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ABSTRACT: The goal of this study was to determine if a multimineral natural product derived from red marine algae could reduce colon polyp formation in mice on a high-fat diet. C57BL/6 mice were maintained for up to 18 mo either on a high-fat "Western-style" diet or on a low-fat diet (AIN 76A), with or without the multimineral-supplement. To summarize, colon polyps were detected in 22 of 70 mice (31%) on the high-fat diet but in only 2 of 70 mice (3%) receiving the mineral-supplemented high-fat diet (P < 0.0001). Colon polyps were detected in 16 of 70 mice (23%) in the low-fat group; not significantly different from high-fat group but significantly higher than the high-fat-supplemented group (P = 0.0006). This was in spite of the fact that the calcium level in the low-fat diet was comparable to the level of calcium in the high-fat diet containing the multimineral-product. Supplementation of the low-fat diet reduced the incidence to 8 of 70 mice (11% incidence). Taken together, these findings demonstrate that a multimineral natural product can protect mice on a high-fat diet against adenomatous polyp formation in the colon. These data suggest that increased calcium alone is insufficient to explain the lower incidence of colon polyps.
Nutrition and Cancer 10/2012; 64(7):1020-8. · 2.78 Impact Factor
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ABSTRACT: Gadolinium, a member of the lanthanoid family of transition metals, interacts with calcium-binding sites on proteins and other biological molecules. The overall goal of the present investigation was to determine if gadolinium could enhance calcium-induced epithelial cell growth inhibition in the colon. Gadolinium at concentrations as low as 1-5 μM combined with calcium inhibits proliferation of human colonic epithelial cells more effectively than calcium alone. Gadolinium had no detectable effect on calcium-induced differentiation in the same cells based on change in cell morphology, induction of E-cadherin synthesis, and translocation of E-cadherin from the cytosol to the cell surface. When the colon epithelial cells were treated with gadolinium and then exposed to increased calcium concentrations, movement of extracellular calcium into the cell was suppressed. In contrast, gadolinium treatment had no effect on ionomycin-induced release of stored intracellular calcium into the cytoplasm. Whether these in vitro observations can be translated into an approach for reducing abnormal proliferation in the colonic mucosa (including polyp formation) is not known. These results do, however, provide an explanation for our recent findings that a multi-mineral supplement containing all of the naturally occurring lanthanoid metals including gadolinium are more effective than calcium alone in preventing colon polyp formation in mice on a high-fat diet.
Biological trace element research 09/2012; · 1.92 Impact Factor
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ABSTRACT: We recently show that CCN3 is a counter-regulatory molecule for the pro-fibrotic protein CCN2, and a potentially novel fibrosis therapy. The goal of this study was to assess the role of CCN3 in fibroproliferative/fibrotic responses in human dermal fibroblasts exposed to Omniscan, one of the gadolinium-based contrast agents associated with development of nephrogenic systemic fibrosis (NSF) a rare but life-threatening disease thought to be complication of NMR diagnostics in renal impaired patients. Human dermal fibroblasts were exposed to Omniscan; or to platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) as controls. Proliferation was assessed along with matrix metalloproteinase-1, tissue inhibitor of metalloproteinases-1 and type 1 procollagen in the absence and presence of CCN3. In parallel, CCN3 production was assessed in control and Omniscan-treated cells. The results showed that PDGF stimulated fibroblast proliferation, production of Timp-1 and MMP-1 whereas exogenous CCN3 inhibited, in a dose response manner, cell proliferation (approx. 50 % max.) and production of MMP-1 (approx 35 % max.) but had little effect on TIMP-1. TGF-β stimulated type 1 procollagen production but not proliferation, Timp-1 or MMP-1 compared to non-TGF-ß treated control cells, and CCN3 treatment blocked (approx. 80 % max.) this up-regulation. Interestingly, untreated, control fibroblasts produced high constitutive levels of CCN3 and concentrations of Omniscan that induced fibroproliferative/fibrogenic changes in dermal fibroblasts correspondingly suppressed CCN3 production. The use of PDGF and TGF-β as positive controls, and the study of differential responses, including that to Omniscan itself, provide the first evidence for a role of fibroblast-derived CCN3 as an endogenous regulator of pro-fibrotic changes, elucidating possible mechanism(s). In conclusion, these data support our hypothesis of a role for fibroblast-derived CCN3 as an endogenous regulator of pro-fibrotic changes in these cells, and suggest that CCN3 may be an important regulatory molecule in NSF and a target for treatment in this and other fibrotic diseases.
Journal of Cell Communication and Signaling 05/2012; 6(2):97-105.
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ABSTRACT: C57BL/6 mice were maintained for up to 18 months on high-fat and low-fat diets with or without a multi-mineral supplement derived from the skeletal remains of the red marine algae Lithothamnion calcareum. Numerous grossly observable liver masses were visible in animals on the "western-style" high-fat diet sacrificed at 12 and 18 months. The majority of the masses were in male mice (20 out of 100 males versus 3 out of 100 females; p = 0.0002). There were more liver masses in animals on the high-fat diet than on the low-fat diet (15 out of 50 on high-fat versus 5 out of 50 on low-fat; p = 0.0254). The multi-mineral supplement reduced the number of liver masses in mice on both diets (3 out of 25 male mice in the low-fat diet group without the supplement versus 1 out of 25 mice with supplement; 12 of 25 male mice in the high-fat diet group without the supplement versus 3 of 25 mice with supplement [p = 0.0129]). Histological evaluation revealed a total of 17 neoplastic lesions (9 adenomas and 8 hepatocellular carcinomas), and 18 pre-neoplastic lesions. Out of eight hepatocellular carcinomas, seven were found in unsupplemented diet groups. Steatosis was widely observed in livers with and without grossly observable masses, but the multi-mineral supplement had no effect on the incidence of steatosis or its severity. Taken together, these findings suggest that a multi-mineral-rich natural product can protect mice against neoplastic and pre-neoplastic proliferative liver lesions that may develop in the face of steatosis.
Biological trace element research 01/2012; 147(1-3):267-74. · 1.92 Impact Factor
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ABSTRACT: Ulcerative dermatitis (UD) is a common, spontaneous condition in mice with a C57BL/6 background. Although initial lesions may be mild, UD is a progressive disease that often results in ulcerations or debilitating fibrotic contractures. In addition, lesions typically are unresponsive to treatment. Euthanasia is often warranted in severe cases, thereby affecting study outcomes through the loss of research subjects. Because the clinical assessment of UD can be subjective, a quantitative scoring method and documentation of the likely time-frame of progression may be helpful in predicting when animals that develop dermatitis should be removed from a study. Such a system may also be helpful in quantitatively assessing success of various treatment strategies and be valuable to clinical laboratory animal veterinarians. In this 1.5-y, prospective cohort study, we followed 200 mice to monitor the development and course of UD. Mice were examined every 2 wk. A clinical sign (alopecia, pruritus, or peripheral lymphadenopathy) was not identified that predicted development of UD lesions in the subsequent 2-wk period. Once UD developed, pruritus, the character of the lesion (single or multiple crust, coalescing crust, erosion, or ulceration), and the size of the lesion were the only parameters that changed (increased) over the course of the disease. Pruritus was a factor in the rapid progression of UD lesions. We used these findings to develop a quantitative scoring system for the severity of UD. This enhanced understanding of the progression of UD and the quantitative scoring system will enhance the monitoring of UD.
Journal of the American Association for Laboratory Animal Science: JAALAS 01/2012; 51(5):586-93. · 0.71 Impact Factor
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ABSTRACT: The purpose of this study was to assess insoluble salts containing gadolinium (Gd(3+)) for effects on human dermal fibroblasts. Responses to insoluble Gd(3+) salts were compared to responses seen with Gd(3+) solubilized with organic chelators, as in the Gd(3+)-based contrast agents (GBCAs) used for magnetic resonance imaging. Insoluble particles of either Gd(3+) phosphate or Gd(3+) carbonate rapidly attached to the fibroblast cell surface and stimulated proliferation. Growth was observed at Gd(3+) concentrations between 12.5 and 125 μM, with toxicity at higher concentrations. Such a narrow window did not characterize GBCA stimulation. Proliferation induced by insoluble Gd(3+) salts was inhibited in the presence of antagonists of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways (similar to chelated Gd(3+)) but was not blocked by an antibody to the platelet-derived growth factor receptor (different from chelated Gd(3+)). Finally, high concentrations of the insoluble Gd(3+) salts failed to prevent fibroblast lysis under low-Ca(2+) conditions, while similar concentrations of chelated Gd(3+) were effective. In conclusion, while insoluble Gd(3+) salts are capable of stimulating fibroblast proliferation, one should be cautious in assuming that GBCA dechelation must occur in vivo to produce the profibrotic changes seen in association with GBCA exposure in the subset of renal failure patients that develop nephrogenic systemic fibrosis.
Biological trace element research 09/2011; 145(2):257-67. · 1.92 Impact Factor
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ABSTRACT: The purpose of this study was to compare each of the 14 naturally occurring lanthanoid metal ions for ability to stimulate pro-fibrotic responses in human dermal fibroblasts. When fibroblasts were exposed to individual lanthanoids over the concentration range of 1-100 μM, increased proliferation was observed with each of the agents as compared with control cells that were already proliferating rapidly in a growth factor-enriched culture medium. Dose-response differences were observed among the individual metal ions. Matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 levels were also increased in response to lanthanoid exposure but type I procollagen production was not. A dose-response relationship between induction of proliferation and increased MMP-1 was observed. Non-lanthanoid transition metal ions (aluminum, copper, cobalt, iron, magnesium, manganese, nickel, and zinc) were examined in the same assays; there was little stimulation with any of these metals. When epidermal keratinocytes were examined in place of dermal fibroblasts, there was no growth stimulation with any of the lanthanoids. Several of the lanthanoid metals inhibited keratinocyte proliferation at higher concentrations (50-100 μM).
Biological trace element research 04/2011; 144(1-3):621-35. · 1.92 Impact Factor
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ABSTRACT: We have recently shown that a multi-mineral extract from the marine red algae, Lithothamnion calcareum, suppresses colon polyp formation and inflammation in mice. In the present study, we used intact human colon tissue in organ culture to compare responses initiated by Ca(2+) supplementation versus the multi-mineral extract. Normal human colon tissue was treated for 2 d in culture with various concentrations of calcium or the mineral-rich extract. The tissue was then prepared for histology/immunohistochemistry, and the culture supernatants were assayed for levels of type I procollagen and type I collagen. At higher Ca(2+) concentrations or with the mineral-rich extract, proliferation of epithelial cells at the base and walls of the mucosal crypts was suppressed, as visualized by reduced Ki67 staining. E-cadherin, a marker of differentiation, was more strongly expressed at the upper third of the crypt and at the luminal surface. Treatment with Ca(2+) or with the multi-mineral extract influenced collagen turnover, with decreased procollagen and increased type I collagen. These data suggest that calcium or mineral-rich extract has the capacity to (1) promote differentiation in human colon tissue in organ culture and (2) modulate stromal function as assessed by increased levels of type I collagen. Taken together, these data suggest that human colon tissue in organ culture (supporting in vivo finding in mice) will provide a valuable model for the preclinical assessment of agents that regulate growth and differentiation in the colonic mucosa.
In Vitro Cellular & Developmental Biology - Animal 01/2011; 47(1):32-8. · 1.31 Impact Factor
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ABSTRACT: The purpose of this study was to assess the effects of gadolinium (Gd3+), provided as gadolinium chloride, on fibroblast function.
Human dermal fibroblasts in monolayer culture and intact skin in organ culture were exposed to the lanthanide metal (1-20 μM).
Increased proliferation was observed, in association with upregulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1, without an apparent increase in production of type I procollagen. A platelet-derived growth factor (PDGF) receptor-blocking antibody inhibited fibroblast proliferation in response to Gd3+ as did inhibitors of signaling pathways--that is, mitogen-activated protein kinase and phosphatidylinositol-3 kinase pathways--that are activated by PDGF.
The responses to gadolinium chloride are similar to responses previously seen with chelated Gd3+ in clinically used magnetic resonance imaging contrast agents. Fibroblast responses appear to reflect Gd3+-induced PDGF receptor activation and downstream signaling. Increased dermal fibroblast proliferation in conjunction with effects on matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 could contribute to the fibroplastic/fibrotic changes seen in the lesional skin of individuals with nephrogenic systemic fibrosis.
Investigative radiology 12/2010; 45(12):769-77. · 4.85 Impact Factor
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ABSTRACT: Nephrogenic systemic fibrosis is a clinical syndrome occurring in a small subset of patients with end-stage renal disease (ESRD). Exposure to certain of the gadolinium-based contrast agents during magnetic resonance imaging appears to be a trigger. The pathogenesis of the disease is largely unknown. The present study addresses potential pathophysiologic mechanisms.
We have compared responses in organ-cultured skin and skin fibroblasts from individuals with ESRD to responses of healthy control subjects to Omniscan treatment.
Treatment of skin from ESRD patients with Omniscan stimulated production of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1, but not type I procollagen. The same treatment also stimulated an increase in hyaluronan production. Similar results were seen with skin from normal controls but basal levels were higher in ESRD patients. Fibroblasts in monolayer culture gave the same responses, but there were no differences based on whether the cells were isolated from the skin of healthy subjects or those with ESRD.
These data indicate that Omniscan exposure alters an enzyme/inhibitor system responsible for regulating collagen turnover in the skin and directly stimulates hyaluronan production. The higher basal levels of type I procollagen, matrix metalloproteinase-1, tissue inhibitor of metalloproteinases-1, and hyaluronan in the skin from ESRD patients could contribute to the sensitivity of this patient population to fibrotic changes, which might be induced by exposure to some of the gadolinium-based contrast agents.
Investigative radiology 11/2010; 45(11):733-9. · 4.85 Impact Factor
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ABSTRACT: PADMA 28 is a multi-component herbal mixture formulated according to an ancient Tibetan recipe. PADMA 28 is known to stimulate collagen production and reduced levels of collagen-degrading matrix metalloproteinases (MMPs). The goal of the present study was to determine whether topical treatment of rat skin with PADMA 28 would improve skin structure/function, and whether subsequently induced abrasion wounds would heal more rapidly in skin that had been pretreated with PADMA 28. Hairless rats were exposed to a potent topical corticosteroid (Temovate) in combination with either DMSO alone or with PADMA 28 given topically. At the end of the treatment period, superficial wounds were created in the skin, and time to wound closure was assessed. Collagen production and matrix-degrading MMPs were assessed. Abrasion wounds in skin that had been pretreated with PADMA 28 healed more rapidly than did wounds in Temovate plus DMSO-treated skin. Under conditions in which improved wound healing was observed, there was an increased collagen production and decreased MMP expression, but no significant epidermal hyperplasia and no evidence of skin irritation. The ability to stimulate collagen production and inhibit collagen-degrading enzymes in skin and facilitate more rapid wound closure without irritation should provide a rationale for development of the herbal preparation as a "skin-repair" agent.
Archives for Dermatological Research 11/2010; 302(9):669-77. · 2.28 Impact Factor
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Hal Blumberg,
Huyen Dinh,
Charles Dean,
Esther S Trueblood,
Keith Bailey,
Donna Shows,
Narasimharao Bhagavathula,
Muhammad Nadeem Aslam, James Varani,
Jennifer E Towne,
John E Sims
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ABSTRACT: Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member, IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis. Inflammatory cytokines thought to be important in psoriasis, such as TNF-α, IL-17A, and IL-23, are upregulated in the mouse skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F family members in psoriasis.
The Journal of Immunology 10/2010; 185(7):4354-62. · 5.79 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae Lithothamnion calcareum could be used as a dietary supplement for chemoprevention against colon polyp formation. A total of 60 C57bl/6 mice were divided into 3 groups based on diet. One group received a low-fat, rodent chow diet (AIN76A). The second group received a high-fat "Western-style" diet (HFWD). The third group was fed the same HFWD with the mineral-rich extract included as a dietary supplement. Mice were maintained on the respective diets for 15 months. Autopsies were performed at the time of death or at the completion of the study. To summarize, the cumulative mortality rate was higher in mice on the HFWD during the 15-month period (55%) than in mice from the low-fat diet or the extract-supplemented high-fat diet groups (20% and 30%, respectively; P < .05 with respect to both). Autopsies revealed colon polyps in 20% of the animals on the HFWD and none in animals of the other 2 groups (P < .05). In addition to the grossly visible polyps, areas of hyperplasia in the colonic mucosa and inflammatory foci throughout the gastrointestinal tract were observed histologically in animals on the high-fat diet. Both were significantly reduced in animals on the low-fat diet and animals on the extract-supplemented HFWD.These data suggest that the mineral-rich algae extract may provide a novel approach to chemoprevention in the colon.
Integrative Cancer Therapies 02/2010; 9(1):93-9. · 2.14 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae Lithothamnion calcareum could be used as a dietary supplement for prevention of bone mineral loss. Sixty C57BL/6 mice were divided into three groups based on diet: the first group received a high-fat Western-style diet (HFWD), the second group was fed the same HFWD along with the mineral-rich extract included as a dietary supplement, and the third group was used as a control and was fed a low-fat rodent chow diet (AIN76A). Mice were maintained on the respective diets for 15 months. Then, long bones (femora and tibiae) from both males and females were analyzed by three-dimensional micro-computed tomography (micro-CT) and (bones from female mice) concomitantly assessed in bone strength studies. Tartrate-resistant acid phosphatase (TRAP), osteocalcin, and N-terminal peptide of type I procollagen (PINP) were assessed in plasma samples obtained from female mice at the time of sacrifice. To summarize, female mice on the HFWD had reduced bone mineralization and reduced bone strength relative to female mice on the low-fat chow diet. The bone defects in female mice on the HFWD were overcome in the presence of the mineral-rich supplement. In fact, female mice receiving the mineral-rich supplement in the HFWD had better bone structure/function than did female mice on the low-fat chow diet. Female mice on the mineral-supplemented HFWD had higher plasma levels of TRAP than mice of the other groups. There were no differences in the other two markers. Male mice showed little diet-specific differences by micro-CT.
Calcified Tissue International 02/2010; 86(4):313-24. · 2.38 Impact Factor
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ABSTRACT: Human skin produces increased amounts of matrix metalloproteinase-1 (MMP-1) when exposed in organ culture to Omniscan, one of the gadolinium-based MRI contrast agents (GBCA). MMP-1, by virtue of its ability to degrade structural collagen, contributes to collagen turnover in the skin. The objective of the present study was to determine whether collagenolytic activity was concomitantly up-regulated with increased enzyme.
Skin biopsies from normal volunteers were exposed in organ culture to Omniscan. Organ culture fluids obtained from control and treated skin were examined for ability to degrade type I collagen. The same culture fluids were examined for levels of MMP-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and complexes of MMP-1 and TIMP-1.
Although MMP-1 was increased in culture fluid from Omniscan-treated skin, there was no increase in collagenolytic activity. In fact, collagenolytic activity declined. Increased production of TIMP-1 was also observed in Omniscan-treated skin, and the absolute amount of TIMP-1 was greater than the amount of MMP-1. Virtually all of the MMP-1 was present in MMP-1-TIMP-1 complexes, but the majority of TIMP-1 was not associated with MMP-1. When human dermal fibroblasts were exposed to TIMP-1 (up to 250 ng/mL), no increase in proliferation was observed, but an increase in collagen deposition into the cell layer was seen.
Gadolinium-based MRI contrast agent exposure has recently been linked to a fibrotic skin condition in patients with impaired kidney function. The mechanism is unknown. The increase in TIMP-1 production and concomitant reduction in collagenolytic activity demonstrated here could result in decreased collagen turnover and increased deposition of collagen in lesional skin.
Investigative radiology 12/2009; 45(1):42-8. · 4.85 Impact Factor
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ABSTRACT: Normal and neoplastic human colon tissue obtained at surgery was used to establish conditions for organ culture. Optimal conditions included an atmosphere of 5% CO2 and 95% O2; tissue partially submerged with mucosa at the gas interface; and serum-free medium with 1.5 mM Ca2+ and a number of growth supplements. Histological, histochemical, and immunohistochemical features that distinguish normal and neoplastic tissue were preserved over a 2-d period. With normal tissue, this included the presence of elongated crypts with small, densely packed cells at the crypt base and mucin-containing goblet cells in the upper portion. Ki67 staining, for proliferating cells, was confined to the lower third of the crypt, while expression of extracellular calcium-sensing receptor was seen in the upper third and surface epithelium. E-cadherin and β-catenin were expressed throughout the epithelium and confined to the cell surface. In tumor tissue, the same disorganized, abnormal glandular structures seen at time zero were present after 2 d. The majority of cells in these structures were mucin-poor, but occasional goblet cells were seen and mucin staining was present. Ki67 staining was seen throughout the abnormal epithelium and calcium-sensing receptor expression was weak and variable. E-cadherin was seen at the cell surface (similar to normal tissue), but in some places, there was diffuse cytoplasmic staining. Finally, intense cytoplasmic and nuclear β-catenin staining was observed in cultured neoplastic tissue.
In Vitro Cellular & Developmental Biology - Animal 11/2009; 46(2):114-22. · 1.31 Impact Factor
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ABSTRACT: Göttingen minipigs were treated topically for 6 d with a novel retinoid (MDI 301) at concentrations ranging from 0.3% to 30% in cream vehicle. Treatment of the minipigs did not adversely affect their health (hematological and necropsy parameters) or produce changes in the skin suggestive of retinoid-induced skin irritation. After killing the animals, skin samples from each treatment site were excised and maintained in organ culture for 6 d. In addition, untreated skin was also maintained in organ culture and treated with MDI 301 (0.1-5 microg/ml). After 3 d, the culture supernatants were collected and analyzed for levels of collagen type I and for matrix metalloproteinases (MMPs). Both skin samples treated in vivo and skin samples exposed to MDI 301 in culture demonstrated increased collagen production. Only slight changes in levels of MMP-2 (gelatinase A) or MMP-9 (gelatinase B) were seen. After 6 d, the organ-cultured skin was fixed in formalin and prepared for histology. The organ-cultured skin was compared to skin that was fixed at killing after in vivo treatment. Epidermal hyperplasia was quantified at various MDI 301 concentrations. In vivo and in vitro treatments showed similar results-although the thickness was not substantially changed on average, there were focal areas of hyperplasia at higher retinoid concentrations. Taken together, these data suggest that MDI 301 enhances collagen production in minipig skin, without irritation. Furthermore, these studies suggest that minipig skin exposed to the retinoid in organ culture is equally predictive as topically treated skin. The in vitro organ culture approach may provide a cost-effective alternative model to that of the intact animal for skin retinoid testing.
In Vitro Cellular & Developmental Biology - Animal 07/2009; 45(9):551-7. · 1.31 Impact Factor
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ABSTRACT: Nephrogenic systemic fibrosis is a clinical syndrome linked with exposure in renal failure patients to gadolinium-based contrast agents (GBCAs) during magnetic resonance imaging. Recently, we demonstrated that GBCA exposure led to increased matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in human skin fibroblasts. The goals of the present work were to assess the relationship between altered MMP-1/TIMP-1 expression and collagen production/deposition, and the intracellular signaling events that lead from GBCA stimulation to altered MMP-1 and TIMP-1 production.
Human dermal fibroblasts were treated with one of the currently used GBCAs (Omniscan). Proliferation was quantified as were levels of MMP-1, TIMP-1, procollagen type I, and collagen type I. Signaling events were concomitantly assessed, and signaling inhibitors were used.
Fibroblasts exposed to Omniscan had increases in both MMP-1 and TIMP-1 levels. Omniscan treatment interfered with collagen turnover, leading to increased type I collagen deposition without an increase in type I procollagen production. U0126, an inhibitor of mitogen-activated protein kinase signaling, and LY294002, a phosphatidylinositol-3 kinase inhibitor, reduced MMP-1 levels. U0126 also reduced TIMP-1 levels, but LY294002 increased TIMP-1.
These data provide evidence for complex regulation of collagen deposition in Omniscan-treated skin. They suggest that the major effect of Omniscan exposure is on an enzyme/inhibitor system that regulates collagen breakdown rather than on collagen production, per se.
Investigative radiology 07/2009; 44(8):433-9. · 4.85 Impact Factor
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ABSTRACT: Healing of superficial skin wounds depends on the proliferation and migration of keratinocytes at the wound margin. When human epidermal keratinocytes were incubated on polymerized type I collagen, they rapidly attached and spread. The cells underwent a proliferative response and, over the subsequent 6-day period, covered the collagen surface with a monolayer of cells. When keratinocytes were plated on collagen that had been fragmented by exposure to matrix metalloproteinase-1 (MMP-1, collagenase-1), the cells attached as readily as to intact collagen but spread more slowly and less completely. Growth was reduced by approximately 50%. Instead of covering the collagen surface, the keratinocytes remained localized to the site of attachment. Keratinocytes on fragmented collagen expressed a more differentiated phenotype as indicated by a higher level of surface E-cadherin. Based on these findings, we suggest that damage to the underlying collagenous matrix may impede efficient keratinocyte function and retard wound closure.
Archives for Dermatological Research 05/2009; 301(7):497-506. · 2.28 Impact Factor
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ABSTRACT: Proliferation and differentiation were assessed in a series of human colon carcinoma cell lines in response to a mineral-rich extract derived from the red marine algae, Lithothamnion calcareum. The extract contains 12% Ca2+, 1% Mg2+, and detectable amounts of 72 trace elements, but essentially no organic material. The red algae extract was as effective as inorganic Ca2+ alone in suppressing growth and inducing differentiation of colon carcinoma cells that are responsive to a physiological level of extracellular Ca2+ (1.4mM). However, with cells that are resistant to Ca2+ alone, the extract was still able to reduce proliferation and stimulate differentiation.
Cancer letters 05/2009; 283(2):186-92. · 4.86 Impact Factor
