Расторопши: семена ранней потенциальных
Перспективы силимарина в кожу photoprotection
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- 5. Silymarin: source and composition
- 6. Silymarin inhibits UV radiation-induced skin carcinogenesis
- 7. Mechanisms of chemoprevention of photocarcinogenesis by silymarin
- 7.1 Anti-oxidant effect of silymarin
- 7.2 Anti-inflammatory effects of silymarin
- 7.3 Silymarin inhibits UVB-induced immune suppression
8. Перспективы силимарина в кожу photoprotectionВ исследованиях, проведенных in vivo в животных моделях с силимарин/силибинин предполагают, что это фитохимических обладает мощным анти-photocarcinogenic способность, которая опосредуется через его противовоспалительное, антиоксидантное и иммуномодулирующее действие УФ-облученной кожи. Применение силимарина в сочетании с солнцезащитные кремы или лосьоны для ухода за кожей может оказать эффективную стратегию для смягчения неблагоприятного биологического воздействия солнечного УФ-излучения, что приведет к защите кожи от различных кожных заболеваний, вызванных чрезмерным воздействием солнца. Необходимы дальнейшие исследования, в человеческой системе, чтобы определить клеточное поглощение, распределение и долгосрочный эффект силимарина в кожу для оптимального их photoprotection. 5. Silymarin: source and compositionSilymarin, a flavanolignan, extracted from the fruits and seeds of the plant milk thistle (Silybum marianum L. Gaertn.) (46). Milk thistle belongs to the family of Asteraceae and primarily is an indigenous plant of Mediterranean region and southwest Europe. Silymarin is a mixture of mainly three flavonolignans, silybin (silibinin), silydianin and silychristin (47, 48). Silibinin is the major (70–80%) and most active biological component of silymarin (Fig. 2). The seeds of milk thistle have been used for the last 2,000 years for liver diseases. Pharmacological studies revealed that silymarin is non-toxic even at higher physiological doses, which suggests its safer use for humans (49). Laboratory studies suggest that there is no significant difference between silymarin and silibinin in terms of chemopreventive or biological activities conducted in several in vitro and in vivo cancer models (50, 51). Silymarin has been primarily used in liver disorders including hepatitis, alcoholic liver diseases and cirrhosis (49, 52, 53) and is also useful for toxin-induced liver toxicity, including poisoning from a fungus called death cap mushroom (Amanita phalloides) (54). Based on the anti-oxidant and anti-inflammatory activity of silymarin, the chemopreventive effect of silymarin has been tested and determined using animal models of chemical carcinogenesis and photocarcinogenesis (7, 55, 56). Since then extensive mechanism-based chemopreventive studies have been performed in vitro in cell culture and in vivo animal models to assess the efficacy of silymarin. Further, as UV-induced inflammation, oxidative stress and immunosuppression are primarily implicated in UV radiation induced skin carcinogenesis; we will discuss the effect of silymarin on these mechanistic pathways or targets. 6. Silymarin inhibits UV radiation-induced skin carcinogenesisIt is well established that multiple environmental and genetic factors contribute to the development of skin cancers however; the most important is chronic exposure of the skin to solar UV radiation. Epidemiological and clinical studies have implicated the solar UV radiation as the major etiological agent in the development of cutaneous malignancy (1–3, 57, 58). Cancer chemoprevention strategies may have the ability to prevent or delay the occurrence of cancer in high-risk populations, such as those with pre-malignant lesions, previous resected cancers or exposure to high levels of environmental carcinogens. Nonmelanoma skin cancers, including basal and squamous cell carcinomas, represent the most common malignant neoplasms in humans (1, 2, 57). Using SKH-1 hairless mouse model, we showed that topical application of silymarin to mouse skin prevented UVB-induced skin carcinogenesis in terms of tumor incidence (percent mice with tumors), tumor multiplicity and tumor size compared to non-silymarin treated mice (7). The anti-carcinogenic effect of silymarin was pronounced against all the stages of photocarcinogenesis such as UV-induced tumor initiation, tumor promotion, and complete carcinogenesis protocols (including initiation+ promotion) (7). Silibinin, which is a major component of silymarin, was also found to inhibit photocarcinogenesis in SKH-1 hairless mice when applied topically (59). Dietary effect of both silymarin and silibinin was also examined against UV radiation-induced skin tumor development in mice. It was found that dietary silibinin also prevented photocarcinogenesis in terms of tumor multiplicity, tumor volume/mouse throughout the experiment, however; only a moderate chemopreventive effect was observed on tumor incidence. Additionally, the treatment of silymarin or silibinin also increased latency period of tumor appearance specifically in complete UVB photocarcinogenesis protocol. The increment in latency period reveals the disease-free survival period of the mice. 7. Mechanisms of chemoprevention of photocarcinogenesis by silymarinThe development of a new chemopreventive or chemotherapeutic agent requires understanding of the molecular mechanism or targets which are affected during the chemoprevention of cancer process. To determine the mechanisms of prevention of skin cancer by silymarin or silibinin, studies were performed to define anti-photocarcinogenic activity using in vitro and in vivo systems. These studies were focused on the effect of silymarin on UVB-induced inflammatory effect, oxidative stress, suppression of immune responses and DNA damaging effects in the skin because the alterations in these biochemical markers by UVB radiation results in several adverse biological effects which leads to photocarcinogenesis. Detailed studies are summarized below: 7.1 Anti-oxidant effect of silymarinSkin is easily accessible and constantly exposed to free radical-generating agents such as solar UV radiation, ozone and other environmental pollutants (4). Studies have shown the involvement of oxidative stress in skin carcinogenesis (4), and also demonstrated that a sophisticated enzymatic and non-enzymatic antioxidant defense system including catalase, superoxide dismutase and glutathione peroxidase counteracts and regulates overall ROS levels to maintain physiological homeostasis. Elevated levels of ROS are detrimental to target cells. It has been shown that UV irradiation of SKH-1 hairless mice results in a significant depletion of antioxidant defense enzymes in the skin (60). Topical treatment of silymarin to SKH-1 hairless mice resulted in inhibition of UVB-induced intracellular production of H2O2, a stable oxidant, in both epidermis and dermis compared with non-silymarin treated animals (35, Fig. 3). It has been found that UVB-induced oxidative stress was significantly inhibited by silymarin through the inhibition of UV-induced infiltration of leukocytes. Skin exposure to UVB radiation also induced the expression of inducible nitric oxide synthase and resulted in increased amount of nitric oxide production compared to that of non-UVB irradiated mice. Topical treatment of silymarin affords significant protection against UVB-induced expression of inducible nitric oxide synthase and subsequently inhibition of nitric oxide production (35). Katiyar et al found that CD11b+ infiltrating cells in UVB-irradiated skin are the major source of oxidative stress (61). Silymarin inhibits UVB-induced oxidative stress through inhibition of infiltrating CD11b+ cell types. Similar effect was also found when UVB-exposed mice were intraperitoneally treated with antibodies specific to CD11b. Thus confirms that silymarin inhibits UVB-induced oxidative stress in mouse skin through targeting CD11b+ cell type (61). Sobodova et al have shown that pretreatment of HaCaT cells with silymarin or its derivatives suppresses UVB-induced photodamage including the reduction in the levels of glutathione, total ROS production and lipid peroxidation in HaCaT cells (62, 63). These information indicated the antioxidant nature of silymarin which have a role in photoprotection of oxidative stress-associated skin disorders including skin cancer. UV-induced oxidative stress mediates activation of mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, and these pathways have been implicated in the tumor development, as summarized in Figure 3 (64). In vivo studies conducted in mouse models indicate that topical application of silibinin inhibits UVB-induced expression levels of ERK1/2 and p38 proteins of MAPK family, and subsequently inhibited the activation of NF-κB/p65 through inhibition of degradation of IκBα and activation of IKKα. As NF-κB-targeted genes play critical roles in inflammation and cellular proliferation, the inhibitory effect of silibinin on NF-κB is significant (65). Together, these antioxidant activities demonstrate that silibinin or silymarin have the ability to protect the skin from the adverse biological effects of UVB radiation via modulation of the MAPK and NF-κB signaling pathways and provide a molecular basis for the anti-carcinogenic effect of silymarin/silibinin in an in vivo animal model. 7.2 Anti-inflammatory effects of silymarinUV-induced inflammatory responses, which are characterized by increased blood flow and vascular permeability, result in the development of edema, erythema, hyperplastic responses, and increases in the levels of cyclooxygenase-2 (COX-2) and prostaglandin (PG) metabolites (4, 66–68). UV-induced inflammation is considered as an early and important event in tumor promotion or the growth of skin tumors. Chronic inflammation plays an important role in all three stages of tumor development, i.e., initiation, promotion and progression (4). Therefore the control on UVB-induced inflammatory responses is considered as an important strategy to prevent skin cancer risk. Topical treatment of silymarin inhibits UVB-induced edema and hyperplastic response in SKH-1 hairless mouse skin when compared with that of non-silymarin treated but UVB exposed mouse (7). It was observed that exposure of both mouse and human skin with UVB induces infiltration of inflammatory leukocytes which are the major source of oxidative stress such as H2O2 and nitric oxide production (32, 69, 70). UV induced infiltration begins significantly after 24 h of UV irradiation and persists up to 72 h compared with the non-UV irradiated control mice. Treatment of silymarin significantly inhibits UV-induced infiltration of leukocytes which further supports the anti-inflammatory effect of silymarin (Fig. 3). Myeloperoxidase is commonly used as a marker of leukocyte infiltration. The increase in myeloperoxidase activity after UVB exposure indicates an influx of leukocytes to the inflamed skin. Topical treatment of silymarin resulted in significant reduction in myeloperoxidase activity both in epidermis and dermis of UV-exposed mouse skin (35). Reduction in myeloperoxidase activity by silymarin suggests the inhibition of UV-induced infiltration of inflammatory leukocytes, and thus anti-inflammatory effect of silymarin in this mouse model. Topical application of silymarin also inhibits UVB-induced expression of COX-2 and its prostaglandin metabolites in the skin (7). These studies suggest that anti-photocarcinogenic activity of silymarin is associated with the inhibition of UVB-induced inflammation and inflammatory mediators in the mouse skin. It is suggested that silymarin may prove to be useful chemopreventive agent against UVB radiation induced inflammation-associated skin diseases including the melanoma and non-melanoma skin cancers in humans, and therefore, more detailed studies with particular emphasis on molecular mechanisms could lead to new strategies for the prevention of inflammation-associated skin diseases in humans. 7.3 Silymarin inhibits UVB-induced immune suppressionSkin exposure to solar UV radiation has been shown to have multiple effects on the immune system (17, 18). Suppression of immune reactions after UVB exposure of the skin suggests that immune factors contribute to the pathogenesis of solar UV light-induced skin cancer in mice and probably in humans as well (2, 71). Epidemiological data indicates that chronically immunosuppressed patients living in regions of intense sun exposure experience an exceptionally high rate of skin cancer (72). This observation supports the evidence that immune surveillance is an important mechanism designed to prevent the generation and maintenance of neoplastic cells (73). The incidence of skin cancers, particularly squamous cell carcinomas, is also increased among organ transplant recipients (74–77). These studies provide evidence in support of the concept that immune suppression promotes the risk of skin cancer development. It has been shown that UV-induced infiltrating cells, particularly MHC+ CD11b+ cells (activated macrophages and neutrophils), have a role in UV-induced suppression of contact hypersensitivity (CHS) response (78). CHS is considered as a T-cell mediated immune response. It was observed that prevention of UV-induced suppression of CHS by silymarin was associated with the reduction in infiltration of MHC+ CD11b+ cell type into UVB-irradiated skin sites. The prevention of infiltration of CD11b+ cells was also supported by the fact that silymarin inhibited the activity of myeloperoxidase, a marker of leukocyte infiltration, in the UVB irradiated skin (35). The blocking of infiltrating leukocytes using anti-CD11b antibody or treatment with soluble complement receptor type-I blocked UV-induced immune suppression and tolerance induction in C3H/HeN mice (78, 79). These observations indicate that prevention of UV-induced suppression of CHS by silymarin is mediated through the suppression of infiltration of MHC+ CD11b+ cell population. Such type of immunological modulation in UV irradiated skin of mouse was also found with the topical treatment of other phytochemicals, such as, green tea polyphenols (80). Therefore, it is evident that selected phytochemicals possess the capability to modulate UV-induced immunological responses in in vivo system. The work in Dr. Katiyar's laboratory has shown that topical application of silymarin inhibits UVB radiation-induced inflammatory responses, oxidative stress, and the induction of photocarcinogenesis in mice (7, 35, 61). It also has been shown that silibinin also inhibits UVB-induced skin photodamage including the inhibition of photocarcinogenesis in mice whether it is applied topically before or after UVB irradiation or given in the diet (59). As UVB-induced immunosuppression has been implicated in the development of photocarcinogenesis, further studies with silymarin were conducted in animals using local and systemic models of CHS. Topical application of silymarin inhibits UVB-induced suppression of CHS response to 2, 4-dinitrofluorobenzene (DNFB), a skin contact sensitizer, in both local and systemic models of contact hypersensitivity (81, & Fig. 3). Similar results were observed when the effects of silibinin on UVB-induced suppression of the CHS response were examined using identical experimental conditions and models. These data provide a first line of evidence that prevention of photocarcinogenesis by silymarin may be, at least in part, due to the prevention of UVB-induced immunosuppression in mice. To define the mechanism by which silymarin inhibits UVB-induced immunosuppression, it was observed that treatment of mice with silymarin inhibits UVB-enhancement of interleukin (IL)-10 levels both in the skin and in the draining lymph nodes (35, 81). IL-10 is considered as an immunosuppressive cytokine. It has been shown that intraperitoneal administration of IL-10 inhibits the sensitization of mice to trinitrophenyl-coupled spleen cells in an assay of delayed type hypersensitivity (82), and that intraperitoneal injection of IL-10 resulted in a significant suppression of the ear swelling response in a model of CHS, suggesting that IL-10 has the ability to block the effector phase of CHS in vivo. It also has been shown that administration of neutralizing antibodies to IL-10 largely inhibited the ability of UV radiation to suppress sensitization to alloantigens (83). In agreement with these observations, it appears that prevention of UVB-induced immunosuppression by silymarin is mediated, at least in part, through the inhibition of UVB-induced increase in IL-10 production in the skin and draining lymph nodes of mice. Topical treatment of mice with silymarin increased the production of IL-12 in the skin and draining lymph nodes of UVB-irradiated C3H/HeN mice. It has been shown that IL-12 has the ability to stimulate the immune system. The role of enhanced levels of IL-12 production in the silymarin-inhibition of the UVB-induced immunosuppression was confirmed using a local CHS model, which showed that i.p. injection of anti-IL-12 antibody before sensitization resulted in the silymarin-treated mice exhibiting UVB-induced suppression of the CHS response to DNFB. This observation was further supported when CHS experiments were conducted in IL-12 knockout (IL-12 KO) mice and their wild-type counterparts (C3H/HeN) in which topical application of silymarin failed to prevent UVB-induced immunosuppression in the IL-12 KO mice but prevent it in wild-type mice. Further, the i.p. injection of recombinant IL-12 to UVB exposed wild-types and IL-12 KO mice both restored CHS response in the mice which support the evidence that IL-12 play a crucial role in prevention of UVB-induced immunosuppression in mice. The immunostimulatory effects of IL-12 have been demonstrated in an in vivo system (84, 85) and IL-12 has been shown to play a role in vivo as a mediator and adjuvant for the induction phase of the CHS response (84). CHS appears to be a Th1 type cell-mediated immune response (86) and the Langerhans cells, which act as critical epidermal antigen presenting cells in the induction phase of CHS (87), have been reported to produce IL-12. After UV exposure, the antigen presenting cells present in the skin migrate to the regional lymph nodes and initiate sensitization. It is possible that silymarin treatment enhances the levels of IL-12 in the draining lymph nodes by increasing the number of antigen presenting cells that migrate from the skin to the regional lymph nodes in UVB-irradiated mice. IL-12 stimulates the development and function of T-cells particularly the development of Th1 type cells by stimulating the production of IFN-γ (88–90). Intraperitoneal injection of IL-12 prevents UV-induced suppression of CHS (91) and overcomes UV-induced hapten-specific tolerance in mice (92). In the CHS model, the silymarin-induced increases in the levels of IL-12 in the draining lymph nodes of the UVB-irradiated mice could tilt the immune response in favor of the development of Th1 type cells. Together with the effect of silymarin on the production of IL-10, the silymarin-induced shift in the cytokine balance of IL-10 and IL-12 appears to be a potential mechanism by which silymarin may reverse or inhibit UVB-induced suppression of contact hypersensitivity response in mice. Similar immunomodulatory effects were observed with other phytochemicals, such as topical treatment of (−)-epigallocatechin-3-gallate (80) and polyphenolic components of green tea in drinking water of mice (93), and they seem to share similar effector mechanisms in vivo animal models. жүктеу/скачать 2.54 Mb. Достарыңызбен бөлісу:
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