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81.
82.
Ana Luisa Kadekaro Renny J. Kavanagh Kazumasa Wakamatsu Shosuke Ito Michelle A. Pipitone Zalfa A. Abdel‐Malek 《Pigment cell & melanoma research》2003,16(5):434-447
Solar ultraviolet radiation (UV) is a major environmental factor that dramatically alters the homeostasis of the skin as an organ by affecting the survival, proliferation and differentiation of various cutaneous cell types. The effects of UV on the skin include direct damage to DNA, apoptosis, growth arrest, and stimulation of melanogenesis. Long‐term effects of UV include photoaging and photocarcinogenesis. Epidermal melanocytes synthesize two main types of melanin: eumelanin and pheomelanin. Melanin, particularly eumelanin, represents the major photoprotective mechanism in the skin. Melanin limits the extent of UV penetration through the epidermal layers, and scavenges reactive oxygen radicals that may lead to oxidative DNA damage. The extent of UV‐induced DNA damage and the incidence of skin cancer are inversely correlated with total melanin content of the skin. Given the importance of the melanocyte in guarding against the adverse effects of UV and the fact that the melanocyte has a low self‐renewal capacity, it is critical to maintain its survival and genomic integrity in order to prevent malignant transformation to melanoma, the most fatal form of skin cancer. Melanocyte transformation to melanoma involves the activation of certain oncogenes and the inactivation of specific tumor suppressor genes. This review summarizes the current state of knowledge about the role of melanin and the melanocyte in photoprotection, the responses of melanocytes to UV, the signaling pathways that mediate the biological effects of UV on melanocytes, and the most common genetic alterations that lead to melanoma. 相似文献
83.
Acetazolamide Inhibits the Level of Tyrosinase and Melanin: An Enzyme Kinetic,In Vitro,In Vivo,and In Silico Studies 下载免费PDF全文
Melanin is the major factor that determines skin color and protects from ultraviolet radiation. In present study we evaluated the anti‐melanogenesis effect of acetazolamide (ACZ) using four different approaches: enzyme kinetic, in vitro, in vivo and in silico. ACZ demonstrated significant inhibitory activity (IC50 7.895 ± 0.24 μm ) against tyrosinase as compared to the standard drug kojic acid (IC50 16.84 ± 0.64 μm ) and kinetic analyses showed that ACZ is a non‐competitive inhibitor without cytotoxic effect. In in vitro experiments, A375 human melanoma cells were treated with 20 or 40 μm of ACZ with or without 50 μm of l ‐DOPA. Western blot results showed that ACZ significantly (P < 0.05) decreased the expression level of tyrosinase at 40 μm . Zebrafish embryos were treated with 10, 20 or 40 μm of ACZ and of positive control kojic acid. At 72 h of treatment with ACZ and kojic acid, ACZ significantly (P < 0.001) decreased the embryos pigmentation to 40.8% of untreated embryos at the dose of 40 μm of ACZ while kojic acid decreased only 25.0% of pigmentation at the same dose of kojic acid. In silico docking were performed against tyrosinase using PyRx tool. Docking studies suggested that His244, Asn260 and His85 are the major interacting residues in the binding site of the protein. In conclusion, our results suggest that ACZ is a good candidate for the inhibition of melanin and it could be used as a lead for developing the drugs for hyperpigmentary disorders and skin whitening. 相似文献
84.
Sunlight has been known as an important cause of skin cancer since around the turn of the 20th Century. A 1977 landmark paper of US scientists Fears, Scotto, and Schneiderman advanced a novel hypothesis whereby cutaneous melanoma was primarily caused by intermittent sun exposure (i.e. periodic, brief episodes of exposure to high-intensity ultraviolet radiation) while the keratinocyte cancers, squamous cell carcinoma and basal cell carcinoma, were primarily caused by progressive accumulation of sun exposure. With respect to cutaneous melanoma, this became known as the intermittent exposure hypothesis. The hypothesis stemmed from analysis of measured ambient ultraviolet radiation and age-specific incidence rates of melanoma and keratinocyte cancers collected as an extension to the US Third National Cancer Survey in several US States. In this perspective paper, we put this novel hypothesis into the context of knowledge at the time, and describe subsequent epidemiological and molecular research into melanoma that elaborated the intermittent exposure hypothesis and ultimately replaced it with a dual pathway hypothesis. Our present understanding is of two distinct biological pathways by which cutaneous melanoma might develop; a nevus prone pathway initiated by early sun exposure and promoted by intermittent sun exposure or possibly host factors; and a chronic sun exposure pathway in sun sensitive people who progressively accumulate sun exposure to the sites of future melanomas. 相似文献
85.
高度恶性肿瘤如肝癌或恶性黑色素瘤病人即使手术治疗,仍然有相当多的病人预后不好,或发生转移。本文研究了自行合成的4-氨基苯酚维甲酰胺(4-HPR),一种维甲酸的衍生物,通过观察对肝癌细胞和恶性黑色素瘤细胞的作用,发现该衍生物具有较强的抑制肝癌细胞迁移能力,7721-k3肝癌细胞的迁移细胞数从对照组的201(27.2,经过6h的作用后即下降到58±5.03(p<0.05,n=4);黑色素瘤细胞则从302±30.1下降到254±25.04(p<0.05,n=4);侵润能力也显著下降,7721-k3细胞穿过人工模拟基底膜的细胞数从对照组的27±13.1下降到11.2±3.3,黑色素瘤细胞则从67.5±10.1下降到24.3±3.2(p<0.05,n=3)。而且发现3μmol/L 4-HPR作用B16黑色素瘤细胞48h可诱导37.11±0.94%细胞的调亡,与相同微克分子浓度的维甲酸相比,具有显著性差别(p<0.05)。但是不能显著诱导7721-k3细胞凋亡。4-HPR诱导B16黑色素瘤细胞凋亡的作用机制尚不清楚,我们利用与肿瘤恶性程度密切有关的乳糖基神经酰胺磺酰基转移酶(CST)基因,转染B16细胞使之高表达以后,可以部分抑制这些细胞对4-HPR诱导凋亡的敏感性,但是不能完全抑制。4-HPR是目前已知毒副作用最小的维生素A类化合物,有可能成为恶性黑色素瘤或肝癌治疗的一个有效的药物。 相似文献
86.
Mei-Ling Chang Yi-Ting Chen Yu-Chia Su John T. Kung 《Journal of biomedical science》2003,10(6):644-650
P14 TCR transgenic CD8+ T cells (LCMV gp33-specific) were activated by antigen in the presence of either IL-2 or IL-2+IL-4 to generate effector cytotoxic T lymphocytes (CTLs). The therapeutic effectiveness of such IL-2- or IL-2+IL-4-grown CTLs was tested in mice that had received intravenous inoculations of B16.gp33 melanoma cells 7 days previously. Administration of P14 CTLs activated by antigen +IL-2+IL-4 was significantly more effective at reducing melanoma colony formation in the lung than those grown in the presence of antigen +IL-2. Highly significant improvement in survival was observed with 80% of B16.gp33-inoculated mice showing long-term survival after therapy with 10×106 antigen +IL-2+IL-4-activated P14 CTLs. Similar therapeutic effectiveness of antigen +IL-2+IL-4-activated P14 CTLs against subcutaneously inoculated B16.gp33 melanoma cells was also found. There was significant reduction in P14 CD8+ T cells in the peripheral blood of B16.gp33-inoculated mice than in mice that did not receive B16.gp33 melanoma cells, indicating possible homing of P14 CD8+ T cells to the site of tumor growth or antigen-induced apoptotic cell death. These results may have implications in tumor therapy using CTLs grown ex vivo, especially during early stages of tumor formation. They also support the concept that the therapeutic effectiveness of CTLs can be governed by the cytokine context in which they are activated. 相似文献
87.
Chih-Hung Lee Wan-Ping Hu Chien-Hui Hong Hsin-Su Yu Wei-Ting Liao Chung-Yu Chen Yeh-Long Chen Bai-Hsiun Chen Gwo-Shing Chen Jeh-Jeng Wang 《Chemico-biological interactions》2009,180(3):360-367
Melanoma is one of the most chemo-resistant cancers. The remission rate of current therapy remains low. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of antitumor antibiotics that binds to N2 of guanine to form a DNA adduct. However, significant cardiotoxicity hampers their clinical use. We have previously synthesized a PBD indole conjugate (IN6CPBD) that induced apoptosis in several cancer cell lines. The purpose of this study was to assess the efficacy and safety of the IN6CPBD for established murine melanoma cells in vivo. IN6CPBD induced more apoptosis than DC-81 as evidenced by sub-G1 distribution, annexin V positivity, and decrease mitochondrial membrane potential (ΔΨmt). The melanomas were established in C57BL/6 mice by injecting B16F10 cells via the tail vein. Three courses of therapy were instituted after day 5 and the mice were sacrificed at day 20. The tumor growth rate in the foot pad was significantly reduced in IN6CPBD-treated mice than that in DC-81- and PBS-treated mice. The tumor burden in the lungs was also reduced significantly in IN6CPBD-treated mice accompanied with the most prominent TUNEL staining. Renal function, and cardiac enzymes were not altered significantly by IN6CPBD or DC-81, however, robust deterioration of liver function was noticed in the DC-81-treated mice. In summary, potent apoptosis could be elicited by the PBD indole conjugate IN6CPBD, accompanied with a better efficacy and less liver function impairment than the mother compound DC-81 in treating established melanoma metastasis in vivo. 相似文献
88.
Effects of representative members of the transforming growth factor-β (TGF-β) family, TGF-β1, activin A and BMP-2, on melanin
content and expression of pigment-producing enzymes were examined in B16 melanoma cells. Treatment with TGF-β1 or activin
A but not with BMP-2 significantly decreased melanin content and expression of Tyrosinase and Tyrp-1, suggesting an inhibitory effect of TGF-β1 and activin A on melanin synthesis. TGF-β1 completely inhibited melanin synthesis
induced by α-melanin stimulating hormone (α-MSH), whereas activin A only slightly did. As compared with parental B16 cells,
the inhibitory effects of TGF-β1 and activin A on melanin content were relative smaller in B16 F10 cells, a subline of B16
cells that contain more pigment. The present study indicates that in addition to TGF-β, activin negatively regulates melanogenesis
in the absence of α-MSH, but that the activity in the presence of α-MSH was slightly different between TGF-β and activin. 相似文献
89.
Beyond vessels: occurrence and regional clustering of vascular endothelial (VE-)cadherin-containing junctions in non-endothelial cells 总被引:1,自引:1,他引:0
Judit Boda-Heggemann Anne Régnier-Vigouroux Werner W. Franke 《Cell and tissue research》2009,335(1):49-65
The genes encoding transmembrane glycoproteins of the cadherin family, i.e., the Ca2+-dependent cell-cell adhesion molecules, are typically expressed in cell-type- or cell-lineage-specific patterns. One of them,
vascular endothelial (VE)-cadherin, is widely considered to be specific for vascular endothelia in which it is either the
sole or the predominant cadherin, often co-existing with N-cadherin. This specificity of VE-cadherin for vascular endothelial
cells is important not only in blood and lymph vessel biology and medicine, but also for cell-type-based diagnoses, notably
those of metastatic tumors. Surprisingly, however, we have recently noted the frequent synthesis, surface exposure, and junction
assembly of VE-cadherin in certain other cells, in which this glycoprotein is clustered into adherens junctions (AJs), either
alone or in combination with N-cadherin and/or cadherin-11. Such cells include mammalian astrocytes and glioma, probably mostly
astrocytoma cells growing in culture, and a specific subtype of astrocytoma in situ. Moreover, VE-cadherin synthesis and AJ
assembly, plus the regional clustering of such AJs in certain domains, are not clonally fixed but can appear again and again
in cells of the progeny of cloned homogeneous-appearing individual cells, thus resulting in clonal cell colonies that are
often heterogeneous in their cadherin junction patterns. We discuss the constitutive presence of VE-cadherin in some non-endothelial
cells with respect to certain architectural features and possible physiological and pathogenic functions of the cells, and
in comparison with recent reports of VE-cadherin-positive melanomas.
This work was supported in part by the Deutsche Krebshilfe (grant 10 2049 Fr1) and the German Ministry for Research and Technology
(Program Regenerative Medicine, START-MSC consortium). 相似文献
90.
Cytotoxic CD8+ T cells are key effectors in the immunotherapy of malignant and viral diseases. However, autologous T cell responses to tumor
antigens presented by self-MHC are usually weak and ineffective. Allo-restricted T cells represent a potent source of tumor-specific
T cells for adoptive immunotherapy. This study reports in vivo anti-melanoma efficacy of the pTRP2-specific allo-restricted
CTLs expanded from the BALB/c splenocytes by multiple stimulations with aAPCs made by coating H-2Kb-Ig/pTRP2 dimeric complexes, anti-CD28 antibody, 4-1BBL molecules and CD83 molecules to cell-sized latex beads. The induced
allo-restricted CTLs exhibited specific lysis against RMA-S cells pulsed with the peptide pTRP2 and H-2Kb+ melanoma cells expressing TRP2, while a murine Lewis lung carcinoma cell line 3LL could not be recognized by the CTLs. The
peptide-specific activity was inhibited by anti-H-2Kb monoclonal antibody Y3. Adoptive transfer of the allo-restricted CTLs specific for malignant melanoma expanded by the aAPCs
can mediate effective anti-melanoma response in vivo. These results suggested that the specific allo-restricted CTLs expanded
by aAPCs coated with an MHC-Ig/peptide complex, anti-CD28 antibody, 4-1BBL and CD83 could be a potential option of specific
immunotherapy for patients with malignant melanoma.
X.-l. Lu and X.-b. Jiang have contributed equally to this work.
An erratum to this article can be found at 相似文献