Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term psoralen plus ultraviolet A radiation (PUVA) therapy is associated with an increased risk of squamous cell carcinoma and malignant melanoma. Genistein (4',5,7-trihydroxyisoflavone), a major isoflavone in soybeans and a specific inhibitor of protein tyrosine kinase, has been shown to inhibit UVB induced skin carcinogenesis in hairless mice. For this study we examined the protective effects of topical genistein on PUVA-induced photodamage. In two separate experiments, genistein in a dimethyl sulfoxide/acetone (1:9) solution was applied to SKH-1 female mice 1 h post 8-methoxy-psoralen dosing and 1 h prior to UVA irradiation. Application of genistein significantly decreased PUVA-induced skin thickening, and greatly diminished cutaneous erythema and ulceration in a dose-dependent manner. Histological examination showed that PUVA treatment of mouse skin induced dramatic inflammatory changes throughout the epidermis; topical genistein prevented these changes without noticeable adverse effects. Cells containing cleaved poly(ADP-ribose) polymerase (PARP) and active caspase-3 were significantly increased in PUVA-treated skin (P < 0.05 and P < 0.0001, respectively) as compared with unexposed control skin. Topical genistein completely inhibited cleavage of PARP and caspase-3. Proliferating cell nuclear antigen (PCNA) positive cells were observed in suprabasal areas of the epidermis and were significantly decreased in PUVA-treated skin compared with both control samples and samples treated with PUVA plus topical genistein (P < 0.005). These results indicate that genistein protects the skin from PUVA-induced photodamage.
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PMID:Effects of the isoflavone 4',5,7-trihydroxyisoflavone (genistein) on psoralen plus ultraviolet A radiation (PUVA)-induced photodamage. 1187 39

SKH-1 hairless mice were irradiated with ultraviolet B (UVB) twice weekly for 20 weeks. These tumor-free mice, which had a high risk of developing skin tumors during the next several months, were then treated topically with caffeine (6.2 micromol) or (-)-epigallocatechin gallate (EGCG; 6.5 micromol) once a day 5 days a week for 18 weeks in the absence of further treatment with UVB. Topical applications of caffeine to these mice decreased the number of nonmalignant and malignant skin tumors per mouse by 44% and 72%, respectively. Topical applications of EGCG decreased the number of nonmalignant and malignant tumors per mouse by 55% and 66%, respectively. Immunohistochemical analysis showed that topical applications of caffeine or EGCG increased apoptosis as measured by the number of caspase 3-positive cells in nonmalignant skin tumors by 87% or 72%, respectively, and in squamous cell carcinomas by 92% or 56%, respectively, but there was no effect on apoptosis in nontumor areas of the epidermis. Topical applications of caffeine or EGCG had a small inhibitory effect on proliferation in nonmalignant tumors as measured by BrdUrd labeling (16-22%), and there was also a similar, but nonsignificant, inhibitory effect on proliferation in malignant tumors. The results suggest a need for further studies to determine whether topical applications of caffeine or EGCG can inhibit sunlight-induced skin cancer in humans.
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PMID:Topical applications of caffeine or (-)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice. 1220 93

Inappropriate apoptosis results in the epidermal hyperplasia as in psoriasis and UVB irradiation has been successfully used to treat this kind of skin disorders. Previously, we reported that the novel phytosphingosine derivative, tetraacetyl phytosphingosine (TAPS) induced apoptosis in HaCaT cells. This study examined the effect of UVB irradiation and/or TAPS on the induction of apoptosis in HaCaT. 10 mJ/cm2 of UVB irradiation or 10 microM of TAPS alone exhibited weak cytotoxicity but co-treatment of UVB and TAPS synergistically enhanced the cytotoxicity and apoptosis in HaCaT. The cells treated with UVB and TAPS showed much higher levels of cleaved caspase-3, -8, -9 and Bax than with UVB or TAPS alone, whereas Bcl-2 level was decreased by co-administration of UVB and TAPS. In hairless mice, co-treatment of UVB and TAPS synergistically increased apoptosis, as shown in the HaCaT co-treated with UVB and TAPS. Furthermore, UVB irradiation caused an increase of apoptotic cells in the epidermis and the TAPS-treated mice showed an increase of apoptotic cells in the dermis as well as in the epidermis. These results suggest that the TAPS co-treatment synergistically increases the level of UVB-induced apoptosis via caspase activation by regulating the level of pro-apoptotic Bax and anti-apoptotic Bcl-2.
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PMID:Potentiation of UVB-induced apoptosis by novel phytosphingosine derivative, tetraacetyl phytosphingosine in HaCaT cell and mouse skin. 1519 27

Inhibition or deletion of cyclooxygenase (COX)-2 has been demonstrated to protect against squamous cell cancer in many studies. Although much effort has focused on COX-2 inhibition, recent work indicates that COX-1 deletion may be nearly as protective. In this study, we used SKH-1 hairless mice in which COX-1 was selectively deleted to examine the role of COX-1 in photocarcinogenesis. After UV exposure, 40-60% less prostaglandin E2 was detected in COX-1-/- animals compared with wild-type (WT) controls. A 4-fold induction of keratinocyte apoptosis was observed in knockouts relative to WT animals, as documented by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and caspase-3 staining. Proliferation was not significantly different in COX-1+/+, COX-1+/-, and COX-1-/- animals. When susceptibility to UV-induced tumor formation was studied, tumor number, average tumor size, and time of tumor onset in COX-1-/- animals were identical to WT controls. Thus, enhanced apoptosis did not alter UV-induced skin carcinogenesis, suggesting other effects are key to nonsteroidal anti-inflammatory drug chemoprevention. These results contrast sharply with data obtained using the classic 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate cancer model in which a prominent protective effect of COX-1-/- is present. The lack of protection observed here confirms cancer mechanisms are distinct in UV- and tumor promotor-induced cancer models and indicates that chemoprevention strategies must specifically address cancer causes to be effective.
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PMID:Cyclooxygenase-1 deletion enhances apoptosis but does not protect against ultraviolet light-induced tumors. 1531 95

Here, we assessed the protective effect of silibinin on UVB-induced skin carcinogenesis in SKH-1 hairless mice. Topical application of silibinin before or immediately after UVB exposure or its dietary feeding resulted in a strong protection against photocarcinogenesis, in terms of tumor multiplicity (60-66%; P < 0.001), tumor volume per mouse (93-97%; P < 0.001) and tumor volume per tumor (80-91%; P < 0.001). Silibinin also moderately inhibited tumor incidence (5-15%; P < 0.01) and delayed tumor latency period (up to 4 weeks; P < 0.01-0.001). To investigate in vivo molecular mechanisms of silibinin efficacy, tumors and uninvolved skin from tumor-bearing mice were examined immunohistochemically for proliferation, p53, apoptosis, and activated caspase-3. Silibinin treatment showed a strong decrease (P < 0.001) in proliferating cell nuclear antigen-positive cells and an increase in p53-positive (P < 0.005-0.001), terminal deoxynucleotidyltransferase-mediated nick end labeling-positive (P < 0.005-0.001), and cleaved caspase-3-positive cells (P < 0.001). Western blot analysis of normal skin and tumor lysates showed that silibinin decreases the levels of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 and associated cyclins A, E, and D1, together with an up-regulation of Cip1/p21, Kip1/p27, and p53. Silibinin also showed a strong phosphorylation of extracellular signal-regulated protein kinase 1/2, stress-activated protein kinase/c-JUN NH2-terminal kinase 1/2, and p38 mitogen-activated protein kinases but inhibited Akt phosphorylation and decreased survivin levels with an increase in cleaved caspase-3. Together, these results show a strong preventive efficacy of silibinin against photocarcinogenesis, which involves the inhibition of DNA synthesis, cell proliferation, and cell cycle progression and an induction of apoptosis. Furthermore, these results also identify in vivo molecular mechanisms of silibinin efficacy against photocarcinogenesis.
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PMID:Silibinin protects against photocarcinogenesis via modulation of cell cycle regulators, mitogen-activated protein kinases, and Akt signaling. 1534 25

Our laboratory has shown that arsenite markedly increased the cancer rate caused by solar-simulation ultraviolet radiation (UVR) in the hairless mouse skin model. In the present study, we investigated how arsenite affected DNA photodamage repair and apoptosis after solar-simulation UVR in the mouse keratinocyte cell line 291.03C. The keratinocytes were treated with different concentrations of sodium arsenite (0.0, 2.5, 5.0 microM) for 24 hr and then were immediately irradiated with a single dose of 0.30 kJ/m2 UVR. At 24 hr after UVR, DNA photoproducts [cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs)] and apoptosis were measured using the enzyme-linked immunosorbent assay and the two-color TUNEL (terminal deoxynucleotide transferase dUTP nick end labeling) assay, respectively. The results showed that arsenite reduced the repair rate of 6-4PPs by about a factor of 2 at 5.0 microM and had no effect at 2.5 microM. UVR-induced apoptosis at 24 hr was decreased by 22.64% at 2.5 microM arsenite and by 61.90% at 5.0 microM arsenite. Arsenite decreased the UVR-induced caspase-3/7 activity in parallel with the inhibition of apoptosis. Colony survival assays of the 291.03C cells demonstrate a median lethal concentration (LC50) of arsenite of 0.9 microM and a median lethal dose (LD50) of UVR of 0.05 kJ/m2. If the present results are applicable in vivo, inhibition of UVR-induced apoptosis may contribute to arsenite's enhancement of UVR-induced skin carcinogenesis.
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PMID:Arsenite-induced alterations of DNA photodamage repair and apoptosis after solar-simulation UVR in mouse keratinocytes in vitro. 1607 67

C/EBP-homologous protein (CHOP)/gadd153 (or CHOP) is a transcription factor induced by endoplasmic reticulum (ER) stress. Forcible overexpression of CHOP causes apoptosis in keratinocytes in culture. Here, we asked whether CHOP might be increased in the skin after UVB (280-320 nm) exposure, thus implicating CHOP in sunburn cell (SBC) formation. SKH-1 hairless mice were exposed to a ultraviolet (UV) source (80 mJ per cm2; approximately 74% UVB, approximately 16% UVA), and skin biopsies examined by immunohistology and immunoprecipitation. Compared with non-irradiated epidermis, CHOP expression was significantly increased at 30 min, and reached maximal levels by 24 h. Similar increases in CHOP following UVB exposure were observed in human buttock skin. The time course of CHOP expression preceded SBC formation and another marker of apoptosis, caspase-3 cleavage. Intracellular CHOP accumulated mainly in cytoplasmic and perinuclear locations, with little remaining in the nucleus. To examine mechanisms, cultured keratinocytes were irradiated in vitro and examined by western blotting. Under conditions that eliminated ER stress because of cell handling, CHOP did not accumulate (and was in fact decreased) in the cells. Thus, induction of CHOP in keratinocytes requires factors present only in the native skin. Overall, the data suggest that CHOP participates in adaptive responses of the epidermis following UVB/UVA exposure in vivo.
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PMID:Ultraviolet light (UVB and UVA) induces the damage-responsive transcription factor CHOP/gadd153 in murine and human epidermis: evidence for a mechanism specific to intact skin. 1609 44

Green tea polyphenols (GTPs) show promise as anticarcinogenic agents and may prevent the development of solar UV radiation-induced skin cancer. Here we investigated the mechanisms by which GTPs prevent UVB-induced skin cancer in mice. Two groups of 6- to 7-wk-old female SKH-1 hairless mice were UVB irradiated (180 mJ/cm(2)) 3 times each week for 24 wk. One group consumed water and the other, water containing 2 g/L GTPs. A control group drank water and was not exposed to UVB radiation. UVB-induced tumors and skin biopsies from the control group were analyzed using immunostaining, Western blotting, and gelatinolytic zymography. Oral administration of GTPs reduced UVB-induced tumor incidence (35%), tumor multiplicity (63%), and tumor growth (55%). The GTPs+UVB group had reduced expression of the matrix metalloproteinases (MMP)-2 and MMP-9, which have crucial roles in tumor growth and metastasis, and enhanced expression of tissue inhibitor of MMP in the tumors compared with mice that were treated with UVB alone. The GTPs+UVB group also had reduced expressions of CD31 and vascular endothelial growth factor, which are essential for angiogenesis, and inhibited expression of proliferating cell nuclear antigen in the tumors compared with the UVB group. Additionally, there were more cytotoxic CD8(+) T cells in the tumors of the GTPs+UVB group than in the UVB group and their tumor cells exhibited greater activation of caspase-3, indicating the apoptotic death of the tumor cells. Taken together, these data suggest that in mice, administration of GTPs affects several biomarkers that are involved in UV-carcinogenesis, including inhibition of angiogenic factors and recruitment of cytotoxic T cells in the tumor microenvironment.
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PMID:Orally administered green tea polyphenols prevent ultraviolet radiation-induced skin cancer in mice through activation of cytotoxic T cells and inhibition of angiogenesis in tumors. 1631 35

[6]-Gingerol, a naturally occurring plant phenol, is one of the major components of fresh ginger (Zingiber officinale Roscoe, Zingiberaceae) and has diverse pharmacologic effects. Here, we describe its novel anti-oxidant, anti-apoptotic, and anti-inflammatory activities in vitro and in vivo. In vitro, pre-treatment with [6]-gingerol reduced UVB-induced intracellular reactive oxygen species levels, activation of caspase-3, -8, -9, and Fas expression. It also reduced UVB-induced expression and transactivation of COX-2. Translocation of NF-kappaB from cytosol to nucleus in HaCaT cells was inhibited by [6]-gingerol via suppression of IkappaBalpha phosphorylation (ser-32). Examination by EMSAs and immunohistochemistry showed that topical application of [6]-gingerol (30 microM) prior to UVB irradiation (5 kJ/m(2)) of hairless mice, also inhibited the induction of COX-2 mRNA and protein, as well as NF-kappaB translocation. These results suggest that [6]-gingerol could be an effective therapeutic agent providing protection against UVB-induced skin disorders.
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PMID:[6]-Gingerol prevents UVB-induced ROS production and COX-2 expression in vitro and in vivo. 1745 43

UV radiation-induced epidermal apoptotic sunburn cells provide a mechanism for eliminating cells with irreparable DNA damage. The UVB (290-320 nm) waveband is mainly responsible, but the role of UVA (320-400 nm) is less clear, and possible waveband interactions have not been examined. Recent studies in mice reveal a protective role for UVA against UVB-induced inflammation and immunosuppression, mediated via cutaneous heme oxygenase (HO). As HO has antiapoptotic properties in other tissues, this study examines the effect of UVA/UVB waveband interaction on apoptosis in the Skh:hr-1 hairless mouse epidermis. Apoptosis was assessed by sunburn cell number, caspase-3-positive cell number, and degree of DNA fragmentation, in mice exposed to radiation sources providing a constant UVB dose with increasing proportions of UVA. The results indicated that as the UVA/UVB ratio was increased, both the sunburn cell and caspase-3-positive cell number decreased, and the degree of DNA fragmentation was reduced. Treatment of mice with the HO inhibitor, tin protoporphyrin-IX, markedly reduced the UVA antiapoptotic effect, confirming a major role for HO. The observations suggest that UVA reduces UVB-induced DNA damage, and may therefore have anti-photocarcinogenic properties that could be harnessed for better photoprotection in humans.
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PMID:Radiation sources providing increased UVA/UVB ratios attenuate the apoptotic effects of the UVB waveband UVA-dose-dependently in hairless mouse skin. 1770 Jun 22


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