Punch biopsies of human skin were obtained 1 day after irradiation with two minimal-erythema doses (MED) from either a UVB light source or a Solar Simulator and incubated in organ culture for 72 h. Organ culture fluids obtained at 24, 48 and 72 h were analyzed for collagenolytic activity and for reactivity with antibodies to matrix metalloproteinase-1 (MMP-1; interstitial collagenase) and MMP-13 (collagenase-3). High levels of collagenolytic activity were seen in organ culture fluid from skin exposed to either light source. MMP-1 was strongly induced in parallel, increasing from less than 100 ng/ml in organ culture fluid from control skin to approximately 1.1 microg/ml in culture fluid from UV-treated skin. Whereas most of the detectable MMP-1 in control culture fluid was represented by the latent form of the enzyme, approximately 50% of the enzyme was present as the active form in organ culture fluid of UV-exposed skin. In contrast, there was no detectable MMP-13 in control organ culture fluid and very little change after UV exposure (less than 100 ng/ml in both cases). Finally, neutralization studies with a blocking antibody to MMP-1 removed 95 +/- 4% of the collagenolytic activity in the organ culture fluid from UV-treated skin. These findings strongly implicate MMP-1 rather than MMP-13 as the major collagenolytic enzyme responsible for collagen damage in photoaging.

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.

An siRNA directed against the extracellular calcium‐sensing receptor (CaSR) was used to down‐regulate this protein in CBS colon carcinoma cells. In additional studies, we utilized a variant of the parental CBS line that demonstrates CaSR expression but does not upregulate this protein in response to extracellular Ca2+. In neither the siRNA‐transfected cells nor the Ca2+‐nonresponsive variant cells did inclusion of Ca2+ in the culture medium inhibit proliferation or induce morphological alterations. Extracellular Ca2+ also failed to induce E‐cadherin production or a shift in β‐catenin from the cytoplasm to the cell membrane. In mock‐transfected cells and in a Ca2+‐responsive variant line derived from the same parental CBS cells, Ca2+ treatment resulted in growth‐reduction. This was accompanied by increased E‐cadherin production and a shift in β‐catenin distribution from the cytoplasm to the cell membrane. Additionally, down‐regulation of c‐myc and cyclin D1 expression was observed in mock‐transfected cells and in the Ca2+‐responsive variant line (along with reduced T cell factor transcriptional activation). Neither c‐myc nor cyclin D1 was significantly down‐regulated in the siRNA‐transfected cells or in the Ca2+‐nonresponsive variant cells upon Ca2+ stimulation. In histological sections of human colon carcinoma CaSR was significantly reduced as compared to the level in normal colonic crypt epithelial cells. Where CaSR expression was high, strong surface staining for E‐cadherin and β‐catenin was observed. Where CaSR expression was reduced, β‐catenin surface expression was likewise reduced. © 2007 Wiley‐Liss, Inc.

The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae, Lithothamnion calcareum (Pallas), could be used as a dietary supplement for chemoprevention against colon polyp formation. Sixty C57bl/6 mice were divided into three 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<0.05 with respect to both). Autopsies revealed colon polyps in 20% of the animals on the HFWD and none in animals of the other two groups (p<0.05). 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.

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