皮肤光老化动物模型的建立

目的:应用中波紫外线(UVB 290-320nm)照射无毛鼠,观察UVB对无毛鼠皮肤纹理、表皮、及真皮基质的影响,建立皮肤光老化动物模型,为临床防治皮肤光老化打下基础。方法:应用皮肤图像分析系统、皮肤组织学及特殊染色方法,对接受中波紫外线照射20周的无毛鼠进行皮肤纹理、表皮、真皮、基底膜、粘多糖、胶原纤维、弹性纤维进行对比观察。结果:无毛鼠经UVB照射20周、总计量5.9J/cm2,皮肤出现粗糙,皮纹加深、加宽。皮肤增厚,表皮增生、伴有角化过度及角化不全。真皮水肿,纤维母细胞增生,弥漫性单核细胞、肥大细胞、嗜中性白细胞侵润。基底膜不规则增厚。胶原含量减少,染色变浅,胶原纤维明显变性,均质化,形成片、块状,变性的胶原纤维延伸至真皮深层。弹性纤维增多变粗,部分增生的弹性纤维聚集、断裂、缠结。结论:中波紫外线引起的皮肤损害是一个慢性炎症过程。真皮及真皮基质的改变是紫外线引起皮肤光老化的病理基础。中波紫外线照射后的无毛鼠的皮肤所发生的变化与临床皮肤光老化疾病一致,因此该模型是较为理想的研究皮肤光老化的动物模型。     

Action spectra for human skin cells: estimates of the relative cytotoxicity of the middle ultraviolet, near ultraviolet, and violet regions of sunlight on epidermal keratinocytes

Action spectra for the cytotoxic action of electromagnetic radiation in the solar range 280-434 nm have been determined for human fibroblasts and epidermal keratinocytes derived from the same foreskin biopsy. The spectra for the two cell types are close to identical and coincide with our previously published data for a human lymphoblastoid line indicating that the mechanism of inactivation of the three human cell types is similar at any given wavelength. Using published data for ultraviolet transmission of human skin and sample spectral irradiance data, we have estimated the relative biological effectiveness of the middle ultraviolet (UVB) (290-320 nm), near ultraviolet (UVA) (320-380 nm), and violet (380-434 nm) regions of sunlight for cytotoxicity at the basal layer of the epidermis. We conclude that the UVB component in noon summer sunlight (the most UVB rich spectral conditions tested) may contribute only about 40% of the total cytotoxic effectiveness of sunlight at 290-434 nm. At lower zenith angles, UVA can account for up to 80% of the cytotoxic effectiveness of the combined UVA and UVB regions. Finally, a comparison of published action spectra data for human erythema with cytotoxicity data corrected for ultraviolet transmission to different depths of the human epidermis suggests that UVA erythema could be causally related to cytotoxicity occurring at an average depth of 40-50 micron into the human epidermis.     

Longwave ultraviolet radiation and promotion of skin cancer

Exposure to solar ultraviolet (UV) radiation is recognized as an important cause of skin cancer. The carcinogenic effects of UV radiation have been attributed almost entirely to wavelengths in the mid-range (UVB, 290-320 nm). However, the development of potent UVB sunscreens has allowed individuals to increase the length of time that they spend sunbathing and, as a consequence, they may be exposed to massive doses of longwave UV radiation (UVA, 320-400 nm). There is now much evidence to suggest that UVA acts to promote tumors that have been initiated by UVB. This review considers possible mechanisms by which UVA promotes tumorigenesis. Evidence is presented which suggests that UVA acts through modulation of protein kinase C.     

Melanoma and use of sunscreens: An EORTC case-control study in germany,belgium and france

Use of sunscreens is widely advocated as a preventive measure against sun-induced skin cancers. However, to date, no epidemiologic study has reported a decreased melanoma risk associated with sunscreen use. We have conducted a case-control study aimed at evaluating the influence of sunscreen use on the occurrence of cutaneous malignant melanoma. In 1991 and 1992, 418 melanoma cases and 438 healthy controls were interviewed in Germany, France and Belgium. The questionnaire used differentiated between regular sunscreens, psoralen sunscreen (prepared with 5-methoxypsoralen, a tanning activator and photocarcinogen), and self-tanning cosmetics (which produce a tan without ultraviolet radiation). After adjusting for age, sex, hair colour and holiday weeks spent each year in sunny resorts, the melanoma risk was of 1.50 (95% CI:1.09–2.06) for regular sunscreens, and of 2.28 (95% CI: 1.28–4.04) for psoralen sunscreens. No melanoma risk was associated with use of self-tanning cosmetics. Among subjects with a poor ability to tan, psoralen sunscreen users displayed a melanoma risk of 4.45 (95% CI: 1.25–15.8) when compared with regular sunscreen users. There was a significant negative interaction between regular sunscreen use and sunburns experienced in adulthood. Use of sunscreens, especially psoralen sunscreen, was associated with higher density of pigmented lesions of the skin. Although we cannot exclude the presence of an unknown confounding factor, our results support the hypothesis that sunscreens do not protect against melanoma, probably because of their ability to delay or avoid sunburn episodes, which may allow prolonged exposure to unfiltered ultraviolet radiation. Serious doubts are raised regarding the safety of sunscreens containing psoralens. © 1995 Wiley-Liss, Inc.     

Induction of protein kinase C activity by ultraviolet radiation

Exposure to ultraviolet (UV) radiation has been well correlated with skin cancer incidence. Long wave UV radiation (320-400 nm, UVA) is a major component of natural sunlight and cosmetic tanning 'salon' light, and has been shown not only to damage DNA and to act as a complete carcinogen, but also to promote ultraviolet B (280-320 nm, UVB) carcinogenesis. The mechanism by which the latter occurs is unknown, but it is believed to be related to the inflammation and irritation which results from UV exposure. In order to examine the possibility that UVA stimulates the same signalling pathway as do the phorbol esters, a class of much more thoroughly characterized skin tumor promoters, we exposed cells in culture to UVA radiation and measured cellular responses related to protein kinase C (PKC) activation. The data presented here demonstrate that a low, physiologic dose of UVA inhibits epidermal growth factor binding and increases PKC activity in cultured mammalian fibroblasts. The increase in cytosolic activity is not completely translocated to the membrane, and can be partially suppressed by puromycin and cycloheximide but not by actinomycin D. These observations are the first evidence to suggest that a protein which has been strongly linked to chemical tumor promotion may also be a critical mediator for UV-induced promotion. The response of cells to UVA is also unique, in that it does not cause a 12-O-tetradecanoyl phorbol-13-acetate-like rapid redistribution of PKC activity followed by down regulation.     

Cancer, soleil et UV. Quelle protection ?

Skin cancer is the most frequently occurring malignancy. It is influenced by an individual’s susceptibility factors (phototype and pigmentary traits) and exposure to solar ultraviolet radiation, although the type of exposure (high intensity and short duration vs. chronic) and pattern of exposure (continuous vs. intermittent) may differ among the three main types of skin cancer. Squamous cell carcinoma is influenced by chronic exposure, while basal cell carcinoma and melanoma are influenced by intermittent exposure, especially during childhood. Artificial UV tanning increases the risk of melanoma and squamous cell carcinomas. The prevention of skin cancer is based on reducing exposure to the sun (seeking shadow and using clothing). There is limited evidence suggesting that the use of sunscreen can prevent squamous cell carcinoma, but its role in preventing basal cell carcinoma and cutaneous melanoma remains uncertain. The use of sunscreen can lead to longer periods of sun exposure. Exposure to solar ultraviolet radiation has been shown to reduce the incidence and lethality of some cancers (breast, colon, prostate and lymphomas). A mechanism involving vitamin D has been hypothesised and is currently under investigation.     

Approaches to the prevention and control of skin cancer

Skin cancer is the most common and the most preventable form of cancer. Nonmelanoma skin cancers are associated with cumulative exposure to ultraviolet radiation, while melanoma is associated with intense episodes of ultraviolet exposure resulting in sunburns. Numerous risk factors are associated with the development of skin cancer. These include exposure to ultraviolet radiation; phenotypic factors such as skin type, eye and hair color, tendency to burn and tan, and having freckles and moles; a personal or family history of skin cancer; and occupational sun exposure. Primary prevention behaviors include applying SPF 15+ sunscreen 30 minutes before exposure, reapplying SPF 15+ sunscreen every 1¹/₂ to 2 hours or after swimming or sweating, dressing in protective clothing, using shade, limiting exposure during peak sun hours, and avoiding artificial sources of ultraviolet radiation such as tanning beds. Secondary prevention behaviors include screening and early detection in combination with education on the primary prevention behaviors. Interventions designed to increase sun protective behaviors have resulted in increased knowledge and attitudes, but limited behavior change. And while skin cancer screenings have shown promising results, few studies have a follow-up component. Future studies should focus on developing effective strategies for making sun protective behaviors routine and determining the effectiveness of skin cancer screening. To inform approaches to the prevention and control of skin cancer, this paper will summarize key primary and secondary preventive behaviors, highlight primary and secondary prevention programs, and identify key unanswered questions in the area of skin cancer prevention and control.     

Accelerated appearance of skin tumors in hairless mice by repeated UV irradiation with initial intense exposure and characterization of the tumors.

Skin tumors were produced on the back of hairless mice, HOS (HR/De), by exposure to ultraviolet B light (UVB, 290-320 nm) with 4 different protocols. The first tumors appeared earlier (in 10 weeks in group I and 7 weeks in group III) when initial intense exposure was given, followed by repeated lower-level exposures, than when the mice were exposed to the repeated UV only (in 16 weeks both in group II and group IV). All mice developed skin tumors earlier in the groups given the repeated UV exposures three times a week than in the groups given the exposures twice a week. Most of the skin tumors produced by the UVB exposure were histologically malignant, being transplantable to nude mice, and the cultured cells grown from the tumors were capable of producing tumors when injected into nude mice. The accelerated development of skin tumors by initial intense exposure and short intervals of repeated exposure observed in this study may have implications for humans who expose themselves to intense sunbathing and UV tanning (burning) by fluorescent sun lamps.     

Accelerated Appearance of Skin Tumors in Hairless Mice by Repeated UV Irradiation with Initial Intense Exposure and Characterization of the Tumors

Skin tumors were produced on the back of hairless mice, HOS (HR/De), by exposure to ultraviolet B light (UVB, 290–320 nm) with 4 different protocols. The first tumors appeared earlier (in 10 weeks in group I and 7 weeks in group III) when initial intense exposure was given, followed by repeated lower-level exposures, than when the mice were exposed to the repeated UV only (in 16 weeks both in group II and group IV). All mice developed skin tumors earlier in the groups given the repeated UV exposures three times a week than in the groups given the exposures twice a week. Most of the skin tumors produced by the UVB exposure were histologically malignant, being transplantable to nude mice, and the cultured cells grown from the tumors were capable of producing tumors when injected into nude mice. The accelerated development of skin tumors by initial intense exposure and short intervals of repeated exposure observed in this study may have implications for humans who expose themselves to intense sunbathing and UV tanning (burning) by fluorescent sun lamps.     

Ultraviolet B but not ultraviolet A radiation initiates melanoma

Cutaneous malignant melanoma is one of the fastest increasing cancers with an incidence that has more than doubled in the last 25 years. Sunlight exposure is strongly implicated in the etiology of cutaneous malignant melanoma and the UV portion of the sunlight spectrum is considered responsible. Data are, however, conflicting on the roles of ultraviolet B [UVB; 280-320 nanometers (nm)] and ultraviolet A (UVA; 320-400 nm), which differ in their ability to initiate DNA damage, cell signaling pathways and immune alterations. To address this issue, we have used specialized optical sources, emitting isolated or combined UVB or UVA wavebands or solar simulating radiation, together with our hepatocyte growth factor/scatter factor-transgenic mouse model of UV-induced melanoma that uniquely recapitulates human disease. Only UVB-containing sources initiated melanoma. These were the isolated UVB waveband (>96% 280-320 nm), the unfiltered F40 sunlamp (250-800 nm) and the solar simulator (290-800 nm). Kaplan-Meier survival analysis indicated that the isolated UVB waveband was more effective in initiating melanoma than either the F40 sunlamp or the solar simulator (modified log rank P < 0.02). The latter two sources showed similar melanoma effectiveness (P = 0.38). In contrast, transgenic mice irradiated with either the isolated UVA waveband (>99.9% 320-400 nm, 150 kJ/m2), or an F40 sunlamp filtered to remove > 96% of the UVB, responded like unirradiated control animals. We conclude that, within the constraints of this animal model, UVB is responsible for the induction of mammalian cutaneous malignant melanoma whereas UVA is ineffective even at doses considered physiologically relevant. This finding may have major implications with respect both to risk assessment from exposure to solar and artificial UVB, and to development of effective protection strategies against melanoma induction by UVB. Moreover, these differences in wavelength effectiveness can now be exploited to identify UV pathways relevant to melanomagenesis.     

Skin cancer prevention behaviours during summer holidays in 14 and 18-year-old Belgian adolescents.

A cross-sectional study was conducted among 602 Belgian adolescents to analyse their sun protection habits. The results show that Belgian adolescents stay in the sun for a long time, even in periods when ultraviolet radiation is very damaging. Of all respondents, 70% exposed themselves for at least 3 h to the sun on sunny days. Most respondents (49%) exposed themselves between 1200 and 1500 h. Almost two-thirds of the respondents (59.3%) reported at least one sunburn in the past year and 26.5% got sunburnt at least twice; 24% used sunbeds more than 6 times per year. Applying sunscreen every 2 h was the most commonly used method by adolescents to protect themselves, although 70% did not use sunscreen regularly. Female students used sunscreen more regularly than male students, and sunbed use was higher among 18-year-olds than 14-year-olds. Our results clearly suggest that respondents with fair skin types are at increased risk of developing skin cancer, because of various high exposure activities accompanied by relatively few protection behaviours. A second risk group consists of students from the two lower educational levels, again because of high exposure levels and less frequent protection behaviours. The risks of sunbed use should be communicated clearly to older adolescents. Hence, these two groups need to receive high priority for cancer prevention activities in Belgium.     

Sunscreen

Skin cancer prevention is increasingly a focus of public health campaigns. The most important avoidable cause of skin cancer is ultraviolet radiation from the sun, but sunscreens are often used in a suboptimal manner, compromising their effectiveness. People may "compensate" for the use of sunscreen by increasing their time in the sun, which can have adverse effects on health. Epidemiologic studies of sunscreen use have suffered from important methodologic limitations. A clearer picture of the impact of sunscreens is emerging from randomized trials that have recently been published or presented. The available evidence supports the current recommendation to "Slip! Slop! Slap!" when in the sun.     

Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice

Topical application of caffeine sodium benzoate (caffeine-SB) immediately after UVB irradiation of SKH-1 mice enhanced UVB-induced apoptosis by a 2- to 3-fold greater extent than occurred after the topical application of an equimolar amount of caffeine. Although topical application of caffeine-SB or caffeine enhanced UVB-induced apoptosis, both substances were inactive on non-UVB-treated normal skin. Topical application of caffeine-SB or caffeine (each has UVB absorption properties) 0.5 h before irradiation with a high dose of UVB decreased UVB-induced thymine dimer formation and sunburn lesions (sunscreen effect). Caffeine-SB was more active than an equimolar amount of caffeine in exerting a sunscreen effect. In additional studies, caffeine-SB strongly inhibited the formation of tumors in UVB-pretreated 'high-risk mice' and in tumor-bearing mice, and the growth of UVB-induced tumors was also inhibited. Caffeine-SB and caffeine are the first examples of compounds that have both a sunscreen effect and enhance UVB-induced apoptosis. Our studies suggest that caffeine-SB and caffeine may be good agents for inhibiting the formation of sunlight-induced skin cancer.     

bcl-2与nm-23在胆囊癌发生及发展中的作用

［目的］探讨抗凋亡基因bel－2和肿瘤转移抑制基因nm－23在原发性胆囊癌发生及发展中的作用。［方法］保用免疫组化方法对38例胆囊癌及30例慢性胆囊炎组织中bcl－2及nm-23对基因蛋白表达进行测定。［结果］胆囊癌中的bcl-2及nm-23的阳性表达分别为60．6％、50．0％,显著高于慢性胆囊炎组织（16．7％、20％,P＜0.01）,且bcl-2和nm－23表达与胆囊癌组织分化程度及临床分期密切相关,nm-23表达与淋巴结转移呈负相关。［结论]bcl-2及nm-23对基因在胆囊癌发生及发展中起重要作用,前者过度表达多见于胆囊癌早期．而后者则决定着胆囊癌的浸润及淋巴结转移,是晚期事件。     

The effects of n-6 polyunsaturated fatty acids on the expression of nm-23 in human cancer cells.

This study examined the effect of n-6 polyunsaturated fatty acids (PUFAs) on the expression of nm-23, a metastasis-suppressor gene, in two highly invasive human cancer cell lines, HT115 and MDA MB 231. A range of n-6 and n-3 PUFAs were tested. We report that while linoleic acid and arachidonic acid reduced the expression of nm-23-H1, gamma linolenic acid (GLA) and its soluble lithium salt markedly increased the expression of the molecules. The stimulation of the expression of nm-23 by GLA was seen at both protein and mRNA levels. Up-regulation of nm-23 was also associated with a reduction of the in vitro invasiveness of these cells. It is concluded that gamma linolenic acid (GLA) enhances the expression of nm-23. This contributes to the inhibition of the in vitro invasion of tumour cells.     

Sunscreens. Update and review

The awareness of sun-induced skin damage has increased in both the lay public and physician. Coincidentally, there has been progress in the development of new ultraviolet-(UV) radiation protecting sunscreens. In this review and update on sunscreens, sunscreen classification, UVB and UVA protection, sunscreen vehicle, and substantivity will be addressed.     

Sunscreen ingredients inhibit inducible nitric oxide synthase (iNOS): a possible biochemical explanation for the sunscreen melanoma controversy

Sunscreen products are rated upon their ability to inhibit visible redness of the skin 24 h after measured doses of ultraviolet (UV) exposure (Sun Protection Factor, SPF). Although sunscreens prevent UV-induced redness, their ability to protect against melanoma or the development of moles is less clear. UV-induced redness occurs in part by the action of nitric oxide (NO), synthesized in the skin. NO is also an important immunoregulatory molecule in the induction of the cell-mediated tumour immune response. In this study, various sunscreen ingredients were tested for their ability to inhibit the production of NO. Four of the five sunscreens tested directly inhibited the conversion of arginine to citrulline by inducible nitric oxide synthase (iNOS) in vitro. These findings suggest that sunscreens may prevent redness partly by UV absorption and partly by inhibition of the skin's inflammatory response. As such, sunscreens might promote instead of protect against melanoma.     

Evaluation of Educational Videos to Increase Skin Cancer Risk Awareness and Sun-Safe Behaviors Among Adult Hispanics

Although skin cancer is less common in Hispanics, they are at higher risk for presenting with more advanced stage skin cancer. We performed semi-structured interviews with Hispanic women that found high concern for photoaging from sun exposure. Based on these results, we developed two short Spanish-language films. The first emphasized photoaging benefits of sun protection, while the second focused on its benefits for skin cancer prevention. Our hypothesis was that the reduction of photoaging would be a more persuasive argument than skin cancer prevention for the adoption of sunscreen use by Hispanic women. Study participants were recruited from beauty salons located in predominantly Hispanic neighborhoods. Each of the two Spanish-language films was approximately 3 min long. A pre-intervention questionnaire assessed subjects’ general knowledge and sunscreen habits, and a second questionnaire administered after viewing both films assessed for improvements in risk perception and inquired about which film was more persuasive. Eighty Hispanics participated ranging in age from 19 to 75. The pre-education survey found that 54 out of 80 believed that fair-skin Hispanics (FS) were at risk for skin cancer, and 44 out of 80 believed that dark-skin Hispanics (DS) were at risk. These numbers increased to 72 (FS) and 69 (DS) after the intervention (p value: <0.0002 FS, <0.0001 DS). Hispanics overwhelmingly selected the video emphasizing the benefits of sun protection for skin cancer prevention as the more persuasive film (74 out of 80). A Spanish-language video has the potential to make an impact in healthy sun-protective behaviors, and information on how to properly apply sunscreen should be included in educational messages.     

Cutaneous malignant melanoma: facts about sunbeds and sunscreen

The incidence of cutaneous malignant melanoma is still increasing in most light-skinned populations. Sunscreen use has been proposed for the primary prevention of melanoma. However, sunscreen use may increase time spent in the sun when users are willing to acquire a tan or to stay in the sun for a long time, which may increase melanoma risk. When sun exposure is not associated with the desire to acquire a tan or stay in the sun for a long time, sunscreen use may prevent squamous cell skin carcinoma. Sun protection should give priority to clothing and sun exposure reduction. Over the last 20 years, tan acquisition through exposure to artificial sources of ultraviolet radiation has become frequent among fair-skinned adolescents and young adults. There is accumulating evidence that sunbed use is associated with melanoma when started before approximately 30 years of age.