Biomedical subjects

Vivienne E Reeve

Publications and source records attributed to Vivienne E Reeve.

13 recordsLinked to original sources

PubMed2006

Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products.

Vitamin D is produced in skin by UVB radiation (290-320 nm) acting on 7-dehydrocholesterol. The hypotheses that the active vitamin D hormone, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), would increase the survival of skin cells after UV irradiation and that surviving cells after 1,25(OH)2D3 treatment would have no increase in DNA damage were tested. The survival of keratinocytes post-UVR was significantly greater after treatment with 1,25(OH)2D3 compared to vehicle (P<0.01). Significant reductions in thymine dimers (TDs) in surviving keratinocytes after UVR were noted in the presence of 1,25(OH)2D3 (P<0.001). Nuclear p53 protein expression increased after UVR and was significantly higher in keratinocytes treated with 1,25(OH)2D3 (P<0.01), whereas NO products were significantly reduced (P<0.05). Both the increase in nuclear accumulation of p53 protein and reduced formation of nitric oxide products may contribute to the reduction in TDs seen with 1,25(OH)2D3 after UVR. Reductions in numbers of sunburn cells (P<0.01) and in TDs (P<0.05) were observed 24 hours after UVR in skin sections from Skh:hr1 mice treated with 1,25(OH)2D3. These results are consistent with the proposal that the vitamin D system in skin may be part of an intrinsic protective mechanism against UV damage.

Animals↗

PubMed2006

Estrogen receptor signaling protects against immune suppression by UV radiation exposure.

The phytoestrogenic isoflavonoid equol is known to protect against solar-simulated UV radiation-induced inflammation, immunosuppression, and skin carcinogenesis. The mechanism may involve antioxidant actions, because equol not only is a radical scavenger but also enhances the induction of a relevant cutaneous antioxidant, metallothionein. However, this study in female hairless mice examined whether the estrogenicity of the isoflavonoid might be responsible. Protection by topically applied equol against photoimmune suppression was found to be strongly and dose-dependently inhibited by the estrogen receptor (ER) antagonist ICI 182,780. Furthermore, ICI 182,780 alone was found to significantly exacerbate immunosuppression resulting from solar-simulated UV radiation irradiation, suggesting a natural role for the ER in photoimmune protection. In support of this role, topical application of the physiological ligand 17-beta-estradiol also provided dose-dependent photoimmune protection, inhibitable by ICI 182,780, that was attributed largely to the inactivation of the downstream actions of cis-urocanic acid, an important endogenous immunosuppressive photoproduct. Thus, a hitherto unrecognized function of the ER as a normal photoprotective immune regulator in the skin was revealed. The relationship between equol and cutaneous metallothionein suggests an association of the ER with this inducible antioxidant in constraining the photoimmune-suppressed state and therefore in the prevention of the facilitation of photocarcinogenesis by this immunological defect. This role for the ER may underlie important gender-specific differences in UV-responsiveness that would reflect different needs for environmental photoprotection in males and females.

Animals↗

PubMed2006

Isoflavonoid photoprotection in mouse and human skin is dependent on metallothionein.

Previous studies report that selected topical isoflavonoids are immunoprotective in both mice and humans, when applied following UV irradiation. Isoflavonoids have documented antioxidant activity, but their mechanism of immunomodulation remains unclear. This study examines whether photoimmunoprotection by the isoflavonoids might result from their interaction with one cutaneous antioxidant known to modulate UV photodamage, metallothionein (MT). In mice bearing a null mutation for MT-I and -II, we found that immunoprotection by the isoflavonoid 4',7-dihydroxyisoflavane (equol) against solar-simulated UV radiation (SSUV) or exogenous cis-urocanic acid was abrogated. Topical equol did not activate MT expression in normal mouse skin, but markedly enhanced the increase in MT expression in murine epidermis following SSUV irradiation. Normal human skin, unlike murine, expressed MT in the basal epidermis. Following SSUV irradiation, topical application of the related synthetic isoflavonoid NV-07alpha to human skin also markedly enhanced epidermal MT expression. The NV-07alpha has been reported previously to protect humans against the UV suppression of Mantoux reactions. Thus, epidermal MT expression appears to protect against photoimmunosuppression in both human and mouse skin. We speculate that equol and its related derivative NV-07alpha may activate the MT gene synergistically with SSUV, to produce the enhanced immunoprotective effect.

Animals↗

PubMed2006

Photoimmunoprotection by UVA (320-400 nm) radiation is determined by UVA dose and is associated with cutaneous cyclic guanosine monophosphate.

The immunomodulating properties of UVA radiation remain controversial. Here, we demonstrate in female inbred Skh:hr-1 mice that single subinflammatory UVA exposures between 1.61 and 580.5 kJ/m(2) are not immunosuppressive. Furthermore, UVA exposures between 16.13 and 580.5 kJ/m(2) provided dose-related immunoprotection against UVB-induced immunosuppression. Higher UVA exposures (870.8-1,161 kJ/m(2)) became inflammatory and immunosuppressive alone, and lost the photoimmunoprotective capacity. We previously reported that UVA photoimmunoprotection depends on the induction of cutaneous heme oxygenase-1, particularly its enzymatic product, carbon monoxide (CO). CO was suggested to activate cutaneous guanylyl cyclase (GC), as the specific GC inhibitor, 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), abrogated CO photoimmunoprotection in the mouse. This study shows that cutaneous cyclic guanosine monophosphate (cGMP) concentration increased only following immunoprotective UVA doses, or immunoprotective topical CO treatment, and cGMP production was inhibited by ODQ. Conversely, cGMP concentration was increased by inhibition of its degradative phosphodiesterase (PDE) with topical sildenafil. The PDE-5 isoform was identified in normal mouse skin. Subsequently, a moderate concentration of sildenafil was shown to simulate the effect of UVA in protecting against photoimmunosuppression by solar-simulated UV radiation or its mediator cis-urocanic acid. Thus, cutaneous cGMP, controlled by its synthesis via CO-activated GC and its degradation by PDE-5, is strongly associated with UVA photoimmunoprotection.

Animals↗

PubMed2005

Ultraviolet A (320-400 nm) modulation of ultraviolet B (290-320 nm)-induced immune suppression is mediated by carbon monoxide.

Accumulating evidence suggests that suberythemogenic ultraviolet A (UVA) (320-400 nm) exposure protects against the immunosuppressive effect of ultraviolet B (290-320 nm) radiation or its epidermal photoproduct, cis-urocanic acid (cis-UCA). In skin, UVA photoimmunoprotection is mediated by the inducible antioxidant stress enzyme, heme oxygenase-1 (HO-1), which degrades heme into carbon monoxide (CO), iron, and biliverdin (reduced to bilirubin), and is important for cell survival under conditions of oxidative stress. The identity of the HO enzymatic product(s) that provide the immunoprotection is unknown. Here we examine the potential of CO to fulfill this role in hairless mouse skin, utilizing a novel CO-releasing molecule (CO-RM) to deliver CO to the skin topically. The CO-RM released CO gradually from the lotion vehicle during 3 h following its preparation, and between 50 and 500 microM, concentration-dependently protected mice against the suppression of contact hypersensitivity by either solar-simulated UV radiation (SSUVR) or cis-UCA, whereas aged CO-depleted CO-RM was inactive. Thus, the CO-RM treatment mimicked UVA-photoimmunoprotection, and identified HO-released CO as the protective mediator, providing evidence that the murine cutaneous immune system is modulated by this gaseous messenger. Preliminary evidence for involvement of guanylyl cyclase was obtained by treatment of the mouse with its specific inhibitor 1H-(1,2,4)oxadiazolo-(4,3-1)quinoxaline-1-one, which abrogated UVA photoimmunoprotection.

Animals↗

PubMed2004

Immunoprotective UVA (320-400 nm) irradiation upregulates heme oxygenase-1 in the dermis and epidermis of hairless mouse skin.

The induction of heme oxygenase-1 (HO-1) by ultraviolet A (UVA) (320-400 nm) radiation provides a protective cellular defence against oxidative stress, and has been well demonstrated in cultured human skin fibroblasts, although keratinocytes were unreactive. The UVA responsiveness of HO-1 however, has not been confirmed in intact skin. Previously, we reported that UVA-inducible HO enzyme activity in mouse skin is protective against UVB-induced immunosuppression. This study identifies the induced HO isoform and its localization in mouse skin irradiated in vivo with such an immunoprotective UVA dose. We found that HO-1 mRNA was expressed in UVA-irradiated skin, but not in normal or UVB-irradiated skin, whereas constitutive HO-2 was always present. UVA-irradiated skin had increased HO enzyme activity and bilirubin content, and decreased heme content, consistent with HO-1 induction. In situ hybridization and immunohistochemical staining localized HO-1 mRNA and protein to both epidermis and dermis, with strongest expression in basal keratinocytes and weaker expression in dermal fibroblast-like and other cells, in contrast with UVA-induced HO-1 in cultured human skin fibroblasts. This suggests that cultured skin cells may not fully represent skin functions in vivo, or that there may be inherent differences between human and hairless mouse skin HO-1 responses.

Animals↗

PubMed2004

Protection from inflammation, immunosuppression and carcinogenesis induced by UV radiation in mice by topical Pycnogenol.

Pycnogenol is a standardized extract of the bark of the French maritime pine, Pinus pinaster Ait., that has multiple biological effects, including antioxidant, anti-inflammatory and anticarcinogenic properties. This study describes the effect of topical application of lotions containing Pycnogenol to Skh:hr hairless mice undergoing minimally inflammatory daily exposures to solar-simulated UV radiation (SSUV). We report that concentrations of Pycnogenol of 0.05-0.2% applied to the irradiated dorsal skin immediately after exposure resulted in dose-dependent reduction of the inflammatory sunburn reaction, measured as its edema component. When mice received three consecutive daily exposures of minimally edematous SSUV, their ability to raise a contact hypersensitivity (CHS) reaction was suppressed by 54%. Pycnogenol lotions applied postirradiation reduced this immunosuppression to 22% (0.05% Pycnogenol) and 13% (0.1% Pycnogenol). Furthermore, when CHS was suppressed by 71% with exogenous treatment with cis-urocanic acid, the putative epidermal mediator of photoimmunosuppression, 0.2% Pycnogenol lotion reduced the immunosuppression to 18%. Chronic exposure to SSUV on 5 days/week for 10 weeks induced skin tumors from 11 weeks in both control mice and in mice receiving daily applications of 0.05% Pycnogenol, but tumor appearance was significantly delayed until 20 weeks in mice receiving 0.2% Pycnogenol. Furthermore, whereas 100% of control mice had at least one tumor by 30 weeks, and mice treated with 0.05% Pycnogenol by 33 weeks, the maximum tumor prevalence in mice treated with 0.2% Pycnogenol was significantly reduced to 85%, with some mice remaining tumor free. Average tumor multiplicity was also significantly reduced by 0.2% Pycnogenol, from 5.2 in control mice to 3.5 at 35 weeks. Thus, topical Pycnogenol offered significant and dose-dependent protection from SSUV-induced acute inflammation, immunosuppression and carcinogenesis, when applied to the skin after daily irradiation. Pycnogenol, therefore, in addition to its recognized health benefits in other organs, appears to have potential in providing photoprotection for humans in a complementary role with sunscreens, having demonstrable activity when applied to the skin after, rather than before, UV exposure.

Adjuvants, Immunologic↗

PubMed2002

Ultraviolet radiation and the contact hypersensitivity reaction in mice.

The article reviews the application of the contact hypersensitivity assay in mice to the science of photoimmunology. The contact hypersensitivity (CHS) reaction, which is suppressed by UV irradiation in mice similarly to their ability to respond immunologically to skin tumors, has been used very profitably to reveal many of the regulating factors that control photoimmunosuppression, such as the identity of the photoreceptors that initiate immunosuppression, the defects induced in the cutaneous antigen presenting pathway, the local cytokine imbalance, and the protective intervention by various molecules, drugs, or interacting UV wavebands. Technical hints to optimize the measurement of the CHS response are suggested, including information on UV radiation wavebands and dosages and sensitivities of different mouse strains.

Animals↗

PubMed2002

Refractoriness of UVA-induced protection from photoimmunosuppression correlates with heme oxygenase response to repeated UVA exposure.

Single suberythemal exposures of UVA radiation have been shown to block the immunosuppressive effects of UVB radiation in the mouse. The immunoprotection is dependent both on the presence of the cytokine, IFN-gamma, and on the induction of the antioxidant stress enzyme, heme oxygenase (HO), in the skin. Recently, the transcriptional response of the HO-1 gene to UVA radiation in cultured human skin fibroblasts was reported to be refractory to a second UVA irradiation. In this study on the hairless mouse, we demonstrate that the inducibility of HO enzyme activity in the skin similarly became refractory to a second UVA irradiation at 24 h but, like the fibroblast response, was restored when the interval between the UVA exposures was increased to 96 h. Under the conditions of refractory HO enzyme induction, the protective effect of UVA radiation against the suppression of contact hypersensitivity induced by UVB radiation or cis-urocanic acid was strongly attenuated but was restored when the interval between UVA exposures was increased to 96 h. The results thus confirm the strong relationship between HO induction and photoimmunoprotection by UVA radiation, and describe a new phenomenon of immunological refractoriness that develops with rapidly repeated UVA exposures.

Animals↗

PubMedDate not supplied

The topical isoflavonoid NV-07alpha reduces solar-simulated UV-induced suppression of Mantoux reactions in humans.

UV radiation suppresses delayed-type hypersensitivity responses to intradermally injected tuberculin purified protein derivative in Mantoux-positive individuals. The effect of the topically administered isoflavonoid NV-07alpha, a synthetic derivative of the isoflavonoid equol, on UV-induced suppression of Mantoux reactions was assessed in 18 healthy Mantoux-positive volunteers. A single, fixed dose of solar-simulated UV radiation was delivered to the volunteers' lower backs. Different concentrations of NV-07alpha or its vehicle were applied to different sites within the irradiated field immediately after UV exposure and again 24 h later. Forty-eight hours after irradiation, Mantoux testing was performed at both the irradiated sites and adjacent, unirradiated sites. The intensity of Mantoux reactions was measured 72 h later with a reflectance erythema meter and by measuring the diameter of each reaction. Although lower concentrations of NV-07alpha (0.5 and 2 mM) did not prevent UV immunosuppression, 4 mM NV-07alpha partially but significantly attenuated UV-induced suppression of Mantoux-induced erythema. Minimal erythema doses were also determined for sites treated with NV-07alpha or its vehicle immediately after UV exposure. NV-07alpha had no significant effects on UV erythema. We conclude that 4 mM NV-07alpha prevented the suppressive effects of UV radiation on Mantoux responses in humans but did not affect UV-induced erythema at the concentrations used.

Administration, Topical↗

PubMedDate not supplied

Protective effect of the isoflavonoid equol against hairless mouse skin carcinogenesis induced by UV radiation alone or with a chemical cocarcinogen.

Isoflavones derived from many edible plants, such as genistein from the soybean, have well-documented antioxidant and estrogenic activity but may also be anticarcinogenic. In this study, we examined the potential of the isoflavone equol [(S)-4',7-dihydroxyisoflavane] to protect from skin carcinogenesis in the hairless mouse. Daily topical applications of equol lotions significantly protected against skin carcinogenesis induced by chronic exposure to solar-simulated UV radiation (SSUV) or by topical treatment with the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or by the combined cocarcinogenic treatment of DMBA followed by chronic SSUV. Monitoring of tumor development for 40 weeks showed significantly delayed tumor appearance and reduced tumor multiplicity in all equol-treated groups. In mice treated with either SSUV or DMBA + SSUV, equol significantly reduced the proportion of tumors progressing from benign papillomas to malignant squamous cell carcinoma (SCC) by 33-58% and reduced the average diameter of SCC by 71-82%. In a short-term study, equol dose dependently inhibited the SSUV induction of the tumor promotion biomarker enzyme, ornithine decarboxylase, in the skin, suggesting the anticarcinogenic activity of equol may be attributed to its inhibition of the tumor promotion phase of carcinogenesis.

Animals↗

PubMedDate not supplied

Protection against photoaging in the hairless mouse by the isoflavone equol.

Topical application of the isoflavone equol immediately following solar-simulated UV (SSUV) radiation exposure has previously been demonstrated to have significant photoprotective effects. Equol reduced both the inflammatory edema and the systemic suppression of the contact hypersensitivity reaction in hairless mice. Furthermore, daily topical equol application immediately following irradiation during a 10-week chronic SSUV exposure regime also reduced photocarcinogenesis severity in the mouse. This study examines the potential for topical equol to prevent photoaging in response to chronic SSUV irradiation for up to 30 weeks. We did not find consistent expression of the characteristic markers of photoaging until 30 weeks, although moderate epidermal hyperplasia and a transient increase in dermal mast cell numbers were evident after 1 week. Daily application of 10 muM equol lotion significantly reduced these early changes. However after 30 weeks of SSUV exposure, photoaging was well developed, as shown histologically by markedly increased epidermal hyperplasia, increased dermal mast cell number, pronounced focal elastotic deposits, degraded dermal collagen and deposition of glycosaminoglycans in the lower dermis. Topical equol treatment protected significantly from each of these impairments, as demonstrated histologically and quantitatively. Additionally, equol was found to have strong antioxidant action against acute UVA (320-400 nm)-induced lipid peroxidation of mouse skin, this property accounting for its antiphotoaging mechanism. The evidence for equol's antiphotoaging activity, taken together with its anti-inflammatory, immunoprotective and anticarcinogenic efficacy against SSUV irradiation in the mouse, suggests that equol could be developed as a helpful topical photoprotective agent for daily use by humans.

Animals↗

PubMedDate not supplied

Radiation sources providing increased UVA/UVB ratios induce photoprotection dependent on the UVA dose in hairless mice.

In studies involving mice in which doses of UVA (320-400 nm) and UVB (290-320 nm) radiation were administered alone or combined sequentially, we observed a protective effect of UVA against UVB-induced erythema/edema and systemic suppression of contact hypersensitivity. The UVA immunoprotection was mediated by the induction of the stress enzyme heme oxygenase-1 (HO-1) in the skin, protection of the cutaneous Th1 cytokines interferon-gamma (IFN-gamma) and IL-12 and inhibition of the UVB-induced expression of the Th2 cytokine IL-10. In this study, we seek evidence for an immunological waveband interaction when UVA and UVB are administered concurrently to hairless mice as occurs during sunlight exposure in humans. A series of spectra providing varying ratios of UVA/UVB were developed, with the UVA ratio increased to approximately 3.5 times the UVA component in solar simulated UV (SSUV). We report that progressively increasing the UVA component of the radiation while maintaining a constant UVB dose resulted in a reduction of both the erythema/edema reaction and the degree of systemic immunosuppression, as measured as contact hypersensitivity. The UVA-enhanced immunoprotection was abrogated in mice treated with a specific HO enzyme inhibitor. UVA-enhanced radiation also upregulated the expression of cutaneous IFN-gamma and IL-12 and inhibited expression of both IL-6 and IL-10, compared with the activity of SSUV. The results were consistent with the previously characterized mechanisms of photoprotection by the UVA waveband alone and suggest that the UVA component of solar UV may have beneficial properties for humans.

Animals↗