 expression, and reduced colony dispersal in TGF-beta1+EGF-treated cultures. Identification of such cooperative signaling networks and their effect on specific invasion-promoting target genes, such as PAI-1, may lead to the development of pathway-specific therapeutics that affect late-stage events in human tumor progression. PMID:20428185

Freytag, Jennifer; Wilkins-Port, Cynthia E; Higgins, Craig E; Higgins, Stephen P; Samarakoon, Rohan; Higgins, Paul J

2010-09-01

239

Dual chain synthetic heparin-binding growth factor analogs  

DOEpatents

The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Zamora, Paul O. (Gaithersburg, MD); Pena, Louis A. (Poquott, NY); Lin, Xinhua (Plainview, NY)

2012-04-24

240

Dual chain synthetic heparin-binding growth factor analogs  

DOEpatents

The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

Zamora, Paul O. (Gaithersburg, MD); Pena, Louis A. (Poquott, NY); Lin, Xinhua (Plainview, NY)

2009-10-06

241

Effects of growth factors on dental stem/progenitor cells.  

PubMed

The primary goal of regenerative endodontics is to restore the vitality and functions of the dentin-pulp complex, as opposed to filing of the root canal with bioinert materials. A myriad of growth factors regulates multiple cellular functions including migration, proliferation, differentiation, and apoptosis of several cell types intimately involved in dentin-pulp regeneration. Recent work showing that growth factor delivery, without cell transplantation, can yield pulp-dentin-like tissues in vivo provides one of the tangible pathways for regenerative endodontics. This review synthesizes knowledge on many growth factors that are known or anticipated to be efficacious in dental pulp-dentin regeneration. PMID:22835538

Kim, Sahng G; Zhou, Jian; Solomon, Charles; Zheng, Ying; Suzuki, Takahiro; Chen, Mo; Song, Songhee; Jiang, Nan; Cho, Shoko; Mao, Jeremy J

2012-07-01

242

FGF-10 and specific structural elements of dermatan sulfate size and sulfation promote maximal keratinocyte migration and cellular proliferation  

PubMed Central

Fibroblast growth factor-10 (FGF-10) is essential for epithelial development, while other members of this family, such as FGF-7, are not. FGF-10 is abundantly released into wounds following injury, and likely an essential growth factor required for this process. To evaluate how activation of this growth factor is controlled, multiple glycosaminoglycans were combined with FGF-10 assayed by measurement of the proliferation of cell lines expressing FGF receptor-2-IIIb, or keratinocyte migration in an in vitro wound repair assay. Dermatan sulfate (DS) exhibited greater potency than heparan sulfate or other chondroitin sulfates found in wounds. Structural variants of DS between 10 and 20 disaccharides containing iduronic acid showed maximal capacity to enable FGF-10 receptor stimulation. Furthermore, FGF-10 and DS markedly enhanced migration of keratinocytes in an in vitro wound scratch assay, while FGF-7 or other glycosaminoglycans did not. These data strongly suggest that FGF-10 activity is uniquely important in wound repair and that specific DS structural properties are necessary to promote FGF-10 function. These observations identify a novel interplay between DS and FGF-10 in mediating wound repair. PMID:19152659

Radek, Katherine A.; Taylor, Kristen R.; Gallo, Richard L.

2009-01-01

243

Characteristic Cytokines Generated by Keratinocytes and Mononuclear Infiltrates in Oral Lichen Planus  

Microsoft Academic Search

Cytokine production was investigated in oral keratinocytes and tissue-infiltrated mononuclear cells (TIMC) obtained from patients with oral lichen planus (OLP). The numbers of cells producing interleukine (IL) -1?, IL-4, IL-6, granulocyte colony-stimulating factor, and tumor necrosis factor-? per 104 cells in keratinocytes from patients with OLP were determined by enzyme-linked immunospot assay. These levels were two to threefold greater than

Tetsuya Yamamoto; Tokio Osaki

1995-01-01

244

Autocrine Hepatocyte Growth Factor Provides a Local Mechanism for Promoting Axonal Growth  

Microsoft Academic Search

In this report, we describe a novel local mechanism necessary for optimal axonal growth that involves hepatocyte growth factor (HGF). Sympathetic neurons of the superior cervical ganglion coexpress bioactive HGF and its receptor, the Met tyrosine kinase, both in vivo and in vitro. Exogenous HGF selectively promotes the growth but not survival of cultured sympathetic neurons; the magnitude of this

Xiu-Ming Yang; Jean G. Toma; Shernaz X. Bamji; Daniel J. Belliveau; Judi Kohn; Morag Park; Freda D. Miller

1998-01-01

245

Growth factors, CD34 positive cells, and fibrin network analysis in concentrated growth factors fraction.  

PubMed

An interesting clinical option for optimizing healing tissue is the use of platelet concentrate. Platelets contain high quantities of growth factors, among these TGF-?1 and VEGF, which are known to be implicated in tissue regeneration. CGF is produced by processing blood samples with a special centrifuge device; three layers are formed: top acellular plasma (PPP), middle CGF and bottom red blood cells (RBC) layers. Given that to date there are no data concerning the biological characteristic of CGF, the aim of this study was to evaluate the presence of TGF-?1 and VEGF in CGF and also in PPP and RBC layers. In addition, since circulating stem cells are recruited from blood to injured tissue for healing we also evaluated the presence of CD34 positive cells. Our data show the presence of TGF-?1 and VEGF in CGF and RBC layers. In addition, we show CD34 positive cells in CGF. PMID:21780251

Rodella, Luigi Fabrizio; Favero, Gaia; Boninsegna, Ramon; Buffoli, Barbara; Labanca, Mauro; Scarì, Giorgio; Sacco, Luigi; Batani, Tiziano; Rezzani, Rita

2011-08-01

246

Stimulation of Fibroblast Cell Growth, Matrix Production, and Granulation Tissue Formation by Connective Tissue Growth Factor  

Microsoft Academic Search

Connective tissue growth factor (CTGF) is a 36- to 38-kDa peptide that is selectively induced by transforming growth factor-? (TGF-?) in fibroblastic cell types. We compared the biologic activities of CTGF with TGF-? on fibroblasts in culture and in animal models of fibroplasia. CTGF was active as a mitogen in monolayer cultures of normal rat kidney fibroblasts. CTGF did not

Ken Frazier; Shawn Williams; Devashish Kothapalli; Helene Klapper; Gary R. Grotendorst

1996-01-01

247

Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer.  

PubMed

Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer, but the clinical benefits are usually transitory. The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab. For this, angiogenesis-focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control. Reverse transcription-PCR was used for results validation. The insulin growth factor 1 (IGF-1) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual anti-VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth. Immunohistochemistry measured multivessel density, Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay measured apoptosis in ovarian cancer xenografts. Bevacizumab and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway. The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone. In summary, IGF-1 activation represents an important mechanism of adaptive escape during anti-VEGF therapy in ovarian cancer. This study provides the rationale for designing bevacizumab-based combination regimens to enhance antitumor activity. PMID:22700681

Shao, Minghai; Hollar, Stacy; Chambliss, Daphne; Schmitt, Jordan; Emerson, Robert; Chelladurai, Bhadrani; Perkins, Susan; Ivan, Mircea; Matei, Daniela

2012-07-01

248

Regulation of Transforming Growth Factor ?1, Platelet-Derived Growth Factor, and Basic Fibroblast Growth Factor by Silicone Gel Sheeting in Early-Stage Scarring  

PubMed Central

Background Hypertrophic scars and keloids are associated with abnormal levels of growth factors. Silicone gel sheets are effective in treating and preventing hypertrophic scars and keloids. There has been no report on the change in growth factors in the scar tissue following the use of silicone gel sheeting for scar prevention. A prospective controlled trial was performed to evaluate whether growth factors are altered by the application of a silicone gel sheet on a fresh surgical scar. Methods Four of seven enrolled patients completed the study. Transforming growth factor (TGF)-?1, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) were investigated immunohistochemically in biopsies taken from five scars at 4 months following surgery. Results In both the epidermis and the dermis, the expression of TGF-?1 (P=0.042 and P=0.042) and PDGF (P=0.043 and P=0.042) was significantly lower in the case of silicone gel sheet-treated scars than in the case of untreated scars. The expression of bFGF in the dermis was significantly higher in the case of silicone gel sheet-treated scars than in the case of untreated scars (P=0.042), but in the epidermis, the expression of bFGF showed no significant difference between the groups (P=0.655). Conclusions The levels of TGF-?1, PDGF, and bFGF are altered by the silicone gel sheet treatment, which might be one of the mechanisms of action in scar prevention. PMID:25606485

Choi, Jaehoon; Lee, Eun Hee; Park, Sang Woo

2015-01-01

249

Characterizing and engineering antibodies against the epidermal growth factor receptor  

E-print Network

Epidermal growth factor receptor (EGFR) signaling leads to cellular proliferation and migration, and thus EGFR dysregulation can significantly contribute to the survival of tumor cells. Aberrant EGFR signaling due to ...

Chao, Ginger

2008-01-01

250

Visualization of growth factor receptor sites in rat forebrain  

SciTech Connect

It is now known that various growth factors may also act in the central nervous system. Among them, it has recently been shown that epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) may possess trophic effects in the mammalian brain. We report here on the respective autoradiographic distribution of (/sup 125/I)EGF and (/sup 125/I)IGF-I receptor binding sites in the rat brain, both during ontogeny and in adulthood. It appears that (/sup 125/I)EGF sites are mostly found in the rat forebrain during brain development. On the other hand, (/sup 125/I)IGF-I sites are more widely distributed both during ontogeny and in adulthood. These results reveal the plasticity of the expression of EGF and IGF-I receptor sites in the mammalian brain. This could be relevant for the respective role of these two growth factors in the development and maintenance of neuronal function.

Quirion, R.; Araujo, D.; Nair, N.P.; Chabot, J.G.

1988-01-01

251

Epidermal growth factor receptor downregulation by small heterodimeric binding proteins  

E-print Network

No single engineered protein has been shown previously to robustly downregulate epidermal growth factor receptor (EGFR), a validated cancer target. A panel of fibronectin-based domains was engineered to bind with picomolar ...

Hackel, Benjamin J.

252

Connective Tissue Growth Factor: Expression in Human Skin In Vivo and Inhibition by Ultraviolet Irradiation  

Microsoft Academic Search

Connective tissue growth factor, which is induced by transforming growth factor ?, has been reported to mediate the stimulatory actions of transforming growth factor ? on type I procollagen synthesis. Connective tissue growth factor is expressed in fibrotic disease such as scleroderma, where it is believed to promote abnormal deposition of collagen. Connective tissue growth factor expression has not been

Taihao Quan; Tianyuan He; Sewon Kang; John J. Voorhees; Gary J. Fisher

2002-01-01

253

Transforming growth factor-? in breast cancer: A working hypothesis  

Microsoft Academic Search

Transforming Growth Factor-ß (TGFß) is the most potent knowninhibitor of the progression of normal mammary epithelial cells through thecell cycle. During the early stages of breast cancer development, thetransformed epithelial cells appear to still be sensitive toTGFß-mediated growth arrest, and TGFß can act as an anti-tumorpromoter. In contrast, advanced breast cancers are mostly refractory toTGFß-mediated growth inhibition and produce large

Michael Reiss; Mary Helen Barcellos-Hoff

1997-01-01

254

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice  

PubMed Central

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin-induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis. PMID:24503019

Schäfer, Matthias; Willrodt, Ann-Helen; Kurinna, Svitlana; Link, Andrea S; Farwanah, Hany; Geusau, Alexandra; Gruber, Florian; Sorg, Olivier; Huebner, Aaron J; Roop, Dennis R; Sandhoff, Konrad; Saurat, Jean-Hilaire; Tschachler, Erwin; Schneider, Marlon R; Langbein, Lutz; Bloch, Wilhelm; Beer, Hans-Dietmar; Werner, Sabine

2014-01-01

255

Sputa nerve growth factor forms a preferable substitute to mouse 7S-? nerve growth factor  

PubMed Central

The NGF (nerve growth factor) from Naja sputatrix has been purified by gel filtration followed by reversed-phase HPLC. The protein showed a very high ability to induce neurite formation in PC12 cells relative to the mouse NGF. Two cDNAs encoding isoforms of NGF have been cloned and an active recombinant NGF, sputa NGF, has been produced in Escherichia coli as a His-tagged fusion protein. Sputa NGF has been found to be non-toxic under both in vivo and in vitro conditions. The induction of neurite outgrowth by this NGF has been found to involve the high-affinity trkA–p75NTR complex of receptors. The pro-survival mechanism of p75NTR has been mediated by the activation of nuclear factor ?B gene by a corresponding down-regulation of inhibitory ?B gene. Real-time PCR and protein profiling (by surface-enhanced laser-desorption–ionization time-of-flight) have confirmed that sputa NGF up-regulates the expression of the endogenous NGF in PC12 cells. Preliminary microarray analysis has also shown that sputa NGF is capable of promoting additional beneficial effects such as the up-regulation of arginine vasopressin receptor 1A, voltage-dependent T-type calcium channel. Hence, sputa NGF forms a new and useful NGF. PMID:15225125

2004-01-01

256

CRITICAL FACTORS CONTROLLING VEGETATION GROWTH ON COMPLETED SANITARY LANDFILLS  

EPA Science Inventory

This study identifies some of the critical factors that affect tree and shrub growth on reclaimed sanitary landfill sites and determines which woody species are adaptable to the adverse growth conditions of such sites. Trees planted at the Edgeboro Landfill, East Brunswick, New J...

257

Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18  

Microsoft Academic Search

Gain of function mutations in fibroblast growth factor (FGF) receptors cause chondrodysplasia and craniosynostosis syndromes. The ligands interacting with FGF receptors (FGFRs) in developing bone have remained elusive, and the mechanisms by which FGF signaling regulates endochondral, periosteal, and intramembranous bone growth are not known. Here we show that Fgf18 is expressed in the perichondrium and that mice homozygous for

Zhonghao Liu; Jingsong Xu; Jennifer S. Colvin; David M. Ornitz

2002-01-01

258

A family of autocrine growth factors in Mycobacterium tuberculosis  

Microsoft Academic Search

Summary Mycobacterium tuberculosis and its close relative, Mycobacterium bovis (BCG) contain five genes whose predicted products resemble Rpf from Micro- coccus luteus . Rpf is a secreted growth factor, active at picomolar concentrations, which is required for the growth of vegetative cells in minimal media at very low inoculum densities, as well as the resuscitation of dormant cells. We show

Galina V. Mukamolova; Obolbek A. Turapov; Danielle I. Young; Arseny S. Kaprelyants; Douglas B. Kell; Michael Young

259

DNA repair in cultured keratinocytes  

SciTech Connect

Most of our understanding of DNA repair mechanisms in human cells has come from the study of these processes in cultured fibroblasts. The unique properties of keratinocytes and their pattern of terminal differentiation led us to a comparative examination of their DNA repair properties. The relative repair capabilities of the basal cells and the differentiated epidermal keratinocytes as well as possible correlations of DNA repair capacity with respect to age of the donor have been examined. In addition, since portions of human skin are chronically exposed to sunlight, the repair response to ultraviolet (UV) irradiation (254 nm) when the cells are conditioned by chronic low-level UV irradiation has been assessed. The comparative studies of DNA repair in keratinocytes from infant and aged donors have revealed no significant age-related differences for repair of UV-induced damage to DNA. Sublethal UV conditioning of cells from infant skin had no appreciable effect on either the repair or normal replication response to higher, challenge doses of UVL. However, such conditioning resulted in attenuated repair in keratinocytes from adult skin after UV doses above 25 J/m2. In addition, a surprising enhancement in replication was seen in conditioned cells from adult following challenge UV doses.

Liu, S.C.; Parsons, S.; Hanawalt, P.C.

1983-07-01

260

Making a tooth: growth factors, transcription factors, and stem cells  

Microsoft Academic Search

Mammalian tooth development is largely dependent on sequential and reciprocal epithelial-mesenchymal interactions. These processes involve a series of inductive and permissive interactions that result in the determination, differentiation, and organization of odontogenic tissues. Multiple signaling molecules, including BMPs, FGFs, Shh, and Wnt proteins, have been implicated in mediating these tissue interactions. Transcription factors participate in epithelial-mesenchymal interactions via linking the

Yan Ding ZHANG; Zhi CHEN; Yi Qiang SONG; Chao LIU; Yi Ping CHEN

2005-01-01

261

Epiprofin orchestrates epidermal keratinocyte proliferation and differentiation.  

PubMed

The basal layer of the epidermis contains stem cells and transit amplifying cells that rapidly proliferate and differentiate further into the upper layers of the epidermis. A number of molecules have been identified as regulators of this process, including p63 (also known as tumor protein 63) and Notch1. However, little is known about the mechanisms that regulate the transitions from stem cell to proliferating or differentiating transit amplifying cell. Here, we demonstrate that epiprofin (Epfn, also known as Sp6) plays crucial distinct roles in these transition stages as a cell cycle regulator and a transcription factor. Epfn knockout mice have a thickened epidermis, in which p63-expressing basal cells form multiple layers owing to the accumulation of premature transit amplifying cells with reduced proliferation and a reduction in the number of differentiating keratinocytes expressing Notch1. We found that low levels of Epfn expression increased the proliferation of human immortalized keratinocyte (HaCaT) cells by increasing EGF responsiveness and superphosphorylation of Rb. By contrast, high levels of Epfn expression promoted cell cycle exit and differentiation, by reducing E2F transactivation and inducing Notch1 expression. Our findings identify multiple novel functions of Epfn in epidermal development. PMID:25344255

Nakamura, Takashi; Yoshitomi, Yasuo; Sakai, Kiyoshi; Patel, Vyomesh; Fukumoto, Satoshi; Yamada, Yoshihiko

2014-12-15

262

Effect of sericin on diabetic hippocampal growth hormone/insulin-like growth factor 1 axis  

PubMed Central

Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats. PMID:25206472

Chen, Zhihong; Yang, Songhe; He, Yaqiang; Song, Chengjun; Liu, Yongping

2013-01-01

263

Serum insulin-like growth factors and insulin-like growth factor-binding proteins: clinical implications  

Microsoft Academic Search

The last decade has been characterized by a major investigative thrust into the physiology of two unique but ubiquitous peptides, insulin-like growth factor (IGF)-I and IGF-II. The regulatory systems that control the tissue bioactivity of the IGFs have been delineated, and subcellular signaling mechanisms have been clarified. Clearly, both tissue and circulating growth factor concentrations are important in defining the

Clifford J. Rosen

1999-01-01

264

Coexpression of epidermal growth factor receptor and transforming growth factor-? is independent of ras mutations in lung adenocarcinoma  

Microsoft Academic Search

The interaction of epidermal growth factor receptor (EGFR) and its ligand transforming growth factor-alpha (TGF-?) leads to an autocrine activation of the ras signaling pathway and putatively its oncogenic activity. It is thus hypothesized that the co-overexpression of EGFR-TGF? will be redundant hence rare in tumors with oncogenic ras mutations. To test this hypothesis, we studied by immunohistochemistry the expression

Eugene T. K. Hsieh; Frances A. Shepherd; Ming-Sound Tsao

2000-01-01

265

P-cadherin potentiates ligand-dependent EGFR and IGF-1R signaling in dysplastic and malignant oral keratinocytes.  

PubMed

Oral and oropharyngeal cancer together constitute the sixth most common cancer worldwide, with over 400,000 new cases diagnosed each year. Early detection is paramount, as the 5-year survival rate for these cancers decreases markedly once tumors have become regionally invasive. In many tissues, including oral epithelia, neoplastic progression is accompanied by alterations in expression of the epithelial cell adhesion molecules E-cadherin and P-cadherin. Oral epithelia is one of only a few tissues in which P-cadherin levels have been noted to increase in dysplasia and well-differentiated carcinomas and decrease in advanced malignancies. In the present study, P-cadherin was overexpressed in both dysplastic and malignant oral keratinocytes to characterize the mechanisms by which aberrantly expressed P-cadherin may modulate tumor progression. We found that P-cadherin was able to potentiate ligand-dependent signaling of insulin-like growth factor 1 receptor (IGF-1R) in malignant keratinocytes and epidermal growth factor receptor (EGFR) in dysplastic cells. P-cadherin prolonged activation of the mitogen-activated protein kinase (MAPK) in both cell lines and also increased the magnitude of AKT phosphorylation in dysplastic cells. P-cadherin overexpression alone was sufficient to increase steady-state levels of the mesenchymal transcription factor Snail, increase cell motility and also induce morphological changes in dysplastic keratinocytes. Taken together, these data suggest that the aberrantly elevated levels of P-cadherin which occur in early oral tumor development may play a critical role in the augmentation of neoplastic signaling networks and in the further acquisition of aggressive phenotypes. PMID:25322858

Lysne, Desseree; Johns, James; Walker, Andrew; Ecker, Rachel; Fowler, Christopher; Lawson, Kathryn R

2014-12-01

266

Sp1 Decoy Transfected to Carcinoma Cells Suppresses the Expression of Vascular Endothelial Growth Factor, Transforming Growth Factor b1, and Tissue Factor and Also Cell Growth and Invasion Activities  

Microsoft Academic Search

Vasculature development is thought to be an important aspect in the growth and metastasis of solid tumors. Among the angiogenic factors produced by tumor cells, vascular endothelial growth factor is considered to be the most potent and pathologically important. The synthesis of this growth factor has been shown to be modulated through Sp1 function following stimulation by tumor necrosis factor

Hiroaki Ishibashi; Kazunori Nakagawa; Mitsuho Onimaru; Emilio J Castellanous; Yasufumi Kaneda; Yutaka Nakashima; Kanemitsu Shirasuna; Katsuo Sueishi

2000-01-01

267

Tpl2 knockout keratinocytes have increased biomarkers for invasion and metastasis.  

PubMed

Skin cancer is the most common form of cancer in the USA, with an estimated two million cases diagnosed annually. Tumor progression locus 2 (Tpl2), also known as MAP3K8, is a serine/threonine protein kinase in the mitogen-activated protein kinase signal transduction cascade. Tpl2 was identified by our laboratory as having a tumor suppressor function in skin carcinogenesis, with the absence of this gene contributing to heightened inflammation and increased skin carcinogenesis. In this study, we used gene expression profiling to compare expression levels between Tpl2 (+/+) and Tpl2 (-) (/-) keratinocytes. We identified over 2000 genes as being differentially expressed between genotypes. Functional annotation analysis identified cancer, cell growth/proliferation, cell death, cell development, cell movement and cell signaling as the top biological processes to be differentially regulated between genotypes. Further microarray analysis identified several candidate genes, including Mmp1b, Mmp2, Mmp9 and Mmp13, involved in migration and invasion to be upregulated in Tpl2 (-) (/-) keratinocytes. Moreover, Tpl2 (-/-) keratinocytes had a significant downregulation in the matrix metalloproteinase (MMP) inhibitor Timp3. Real-time PCR validated the upregulation of the MMPs in Tpl2 (-/-) keratinocytes and zymography confirmed that MMP2 and MMP9 activity was higher in conditioned media from Tpl2 (-/-) keratinocytes. Immunohistochemistry confirmed higher MMP9 staining in 12-O-tetradecanoylphorbol-13-acetate-treated skin from Tpl2 (-/-) mice and grafted tumors formed from v-ras(Ha) retrovirus-infected Tpl2 (-/-) keratinocytes. Additionally, Tpl2 (-/-) keratinocytes had significantly higher invasion, malignant conversion rates and increased endothelial cell tube formation when compared with Tpl2 (+/+) keratinocytes. In summary, our studies reveal that keratinocytes from Tpl2 (-/-) mice demonstrate a higher potential to be invasive and metastatic. PMID:24067898

Decicco-Skinner, Kathleen L; Jung, Sarah A; Tabib, Tracy; Gwilliam, J Curtis; Alexander, Hepzibha; Goodheart, Sarah E; Merchant, Anand S; Shan, Mengge; Garber, Caroline; Wiest, Jonathan S

2013-12-01

268

47 CFR 36.604 - Calculation of the rural growth factor.  

Code of Federal Regulations, 2010 CFR

...false Calculation of the rural growth factor. 36.604 Section...COSTS, REVENUES, EXPENSES, TAXES AND RESERVES FOR TELECOMMUNICATIONS...604 Calculation of the rural growth factor. The Rural Growth Factor (RGF) is...

2010-10-01

269

47 CFR 36.604 - Calculation of the rural growth factor.  

Code of Federal Regulations, 2012 CFR

... Calculation of the rural growth factor. 36.604 Section...COSTS, REVENUES, EXPENSES, TAXES AND RESERVES FOR TELECOMMUNICATIONS... Calculation of the rural growth factor. (a) Until July 30, 2012, the Rural Growth Factor (RGF)...

2012-10-01

270

47 CFR 36.604 - Calculation of the rural growth factor.  

Code of Federal Regulations, 2013 CFR

... Calculation of the rural growth factor. 36.604 Section...COSTS, REVENUES, EXPENSES, TAXES AND RESERVES FOR TELECOMMUNICATIONS... Calculation of the rural growth factor. (a) Until July 30, 2012, the Rural Growth Factor (RGF)...

2013-10-01

271

47 CFR 36.604 - Calculation of the rural growth factor.  

Code of Federal Regulations, 2011 CFR

...false Calculation of the rural growth factor. 36.604 Section...COSTS, REVENUES, EXPENSES, TAXES AND RESERVES FOR TELECOMMUNICATIONS...604 Calculation of the rural growth factor. The Rural Growth Factor (RGF) is...

2011-10-01

272

Role of Vascular Endothelial Growth Factor in Portal Hypertensive Gastropathy  

Microsoft Academic Search

Background and Aims: Portal hypertensive gastropathy (PHG) is now recognized as a distinct entity; however, the angiogenesis in the portal hypertensive gastric mucosa has yet to be elucidated. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in both physiological and pathological angiogenesis. The aim of this study was thus to examine the function of VEGF in the

Kouji Tsugawa; Makoto Hashizume; Shinichirou Migou; Fumiaki Kishihara; Hirofumi Kawanaka; Morimasa Tomikawa; Keizo Sugimachi

2000-01-01

273

Therapeutic potential of nerve growth factor in Alzheimer's disease  

Microsoft Academic Search

The loss of basal forebrain cholinergic neurons is thought to be an important contributing factor in the cognitive impairments associated with Alzheimer's disease. Based on its efficacy in several in vivo models of basal forebrain cholinergic neuronal degeneration in adult animals, nerve growth factor (NGF) is being considered as a therapeutic candidate for the treatment of this disorder. In rats

Michael S. Saporito; Susan Carswell

1997-01-01

274

The role of vascular endothelial growth factor in pathological angiogenesis  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is a diffusible endothelial cell-specific mitogen and angiogenic factor that can also increase vascular permeability. By alternative splicing of mRNA, VEGF may exist as one of four different isoforms that have similar biological activities but differ markedly in targeting and bioavailability. The VEGF receptors are specifically expressed in the cell surface of vascular endothelial cells.

Napoleone Ferrara

1995-01-01

275

Nerve Growth Factor Potentiates the Neurotoxicity of ? Amyloid  

NASA Astrophysics Data System (ADS)

The role of growth factors in the pathogenesis of Alzheimer disease is unknown. The ?-amyloid protein accumulates abnormally in the brain in Alzheimer disease and is neurotoxic to differentiated hippocampal neurons in culture. Nerve growth factor (NGF) increased the neurotoxic potency of a ?-amyloid polypeptide by a factor of ?100,000, which resulted in a reduction of the ?-amyloid neurotoxic EC50 from 0.1 ?M to 1 pM. This potentiating effect of NGF was reversed by a monoclonal antibody against NGF and was not observed for a variety of other neurotrophic growth factors. Exposure of hippocampal neurons to very low concentrations of ? amyloid alone resulted in a marked induction of immunoreactive NGF receptors. Addition of NGF with ? amyloid resulted in the appearance of neurodegenerative changes in NGF receptor-positive neurons. The early and profound degeneration of hippocampal and basal forebrain cholinergic neurons that occurs in Alzheimer disease may result from a neurotoxic interaction of ? amyloid with NGF.

Yankner, Bruce A.; Caceres, Alfredo; Duffy, Lawrence K.

1990-11-01

276

The Effects of Insulin-Like Growth Factor-1 Gene Therapy and Cell Transplantation on Rat Acute Wound Model  

PubMed Central

Background: Wound healing is a complex process. Different types of skin cells, extracellular matrix and variety of growth factors are involved in wound healing. The use of recombinant growth factors in researches and production of skin substitutes are still a challenge. Objectives: Much research has been done on the effects of gene therapy and cell therapy on wound healing. In this experimental study, the effect of insulin-like growth factor (IGF-1) gene transfer in fibroblast cells was assessed on acute dermal wound healing. Materials and Methods: Fibroblasts were cultured and transfected with IGF-1. Lipofectamine 2000 was used as a reagent of transfection. Transgene expression levels were measured by the enzyme linked immunosorbent assay (ELISA). To study in vivo, rats (weighing 170-200 g) were randomly divided into three groups (five/group) and full-thickness wounds were created on the dorsum region. Suspensions of transfected fibroblast cells were injected into the wound and were compared with wounds treated with native fibroblast cells and normal saline. For the microscopic examination, biopsy was performed on day seven. Results: In vitro, the maximum expression of IGF1 (96.95 pg/mL) in transfected fibroblast cells was 24 hours after gene transfer. In vivo, it was clear that IGF-1 gene therapy caused an increase in the number of keratinocyte cells during the wound healing process (mean of group A vs. group B with P value = 0.01, mean of group A vs. group C with P value = 0.000). Granulation of tissue formation in the transfected fibroblast group was more organized when compared with the normal saline group and native fibroblast cells. Conclusions: This study indicated that the optimization of gene transfer increases the expression of IGF-1. High concentrations of IGF-1, in combination with cell therapy, have a significant effect on wound healing.

Talebpour Amiri, Fereshteh; Fadaei Fathabadi, Fatemeh; Mahmoudi Rad, Mahnaz; Piryae, Abbas; Ghasemi, Azar; Khalilian, Alireza; Yeganeh, Farshid; Mosaffa, Nariman

2014-01-01

277

Growth factor-independent proliferation of rat mammary carcinoma cells by autocrine secretion of neu-differentiation factor/heregulin and transforming growth factor-alpha.  

PubMed

Serially transplantable rat mammary tumor (RMT) cells are not dependent on exogenous epidermal growth factor (EGF) and insulin-like growth factor-I for continuous growth in serum-free medium. Previously, we found that conditioned medium obtained from these cells contained EGF-like mitogenic activity and stimulated tyrosine phosphorylation of a 185-kDa protein in EGF-dependent mammary epithelial cells. This protein is distinct from the EGF receptor and resembles a 185-kDa tyrosine-phosphorylated protein present in RMT cells themselves. The results of the studies reported here indicate that the tyrosine-phosphorylated p185 detected in growth factor-independent RMT cells and in human mammary epithelial cells exposed to RMT-conditioned medium was activated erbB-2 protein. Partial purification of the activating factor present in RMT-conditioned medium yielded a heparin-binding growth factor with biochemical properties similar to those of neu differentiation factor/heregulin (NDF/HRG). RNA-polymerase chain reaction analysis demonstrated that RMT cells expressed mRNA for NDF/HRG, and western-blot analysis confirmed the presence of the 45-kDa secreted form of NDF/HRG in conditioned medium from the growth factor-independent RMT cells. The biological activity of partially purified rat NDF/HRG was examined and found to be the same as that of the pure growth factor. In addition, we found that RMT-conditioned medium, fractionated on an anion-exchange column and by reverse-phase high-pressure liquid chromatography, contained a potent EGF-like growth factor that was distinct from NDF/HRG. This factor competes with 125I-EGF for binding to EGF receptors and has an apparent molecular mass of 6600 Da. This factor copurifies by high-pressure liquid chromatography with pure transforming growth factor-alpha (TGF-alpha), and the cells are positive for TGF-alpha mRNA. Thus, growth factor-independent RMT cells also synthesize and secrete TGF-alpha. These results indicate that growth factor-independent cells secrete two growth factors with overlapping biological activities and suggest that autocrine loops mediated by these factors are important in the growth factor-independent proliferation of the RMT cells. PMID:8599580

Ethier, S P; Langton, B C; Dilts, C A

1996-02-01

278

Aloe-emodin inhibits proliferation of adult human keratinocytes in vitro.  

PubMed

Aloe-emodin (AE) is a plant-derived hydroxyanthraquinone with several biological activities. It is present in a variety of skin-conditioning agents containing aloe extracts, but its influence on keratinocyte growth was not examined so far. We investigated the influence of AE on human keratinocyte proliferation and apoptosis in vitro. AE significantly inhibited proliferation of cultivated human keratinocytes at 5 ?M concentration, as revealed by incorporation of radioactive thymidine. The antiproliferative effect of AE was accompanied with induction of apoptosis, but not necrosis, as demonstrated by flow cytometric analysis and lactate dehydrogenase release assay. Based on the half maximal inhibitory concentration values, we demonstrated that AE may impair proliferation of keratinocytes at concentrations far below the industry standards for commercial products containing aloe extracts. Therefore, further research of AE effects on the human skin and proper labeling of products are necessary for maximizing benefits from aloe extracts and to avoid undesired responses. PMID:23089351

Popadic, Dusan; Savic, Emina; Ramic, Zorica; Djordjevic, Vladimir; Trajkovic, Vladimir; Medenica, Ljiljana; Popadic, Svetlana

2012-01-01

279

Insulinlike growth factor 1 and insulinlike growth factor 3: Indices of intestinal failure in children  

Microsoft Academic Search

Background\\/Purpose: A number of pediatric patients with short bowel syndrome (SBS) manifest growth failure despite aggressive nutritional support. Exogenous growth hormone (GH) therapy in children with SBS has proved disappointing. The purpose of this study was to determine if there were characteristic patterns of GH, IGF-1, or IGFBP-3 levels in pediatric SBS patients with profound growth failure in an effort

Edward M Barksdale; Anita N Koehler; Jane Anne Yaworski; Mary Gardner; Jorge Reyes

1999-01-01

280

Insulin-like 3-induced rat preantral follicular growth is mediated by growth differentiation factor 9.  

PubMed

The communication of somatic cells and oocytes by intrafollicular paracrine factors is essential for follicular growth in the ovary. Insulin-like 3 (INSL3) is a theca cell-secreted paracrine factor. Androgens and growth differentiation factor 9 (GDF9), an oocyte-derived growth factor, are essential for follicular development. Using a rat preantral follicle culture model, we examined in the present study the influence of INSL3 on preantral follicular growth and the molecular mechanisms involved. We have observed that the receptor for INSL3, relaxin/insulin-like family peptide receptor 2 (RXFP2), was exclusively expressed in oocytes. Recombinant INSL3 stimulated Gdf9 expression, preantral follicular growth, and testosterone synthesis in vitro. Inhibition of the cAMP/protein kinase A signaling pathway (with cAMP antagonist, 8-bromoadenosine 3',5'-cyclic monophosphorothioate, Rp-isomer) attenuated INSL3-induced Gdf9 expression and preantral follicular growth. Moreover, knocking down Gdf9 expression (with small interfering RNA) or inhibiting GDF9 signaling (with SB431542, an activin receptor-like kinase receptor 5 inhibitor, or specific inhibitor of mothers against decapentaplegic homolog 3) or androgen action (with flutamide, an androgen receptor antagonist) suppressed INSL3-induced preantral follicular growth. In addition, LH and DHT regulated the expression of Insl3 mRNA in preantral follicles. These observations suggest that INSL3 is a key theca cell-derived growth factor for preantral follicle and that its action is mediated by GDF9. PMID:24169563

Xue, Kai; Kim, Ji Young; Liu, Jia-yin; Tsang, Benjamin K

2014-01-01

281

Tunable dual growth factor delivery from polyelectrolyte multilayer films  

PubMed Central

A promising strategy to accelerate joint implant integration and reduce recovery time and failure rates is to deliver a combination of certain growth factors to the integration site. There is a need to control the quantity of growth factors delivered at different times during the healing process to maximize efficacy. Polyelectrolyte multilayer (PEM) films, built using the layer-by-layer (LbL) technique, are attractive for releasing controlled amounts of potent growth factors over a sustained period. Here, we present PEM films that sequester physiological amounts of osteogenic rhBMP-2 (recombinant human bone morphogenetic protein - 2) and angiogenic rhVEGF165 (recombinant human vascular endothelial growth factor) in different ratios in a degradable [poly(?-amino ester)/polyanion/growth factor/ polyanion] LbL tetralayer repeat architecture where the biologic load scaled linearly with the number of tetralayers. No burst release of either growth factor was observed as the films degraded. The release of rhBMP-2 was sustained over a period of 2 weeks, while rhVEGF165 eluted from the film over the first 8 days. Both growth factors retained their efficacy, as quantified with relevant in vitro assays. rhBMP-2 initiated a dose dependent differentiation cascade in MC3T3-E1S4 pre-osteoblasts while rhVEGF165 upregulated HUVEC proliferation, and accelerated closure of a scratch in HUVEC cell cultures in a dose dependent manner. In vivo, the mineral density of ectopic bone formed de novo by rhBMP-2/rhVEGF165 PEM films was approximately 33% higher than when only rhBMP-2 was introduced, with a higher trabecular thickness, which would indicate a decrease in the risk of osteoporotic fracture. Bone formed throughout the scaffold when both growth factors were released, which suggests more complete remodeling due to an increased local vascular network. This study demonstrates a promising approach to delivering precise doses of multiple growth factors for a variety of implant applications where control over spatial and temporal release profile of the biologic is desired. PMID:21645919

Shah, Nisarg J.; Macdonald, Mara L.; Beben, Yvette M.; Padera, Robert F.; Samuel, Raymond E.; Hammond, Paula T.

2011-01-01

282

Factor Determinants of Total Factor Productivity Growth in the Malaysian Hotel Industry: A Stochastic Frontier Approach  

Microsoft Academic Search

This study applies stochastic frontier analysis to data on Malaysian hotels from 2002 to 2004 to decompose total factor productivity growth into technical progress and technical efficiency change. The study also identifies the factors that determine each total factor productivity component. For this time period, Malaysian hotels operated at an average efficiency of 41 percent; and average technical efficiency change,

Sangho Kim

2011-01-01

283

Isolation, cultivation and transfection of human keratinocytes.  

PubMed

Human keratinocytes could be used in the repair of damaged skin, in tissue engineering applications, gene therapy and recently, the generation of iPS cells. We isolated human keratinocytes from foreskin and subsequently cultured them on fibronectin, collagen type I, gelatin and laminin-coated dishes that contained three different types of serum-free medium (epilife, KSM or CnT). We developed improved conditions for efficient transfection of these human keratinocytes by testing three common transfection methods and a GFP plasmid vector. The isolated cells showed typical keratinocyte morphology and expressed the epithelial cell specific antigen, cytokeratin 14. Collagen type 1, epilife medium and lipofectamin 2000 gave the best results for isolation and transfection of human keratinocytes. Our protocol can be used as a reproducible, simple and efficient method for isolation, cultivation and genetic manipulation of human keratinocytes, which may be useful in cell and gene therapy applications. PMID:24323435

Zare, Sona; Zarei, Mohammad Ali; Ghadimi, Tayyeb; Fathi, Fardin; Jalili, Ali; Hakhamaneshi, Mohammad Saeed

2014-04-01

284

Arsenite suppresses Notch1 signaling in human keratinocytes  

PubMed Central

Arsenic is a well known human skin carcinogen whose mechanism of action remains to be elucidated. In this work using cultured human epidermal cells, arsenite suppressed accumulation of the transcriptionally active intracellular domain of Notch1. The cells responded to an active peptide from the Notch1 ligand, Jagged1, with increased levels of differentiation marker mRNAs and decreased colony forming ability. Arsenite suppressed Jagged1 effects and expression of Jagged1 mRNA as well. Moreover, exposure of the cells to a ?-secretase inhibitor prevented Notch1 processing, decreased cell size and differentiation marker expression and increased proliferative potential, all effects that occur with arsenite treatment. Thus, arsenite action in suppressing keratinocyte differentiation while maintaining germinative capability could be due to inhibition of Notch1 signaling subsequent to ligand binding. This work also revealed that such arsenite action depends upon epidermal growth factor receptor kinase activity. These findings may help explain how arsenite, by decreasing generation of the tumor suppressor Notch1, contributes to skin carcinogenesis. PMID:18633435

Reznikova, Tatiana V.; Phillips, Marjorie A.; Rice, Robert H.

2010-01-01

285

Overexpression of Epigen during Embryonic Development Induces Reversible, Epidermal Growth Factor Receptor-Dependent Sebaceous Gland Hyperplasia  

PubMed Central

The epidermal growth factor receptor (EGFR) system is a key regulator of epithelial development and homeostasis. Its functions in the sebaceous gland (SG), however, remain poorly characterized. In this study, using a transgenic mouse line with tissue-specific and inducible expression of the EGFR ligand epigen, we showed that increased activation of the EGFR in skin keratinocytes results in enlarged SGs and increased sebum production. The phenotype can be reverted by interrupting transgene expression and is EGFR dependent, as gland size and sebum levels return to normal values after crossing to the EGFR-impaired mouse line Wa5. Intriguingly, however, the SG enlargement appears only if EGFR activation occurs before birth. Importantly, the enlarged sebaceous glands are associated with an increased expression of the transcription factor MYC and of the transmembrane proteins LRIG1, an established negative-feedback regulator of the EGFR/ERBB tyrosine kinase receptors and a stem cell marker. Our findings identify EGFR signaling as a major pathway determining SG activity and suggest a functional relationship between the EGFR/ERBB system and MYC/LRIG1 in the commitment of stem cells toward specific progenitor cell types, with implications for our understanding of their role in tissue development, homeostasis, and disease. PMID:24891618

Dahlhoff, Maik; Frances, Daniela; Kloepper, Jennifer E.; Paus, Ralf; Schäfer, Matthias; Niemann, Catherin

2014-01-01

286

Associated factors for accelerated growth in childhood: a systematic review.  

PubMed

Several studies have shown that accelerated growth in the postnatal period is critical for the development of chronic diseases. The term catch-up has been used for the accelerated growth of children who have suffered some sort of restriction of nutrition or oxygen supply. However, accelerated growth has been observed among children who have an appropriate birth weight for their gestational age (AGA) and with no apparent morbidity. Therefore, this systematic review was carried out on the associated factors of accelerated growth, or catch-up, using the Medline/Pubmed database. Only cohort studies written in Portuguese, English or Spanish, with children between zero and 12 years old who presented accelerated growth or catch-up as the outcome were included. Out of the 2,155 articles found, 9 were selected. There is no uniformity in the operational definition of accelerated growth, or in the concept of catch-up. According to this review, accelerated growth is associated with primiparity, maternal smoking during pregnancy, lower birth weight, and early weaning. The main limitations in the available literature are the high number of follow-up losses and the lack of control for confounding factors. The determinants of accelerated growth still need to be studied further, especially among AGA children. PMID:22547159

Chrestani, Maria Aurora; Santos, Iná S; Horta, Bernardo L; Dumith, Samuel C; de Oliveira Dode, Maria Alice Souza

2013-04-01

287

Exogenous stimulation with Eclipta alba promotes hair matrix keratinocyte proliferation and downregulates TGF-?1 expression in nude mice.  

PubMed

Eclipta alba (L.) Hassk (E. alba) is a traditionally acclaimed medicinal herb used for the promotion of hair growth. However, to the best of our knowledge, no report has been issued to date on its effects on genetically distorted hair follicles (HFs). In this study, we aimed to identify an agent (stimuli) that may be beneficial for the restoration of human hair loss and which may be used as an alternative to synthetic drugs. We investigated the effects of petroleum ether extract (PEE) and different solvent fractions of E. alba on HFs of nude mice. Treatment was performed by topical application on the backs of nude mice and the changes in hair growth patterns were evaluated. Histological analysis was carried out to evaluate the HF morphology and the structural differences. Immunohistochemical (IHC) staining was performed to visualize follicular keratinocyte proliferation. The histological assessments revealed that the PEE-treated skin specimens exhibited prominent follicular hypertrophy. Subsequently, IHC staining revealed a significant increase (p<0.001) in the number of follicular keratinocytes in basal epidermal and matrix cells. Our results also demonstrated that PEE significantly (p<0.001) reduced the levels of transforming growth factor-?1 (TGF-?1) expression during early anagen and anagen-catagen transition. Our results suggest that PEE of E. alba acts as an important exogenous mediator that stimulates follicular keratinocyte proliferation and delays terminal differentiation by downregulating TGF-?1 expression. Thus, this study highlights the potential use of PEE of E. alba in the treatment of certain types of alopecia. PMID:25484129

Begum, Shahnaz; Lee, Mi Ra; Gu, Li Juan; Hossain, Jamil; Sung, Chang Keun

2015-02-01

288

Insulinlike Growth Factor 1 in Controls and Growth-Retarded Fetuses  

Microsoft Academic Search

Objectives: To establish a reference range of insulinlike growth factor 1 (IGF-1) values in normal fetuses and to assess whether intrauterine growth retardation is associated with increased or decreased IGF-1 levels. Methods: Retrospective analysis of blood samples collected from 64 fetuses who underwent blood sampling at 18–38 weeks’ gestation was performed: 40 fetuses, who were considered controls, were appropriately grown

Luisa Bocconi; Fabio Mauro; Silvia E. Maddalena; Cinzia De Iulio; Amedea S. Tirelli; Elisabetta Pace; Umberto Nicolini

1998-01-01

289

Human Keratinocytes Are Vanilloid Resistant  

Microsoft Academic Search

BackgroundUse of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain\\/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca2+-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular

László Pecze; Kornélia Szabó; Márta Széll; Katalin Jósvay; Krisztián Kaszás; Erzsébet Kúsz; Tamás Letoha; János Prorok; István Koncz; András Tóth; Lajos Kemény; Csaba Vizler; Zoltán Oláh; Leslie B. Vosshall

2008-01-01

290

Advances in pubertal growth and factors influencing it: Can we increase pubertal growth?  

PubMed Central

Puberty is a period of development characterized by partially concurrent changes which includes growth acceleration, alteration in body composition and appearance of secondary sex characteristics. Puberty is characterized by an acceleration and then deceleration in skeletal growth. The initiation, duration and amount of growth vary considerably during the growth spurt. Pubertal growth and biological maturation are dynamic processes regulated by a variety of genetic and environmental factors. Changes in skeletal maturation and bone mineral accretion concomitant with the stage of pubertal development constitute essential components in the evaluation of growth during this pubertal period. Genetic, endocrine and nutritional factors and ethnicity contribute variably to the amount of growth gained during this important period of rapid changes. Many studies investigated the possibility of increasing pubertal growth to gain taller final adult height in adolescents with idiopathic short stature (ISS). The pattern of pubertal growth, its relation to sex maturity rating and factors affecting them has been addressed in this review. The results of different trials to increase final adult height of adolescents using different hormones have been summarized. These data enables Endocrinologists to give in-depth explanations to patients and families about the efficacy and clinical significance as well as the safety of using these therapies in the treatment of adolescents with ISS. PMID:25538878

Soliman, Ashraf; De Sanctis, Vincenzo; Elalaily, Rania; Bedair, Said

2014-01-01

291

Dysregulation of the fibroblast growth factor system in major depression  

PubMed Central

In this report we describe findings that imply dysregulation of several fibroblast growth factor (FGF) system transcripts in frontal cortical regions of brains from human subjects with major depressive disorder (MDD). This altered gene expression was discovered by microarray analysis of frontal cortical tissue from MDD, bipolar, and nonpsychiatric control subjects and was verified by quantitative real-time PCR analysis and, importantly, in a separate cohort of MDD subjects. Furthermore, we show, through a separate analysis of specific serotonin reuptake inhibitor (SSRI)-treated and non-SSRI-treated MDD subjects that the observed changes in expression of FGF transcripts are not secondary to drug treatment. Rather, changes in specific FGF transcripts are attenuated by SSRIs and may thus be partially responsible for the mechanism of action of these drugs. We also make available the gene-expression profile of all of the other growth factors and growth factor receptors detected in these postmortem samples. PMID:15483108

Evans, S. J.; Choudary, P. V.; Neal, C. R.; Li, J. Z.; Vawter, M. P.; Tomita, H.; Lopez, J. F.; Thompson, R. C.; Meng, F.; Stead, J. D.; Walsh, D. M.; Myers, R. M.; Bunney, W. E.; Watson, S. J.; Jones, E. G.; Akil, H.

2004-01-01

292

Growth factors with heparin binding affinity in human synovial fluid  

SciTech Connect

Synovial effusions were obtained from the knees of 15 subjects with joint trauma, menisceal or ligamentous injury, or osteoarthritis. Heparin-Sepharose affinity chromatography of these synovial fluids revealed, in general, three major peaks of mitogenic activity as measured by incorporation of /sup 3/H-thymidine into 3T3 cells. Gradient elution patterns showed activities at 0.5M NaCl, which is characteristic of platelet derived growth factor, and at 1.1 M NaCl and 1.6M NaCl, indicative of acidic and basic fibroblast growth factors, respectively. The identities of these mitogenic fractions were confirmed by specific immunologic and receptor-binding assays. The presence of platelet derived, acidic and basic fibroblast growth factors in the synovial fluid may contribute to wound healing in the arthritic joint.

Hamerman, D.; Taylor, S.; Kirschenbaum, I.; Klagsbrun, M.; Raines, E.W.; Ross, R.; Thomas, K.A.

1987-12-01

293

Fibroblast growth factor 2 isoforms and cardiac hypertrophy  

Microsoft Academic Search

Fibroblast growth factor 2 (FGF-2), a multifunctional polypeptide that affects cell growth and differentiation and becomes upregulated by stress, is expressed as AUG-initiated 18 kDa FGF-2 or CUG-initiated 21-34 kDa (hi-FGF-2) isoforms. Animal models have provided strong evidence that FGF-2 is essential for the manifestation of overload- and angiotensin-induced cardiac hypertrophy. Nevertheless, studies to-date have not discriminated between the activities

Elissavet Kardami; Zhi-Sheng Jiang; Sarah K. Jimenez; Cheryl J. Hirst; Farah Sheikh; Peter Zahradka; Peter A. Cattini

2004-01-01

294

Basic fibroblast growth factor in rat salivary glands  

Microsoft Academic Search

We studied the occurrence and localization of basic fibroblast growth factor (bFGF) in rat salivary glands using a specific monoclonal antibody. It was shown that the extract of rat salivary glands has a pronounced stimulatory activity on the growth of bovine capillary endothelial cells, which is blocked by the addition of an antibody against bFGF. The concentration of bFGF in

Osamu Amano; Yoshino Yoshitake; Katsuzo Nishikawa; Shoichi Iseki

1993-01-01

295

Anti-vascular endothelial growth factor therapy for malignant glioma  

Microsoft Academic Search

Glioblastomas are among the most vascular tumors because they oversecrete vascular endothelial growth factor (VEGF), a potent\\u000a stimulator of angiogenesis. Consequently, new drug regimens are being developed to target the VEGF signaling pathway in an\\u000a attempt to halt tumor growth. Antibodies that bind VEGF, decoy molecules that sequester VEGF, and small molecule tyrosine\\u000a kinase inhibitors that block receptor activation are

Elizabeth R. Gerstner; A. Gregory Sorensen; Rakesh K. Jain; Tracy T. Batchelor

2009-01-01

296

The antiepidermal growth factor receptor monoclonal antibody cetuximab\\/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression  

Microsoft Academic Search

We have previously shown that the antiepidermal growth factor receptor monoclonal antibody cetuximab (C225; Erbitux), which was recently approved for the treatment of metastatic colorectal cancer, has antiangiogenic properties, inhibiting vascular endothelial growth factor (VEGF) secretion in culture and in animal models. Here, we have furthered the study by demonstrating that cetuximab reduces cellular levels of hypoxia-inducible factor-1 alpha (HIF-1?),

Rodney B Luwor; Yang Lu; Xinqun Li; John Mendelsohn; Zhen Fan

2005-01-01

297

Sustained Immobilization of Growth Factor Proteins Based on Functionalized Parylenes.  

PubMed

Protein molecules immobilized on biomaterial surfaces are performed based on oriented conjugation or replaced mimicking peptides. The sustainable immobilization of growth factor proteins using functionalized parylene coatings is demonstrated in this study. Site-specific and nonspecific immobilization approaches are realized to conjugate bone morphogenetic protein (BMP-2). The binding affinities and conformational changes of BMP-2 are confirmed by QCM and SPR characterizations. Osteoinduction of stem cells is examined by ALP activity on the BMP-2 modified surfaces. Finally, immobilizations and equally sustained biological functions of vascular endothelial growth factor (VEGF) and a mimicking peptide of KLTWQELYQLKYKG (QK) are also examined and confirmed. PMID:25434778

Chen, Yung-Chih; Sun, Ting-Pi; Su, Chiao-Tzu; Wu, Jyun-Ting; Lin, Chih-Yeh; Yu, Jiashing; Huang, Chao-Wei; Chen, Chia-Jie; Chen, Hsien-Yeh

2014-12-01

298

Transforming growth factor-b signaling and ubiquitinators in cancer  

Microsoft Academic Search

Transforming growth factor-b (TGF-b) represents a large family of growth and differentiation factors that mobilize complex signaling networks to regulate cellular differentiation, proliferation, motility, adhesion, and apoptosis. TGF-b signaling is tightly regulated by multiple complex mechanisms, anditsderegulationplaysakeyroleintheprogressionofmanyformsofcancer.Uponligandbinding, TGF-bsignalsaretransducedbySmadproteins,whichinturnaretightlydependentonmodulationby adaptorproteinssuchasembryonicliverfodrin,Smadanchorforreceptoractivation,filamin,andcrkl. A furtherlayerofregulationisimposed byubiquitin-mediatedtargeting andproteasomaldegradation ofspecificcomponentsoftheTGF-bsignalingpathway.Thisreviewfocusesontheubiquitinatorsthat regulate TGF-b signaling and the association of these ubiquitin ligases with various forms of cancer. Delineating

Eric Glasgow; Lopa Mishra

299

Constitution of fibrin-based niche for in vitro differentiation of adipose-derived mesenchymal stem cells to keratinocytes.  

PubMed

Epithelialization of chronic cutaneous wound is troublesome and may require use of skin/cell substitutes. Adipose-derived mesenchymal stem cells (ADMSCs) have immense potential as autologous cell source for treating wounds; they can cross the germ layer boundary of differentiation and regenerate skin. When multipotent adult stem cells are considered for skin regeneration, lineage committed keratinocytes may be beneficial to prevent undesirable post-transplantation outcome. This study hypothesized that ADMSCs may be directed to epidermal lineage in vitro on a specifically designed biomimetic and biodegradable niche. Cells were seeded on the test niche constituted with fibrin, fibronectin, gelatin, hyaluronic acid, laminin V, platelet growth factor, and epidermal growth factor in the presence of cell-specific differentiation medium (DM). The ADMSCs grown on bare tissue culture polystyrene surface in DM is designated DM-control and those grown in basal medium (BM) is the BM-control. Lineage commitment was monitored with keratinocyte-specific markers such as cytokeratin 14, cytokeratin 5, cytokeratin 19, and integrin ?6 at the transcriptional/translational level. The in vitro designed biomimetic fibrin composite matrix may have potential application as cell transplantation vehicle. PMID:25469318

Sivan, Unnikrishnan; Jayakumar, K; Krishnan, Lissy K

2014-12-01

300

Cytokines and growth factors which regulate bone cell function  

NASA Astrophysics Data System (ADS)

Everybody knows that growth factors are most important in making bone. Hormones enhance bone formation from a long distance. Growth factors promote bone formation as an autocrine or paracrine factor in nearby bone. BMP-2 through BMP-8 are in the TGF-? family. BMP makes bone by enchondral ossification. In bone, IGF-II is most abundant, second, TGF-?, and third IGF-I. TGF-? enhances bone formation mainly by intramembranous ossification in vivo. TGF-? affects both cell proliferation and differentiation, however, TGF-? mainly enhances bone formation by intramembranous ossification. Interestingly, TGF-? is increased by estrogen(E 2), androgen, vitamin D, TGF-? and FGF. IGF-I and IGF-II also enhance bone formation. At present it remains unclear why IGF-I is more active in bone formation than IGF-II, although IGF-II is more abundant in bone compared to IGF-I. However, if only type I receptor signal transduction promotes bone formation, the strong activity of IGF-I in bone formation is understandable. GH, PTH and E 2 promotes IGF-I production. Recent data suggest that hormones containing vitamin D or E 2 enhance bone formation through growth factors. Therefore, growth factors are the key to clarifying the mechanism of bone formation.

Seino, Yoshiki

301

The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease  

Microsoft Academic Search

SUMMARY: Vascular endothelial growth factors (VEGFs) are a family of secreted polypeptides with a highly conserved receptor-binding cystine-knot structure similar to that of the platelet-derived growth factors. VEGF-A, the founding member of the family, is highly conserved between animals as evolutionarily distant as fish and mammals. In vertebrates, VEGFs act through a family of cognate receptor kinases in endothelial cells

David IR Holmes; Ian Zachary

2005-01-01

302

Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer  

PubMed Central

Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non–small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed. PMID:20975071

Maki, Robert G.

2010-01-01

303

Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.  

PubMed Central

Vascular permeability factor (VPF) is an Mr 40-kD protein that has been purified from the conditioned medium of guinea pig line 10 tumor cells grown in vitro, and increases fluid permeability from blood vessels when injected intradermally. Addition of VPF to cultures of vascular endothelial cells in vitro unexpectedly stimulated cellular proliferation. VPF promoted the growth of new blood vessels when administered into healing rabbit bone grafts or rat corneas. The identity of the growth factor activity with VPF was established in four ways: (a) the molecular weight of the activity in preparative SDS-PAGE was the same as VPF (Mr approximately 40 kD); (b) multiple isoforms (pI greater than or equal to 8) for both VPF and the growth-promoting activity were observed; (c) a single, unique NH2-terminal amino acid sequence was obtained; (d) both growth factor and permeability-enhancing activities were immunoadsorbed using antipeptide IgG that recognized the amino terminus of VPF. Furthermore, 125I-VPF was shown to bind specifically and with high affinity to endothelial cells in vitro and could be chemically cross-linked to a high-molecular weight cell surface receptor, thus demonstrating a mechanism whereby VPF can interact directly with endothelial cells. Unlike other endothelial cell growth factors, VPF did not stimulate [3H]thymidine incorporation or promote growth of other cell types including mouse 3T3 fibroblasts or bovine smooth muscle cells. VPF, therefore, appears to be unique in its ability to specifically promote increased vascular permeability, endothelial cell growth, and angio-genesis. Images PMID:2478587

Connolly, D T; Heuvelman, D M; Nelson, R; Olander, J V; Eppley, B L; Delfino, J J; Siegel, N R; Leimgruber, R M; Feder, J

1989-01-01

304

Transforming Growth Factor-? in Brain Functions and Dysfunctions  

Microsoft Academic Search

Transforming growth factor-?s (TGF-?s) belong to a superfamily of related peptides that play pivotal roles in intercellular\\u000a communication. Among these biological agents, TGF-?1 has been involved in a number of brain functions and dysfunctions throughout\\u000a life, ranging from neurogenesis to neurodegeneration. Animal models mimicking some aspects of human brain pathologies have\\u000a led to the idea that TGF-? may be a

Denis Vivien; Karim Benchenane; Carine Ali

305

Thyroid autocrine factors: regulation of secretion of insulin-like growth factor binding proteins from sheep thyroid cells by autocrine basic fibroblast growth factor.  

PubMed

The mRNA for basic fibroblast growth factor has been detected in primary cultures of sheep thyroid cells. RNA species of 2.0 kb, 3.3 kb and 7.2 kb have been identified. The effects of this autocrine factor on the production of insulin-like growth factor binding proteins (IGFBPs) have been examined. bFGF enhanced the secretion of IGFBP-2 and, like epidermal growth factor (EGF) and the tumour promoting phorbol ester (TPA), induced the appearance of IGFBP-3. We conclude that bFGF is synthesized by sheep thyroid cells and has autocrine potential since it can regulate the secretion of other thyroid autocrine factors which, in turn, may regulate thyroid growth and function. PMID:1726926

Eggo, M C; Islam, S; Sheppard, M C

1991-12-01

306

Ligand Targeting of EphA2 Enhances Keratinocyte Adhesion and Differentiation via Desmoglein 1  

PubMed Central

EphA2 is a receptor tyrosine kinase that is engaged and activated by membrane-linked ephrin-A ligands residing on adjacent cell surfaces. Ligand targeting of EphA2 has been implicated in epithelial growth regulation by inhibiting the extracellular signal-regulated kinase 1/2 (Erk1/2)-mitogen activated protein kinase (MAPK) pathway. Although contact-dependent EphA2 activation was required for dampening Erk1/2-MAPK signaling after a calcium switch in primary human epidermal keratinocytes, the loss of this receptor did not prevent exit from the cell cycle. Incubating keratinocytes with a soluble ephrin-A1-Fc peptide mimetic to target EphA2 further increased receptor activation leading to its down-regulation. Moreover, soluble ligand targeting of EphA2 restricted the lateral expansion of epidermal cell colonies without limiting proliferation in these primary cultures. Rather, ephrin-A1-Fc peptide treatment promoted epidermal cell colony compaction and stratification in a manner that was associated with increased keratinocyte differentiation. The ligand-dependent increase in keratinocyte adhesion and differentiation relied largely upon the up-regulation of desmoglein 1, a desmosomal cadherin that maintains the integrity and differentiated state of suprabasal keratinocytes in the epidermis. These data suggest that keratinocytes expressing EphA2 in the basal layer may respond to ephrin-A1–based cues from their neighbors to facilitate entry into a terminal differentiation pathway. PMID:20861311

Lin, Samantha; Gordon, Kristin; Kaplan, Nihal

2010-01-01

307

[Study on the osteoblast and the growth factors of bone tissue engineering].  

PubMed

To build artificial bone with osteoblast and growth factors is one of popular studies on current bone tissue engineering. This paper has reviewed current studies on the function of the growth factors and the resource, isolation and culture of the osteoblast. It also introduces the interaction of the growth factors, and the development in the transgenosis of the relative growth factors. PMID:12901113

Zhang, L H; Zhang, Q Q

2001-12-01

308

Insulin-Like Growth Factor I (IGF-1) Ec/Mechano Growth Factor – A Splice Variant of IGF-1 within the Growth Plate  

PubMed Central

Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation. PMID:24146828

Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

2013-01-01

309

Heparin-Binding Epidermal Growth Factor-like Growth Factor/Diphtheria Toxin Receptor in Normal and Neoplastic Hematopoiesis  

PubMed Central

Heparin-binding EGF-like growth factor (HB-EGF) belongs to the EGF family of growth factors. It is biologically active either as a molecule anchored to the membrane or as a soluble form released by proteolytic cleavage of the extracellular domain. HB-EGF is involved in relevant physiological and pathological processes spanning from proliferation and apoptosis to morphogenesis. We outline here the main activities of HB-EGF in connection with normal or neoplastic differentiative or proliferative events taking place primitively in the hematopoietic microenvironment. PMID:23888518

Vinante, Fabrizio; Rigo, Antonella

2013-01-01

310

Transforming growth factor ? induces angiogenesis and neurogenesis following stroke  

Microsoft Academic Search

The cytokine transforming growth factor ? (TGF?) has proangiogenic and proneurogenic effects and can potentially reduce infarct volumes. Therefore, we administered TGF? or vehicle directly into the area surrounding the infarct in female mice that received gender-mismatched bone marrow transplants from green fluorescent protein (GFP)–expressing males prior to undergoing permanent middle cerebral artery occlusion. Newborn cells were tracked with bromodeoxyuridine

R. R. Leker; Z. E. Toth; T. Shahar; R. Cassiani-Ingoni; I. Szalayova; A. Bratincsák; E. Mezey

2009-01-01

311

Vascular Endothelial Growth Factor Attenuates Myocardial Ischemia-Reperfusion Injury  

Microsoft Academic Search

Background. Hypoxic endothelial cell activation plays a key role in the myocardial dysfunction resulting from ischemia-reperfusion injury. Recent evidence suggests that vascular endothelial growth factor (VEGF) may, in addition to promoting angiogenesis, modulate various aspects of endothelial function and repair. We examined whether administration of VEGF in the cardioplegic solution might have a beneficial effect on myocardial ischemia-reperfusion injury in

Zhengyu Luo; Maurizio Diaco; Toyoaki Murohara; Napoleone Ferrara; Jeffrey M Isner; James F Symes

1997-01-01

312

Controlled growth factor release from synthetic extracellular matrices  

NASA Astrophysics Data System (ADS)

Polymeric matrices can be used to grow new tissues and organs, and the delivery of growth factors from these matrices is one method to regenerate tissues. A problem with engineering tissues that exist in a mechanically dynamic environment, such as bone, muscle and blood vessels, is that most drug delivery systems have been designed to operate under static conditions. We thought that polymeric matrices, which release growth factors in response to mechanical signals, might provide a new approach to guide tissue formation in mechanically stressed environments. Critical design features for this type of system include the ability to undergo repeated deformation, and a reversible binding of the protein growth factors to polymeric matrices to allow for responses to repeated stimuli. Here we report a model delivery system that can respond to mechanical signalling and upregulate the release of a growth factor to promote blood vessel formation. This approach may find a number of applications, including regeneration and engineering of new tissues and more general drug-delivery applications.

Lee, Kuen Yong; Peters, Martin C.; Anderson, Kenneth W.; Mooney, David J.

2000-12-01

313

Peripheral nerve repair with nerve growth factor and fibrin matrix  

Microsoft Academic Search

A fibrin sealant matrix (FS) with or without a nerve growth factor (NGF) has been used to improve the recovery of severed peripheral nerves, and these have been compared with the results of using only the standard epineural suture (SUT). Regeneration in the early phase (up to 6 days) was measured by the pinch test. The functional recovery process (up

L. Zeng; A. Worseg; H. Redl; G. Schlag

1994-01-01

314

NEUROBIOLOGICAL EFFECTS OF COLCHICINE: MODULATION BY NERVE GROWTH FACTOR  

EPA Science Inventory

To study the effects of exogenously applied nerve growth factor (NGF) on colchicine-induced neurodegeneration in the dentate gyrus of the rat hippocampal formation, male Fischer 344 rats (n=75) weighing 275-325 grams received colchicine [COLCH; 2.5 ug/site in 0.5 ul of artificial...

315

An Atomic Resolution Structure for Human Fibroblast Growth Factor 1  

E-print Network

An Atomic Resolution Structure for Human Fibroblast Growth Factor 1 Matthew J. Bernett. The backbone atoms of each structurally conserved region of the symmetry-related subdomains in FGF-1 overlay and Biochemistry, Florida State University, Tallahassee, Florida ABSTRACT A 1.10-Ã? atomic resolution X

Blaber, Michael

316

Fibroblast Growth Factor-2 Alters the Nature of Extinction  

ERIC Educational Resources Information Center

These experiments examined the effects of the NMDA-receptor (NMDAr) antagonist MK801 on reacquisition and re-extinction of a conditioned fear that had been previously extinguished before injection of fibroblast growth factor-2 (FGF2) or vehicle. Recent findings have shown that relearning and re-extinction, unlike initial learning and extinction,…

Graham, Bronwyn M.; Richardson, Rick

2011-01-01

317

Expression of vascular endothelial growth factor in tuberculous meningitis  

Microsoft Academic Search

The pathogenesis of tuberculous meningitis is still unclear. Recently, vascular endothelial growth factor (VEGF) was found to be associated with inflammatory diseases and we found the increased serum level of VEGF in pulmonary tuberculosis. We hypothesized that VEGF might be associated with the pathogenesis of tuberculous meningitis and measured serum and cerebrospinal fluid (CSF) levels of VEGF in 28 patients

Wataru Matsuyama; Teruto Hashiguchi; Fujio Umehara; Eiji Matsuura; Masaharu Kawabata; Kimiyoshi Arimura; Ikurou Maruyama; Mitsuhiro Osame

2001-01-01

318

Cerebrospinal fluid hepatocyte growth factor level in meningitis  

Microsoft Academic Search

Background and Purpose: Hepatocyte growth factor (HGF) is a multifunctional cytokine that has been found to be elevated in tuberculous and bacterial meningitis, but no evaluation has been undertaken of its usefulness in identifying various forms of aseptic meningitis. Methods: In a retrospective study, the levels of HGF in the cerebrospinal fluid of 65 patients were measured prior to treatment.

Cheng-Len Sy; Hung-Chin Tsai; Shue-Ren Wann; Susan Shin-Jung Lee; Yung-Ching Liu; Yao-Shen Chen

2008-01-01

319

Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas  

Microsoft Academic Search

Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endo- thelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. As a first approach, cDNA array analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various

Cristina Blazquez; Luis Gonzalez-Feria; Luis Alvarez; Amador Haro; M. Llanos Casanova; Manuel Guzman

320

Epidermal growth factor requirement for development of cultured mammary gland  

Microsoft Academic Search

The mouse mammary gland in serum-free whole organ culture can be manipulated hormonally to undergo one complete physiological cycle consisting of lobuloalveolar development1, functional differentiation and regression2, mimicking processes that occur in vivo. A second cycle has not previously been achieved in vitro. The present study has identified a specific requirement for epidermal growth factor (EGF) in the morphological development

Quentin J. Tonelli; Sam Sorof

1980-01-01

321

ARTICLE IN PRESS Platelet-derived growth factor regulates oligodendrocyte  

E-print Network

ARTICLE IN PRESS Platelet-derived growth factor regulates oligodendrocyte progenitor numbers such as multiple sclerosis, it will be important to understand the mechanisms that control oligodendrocyte­xxx sclerosis (MS) (Franklin, 2002; Ludwin, 1987). A major source of remyelinating oligodendrocytes is thought

Richardson, William D.

322

Transforming growth factor-? in breast cancer: too much, too late  

Microsoft Academic Search

The contribution of transforming growth factor (TGF)? to breast cancer has been studied from a myriad perspectives since seminal studies more than two decades ago. Although the action of TGF? as a canonical tumor suppressor in breast is without a doubt, there is compelling evidence that TGF? is frequently subverted in a malignant plexus that drives breast cancer. New knowledge

Mary Helen Barcellos-Hoff; Rosemary J Akhurst

2009-01-01

323

Thrombopoietic growth factors in the treatment of immune thrombocytopenic purpura.  

PubMed

Immune thrombocytopenic purpura (ITP) is a relatively common blood disorder related to the production of anti-platelet antibodies. It is now clear that platelet production is also substantially impaired in most patients. After the cloning of TPO and analogs, there were reported therapeutic successes in a few refractory ITP patients, but neutralizing antibodies led to the withdrawal of first-generation thrombopoietic growth factor from development. Second-generation thrombopoietic growth factors are now available that stimulate c-mpl but share no homology with the native hormone. Second-generation thrombopoietic growth factors have shown responses in 50-80% of ITP patients with only modest toxicity, and thus they offer another therapeutic option. The first of these agents to enter clinical trials and to be approved by the FDA is romiplostim, a once weekly subcutaneous peptibody. Eltrombopag is the second FDA-approved thrombopoietic growth factor and has the advantage of oral formulation. Some concerns persist on the potential of these agents to cause increased thrombosis risk, rebound thrombocytopenia on drug withdrawal, reticulin fibrosis of the marrow, and induction of malignancy, but these have not emerged as major problems in clinical trials. PMID:20378370

Wang, Tingting; Wang, Zhao; Yang, Renchi

2011-03-01

324

Total Chemical Synthesis of Biologically Active Vascular Endothelial Growth Factor  

SciTech Connect

The 204-residue covalent-dimer vascular endothelial growth factor (VEGF, see picture) with full mitogenic activity was prepared from three unprotected peptide segments by one-pot native chemical ligations. The covalent structure of the synthetic VEGF was confirmed by precise mass measurement, and the three-dimensional structure of the synthetic protein was determined by high-resolution X-ray crystallography.

Mandal, Kalyaneswar; Kent, Stephen B.H. (UC)

2011-09-15

325

Preferential tendon stem cell response to growth factor supplementation.  

PubMed

Tendon injuries are increasingly prevalent around the world, accounting for more than 100 000 new clinical cases/year in the USA alone. Cell-based therapies have been proposed as a therapeutic strategy, with recent data advocating the use of tendon stem cells (TSCs) as a potential cell source with clinical relevance for tendon regeneration. However, their in vitro expansion is problematic, as they lose their multipotency and change their protein expression profile in culture. Herein, we ventured to assess the influence of insulin-like growth factor 1 (IGF-1), growth and differentiation factor-5 (GDF-5) and transforming growth factor-?1 (TGF?1) supplementation in TSC culture. IGF-1 preserved multipotency for up to 28?days. Upregulation of decorin and scleraxis expression was observed as compared to freshly isolated cells. GDF-5 treated cells exhibited reduced differentiation along adipogenic and chondrogenic pathways after 28?days, and decorin, scleraxis and collagen type I expression was increased. After 28?days, TGF?1 supplementation led to increased scleraxis, osteonectin and collagen type II expression. The varied responses to each growth factor may reflect their role in tendon repair, suggesting that: GDF-5 promotes the transition of tendon stem cells towards tenocytes; TGF?1 induces differentiation along several pathways, including a phenotype indicative of fibrocartilage or calcified tendon, common problems in tendon healing; and IGF-1 promotes proliferation and maintenance of TSC phenotypes, thereby creating a population sufficient to have a beneficial effect. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24474722

Holladay, Carolyn; Abbah, Sunny-Akogwu; O'Dowd, Colm; Pandit, Abhay; Zeugolis, Dimitrios I

2014-01-29

326

The Hematopoietic Growth Factors in Acute Leukemia: US Perspective  

Microsoft Academic Search

\\u000a The role of myeloid growth factors (GFs) in the management of acute leukemias has been evaluated extensively in multiple clinical\\u000a trials. Granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF) have been given prior to, concurrently\\u000a with, and\\/or sequentially after the chemotherapy with the goal of reducing the duration of neutropenia and consequently, the\\u000a incidence and severity of infections, as

Olga Frankfurt; Martin S. Tallman

327

Changes in Keratinocyte Maturation During Wound Healing  

Microsoft Academic Search

Changes in the presence and distribution of maturation markers in human epidermis following injury have been studied with the goal of understanding the nature of keratinocyte responses to environmental stress. Wound healing has been compared with normal, uninjured epidermis, psoriatic epidermis, and cultured keratinocytes. To distinguish keratinization pathways expressed during wound healing, we have used fluorescence microscopy to detect the

Jonathan N. Mansbridge; Merrill Knapp

1987-01-01

328

Fibroblast Growth Factors Stimulate Hair Growth through ?-Catenin and Shh Expression in C57BL/6 Mice  

PubMed Central

Growth factors are involved in the regulation of hair morphogenesis and cycle hair growth. The present study sought to investigate the hair growth promoting activities of three approved growth factor drugs, fibroblast growth factor 10 (FGF-10), acidic fibroblast growth factor (FGF-1), and basic fibroblast growth factor (FGF-2), and the mechanism of action. We observed that FGFs promoted hair growth by inducing the anagen phase in telogenic C57BL/6 mice. Specifically, the histomorphometric analysis data indicates that topical application of FGFs induced an earlier anagen phase and prolonged the mature anagen phase, in contrast to the control group. Moreover, the immunohistochemical analysis reveals earlier induction of ?-catenin and Sonic hedgehog (Shh) in hair follicles of the FGFs-treated group. These results suggest that FGFs promote hair growth by inducing the anagen phase in resting hair follicles and might be a potential hair growth-promoting agent.

Lin, Wei-hong; Xiang, Li-Jun; Shi, Hong-Xue; Zhang, Jian; Jiang, Li-ping; Cai, Ping-tao; Lin, Zhen-Lang; Lin, Bei-Bei; Huang, Yan; Zhang, Hai-Lin; Fu, Xiao-Bing; Guo, Ding-Jiong; Li, Xiao-Kun; Wang, Xiao-Jie; Xiao, Jian

2015-01-01

329

Overexpression of Vascular Permeability Factor\\/Vascular Endothelial Growth Factor and its Receptors in Psoriasis  

Microsoft Academic Search

Summary Psoriatic skin is characterized by microvascular hyperpermeability and angioproliferation, but the mechanisms responsible are unknown. We report here that the hyperplastic epidermis of psoriatic skin expresses strikingly increased amounts of vascular permeability factor (VPF; vascular endothelial growth factor), a selective endothelial cell mitogen that enhances microvascular permeability. Moreover, two VPF receptors, kdr and fit-l, are overexpressed by papillary dermal

Michael Detmar; Lawrence F. Brown; Kevin P. Claffey; Kiang-Teck Yeo; Olivier Kocher; Robert W. Jackman; Brygida Berse; Harold F. Dvorak

1994-01-01

330

Epidermal growth factor receptor and human fetoplacental development.  

PubMed

Alteration of placental development directly interferes with fetal growth. Epidermal growth factor (EGF) plays a major role in placental implantation, growth and differentiation. EGF acts on its placental target cells, i.e. the trophoblasts, via a specific receptor (EGFR) which belongs to the tyrosine kinase receptor family. Abundant placental EGF receptors are located in the brush border at the fetomaternal interface. EGFR expression is modulated by trophoblast differentiation and by hormones or toxic substances such as smoke. Interestingly, in microvilli purified from placentae of infants with intrauterine growth retardation (IUGR) a decrease or absence of tyrosine kinase activity is observed. This suggests that an alteration of EGFR biological activity might interfere with the fetoplacental unit development. PMID:7735366

Evain-Brion, D; Alsat, E

1994-01-01

331

Gelatin methacrylate microspheres for controlled growth factor release.  

PubMed

Gelatin has been commonly used as a delivery vehicle for various biomolecules for tissue engineering and regenerative medicine applications due to its simple fabrication methods, inherent electrostatic binding properties, and proteolytic degradability. Compared to traditional chemical cross-linking methods, such as the use of glutaraldehyde (GA), methacrylate modification of gelatin offers an alternative method to better control the extent of hydrogel cross-linking. Here we examined the physical properties and growth factor delivery of gelatin methacrylate (GMA) microparticles (MPs) formulated with a wide range of different cross-linking densities (15-90%). Less methacrylated MPs had decreased elastic moduli and larger mesh sizes compared to GA MPs, with increasing methacrylation correlating to greater moduli and smaller mesh sizes. As expected, an inverse correlation between microparticle cross-linking density and degradation was observed, with the lowest cross-linked GMA MPs degrading at the fastest rate, comparable to GA MPs. Interestingly, GMA MPs at lower cross-linking densities could be loaded with up to a 10-fold higher relative amount of growth factor than conventional GA cross-linked MPs, despite the GA MPs having an order of magnitude greater gelatin content. Moreover, a reduced GMA cross-linking density resulted in more complete release of bone morphogenic protein 4 and basic fibroblast growth factor and accelerated release rate with collagenase treatment. These studies demonstrate that GMA MPs provide a more flexible platform for growth factor delivery by enhancing the relative binding capacity and permitting proteolytic degradation tunability, thereby offering a more potent controlled release system for growth factor delivery. PMID:25463489

Nguyen, Anh H; McKinney, Jay; Miller, Tobias; Bongiorno, Tom; McDevitt, Todd C

2015-02-01

332

Vascular endothelial growth factor signaling in hypoxia and inflammation.  

PubMed

Infection, cancer and cardiovascular diseases are the major causes for morbidity and mortality in the United States according to the Center for Disease Control. The underlying etiology that contributes to the severity of these diseases is either hypoxia induced inflammation or inflammation resulting in hypoxia. Therefore, molecular mechanisms that regulate hypoxia-induced adaptive responses in cells are important areas of investigation. Oxygen availability is sensed by molecular switches which regulate synthesis and secretion of growth factors and inflammatory mediators. As a consequence, tissue microenvironment is altered by re-programming metabolic pathways, angiogenesis, vascular permeability, pH homeostasis to facilitate tissue remodeling. Hypoxia inducible factor (HIF) is the central mediator of hypoxic response. HIF regulates several hundred genes and vascular endothelial growth factor (VEGF) is one of the primary target genes. Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions. PMID:24610033

Ramakrishnan, S; Anand, Vidhu; Roy, Sabita

2014-03-01

333

Epidermal growth factor and epidermal growth factor-receptor expression in the mouse dental follicle during tooth eruption  

Microsoft Academic Search

When the role of exogenous epidermal growth factor (EGF) during tooth eruption was first demonstrated it was strongly suggested that EGF was a natural regulator of eruption. Recent immunohistochemical studies have shown that EGF and EGF-receptors are localized in the dental follicle, alveolar bone and ameloblasts before and during the prefunctional stage of eruption. Localization of mRNA for EGF has

Bhavna Shroff; Jeffrey E. Kashner; Jennifer D. Keyser; Carla Hebert; Kathleen Norris

1996-01-01

334

Vascular endothelial growth factor acts primarily via platelet-derived growth factor receptor ? to promote proliferative vitreoretinopathy.  

PubMed

Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration-approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor ?. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor ?. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti-VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated. PMID:25261788

Pennock, Steven; Haddock, Luis J; Mukai, Shizuo; Kazlauskas, Andrius

2014-11-01

335

Stimulation of body weight increase and epiphyseal cartilage growth by insulin like growth factor  

NASA Technical Reports Server (NTRS)

The ability of insulin-like growth factor (IGF) to induce growth in hypophysectomized immature rats was tested by continuous infusion of the partially purified factor at daily doses of 6, 21, and 46 mU for an 8-day period. A dose-dependent growth of the proximal epiphyseal cartilage of the tibia and an associated stimulation of the primary spongiosa were produced by these amounts of IGF. The two highest doses of IGF also resulted in dose-dependent increases of body weight. Gel permeation of the sera at neutrality showed that the large-molecular-weight IGF binding protein was not induced by the infusion of IGF, whereas it ws generated in the sera of hypophysectomized rats that were infused with daily doses of 86 mU of human growth hormone.

Ellis, S.

1981-01-01

336

ZIP2 protein, a zinc transporter, is associated with keratinocyte differentiation.  

PubMed

Zinc is essential for the proper functioning of various enzymes and transcription factors, and its homeostasis is rigorously controlled by zinc transporters (SLC39/ZIP, importers; SLC30/ZnT, exporters). Skin disease is commonly caused by a zinc deficiency. Dietary and inherited zinc deficiencies are known to cause alopecia and the development of vesicular or pustular dermatitis. A previous study demonstrated that zinc played crucial roles in the survival of keratinocytes and their unique functions. High levels of zinc have been detected in the epidermis. Epidermal layers are considered to use a mechanism that preferentially takes in zinc, which is involved with the unique functions of keratinocytes. However, few studies have investigated the ZIP (Zrt- and Irt-like protein) proteins specifically expressed in keratinocytes and their functions. We explored the ZIP proteins specifically expressed in the epidermis and analyzed their functions. Gene expression analysis showed that the expression of ZIP2 was consistently higher in the epidermis than in the dermis. Immunohistochemistry analysis confirmed the expression of ZIP2 in differentiating keratinocytes. The expression of ZIP2 was found to be up-regulated by the differentiation induction of cultured keratinocytes. Intracellular zinc levels were decreased in keratinocytes when ZIP2 was knocked down by siRNA, and this subsequently inhibited the differentiation of keratinocytes. Moreover, we demonstrated that ZIP2 knockdown inhibited the normal formation of a three-dimensional cultured epidermis. Taken together, the results of this study suggest that ZIP2, a zinc transporter expressed specifically in the epidermis, and zinc taken up by ZIP2 are necessary for the differentiation of keratinocytes. PMID:24936057

Inoue, Yu; Hasegawa, Seiji; Ban, Sadanori; Yamada, Takaaki; Date, Yasushi; Mizutani, Hiroshi; Nakata, Satoru; Tanaka, Masahiko; Hirashima, Naohide

2014-08-01

337

Transforming growth factor (TGF)-. alpha. in human milk  

SciTech Connect

Transforming growth factor (TGF)-{alpha} and epidermal growth factor (EGF) were measured in human milk by means of homologous radioimmunoassay. As previously reported, EGF concentration in the colostrum was approximately 200 ng/ml and decreased to 50 ng/ml by day 7 postpartum. The value of immunoreactive (IR)-TGF-{alpha} was 2.2-7.2 ng/ml, much lower than that of EGF. In contrast to EGF, the concentration of IR-TGF-{alpha} was fairly stable during the 7 postpartum days. There was no relationship between the concentrations of IR-TGF-{alpha} and IR-EGF, suggesting that the regulatory mechanism in the release of the two growth factors is different. On gel-chromatography using a Sephadex G-50 column, IR-EGF appeared in the fraction corresponding to that of authentic human EGF, while 70%-80% of the IR-TGF-{alpha} was eluted as a species with a molecular weight greater than that of authentic human TGF-{alpha}. Although the physiological role of TGF-{alpha} in milk is not known, it is possible that it is involved in the development of the mammary gland and/or the growth of newborn infants.

Okada, Masaki; Wakai, Kae; Shizume, Kazuo (Research Institute for Growth Sciences, Tokyo (Japan)); Iwashita, Mitsutoshi (Tokyo Women's Medical College (Japan)); Ohmura, Eiji; Kamiya, Yoshinobu; Murakami, Hitomi; Onoda, Noritaka; Tsushima, Toshio

1991-01-01

338

Epidermal Homeostasis: The Role of the Growth Hormone and Insulin-Like Growth Factor Systems  

Microsoft Academic Search

GH and IGF-I and -II were first identified by their endocrine activity. Specifically, IGF-I was found to mediate the linear growth-promoting actions of GH. It is now evident that these two growth factor systems also exert widespread activity throughout the body and that their actions are not always interconnected. The literature highlights the importance of the GH and IGF systems

STEPHANIE R. EDMONDSON; SUSAN P. THUMIGER; GEORGE A. WERTHER; CHRISTOPHER J. WRAIGHT

2003-01-01

339

Lactobacillus rhamnosus GG inhibits the toxic effects of Staphylococcus aureus on epidermal keratinocytes.  

PubMed

Few studies have evaluated the potential benefits of the topical application of probiotic bacteria or material derived from them. We have investigated whether a probiotic bacterium, Lactobacillus rhamnosus GG, can inhibit Staphylococcus aureus infection of human primary keratinocytes in culture. When primary human keratinocytes were exposed to S. aureus, only 25% of the keratinocytes remained viable following 24 h of incubation. However, in the presence of 10(8) CFU/ml of live L. rhamnosus GG, the viability of the infected keratinocytes increased to 57% (P = 0.01). L. rhamnosus GG lysates and spent culture fluid also provided significant protection to keratinocytes, with 65% (P = 0.006) and 57% (P = 0.01) of cells, respectively, being viable following 24 h of incubation. Keratinocyte survival was significantly enhanced regardless of whether the probiotic was applied in the viable form or as cell lysates 2 h before or simultaneously with (P = 0.005) or 12 h after (P = 0.01) S. aureus infection. However, spent culture fluid was protective only if added before or simultaneously with S. aureus. With respect to mechanism, both L. rhamnosus GG lysate and spent culture fluid apparently inhibited adherence of S. aureus to keratinocytes by competitive exclusion, but only viable bacteria or the lysate could displace S. aureus (P = 0.04 and 0.01, respectively). Furthermore, growth of S. aureus was inhibited by either live bacteria or lysate but not spent culture fluid. Together, these data suggest at least two separate activities involved in the protective effects of L. rhamnosus GG against S. aureus, growth inhibition and reduction of bacterial adhesion. PMID:25015889

Mohammedsaeed, Walaa; McBain, Andrew J; Cruickshank, Sheena M; O'Neill, Catherine A

2014-09-01

340

The inhibition of EGF-dependent proliferation of keratinocytes by tyrphostin tyrosine kinase blockers.  

PubMed

Protein tyrosine kinase blockers of the tyrphostin family inhibited the EGF-dependent proliferation of human and guinea pig keratinocytes grown in culture and induced their growth arrest. These blockers also significantly inhibited the growth of epidermal keratinocytes, but not of dermal cells, in whole skin organ culture from both guinea pig and human origin. The antiproliferative activity of these tyrphostins correlated quantitatively with their potency as inhibitors of EGF receptor autophosphorylation and the EGF-dependent protein phosphorylation of intracellular target proteins in the keratinocyte. Furthermore, no significant cell cytotoxicity or reduction in serine and threonine phosphorylation of many intracellular polypeptides were observed upon incubation of the cells with tyrphostins like AG213. The complete growth arrest induced by the tyrphostins is fully reversible and upon their removal the keratinocytes resumed their growth with the original growth rate. Because of the nontoxic nature of these compounds and their growth-arresting properties, we suggest their use as agents to treat hyperproliferative conditions of human skin. PMID:1709168

Dvir, A; Milner, Y; Chomsky, O; Gilon, C; Gazit, A; Levitzki, A

1991-05-01

341

Lifetime growth in wild meerkats: incorporating life history and environmental factors into a standard growth model.  

PubMed

Lifetime records of changes in individual size or mass in wild animals are scarce and, as such, few studies have attempted to model variation in these traits across the lifespan or to assess the factors that affect them. However, quantifying lifetime growth is essential for understanding trade-offs between growth and other life history parameters, such as reproductive performance or survival. Here, we used model selection based on information theory to measure changes in body mass over the lifespan of wild meerkats, and compared the relative fits of several standard growth models (monomolecular, von Bertalanffy, Gompertz, logistic and Richards). We found that meerkats exhibit monomolecular growth, with the best model incorporating separate growth rates before and after nutritional independence, as well as effects of season and total rainfall in the previous nine months. Our study demonstrates how simple growth curves may be improved by considering life history and environmental factors, which may be particularly relevant when quantifying growth patterns in wild populations. PMID:22108854

English, Sinéad; Bateman, Andrew W; Clutton-Brock, Tim H

2012-05-01

342

Regulation of GM-CSF and IL-3 production from the murine keratinocyte cell line PAM 212 following exposure to ultraviolet radiation  

SciTech Connect

Ultraviolet radiation (UVR) exposure induces profound changes in the synthesis and secretion of various cytokines both in vivo and in vitro. Little is known regarding the mechanism of these responses. This investigation evaluated the effects of UVR on the ability of a murine keratinocyte line (PAM 212) to produce interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF). Subconfluent rapidly dividing PAM 212 cells were shown by RNA slot-blot hybridization studies to have increased levels of mRNA for both IL-3 and GM-CSF within 1 h of UVR exposure. However, only GM-CSF-specific bioactivity, as determined by antibody neutralization studies, was shown to increase above baseline in cell supernatants. Cells grown to confluence responded differently to UVR. Under these culture conditions an apparent decrease in bioactivity was detected after UVR exposure for both growth factors, and no change in mRNA levels was detected. In addition to culture density, removal of extracellular calcium or sodium during irradiation, treatment with amiloride, or inhibition of new mRNA synthesis with cordycepin was shown to influence the UVR-induced alteration in release of IL-3 or GM-CSF bioactivity from both confluent and subconfluent PAM 212 cells. These results demonstrate that UVR influences the release of the colony stimulating factors GM-CSF and IL-3 from keratinocyte, and suggests that the state of cell growth and conditions of membrane ion transport influence the mechanisms regulating secretion of those factors.

Gallo, R.L.; Staszewski, R.; Sauder, D.N.; Knisely, T.L.; Granstein, R.D. (Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Boston (USA))

1991-08-01

343

Growth Factors and Gene Expression: Fresh Insights from Arrays  

NSDL National Science Digital Library

Gene array technology allows researchers to evaluate patterns of gene expression at a genome-wide level. Two recent papers have applied this powerful technique to characterize how gene expression is changed in response to growth factors and mitogens. The studies focus on two important questions concerning specificity in signal transduction. First, are the multiple signaling pathways activated by a single growth factor receptor used to activate gene expression, and if so, do these pathways act combinatorially? Second, how does the initial genetic response of a cell to a signal stimulus relate to the patterns of gene expression that determine that cell's ultimate biological response to the stimulus? Hill and Treisman take a critical look at what these array technology studies tell us concerning these questions and discuss technical issues arising from them.

Caroline S. Hill (Developmental Signalling Laboratory; REV)

1999-10-12

344

Regulation of MAPKs by growth factors and receptor tyrosine kinases  

PubMed Central

Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. We concentrate on the four linear mitogen-activated protein kinase (MAPK) cascades, and highlight organizational and functional features relevant to their action downstream to RTKs. Two cellular outcomes of growth factor action, namely proliferation and migration, are critically regulated by MAPKs and we detail the underlying molecular mechanisms. Hyperactivation of MAPKs, primarily the Erk pathway, is a landmark of cancer. We describe the many links of MAPKs to tumor biology and review studies that identified machineries permitting prolongation of MAPK signaling. Models attributing signal integration to both phosphorylation of MAPK substrates and to MAPK-regulated gene expression may shed light on the remarkably diversified functions of MAPKs acting downstream to activated RTKs. PMID:17306385

Katz, Menachem; Amit, Ido; Yarden, Yosef

2009-01-01

345

Adipocytokines, gut hormones and growth factors in anorexia nervosa.  

PubMed

Anorexia nervosa is a complex eating disorder of unknown etiology which affects adolescent girls and young women and leads to chronic malnutrition. Clinical manifestations of prolonged semistarvation include a variety of physical features and psychiatric disorders. The study of different biological factors involved in the pathophysiology of anorexia nervosa is an area of active interest. In this review we have described the role of adipocytokines, neurotrophins, peptides of the gastrointestinal system and growth factors in appetite regulation, energy balance and insulin sensitivity in anorexia nervosa patients. PMID:21699889

Kowalska, Irina; Karczewska-Kupczewska, Monika; Str?czkowski, Marek

2011-09-18

346

Hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility  

PubMed Central

Disrupted ontogeny of forebrain inhibitory interneurons leads to neurological disorders, including epilepsy. Adult mice lacking the urokinase plasminogen activator receptor (Plaur) have decreased numbers of neocortical GABAergic interneurons and spontaneous seizures, attributed to a reduction of hepatocyte growth factor/scatter factor (HGF/SF). We report that by increasing endogenous HGF/SF concentration in the postnatal Plaur null mouse brain maintains the interneuron populations in the adult, reverses the seizure behavior and stabilizes the spontaneous electroencephalogram activity. The perinatal intervention provides a pathway to reverse potential birth defects and ameliorate seizures in the adult. PMID:19853606

Bae, Mihyun H.; Bissonette, Gregory B.; Mars, Wendy M.; Michalopoulos, George K.; Achim, Cristian L.; Depireux, Didier A.; Powell, Elizabeth M.

2009-01-01

347

Vascular Endothelial Growth Factor: Basic Science and Clinical Progress  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine ki- nases Flt-1 (VEGFR-1) and Flk-1\\/KDR (VEGFR-2) are high- affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by

NAPOLEONE FERRARA

2004-01-01

348

Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor  

Microsoft Academic Search

· Background: Ocular diseases caused by neovascularization are among the leading causes of blindness. No specific pharmacological\\u000a treatment is available. Among potential drugs, thalidomide deserves special interest since a wide body of clinical experience\\u000a exists. However, its antiangiogenic effect is controversial. We therefore investigated the effect of thalidomide on corneal\\u000a angiogenesis induced by vascular endothelial growth factor (VEGF), which has

Friedrich E. Kruse; Antonia M. Joussen; Klaus Rohrschneider; Matthias D. Becker; Hans E. Völcker

1998-01-01

349

Factors associated with detrimental effects of rhizobacteria on plant growth  

Microsoft Academic Search

Some of the factors interfering with the specific response of young common bean plants to two rhizosphere fluorescent pseudomonads\\u000a were studied. These two bacterial strains produced symptoms in foliar plant parts and reduced yield in beans and several other\\u000a plant species when inoculated on roots. Sensitivity in the plants subjected to bacterial application was highest at early\\u000a growth stages (up

S. Alström

1987-01-01

350

Fetal and infant growth and cardiovascular risk factors in women  

Microsoft Academic Search

AbstractObjective: To examine whether cardiovascular risk factors in women are related to fetal and infant growth.Design: Follow up study of women born 1923-30 whose birth weights and weights at one year were recorded.Setting: Hertfordshire.Subjects: 297 women born and still living in East Hertfordshire.Main outcome measures: Plasma glucose and insulin concentrations during a standard oral glucose tolerance test; fasting plasma proinsulin

C H D Fall; C Osmond; D J P Barker; P M S Clark; C N Hales; Y Stirling; T W Meade

1995-01-01

351

Epidermal Growth Factor Receptor Signal TransActivation  

Microsoft Academic Search

\\u000a Coordination of complex cell functions is achieved by the regulated information transfer along linear signalling pathways.\\u000a It has become apparent, however, that these linear pathways are not free-standing entities but parts of larger networks. Transactivation\\u000a of the epidermal growth factor receptor (EGFR) represents the paradigm for communication between G protein-coupled receptors\\u000a (GPCRs) and receptor tyrosine kinases (RTKs). Recent studies provided

Stefan Hart; Andreas Gschwind; Andreas Roidl; Axel Ullrich

352

Liposome targeting to tumors using vitamin and growth factor receptors  

Microsoft Academic Search

Liposome-encapsulated anticancer drugs reveal their potential for increased therapeutic efficacy and decreased nonspecific toxicities due to their ability to enhance the delivery of chemotherapeutic agents to solid tumors. Advances in liposome technology have resulted in the development of ligand-targeted liposomes capable of selectively increasing the efficacy of carried agents against receptor-bearing tumor cells. Receptors for vitamins and growth factors have

Daryl C. Drummond; Keelung Hong; John W. Park; Christopher C. Benz; Dmitri B. Kirpgtin

2000-01-01

353

The ontogeny of epidermal growth factor receptors during mouse development  

Microsoft Academic Search

In an attempt to understand the role(s) of epidermal growth factor (EGF) in vivo during murine development, we have examined the ¹²⁵I-EGF binding characteristics of EGF-receptors in membrane preparations of tissues from the 12th day of gestation to parturition. Using autoradiography, the earliest time that we could detect EGF-receptors was on trophoblast cells cultured for 3 days as blastocyst outgrowths.

E. D. Adamson; J. Meek

1984-01-01

354

Growth factor release from amylopectin hydrogel based on copper coordination  

Microsoft Academic Search

This paper describes a biodegradable hydrogel matrix releasing basic fibroblast growth factor (bFGF) on the basis of protein metal coordination with the protein drug. The biodegradable hydrogel was prepared from amylopectin by its crosslinking with ethylene glycol diglycidyl ether, followed by introduction of diethylenetriaminepentaacetic acid (DTPA) residues for copper chelation. When bFGF was incorporated into the DTPA-introduced amylopectin hydrogel after

Yasuhiko Tabata; Yasuhiro Matsui; Yoshito Ikada

1998-01-01

355

Herpesvirus-Mediated Systemic Delivery of Nerve Growth Factor  

Microsoft Academic Search

Sustained systemic dissemination of therapeutic proteins from peripheral sites is an attractive prospect for gene therapy applications. Replication-defective genomic herpes simplex virus type 1 (HSV-1) vectors were evaluated for their ability to express nerve growth factor (NGF) as a model gene product both locally and systemically. Intra-articular inoculation of NGF expression vectors in rabbits resulted in significant increases in joint

Darren Wolfe; William F. Goins; Theodore J. Kaplan; Saverio V. Capuano; Julie Fradette; Michael Murphey-Corb; Paul D. Robbins; Justus B. Cohen; Joseph C. Glorioso

2001-01-01

356

Fibroblast growth factor 23 as a phosphotropic hormone and beyond  

Microsoft Academic Search

Fibroblast growth factor 23 (FGF23) is produced by bone and reduces serum phosphate by inhibiting proximal tubular phosphate\\u000a reabsorption and intestinal phosphate absorption. Excess actions of FGF23 cause several kinds of hypophosphatemic rickets\\/osteomalacia\\u000a while deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis. In addition, FGF23 has been shown to prevent\\u000a the development of hyperphosphatemia during the progression of chronic

Seiji Fukumoto; Yuichiro Shimizu

357

Purification of human platelet-derived growth factor  

SciTech Connect

The paper describes a method for purification of human platelet-derived growth factor (PDGF) from outdated platelet-rich plasma (PRP) using commonly available laboratory reagents and yielding a mitogen purified 800,000-fold over the starting material. (/sup 3/H)thymidine incorporation into DNA of cultured cells responsive to PDGF represents the most readily available method to follow its purification and define the biological activity of a purified preparation. Other assays to quantitate PDGF include radioreceptor assay and radioimmunoassay.

Raines, E.W.; Ross, R.

1985-01-01

358

Transforming growth factor-? in T-cell biology  

Microsoft Academic Search

Strict control of T-cell homeostasis is required to permit normal immune responses and prevent undesirable self-targeted responses. Transforming growth factor-? (TGF-?) has been shown to have an essential role in that regulation. Owing to its broad expression, and inhibitory effects on multiple cell types of the immune system, TGF-? regulation is complex. Through advances in cell-specific targeting of TGF-? signalling

Leonid Gorelik; Richard A. Flavell

2002-01-01

359

Management of skin toxicity of epidermal growth factor receptor inhibitors  

Microsoft Academic Search

Epidermal growth factor receptor (EGFR)-targeted therapies (monoclonal antibodies such as cetuximab and panitumumab as well\\u000a as tyrosine kinase inhibitors like erlotinib and gefitinib) are responsible for a unique constellation of mechanism-based,\\u000a class-specific side effects on the skin. Besides the well-known acneiform eruption, this skin toxicity consists of xerosis\\u000a (leading to eczema and fissures), paronychia, hair changes, telangiectasia, hyperpigmentation, and mucosal

Siegfried Segaert

2008-01-01

360

Synergistic Action of Fibroblast Growth Factor-2 and Transforming Growth Factor-beta1 Enhances Bioprinted Human Neocartilage Formation  

PubMed Central

Bioprinting as a promising but unexplored approach for cartilage tissue engineering has the advantages of high throughput, digital control, and highly accurate placement of cells and biomaterial scaffold to the targeted 3D locations with simultaneous polymerization. This study tested feasibility of using bioprinting for cartilage engineering and examined the influence of cell density, growth and differentiation factors. Human articular chondrocytes were printed at various densities, stimulated transiently with growth factors and subsequently with chondrogenic factors. Samples were cultured for up to 4 weeks to evaluate cell proliferation and viability, mechanical properties, mass swelling ratio, water content, gene expression, ECM production, DNA content, and histology. Bioprinted samples treated with FGF-2/TGF-?1 had the best chondrogenic properties among all groups apparently due to synergistic stimulation of cell proliferation and chondrogenic phenotype. ECM production per chondrocyte in low cell density was much higher than that in high cell seeding density. This finding was also verified by mechanical testing and histology. In conclusion, cell seeding density that is feasible for bioprinting also appears optimal for human neocartilage formation when combined with appropriate growth and differentiation factors. PMID:22508498

Cui, Xiaofeng; Breitenkamp, Kurt; Lotz, Martin; D’Lima, Darryl

2012-01-01

361

Alternative protocols to induce chondrogenic differentiation: transforming growth factor-? superfamily.  

PubMed

Mesenchymal stem cells (MSCs) are an accepted candidate for cell-based therapy of multiple diseases. The interest in MSCs and their possible application in cell therapy have resulted in a better understanding of the basic biology of these cells. Recently, like aggregation and transforming growth factor beta (TGF?) delivery, hypoxia has been indicated as crucial for complete chondrogenesis. The aim of this study was to test different culture conditions for directing stem cell differentiation into the chondrogenic lineage in vitro by testing different TGF? superfamily members into the culture media under normoxic conditions. All chondrogenic culture conditions used allowed the differentiation of bone marrow-MSCs (BM-MSCs) into chondrogenic lineage. Chondrogenic induction capacity depended on the growth factor added to the culture media. In particular, the chondrogenic culture condition that better induced chondrogenesis was the medium that included the combination of three growth factors: bone morphogenetic protein-2 (BMP-2), BMP-7 and TGF?-3. In this culture media, differentiated cells showed the highest levels expression of two markers of chondrogenesis, SOX9 and COL2A1, compared to the control points (p < 0.05, two-tailed t test). In our experimental conditions, the combination of BMP-2, BMP-7 and TGF?-3 was the most effective in promoting chondrogenesis of BM-MSCs. These results underline the importance of determining in each experimental design the best protocol for in vitro directing stem cell differentiation into the chondrogenic lineage. PMID:25204398

Cicione, Claudia; Muiños-López, Emma; Hermida-Gómez, Tamara; Fuentes-Boquete, Isaac; Díaz-Prado, Silvia; Blanco, Francisco J

2014-09-10

362

Epidermal growth factor receptor inhibitor therapy for recurrent respiratory papillomatosis  

PubMed Central

The epidermal growth factor pathway has been implicated in various tumors, including human papillomavirus (HPV) lesions such as recurrent respiratory papillomatosis (RRP). Due to the presence of epidermal growth factor receptors in RRP, epidermal growth factor receptor (EGFR) inhibitors have been utilized as adjuvant therapy. This case series examines the response to EGFR inhibitors in RRP. Four patients with life-threatening RRP were treated with EGFR inhibitors. Operative frequency and anatomical Derkay scores were calculated prior to, and following EGFR inhibitor treatment via retrospective chart review. The anatomical Derkay score decreased for all four patients after initiation of EGFR inhibitor therapy. In one patient, the operative frequency increased after switching to an intravenous inhibitor after loss of control with an oral inhibitor. In the other patients there was a greater than 20% decrease in operative frequency in one and a more than doubling in the time between procedures in two.  This study suggests that EGFR inhibitors are a potential adjuvant therapy in RRP and deserve further study in a larger number of patients. PMID:24795806

Sidman, James D.

2013-01-01

363

Intrinsic Differences between Oral and Skin Keratinocytes  

PubMed Central

Keratinocytes cover both the skin and some oral mucosa, but the morphology of each tissue and the behavior of the keratinocytes from these two sites are different. One significant dissimilarity between the two sites is the response to injury. Oral mucosal wounds heal faster and with less inflammation than equivalent cutaneous wounds. We hypothesized that oral and skin keratinocytes might have intrinsic differences at baseline as well as in the response to injury, and that such differences would be reflected in gene expression profiles. PMID:25198578

Turabelidze, Anna; Guo, Shujuan; Chung, Allison Yen; Chen, Lin; Dai, Yang; Marucha, Phillip T.; DiPietro, Luisa A.

2014-01-01

364

Associations of intrauterine growth restriction with placental pathological factors, maternal factors and fetal factors; clinicopathological findings of 257 Japanese cases.  

PubMed

Intrauterine growth restriction (IUGR) is the leading cause of fetal mortality and morbidity. As an etiology, each of placental findings, maternal factors and fetal factors has been reported to be associated with IUGR, although a comprehensive approach to examine all of these parameters as a cause of IUGR has not been reported. In the present study, therefore, we comprehensively examined the placental findings and maternal and fetal factors in the cases of IUGR (n=257, mean maternal age, 30 years; gestational weeks, 34 weeks) and normal growth pregnancies (n=258, mean maternal age, 30 years; gestational weeks, 33 weeks), and determined risk factors for IUGR. The prevalence of pregnancy hypertension (PHT) (19% vs. 8%, P<0.01), smoking habit (3% vs. 0.7%, P<0.05) and fetal anomaly (3.5% vs. 0.8%, P<0.05) were higher in IUGR cases than normal growth pregnancies. Pathologically, the prevalence of infarction (33% vs. 14%, P<0.05), fetal vessel thrombosis (22% vs. 6%, P<0.001) and chronic villitis (11% vs. 3%, P<0.001) were higher in IUGR cases than those in normal growth pregnancies. A multivariable regression analysis revealed that maternal factors (PHT), fetal factors (anomaly), and placental findings (infarction, fetal vessel thrombosis, and chronic villitis) are independently associated with increased risk of IUGR (all P<0.01). PMID:23233065

Sato, Y; Benirschke, K; Marutsuka, K; Yano, Y; Hatakeyama, K; Iwakiri, T; Yamada, N; Kodama, Y; Sameshima, H; Ikenoue, T; Asada, Y

2013-01-01

365

KLF10, transforming growth factor-{beta}-inducible early gene 1, acts as a tumor suppressor  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer KLF10{sup -/-} mice exhibited accelerated papilloma development after DMBA/TPA treatment. Black-Right-Pointing-Pointer KLF10{sup -/-} keratinocytes showed increased proliferation and apoptosis. Black-Right-Pointing-Pointer KLF10{sup -/-} MEFs yielded more colonies than wild-type one with H-Ras transfection. Black-Right-Pointing-Pointer KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription. Black-Right-Pointing-Pointer KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription. -- Abstract: Krueppel-like factor 10 (KLF10) has been suggested to be a putative tumor suppressor. In the present study, we generated KLF10 deficient mice to explore this hypothesis in vivo. KLF10 deficient mice exhibited increased predisposition to skin tumorigenesis and markedly accelerated papilloma development after DMBA/TPA treatment. On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis. In colony formation assays after oncogenic H-Ras transfection, KLF10 deficient mouse embryonic fibroblasts (MEFs) yielded more colonies than wild-type MEFs. Furthermore, KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription, which was independent of p53 and Sp1 binding sites in p21{sup WAF1/CIP1} promoter. This study demonstrates that KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription.

Song, Ki-Duk [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of) [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of); Laboratory of Protein Engineering and Comparative Immunology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-921 (Korea, Republic of); Kim, Duk-Jung [The Institute of Hankook Life Science, 7-9 Myungryun-dong, Jongno-gu, Seoul 110-521 (Korea, Republic of)] [The Institute of Hankook Life Science, 7-9 Myungryun-dong, Jongno-gu, Seoul 110-521 (Korea, Republic of); Lee, Jong Eun [Department of Anatomy, College of Medicine, Yonsei University, Seoul 120-752 (Korea, Republic of)] [Department of Anatomy, College of Medicine, Yonsei University, Seoul 120-752 (Korea, Republic of); Yun, Cheol-Heui [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of) [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of); Laboratory of Protein Engineering and Comparative Immunology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-921 (Korea, Republic of); Lee, Woon Kyu, E-mail: wklee@inha.ac.kr [Laboratory of Developmental Genetics, School of Medicine, Inha University, Incheon 400-712 (Korea, Republic of); Brain Korea 21 Center for Advanced Medical Education, School of Medicine, Inha University, Incheon 400-712 (Korea, Republic of)

2012-03-09

366

Enhancement of intestinal growth in neonatal rats by epidermal growth factor in milk  

SciTech Connect

Breast milk has been shown to enhance neonatal intestinal growth. Because epidermal growth factor (EGF) is present in the milk of various mammalian species, the hypothesis was tested that EGF in rodent milk mediates, in part, the breast milk-enhanced intestinal growth in neonatal rat. Fifty-eight rat pups fed artificial formal that contained 1.2, 3.0, and 6.0 {mu}g/ml EGF for 39 h had greater incorporation of ({sup 3}H)thymidine into DNA and DNA content of intestine than 29 pups fed unsupplemented formula. Pups fed EGF for 5 days had significantly greater body weight, intestinal weight, length, and DNA content than control pups. Conversely, pups fed pooled rat milk containing rabbit-derived antibody to EGF for 39 h had intestines of lower weight that contained less DNA than animals fed rat milk containing normal rabbit serum. EGF appears to mediate, in part, breast milk-enhanced neonatal intestinal growth.

Berseth, C.L. (Mayo Clinic and Mayo Foundation, Rochester, MN (USA))

1987-11-01

367

Basic fibroblast growth factor enhances nerve growth factor receptor gene promoter activity in human neuroblastoma cell line CHP100.  

PubMed Central

The human neuroblastoma cell line CHP100 provides a useful model system in which to study the molecular mechanisms of transcriptional regulation of the low-affinity nerve growth factor receptor (NGFR) gene during neuronal development. Basic fibroblast growth factor (bFGF) induced morphological changes in CHP100 cells, including flattening of cell bodies and neurite outgrowth. bFGF also increased p75NGFR immunoreactivity, as assessed by immunocytochemistry, and increased p75NGFR mRNA levels, as assessed by Northern (RNA) blot analysis. A chimeric gene consisting of 6.7 kb of the 5'-flanking region of the human NGFR gene linked to the chloramphenicol acetyltransferase gene was constructed. In stable transformants of CHP100 cells, 10 ng of bFGF per ml induced an eightfold increase in chloramphenicol acetyltransferase activity. These results indicate that upstream elements of the NGFR gene mediate transcriptional regulation by bFGF. Images PMID:1314950

Taiji, M; Taiji, K; Deyerle, K L; Bothwell, M

1992-01-01

368

The structure of granulocyte-colony-stimulating factor and its relationship to other growth factors.  

PubMed Central

We have determined the three-dimensional structure of recombinant human granulocyte-colony-stimulating factor by x-ray crystallography. Phases were initially obtained at 3.0-A resolution by multiple isomorphous replacement and were refined by solvent flattening and by averaging of the electron density of the three molecules in the asymmetric unit. The current R factor is 21.5% for all data between 6.0- and 2.2-A resolution. The structure is predominantly helical, with 104 of the 175 residues forming a four-alpha-helix bundle. The only other secondary structure is also helical. In the loop between the first two long helices a four-residue 3(10)-helix is immediately followed by a 6-residue alpha-helix. Three residues in the short connection between the second and third bundle helices form almost one turn of left-handed helix. The up-up-down-down connectivity with two long crossover connections has been reported previously for five other proteins, which like granulocyte-colony-stimulating factor are all signaling ligands: growth hormone, granulocyte/macrophage-colony-stimulating factor, interferon beta, interleukin 2, and interleukin 4. Structural similarity among these growth factors occurs despite the absence of similarity in their amino acid sequences. Conservation of this tertiary structure suggests that these different growth factors might all bind to their respective sequence-related receptors in an equivalent manner. Images Fig. 2 PMID:7685117

Hill, C P; Osslund, T D; Eisenberg, D

1993-01-01

369

Enhanced Hepatocyte Growth Factor Signaling by Type II Transforming Growth Factor-B Receptor Knockout Fibroblasts Promotes Mammary Tumorigenesis  

Microsoft Academic Search

Transforming growth factor-B (TGF-B) plays complex dual roles as an inhibitor and promoter of tumor progression. Although the influence of the stromal microenvironment on tumor progression is well recognized, little is known about the functions of TGF-B signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type II TGF-B receptor was selectively knocked out in fibroblasts

Nikki Cheng; Anna Chytil; Yu Shyr; Alison Joly

2007-01-01

370

Isolation of Brain Fibroblast Growth Factor by Heparin-Sepharose Affinity Chromatography: Identity with Pituitary Fibroblast Growth Factor  

Microsoft Academic Search

Brain and pituitary fibroblast growth factors (FGF) have been purified to apparent homogeneity from crude tissue extracts by a three-step procedure, including salt precipitation, ion-exchange chromatography, and heparin-Sepharose affinity chromatography. Brain and pituitary FGF have similar amino acid compositions and are indistinguishable with respect to molecular weight (16,000 by polyacrylamide gel electrophoresis), retention behavior in reversed-phase high-performance liquid chromatography, and

Denis Gospodarowicz; Jannie Cheng; Ge-Ming Lui; Andrew Baird; Peter Bohlent

1984-01-01

371

Epidermal growth factor receptor as a therapeutic target in glioblastoma.  

PubMed

Glioblastoma represents one of the most challenging problems in neurooncology. Among key elements driving its behavior is the transmembrane epidermal growth factor receptor family, with the first member epidermal growth factor receptor (EGFR) centered in most studies. Engagement of the extracellular domain with a ligand activates the intracellular tyrosine kinase (TK) domain of EGFR, leading to autophosphorylation and signal transduction that controls proliferation, gene transcription, and apoptosis. Oncogenic missense mutations, deletions, and insertions in the EGFR gene are preferentially located in the extracellular domain in glioblastoma and cause constitutive activation of the receptor. The mutant EGFR may also transactivate other cell surface molecules, such as additional members of the EGFR family and the platelet-derived growth factor receptor, which ignite signaling cascades that synergize with the EGFR-initiated cascade. Because of the cell surface location and increased expression of the receptor along with its important biological function, EGFR has triggered much effort for designing targeted therapy. These approaches include TK inhibition, monoclonal antibody, vaccine, and RNA-based downregulation of the receptor. Treatment success requires that the drug penetrates the blood-brain barrier and has low systemic toxicity but high selectivity for the tumor. While the blockade of EGFR-dependent processes resulted in experimental and clinical treatment success, cells capable of using alternative signaling ultimately escape this strategy. A combination of interventions targeting tumor-specific cell surface regulators along with convergent downstream signaling pathways will likely enhance efficacy. Studies on EGFR in glioblastoma have revealed much information about the complexity of gliomagenesis and also facilitated the development of strategies for targeting drivers of tumor growth and combination therapies with increasing complexity. PMID:23575987

Kalman, B; Szep, E; Garzuly, F; Post, D E

2013-06-01

372

An expandable, inducible hemangioblast state regulated by fibroblast growth factor.  

PubMed

During development, the hematopoietic and vascular lineages are thought to descend from common mesodermal progenitors called hemangioblasts. Here we identify six transcription factors, Gata2, Lmo2, Mycn, Pitx2, Sox17, and Tal1, that "trap" murine cells in a proliferative state and endow them with a hemangioblast potential. These "expandable" hemangioblasts (eHBs) are capable, once released from the control of the ectopic factors, to give rise to functional endothelial cells, multilineage hematopoietic cells, and smooth muscle cells. The eHBs can be derived from embryonic stem cells, from fetal liver cells, or poorly from fibroblasts. The eHBs reveal a central role for fibroblast growth factor, which not only promotes their expansion, but also facilitates their ability to give rise to endothelial cells and leukocytes, but not erythrocytes. This study serves as a demonstration that ephemeral progenitor states can be harnessed in vitro, enabling the creation of tractable progenitor cell lines. PMID:25458896

Vereide, David T; Vickerman, Vernella; Swanson, Scott A; Chu, Li-Fang; McIntosh, Brian E; Thomson, James A

2014-12-01

373

An Expandable, Inducible Hemangioblast State Regulated by Fibroblast Growth Factor  

PubMed Central

Summary During development, the hematopoietic and vascular lineages are thought to descend from common mesodermal progenitors called hemangioblasts. Here we identify six transcription factors, Gata2, Lmo2, Mycn, Pitx2, Sox17, and Tal1, that “trap” murine cells in a proliferative state and endow them with a hemangioblast potential. These “expandable” hemangioblasts (eHBs) are capable, once released from the control of the ectopic factors, to give rise to functional endothelial cells, multilineage hematopoietic cells, and smooth muscle cells. The eHBs can be derived from embryonic stem cells, from fetal liver cells, or poorly from fibroblasts. The eHBs reveal a central role for fibroblast growth factor, which not only promotes their expansion, but also facilitates their ability to give rise to endothelial cells and leukocytes, but not erythrocytes. This study serves as a demonstration that ephemeral progenitor states can be harnessed in vitro, enabling the creation of tractable progenitor cell lines. PMID:25458896

Vereide, David T.; Vickerman, Vernella; Swanson, Scott A.; Chu, Li-Fang; McIntosh, Brian E.; Thomson, James A.

2014-01-01

374

Transcriptional Regulation of Fibroblast Growth Factor 21 Expression  

PubMed Central

Fibroblast growth factor 21 (FGF21) is an attractive target for treating metabolic disease due to its wide-ranging beneficial effects on glucose and lipid metabolism. Circulating FGF21 levels are increased in insulin-resistant states; however, endogenous FGF21 fails to improve glucose and lipid metabolism in obesity, suggesting that metabolic syndrome is an FGF21-resistant state. Therefore, transcription factors for FGF21 are potential drug targets that could increase FGF21 expression in obesity and reduce FGF21 resistance. Despite many studies on the metabolic effects of FGF21, the transcriptional regulation of FGF21 gene expression remains controversial and is not fully understood. As the FGF21 transcription factor pathway is one of the most promising targets for the treatment of metabolic syndrome, further investigation of FGF21 transcriptional regulation is required. PMID:25031882

Bae, Kwi-Hyun; Kim, Jung-Guk

2014-01-01

375

Synergistic and multidimensional regulation of plasminogen activator inhibitor type 1 expression by transforming growth factor type ? and epidermal growth factor  

SciTech Connect

The major physiological inhibitor of plasminogen activator, type I plasminogen activator inhibitor (PAI-1), controls blood clotting and tissue remodeling events that involve cell migration. Transforming growth factor type ? (TGF?) and epidermal growth factor (EGF) interact synergistically to increase PAI-1 mRNA and protein levels in human HepG2 and mink Mv1Lu cells. Other growth factors that activate tyrosine kinase receptors can substitute for EGF. EGF and TGF? regulate PAI-1 by synergistically activating transcription, which is further amplified by a decrease in the rate of mRNA degradation, the latter being regulated only by EGF. The combined effect of transcriptional activation and mRNA stabilization results in a rapid 2-order of magnitude increase in the level of PAI-1. TGF? also increases the sensitivity of the cells to EGF, thereby recruiting the cooperation of EGF at lower than normally effective concentrations. The contribution of EGF to the regulation of PAI-1 involves the MAPK pathway, and the synergistic interface with the TGF? pathway is downstream of MEK1/2 and involves phosphorylation of neither ERK1/2 nor Smad2/3. Synergism requires the presence of both Smad and AP-1 recognition sites in the promoter. This work demonstrates the existence of a multidimensional cellular mechanism by which EGF and TGF? are able to promote large and rapid changes in PAI-1 expression.

Song, Xiaoling; Thalacker, F.W.; Nilsen-Hamilton, Marit

2012-04-06

376

Insulin-like growth factor-I: clinical studies.  

PubMed

Insulin-like growth factor-I (IGF-I) has endocrine, autocrine and paracrine properties. Receptors for IGF-I are present on virtually all cell types but are located mainly on cells of mesenchymal origin, such as fibroblasts, chondrocytes and osteoblasts. Growth hormone (GH)-dependent and GH-independent actions of IGF-I have been implicated in normal and abnormal bone growth, diabetes mellitus, malnutrition, cancer, thyroid disease and hematological diseases. The availability of recombinant human IGF-I (rhIGF-I) has led to new treatments for GH-resistant Laron dwarfism and certain diseases associated with severe insulin resistance. IGF-I has recently been investigated as a neurotrophic factor. Phase II efficacy trials with patients with neurological disease such as traumatic brain injury, myotonic dystrophy and amyotrophic lateral sclerosis have shown that rhIGF-I has efficacy on various outcome parameters. Treatment with rhIGF-I may result in reversible side effects of which increased heart rate, papilledema, ophthalmologic and intracranial hypertension, facial and generalized edema, and weight gain are noteworthy. PMID:15094866

Vos, P E; Koppeschaar, H P; de Vries, W R; Wokke, J H

1998-01-01

377

Fibroblast growth factor (FGF) signaling in development and skeletal diseases  

PubMed Central

Fibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLC?. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development.

Teven, Chad M.; Farina, Evan M.; Rivas, Jane; Reid, Russell R.

2014-01-01

378

The LRIG family: enigmatic regulators of growth factor receptor signaling.  

PubMed

The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins contains three vertebrate members (LRIG1, LRIG2 and LRIG3) and one member each in flies (Lambik) and worms (Sma-10). LRIGs have stepped into the spotlight as essential regulators of growth factor receptors, including receptor tyrosine and serine/threonine kinases. LRIGs have been found to both negatively (LRIG1 and LRIG3) and positively (Sma-10 and LRIG3) regulate growth factor receptor expression and signaling, although the precise molecular mechanisms by which LRIGs function are not yet understood. The most is known about LRIG1, which was recently demonstrated to be a tumor suppressor. Indeed, in vivo experiments reinforce the essential link between LRIG1 and repression of its targets for tissue homeostasis. LRIG1 has also been identified as a stem cell marker and regulator of stem cell quiescence in a variety of tissues, discussed within. Comparably, less is known about LRIG2 and LRIG3, although studies to date suggest that their functions are largely distinct from that of LRIG1 and that they likely do not serve as growth/tumor suppressors. Finally, the translational applications of expressing soluble forms of LRIG1 in LRIG1-deficient tumors are being explored and hold tremendous promise. PMID:25183430

Simion, Catalina; Cedano-Prieto, Maria Elvira; Sweeney, Colleen

2014-12-01

379

Construction of chimeric human epidermal growth factor containing short collagen-binding domain moieties for use as a wound tissue healing agent.  

PubMed

Among the various human growth factors, epidermal growth factor (hEGF, consisting of 53 amino acids) has various effects on cell regeneration, stimulation of proliferation, migration of keratinocytes, formation of granulation tissues, and stimulation of fibroblast motility, which are important for wound healing. Due to their multiple activities, EGF is used as pharmaceutical and cosmetic agents. However, their low productivity, limited target specificity and short half-life inhibit the application of EGF as therapeutic agents. To overcome these obstacles, we fused the collagen-binding domain (CBD) of Vibrio mimicus metalloprotease to EGF protein. 18 or 12 amino acids (aa) (of the 33 total amino acids), which were essential for collagen-binding activity, were combined with the N- and C-termini of EGF. We constructed, expressed and purified EGF (53 aa)-CBD (18 aa), EGF (53 aa)-CBD (12 aa), CBD (18 aa)-EGF (53 aa) and CBD (12 aa)-EGF (53 aa). These purified recombinant proteins increased the numbers of cells in treated specimens compared to non-treated specimens and control hEGF samples. The collagen-binding activities were also evaluated. Furthermore, CBD-hybridized hEGF induced phosphorylation of the EGF receptor. These results suggested that fusion proteins could be applicable as small therapeutic agents in wound tissue healing. PMID:25152055

Kim, Dong-Gyun; Kim, Eun-Young; Kim, Yu-Ri; Kong, In-Soo

2014-08-18

380

Comparisons of norcantharidin cytotoxic effects on oral cancer cells and normal buccal keratinocytes  

Microsoft Academic Search

Norcantharidin (NCTD) is the demethylated analogue of cantharidin. In this study, multi-parameter assessments of morphological alterations, clonogenic efficiency, cell growth curves, DNA synthesis, and DNA strand break were employed to determine and compare the cytotoxic effects of NCTD on oral cancer KB cell line and normal buccal keratinocytes. The results showed NCTD induced significant cytotoxicity in KB cells after 24

S. H Kok; C. Y Hong; M. Y. P Kuo; C. H. K Lee; J. J Lee; I. U Lou; M. S Lee; M Hsiao; S. K Lin

2003-01-01

381

Age-related changes in Serum Growth Hormone, Insulin-like Growth Factor1 and Somatostatin in System Lupus Erythematosus  

Microsoft Academic Search

BACKGROUND: Systemic lupus erythematosus is an age- and gender-associated autoimmune disorder. Previous studies suggested that defects in the hypothalamic\\/pituitary axis contributed to systemic lupus erythematosus disease progression which could also involve growth hormone, insulin-like growth factor-1 and somatostatin function. This study was designed to compare basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels in female systemic lupus erythematosus

Charles W Denko; Charles J Malemud

2004-01-01

382

Regulation of mTOR complex 1 in response to growth factors and nutrients  

E-print Network

In multicellular organisms, cells ensure the simultaneous availability of growth factors and nutrients before they invest in cellular processes that lead to growth. The TOR kinase is a master regulator of cellular growth ...

Sancak, Yasemin S. (Yasemin Shechner)

2010-01-01

383

Insulin-like Growth Factors and Kidney Disease.  

PubMed

Insulin-like growth factors (IGF-1 and IGF-2) are necessary for normal growth and development. They are related structurally to proinsulin and promote cell proliferation, differentiation, and survival, as well as insulin-like metabolic effects, in most cell types and tissues. In particular, IGFs are important for normal pre- and postnatal kidney development. IGF-1 mediates many growth hormone actions, and both growth hormone excess and deficiency are associated with perturbed kidney function. IGFs affect renal hemodynamics both directly and indirectly by interacting with the renin-angiotensin system. In addition to the IGF ligands, the IGF system includes receptors for IGF-1, IGF-2/mannose-6-phosphate, and insulin, and a family of 6 high-affinity IGF-binding proteins that modulate IGF action. Disordered regulation of the IGF system has been implicated in a number of kidney diseases. IGF activity is enhanced in early diabetic nephropathy and polycystic kidneys, whereas IGF resistance is found in chronic kidney failure. IGFs have a potential role in enhancing stem cell repair of kidney injury. Most IGF actions are mediated by the tyrosine kinase IGF-1 receptor, and inhibitors recently have been developed. Further studies are needed to determine the optimal role of IGF-based therapies in kidney disease. PMID:25151409

Bach, Leon A; Hale, Lorna J

2015-02-01

384

Malignant Transformation of Mouse Primary Keratinocytes by Harvey Sarcoma Virus and Its Modulation by Surrounding Normal Cells  

NASA Astrophysics Data System (ADS)

The activated ras oncogene that is present in Harvey sarcoma virus is able to induce malignant transformation of pure cultures of mouse primary keratinocytes. Malignant transformation of these cells is demonstrated by their ability to form carcinomas when grafted back onto syngeneic animals. However, expression of the malignant phenotype by the ras-transformed keratinocytes is drastically inhibited by the presence of normal dermal fibroblasts. This inhibitory effect depends on the ratio of fibroblasts to keratinocytes. It can be observed with mitomycin C-treated growth-arrested dermal fibroblasts and not with other cells, such as normal keratinocytes or established fibroblasts. Thus, a cellular environment approximating normal tissue can suppress tumor formation triggered by a single oncogene.

Dotto, Gian Paolo; Weinberg, Robert A.; Ariza, Aurelio

1988-09-01

385

Human Papilloma Viral DNA Replicates as a Stable Episome in Cultured Epidermal Keratinocytes  

NASA Astrophysics Data System (ADS)

Human papilloma virus (HPV) is poorly understood because systems for its growth in tissue culture have not been developed. We report here that cultured human epidermal keratinocytes could be infected with HPV from plantar warts and that the viral DNA persisted and replicated as a stable episome. There were 50-200 copies of viral DNA per cell and there was no evidence to indicate integration of viral DNA into the cellular genome. There was also no evidence to suggest that viral DNA underwent productive replication. We conclude that cultured human epidermal keratinocytes may be a model for the study of certain aspects of HPV biology.

Laporta, Robert F.; Taichman, Lorne B.

1982-06-01

386

Clinical significance of growth differentiation factor 11 in colorectal cancer.  

PubMed

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-beta superfamily and bone morphogenetic protein (BMP) subfamily, plays a role in regulation of development and differentiation. Although some members of BMP subfamily have been reported to correlate with cancer, the significance of GDF11 has not been studied in a clinical oncology setting. The current study explored the clinicopathological significance of GDF11 expression in colorectal cancer. Quantitative real-time reverse transcription-PCR in colorectal cancer specimens obtained from 130 patients showed that GDF11 mRNA expression in cancer tissue was significantly higher than in normal tissue (p=0.001). Tumors were classified as high GDF11 expression (n=65) or low GDF11 expression (n=65). Patients whose tumors had high GDF11 expression showed a high frequency of lymph node metastasis (p=0.049) and had more cancer-related deaths (p=0.040). Furthermore, the patients with high GDF11 expression had significantly poorer overall survival than those with low expression (p=0.0334). Although multivariate analysis showed that GDF11 was not an independent prognostic factor, these findings suggest that GDF11 may be a novel diagnostic and prognostic biomarker in patients with colorectal cancer. PMID:17912435

Yokoe, Takeshi; Ohmachi, Takahiro; Inoue, Hiroshi; Mimori, Koshi; Tanaka, Fumiaki; Kusunoki, Masato; Mori, Masaki

2007-11-01

387

Vascular Endothelial Growth Factor Receptor-1 Modulates Vascular Endothelial Growth Factor-Mediated Angiogenesis via Nitric Oxide  

PubMed Central

The known responses of vascular endothelial growth factor (VEGF) are mediated through VEGF receptor-2 (VEGFR-2/KDR) in endothelial cells. However, it is unknown whether VEGFR-1 (Flt-1) is an inert decoy or a signaling receptor for VEGF during physiological or pathological angiogenesis. Here we report that VEGF-stimulated nitric oxide (NO) release is inhibited by blockade of VEGFR-1 and that VEGFR-1 via NO negatively regulates of VEGFR-2-mediated proliferation and promotes formation of capillary networks in human umbilical vein endothelial cells (HUVECs). Inhibition of VEGFR-1 in a murine Matrigel angiogenesis assay induced large aneurysm-like structures. VEGF-induced capillary growth over 14 days was inhibited by anti-VEGFR-2-blocking antibody as determined by reduced tube length between capillary connections (P < 0.0001) in an in vitro angiogenesis assay. In contrast, loss of VEGFR-1 activity with a neutralizing anti-VEGFR-1 antibody resulted in an increase in the accumulation of endothelial cells (P < 0.0001) and a dramatic decrease in the number of capillary connections that were restored by the addition of NO donor. Porcine aortic endothelial (PAE) cells expressing human VEGFR-1 but not VEGFR-2 plated on growth factor-reduced Matrigel rearranged into tube-like structures that were prevented by anti-VEGFR-1 antibody or a cGMP inhibitor. VEGF stimulated NO release from VEGFR-1- but not VEGFR-2-transfected endothelial cells and placenta growth factor-1 stimulated NO release in HUVECs. Blockade of VEGFR-1 increased VEGF-mediated HUVEC proliferation that was inhibited by NO donors, and potentiated by NO synthase inhibitors. These data indicate that VEGFR-1 is a signaling receptor that promotes endothelial cell differentiation into vascular tubes, in part by limiting VEGFR-2-mediated endothelial cell proliferation via NO, which seems to be a molecular switch for endothelial cell differentiation. PMID:11549592

Bussolati, Benedetta; Dunk, Caroline; Grohman, Malcolm; Kontos, Christopher D.; Mason, Justin; Ahmed, Asif

2001-01-01

388

Eosinophil Cytokines, Chemokines, and Growth Factors: Emerging Roles in Immunity  

PubMed Central

Eosinophils derive from the bone marrow and circulate at low levels in the blood in healthy individuals. These granulated cells preferentially leave the circulation and marginate to tissues, where they are implicated in the regulation of innate and adaptive immunity. In diseases such as allergic inflammation, eosinophil numbers escalate markedly in the blood and tissues where inflammatory foci are located. Eosinophils possess a range of immunomodulatory factors that are released upon cell activation, including over 35 cytokines, growth factors, and chemokines. Unlike T and B cells, eosinophils can rapidly release cytokines within minutes in response to stimulation. While some cytokines are stored as pre-formed mediators in crystalloid granules and secretory vesicles, eosinophils are also capable of undergoing de novo synthesis and secretion of these immunological factors. Some of the molecular mechanisms that coordinate the final steps of cytokine secretion are hypothesized to involve binding of membrane fusion complexes comprised of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs). These intracellular receptors regulate the release of granules and vesicles containing a range of secreted proteins, among which are cytokines and chemokines. Emerging evidence from both human and animal model-based research has suggested an active participation of eosinophils in several physiological/pathological processes such as immunomodulation and tissue remodeling. The observed eosinophil effector functions in health and disease implicate eosinophil cytokine secretion as a fundamental immunoregulatory process. The focus of this review is to describe the cytokines, growth factors, and chemokines that are elaborated by eosinophils, and to illustrate some of the intracellular events leading to the release of eosinophil-derived cytokines. PMID:25426119

Davoine, Francis; Lacy, Paige

2014-01-01

389

Rapamycin promotes Schwann cell migration and nerve growth factor secretion  

PubMed Central

Rapamycin, similar to FK506, can promote neural regeneration in vitro. We assumed that the mechanisms of action of rapamycin and FK506 in promoting peripheral nerve regeneration were similar. This study compared the effects of different concentrations of rapamycin and FK506 on Schwann cells and investigated effects and mechanisms of rapamycin on improving peripheral nerve regeneration. Results demonstrated that the lowest rapamycin concentration (1.53 nmol/L) more significantly promoted Schwann cell migration than the highest FK506 concentration (100?mol/L). Rapamycin promoted the secretion of nerve growth factors and upregulated growth-associated protein 43 expression in Schwann cells, but did not significantly affect Schwann cell proliferation. Therefore, rapamycin has potential application in peripheral nerve regeneration therapy. PMID:25206862

Liu, Fang; Zhang, Haiwei; Zhang, Kaiming; Wang, Xinyu; Li, Shipu; Yin, Yixia

2014-01-01

390

Anti-Vascular Endothelial Growth Factor Therapy in Breast Cancer  

PubMed Central

Neo-angiogenesis is a critical process for tumor growth and invasion and has become a promising target in cancer therapy. This manuscript reviews three currently relevant anti-angiogenic agents targeting the vascular endothelial growth factor system: bevacizumab, ramucirumab and sorafenib. The efficacy of anti-angiogenic drugs in adjuvant therapy or as neo-adjuvant treatment has been estimated in clinical trials of advanced breast cancer. To date, the overall observed clinical improvements are unconvincing, and further research is required to demonstrate the efficacy of anti-angiogenic drugs in breast cancer treatments. The outcomes of anti-angiogenic therapy have been highly variable in terms of tumor response. New methods are needed to identify patients who will benefit from this regimen. The development of biomarkers and molecular profiling are relevant research areas that may strengthen the ability to focus anti-angiogenic therapy towards suitable patients, thereby increase the cost-effectiveness, currently estimated to be inadequate. PMID:25514409

Kristensen, Tina Bøgelund; Knutsson, Malin L. T.; Wehland, Markus; Laursen, Britt Elmedal; Grimm, Daniela; Warnke, Elisabeth; Magnusson, Nils E.

2014-01-01

391

Epidermal Growth Factor Receptor (EGFR) Crosstalks in Liver Cancer  

PubMed Central

Hepatocarcinogenesis is a complex multistep process in which many different molecular pathways have been implicated. Hepatocellular carcinoma (HCC) is refractory to conventional chemotherapeutic agents, and the new targeted therapies are meeting with limited success. Interreceptor crosstalk and the positive feedback between different signaling systems are emerging as mechanisms of targeted therapy resistance. The identification of such interactions is therefore of particular relevance to improve therapeutic efficacy. Among the different signaling pathways activated in hepatocarcinogenesis the epidermal growth factor receptor (EGFR) system plays a prominent role, being recognized as a “signaling hub” where different extracellular growth and survival signals converge. EGFR can be transactivated in response to multiple heterologous ligands through the physical interaction with multiple receptors, the activity of intracellular kinases or the shedding of EGFR-ligands. In this article we review the crosstalk between the EGFR and other signaling pathways that could be relevant to liver cancer development and treatment. PMID:24212818

Berasain, Carmen; Latasa, María Ujue; Urtasun, Raquel; Goñi, Saioa; Elizalde, María; Garcia-Irigoyen, Oihane; Azcona, María; Prieto, Jesús; Ávila, Matías A.

2011-01-01

392

Eicosanoids and Keratinocytes in Wound Healing  

PubMed Central

Significance: Eicosanoids are biologically active lipid mediators derived from arachidonic acid that are important in injury and inflammatory responses. Cyclooxygenase-1 and cyclooxygenase-2 mediate the production of prostanoids, whereas 5-lipoxygenase mediates the production of leukotrienes and hydroxyeicosatetraenoic acids. These lipid mediators have traditionally been known to recruit cells of the immune system to a site of injury and inflammation. However, they also interact with various cells that are resident to the wound bed, including modulation of keratinocyte activity. Recent Advances: Recent work has identified multiple prostanoid and leukotriene receptors on keratinocytes, indicating that eicosanoids directly interact with them. Recent work also shows that keratinocytes are capable of producing prostanoids and leukotrienes. Critical Issues: Much of the critical work has been performed in cell culture and mouse in vivo models. This has greatly expanded our understanding of the eicosanoid interactions with keratinocytes and wound healing in general. However, few of these in vivo models have been able to critically evaluate keratinocyte migration and re-epithelialization. Future Directions: As research continues in this exciting field, the cellular pathways stimulated by the eicosanoids will become better defined. Future research with excisional wound models in mice and pigs and ex vivo human skin models will better isolate the contribution of eicosanoid-mediated effects on keratinocyte migration and re-epithelialization. PMID:25032067

Sivamani, Raja K.

2014-01-01

393

Proteome profiling of keratinocytes transforming to malignancy.  

PubMed

To shed light on the multistep process of squamous cell carcinoma development and the underlying pathologic mechanisms, we performed comparative proteome analysis of keratinocytes, keratinocytes stimulated with Il-1beta, and A431 epidermoid carcinoma cells. Fractionation of the cells into supernatant, nucleus, and cytoplasm was followed by protein separation, proteolytic digest, and nano-LC separation, and fragmentation using an ion trap mass spectrometer. Specific bioinformatics tools were used to generate a list of keratinocyte-specific proteins. Ninety percent of these proteins were found to be upregulated in keratinocytes versus the A431 cells. Classification of the identified proteins by biologic function and gene set enrichment analysis revealed that keratinocytes produced more proteins involved in cell differentiation, cell adhesion, cell junction, calcium ion, calmodulin binding, cytoskeleton organization, and cytokinesis, whereas A431 produced more proteins involved in cell cycle checkpoint, cell cycle process, RNA processing and transport, DNA damage and repair, RNA and DNA binding, and chromatin remodeling. The protein signatures of A431 and normal keratinocytes treated with IL-1beta showed marked similarity, confirming that inflammation is an important step in malignant transformation in nonmelanoma skin cancer. Thus, proteome profiling and bioinformatic processing may support the understanding of the underlying mechanisms, with the potential to facilitate development of early biomarkers and patient-tailored therapy. PMID:25395074

Paulitschke, Verena; Gerner, Christopher; Hofstätter, Elisabeth; Mohr, Thomas; Mayer, Rupert Laurenz; Pehamberger, Hubert; Kunstfeld, Rainer

2015-02-01

394

Fibroblast growth factor receptor 3 effects on proliferation and telomerase activity in sheep growth plate chondrocytes  

PubMed Central

Background Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Thyroid hormone (T3) plays a role in cellular maturation of growth plate chondrocytes and a known target of T3 is FGFR3. The present study addressed whether reduced FGFR3 expression enhanced telomerase activity, mRNA expression of telomerase reverse transcriptase (TERT) and RNA component of telomerase (TR), and chondrocyte proliferation, and whether the stimulation of FGFR3 by T3 evoked the opposite response. Results Sheep growth-plate proliferative zone chondrocytes were cultured and transfected with siRNA to reduce FGFR3 expression; FGFR3 siRNA reduced chondrocyte FGFR3 mRNA and protein resulting in greater proliferation and increased TERT mRNA expression and telomerase activity (p?growth plate may be partially mediated through the FGFR3 pathway. Conclusions The results suggest that FGFR3 inhibits chondrocyte proliferation by down-regulating TERT expression and reducing telomerase activity indicating an important role for telomerase in sustaining chondrocyte proliferative capacity during bone elongation. PMID:23216972

2012-01-01

395

Alterations in insulin-like growth factor-1 gene and protein expression and type 1 insulin-like growth factor receptors in the brains of ageing rats  

Microsoft Academic Search

Ageing in mammals is characterized by a decline in plasma levels of insulin-like growth factor-1 that appears to contribute to both structural and functional changes in a number of tissues. Although insulin-like growth factor-1 has been shown to provide trophic support for neurons and administration of insulin-like growth factor-1 to ageing animals reverses some aspects of brain ageing, age-related changes

W. E Sonntag; C. D Lynch; S. A Bennett; A. S Khan; P. L Thornton; P. T Cooney; R. L Ingram; T McShane; J. K Brunso-Bechtold

1999-01-01

396

Growth-dependent changes in endothelial factors regulating arteriolar tone.  

PubMed

Previous studies from this laboratory suggest that during maturation, rapid microvascular growth is accompanied by changes in the mechanisms responsible for regulation of tissue blood flow. To further define these changes, we studied isolated gracilis muscle arterioles from weanling ( approximately 25 days) and juvenile ( approximately 44 days) Sprague-Dawley rats to test the hypothesis that endothelial mechanisms for the control of arteriolar tone are altered with growth. Responses to the endothelium-dependent dilator acetylcholine (ACh) were greater in weanling arterioles (WA) than in juvenile arterioles (JA), whereas there were no consistent differences between age groups in arteriolar responses to other endothelium-dependent agonists (A-23187, vascular endothelial growth factor, and simvastatin). Inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-l-arginine methyl ester (l-NAME) attenuated ACh-induced dilation in JA but not in WA. In JA, combined inhibition of NOS and cyclooxygenase (with indomethacin) reduced the dilator responses to ACh and simvastatin by approximately 90% and approximately 70%, respectively, but had no effect in WA. Cytochrome P450 epoxygenase inhibition [with 2-(propargyloxyphenyl) hexanoic acid] had no effect on responses to ACh or simvastatin in either age group. Inhibition of Ca(2+)-activated or ATP-dependent potassium channels (with tetraethylammonium or glibenclamide, respectively) reduced these arteriolar responses in JA but not those in WA. These findings suggest that in fully grown microvascular networks, endothelium-dependent arteriolar dilation is mediated by the combined release of endothelial nitric oxide and vasodilator prostanoids, and in part through activation of Ca(2+)-activated and ATP-dependent potassium channels. However, during earlier microvascular growth, this dilation is mediated by other factors yet to be identified. This may have significant implications for the regulation of tissue perfusion during microvascular development. PMID:16936004

Samora, Julie Balch; Frisbee, Jefferson C; Boegehold, Matthew A

2007-01-01

397

Activation of the androgen receptor by polypeptide growth factors and cellular regulators  

Microsoft Academic Search

The polypeptide growth factors insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), and transforming growth factor-a (TGF-a); second-messenger cyclic adenosine monophosphate (cAMP); protein kinase activators; and neurotransmitters were found to activate the estrogen (ER), progesterone (PR), and glucocorticoid receptor (GR) either in the absence of their natural ligands or synergistically with the respective hormone. There is now evidence of

Z. Culig; A. Hobisch; M. V. Cronauer; A. Hittmair; C. Radmayr; G. Bartsch; H. Klocker

1995-01-01

398

EGF-related growth factors in the pathogenesis of murine ARPKD1  

Microsoft Academic Search

EGF-related growth factors in the pathogenesis of murine ARPKD.BackgroundEpidermal growth factor (EGF), transforming growth factor-? (TGF-?) and their receptor, EGFR, play key roles in polycystic kidney disease (PKD) pathogenesis. Renal expression of two related growth factors, amphiregulin and heparin-binding EGF, has not been examined previously in PKD. The aims of this study of murine autosomal-recessive polycystic kidney disease (ARPKD) were

KATHERINE MACRAE DELL; RAGHAD NEMO; William E. Sweeney; Ellis D. Avner

2004-01-01

399

It''s not factor accumulation: Styl-ized facts and growth models  

Microsoft Academic Search

Abstract: We document five stylized facts of economic growth. (1) The “residual” rather than factor accumulation,accounts for most of the income and growth differences across nations. (2) Income diverges over the long run. (3) Factor accumulation,is persistent while growth is not persistent and the growth path of countries exhibits remarkable variation across countries. (4) Economic activity is highly concentrated, with

W. Easterly; R. Levine

2000-01-01

400

Vascular Endothelial Growth Factor Receptor -2 in Breast Cancer  

PubMed Central

Investigations over the last decade have established the essential role of growth factors and their receptors during angiogenesis and carcinogenesis. The vascular endothelial growth factor receptor (VEGFR) family in mammals contains three members, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4), which are transmembrane tyrosine kinase receptors that regulate the formation of blood and lymphatic vessels. In the early 1990s, the above VEGFR were structurally characterized by cDNA cloning. Among these three receptors, VEGFR-2 is generally recognized to have a principal role in mediating VEGF-induced responses. VEGFR-2 is considered as the earliest marker for endothelial cell development. Importantly, VEGFR-2 directly regulates tumor angiogenesis. Therefore, several inhibitors of VEGFR-2 have been developed and many of them are now in clinical trials. In addition to targeting endothelial cells, the VEGF/VEGFR-2 system works as an essential autocrine/paracrine process for cancer cell proliferation and survival. Recent studies mark the continuous and increased interest in this related, but distinct, function of VEGF/VEGFR-2 in cancer cells: the autocrine/paracrine loop. Several mechanisms regulate VEGFR-2 levels and modulate its role in tumor angiogenesis and physiologic functions, i.e.: cellular localization/trafficking, regulation of cis-elements of promoter, epigenetic regulation and signaling from Notch, cytokines/growth factors and estrogen, etc. In this review, we will focus on updated information regarding VEGFR-2 research with respect to the molecular mechanisms of VEGFR-2 regulation in human breast cancer. Investigations in the activation, function, and regulation of VEGFR-2 in breast cancer will allow the development of new pharmacological strategies aimed at directly targeting cancer cell proliferation and survival. PMID:20462514

Guo, Shanchun; Colbert, Laronna S.; Fuller, Miles; Zhang, Yuanyuan; Gonzalez-Perez, Ruben R.

2010-01-01