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1.
Br J Dermatol ; 172(2): 354-64, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25533330

RESUMO

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and aberrant keratinocyte differentiation. We have shown that treatment of reconstituted human skin with delphinidin, an anthocyanidin, present in pigmented fruits and vegetables, increased the expression and processing of caspase-14, which is involved in cornification. Delphinidin also increases the expression of epidermal differentiation marker proteins. OBJECTIVES: To determine whether topical application of delphinidin can modulate pathological markers of psoriasiform lesions in flaky skin mice and if this is associated with increased epidermal differentiation and a reduction in proliferation and inflammation. METHODS: Five-week-old female homozygous flaky skin mice (fsn/fsn) were treated topically with delphinidin (0·5 mg cm(-2) and 1 mg cm(-2) skin areas, respectively), five times a week, up to 14 weeks of age. RESULTS: Treatment of flaky skin mice with delphinidin resulted in a reduction in (i) pathological markers of psoriasiform lesions; (ii) infiltration of inflammatory cells; and (iii) mRNA and protein expression of inflammatory cytokines. Delphinidin treatment also increased the expression and processing of caspase-14, and expression of filaggrin, loricrin, keratin-1 and keratin-10. Furthermore, there was a decrease in the expression of markers for cell proliferation (proliferating cell nuclear antigen and keratin-14) and modulation of tight junction proteins (occludin and claudin-1). In addition, delphinidin treatment increased the expression of activator protein-1 transcription factor proteins (JunB, JunD, Fra1 and Fra2). CONCLUSIONS: Delphinidin could be a promising agent for treatment of psoriasis and other hyperproliferative skin disorders.


Assuntos
Antocianinas/farmacologia , Fármacos Dermatológicos/farmacologia , Psoríase/prevenção & controle , Animais , Antocianinas/administração & dosagem , Caspase 14/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Claudina-1/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Feminino , Proteínas Filagrinas , Proteínas de Filamentos Intermediários/metabolismo , Leucócitos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Ocludina/metabolismo
2.
Mini Rev Med Chem ; 11(14): 1200-15, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22070679

RESUMO

Polyphenols are a large family of naturally occurring plant products and are widely distributed in plant foods, such as, fruits, vegetables, nuts, flowers, bark and seeds, etc. These polyphenols contribute to the beneficial health effects of dietary products. Clinical and epidemiological studies suggest that exposure of the skin to environmental factors/pollutants, such as solar ultraviolet (UV) radiation induce harmful effects and leads to various skin diseases including the risk of melanoma and non-melanoma skin cancers. The incidence of non-melanoma skin cancer, comprising of squamous cell carcinoma and basal cell carcinoma, is a significant public health concern world-wide. Exposure of the skin to solar UV radiation results in inflammation, oxidative stress, DNA damage, dysregulation of cellular signaling pathways and immunosuppression thereby resulting in skin cancer. The regular intake of natural plant products, especially polyphenols, which are widely present in fruits, vegetables, dry legumes and beverages have gained considerable attention as protective agents against the adverse effects of UV radiation. In this article, we first discussed the impact of polyphenols on human health based on their structure-activity relationship and bioavailability. We then discussed in detail the photoprotective effects of some selected polyphenols on UV-induced skin inflammation, proliferation, immunosuppression, DNA damage and dysregulation of important cellular signaling pathways and their implications in skin cancer management. The selected polyphenols include: green tea polyphenols, pomegranate fruit extract, grape seed proanthocyanidins, resveratrol, silymarin, genistein and delphinidin. The new information on the mechanisms of action of these polyphenols supports their potential use in skin photoprotection and prevention of photocarcinogenesis in humans.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticarcinógenos/uso terapêutico , Polifenóis/uso terapêutico , Neoplasias Cutâneas/prevenção & controle , Pele/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Anticarcinógenos/farmacocinética , Anticarcinógenos/farmacologia , Reparo do DNA/efeitos dos fármacos , Humanos , Polifenóis/farmacocinética , Polifenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Pele/efeitos da radiação , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo
3.
Oncogene ; 26(5): 673-82, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16862172

RESUMO

Cigarette smoke is a powerful inducer of inflammatory responses resulting in disruption of major cellular pathways with transcriptional and genomic alterations driving the cells towards carcinogenesis. Cell culture and animal model studies indicate that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol present in green tea, possesses potent anti-inflammatory and antiproliferative activity capable of selectively inhibiting cell growth and inducing apoptosis in cancer cells without adversely affecting normal cells. Here, we demonstrate that EGCG pretreatment (20-80 microM) of normal human bronchial epithelial cells (NHBE) resulted in significant inhibition of cigarette smoke condensate (CSC)-induced cell proliferation. Nuclear factor-kappaB (NF-kappaB) controls the transcription of genes involved in immune and inflammatory responses. In most cells, NF-kappaB prevents apoptosis by mediating cell survival signals. Pretreatment of NHBE cells with EGCG suppressed CSC-induced phosphorylation of IkappaBalpha, and activation and nuclear translocation of NF-kappaB/p65. NHBE cells transfected with a luciferase reporter plasmid containing an NF-kappaB-inducible promoter sequence showed an increased reporter activity after CSC exposure that was specifically inhibited by EGCG pretreatment. Immunoblot analysis showed that pretreatment of NHBE cells with EGCG resulted in a significant downregulation of NF-kappaB-regulated proteins cyclin D1, MMP-9, IL-8 and iNOS. EGCG pretreatment further inhibited CSC-induced phosphorylation of ERK1/2, JNK and p38 MAPKs and resulted in a decreased expression of PI3K, AKT and mTOR signaling molecules. Taken together, our data indicate that EGCG can suppress NF-kappaB activation as well as other pro-survival pathways such as PI3K/AKT/mTOR and MAPKs in NHBE cells, which may contribute to its ability to suppress inflammation, proliferation and angiogenesis induced by cigarette smoke.


Assuntos
Anticarcinógenos/farmacologia , Brônquios/efeitos dos fármacos , Catequina/análogos & derivados , NF-kappa B/metabolismo , Fumaça , Chá , Antioxidantes , Apoptose/efeitos dos fármacos , Brônquios/citologia , Brônquios/metabolismo , Catequina/farmacologia , Ciclina D1/metabolismo , Ciclo-Oxigenase 2/metabolismo , DNA/genética , DNA/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/genética , Fosforilação/efeitos dos fármacos , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Oncogene ; 26(24): 3559-71, 2007 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-17146435

RESUMO

It has become clear that ultraviolet A (UVA) radiation from the solar spectrum is a major environmental challenge to the skin. This necessitates developing novel mechanism-based agents capable of ameliorating UVA-induced effects in the skin. We recently described a novel antioxidant, 3-O-Caffeoyl-1-methylquinic acid (MCGA3) from leaves of bamboo. Here, we investigated the photochemopreventive effects of MCGA3 against UVA-mediated apoptosis in immortalized HaCaT keratinocytes. Pretreatment of MCGA3 rendered cells more sensitive to subsequent UVA irradiation-induced apoptosis as well as completely reversed UVA-induced sustained phosphorylation of extracellular signal-regulated kinase 1/2 and protein kinase Calpha, downregulation of p21, and reactive oxygen species generation. Interestingly, MCGA3 itself effectively induced p21 protein and mRNA levels. Silencing of p21 by RNA interference revealed a pivotal role of p21 in generating G(1)-S arrest and in enhancing UVA-mediated apoptosis. Transcriptional activation of p21 by MCGA3 was mediated through the proximal region of multiple Sp1 sites regardless of p53-binding site in p21 promoter, and this effect was augmented by desferroioxamine, an iron chelating agent. Additional studies suggested that iron chelation-driven hypoxia by MCGA3 may function in activation of p21. MCGA3 could be a useful agent to prevent photocarcinogenesis via apoptotic elimination of p53 mutant and DNA-repair defective cells caused by UVA radiation.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Ácido Quínico/análogos & derivados , Apoptose/fisiologia , Apoptose/efeitos da radiação , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Quelantes de Ferro/farmacologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ácido Quínico/farmacologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Ativação Transcricional , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta/efeitos adversos
5.
Toxicol Appl Pharmacol ; 176(2): 110-7, 2001 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11601887

RESUMO

Exposure of normal human epidermal keratinocytes (NHEK) to UVB radiation induces intracellular release of hydrogen peroxide (oxidative stress) and phosphorylation of mitogen-activated protein kinase cell signaling pathways. Here, we demonstrate that pretreatment of NHEK with (-)-epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, inhibits UVB-induced hydrogen peroxide (H(2)O(2)) production and H(2)O(2)-mediated phosphorylation of MAPK signaling pathways. We found that treatment of EGCG (20 microg/ml of media) to NHEK before UVB (30 mJ/cm(2)) exposure inhibited UVB-induced H(2)O(2) production (66-80%) concomitant with the inhibition of UVB-induced phosphorylation of ERK1/2 (57-80%), JNK (53-83%), and p38 (50-77%) proteins. To demonstrate whether UVB-induced phosphorylation of MAPK occurs via UVB-induced H(2)O(2) (oxidative stress) production, NHEK were treated with the oxidant H(2)O(2). Treatment of H(2)O(2) to NHEK resulted in phosphorylation of ERK1/2, JNK, and p38. Using the same in vitro system, when these cells were pretreated with EGCG or with the known antioxidant ascorbic acid (as positive control), H(2)O(2)-induced phosphorylation of ERK1/2, JNK, and p38 was found to be significantly inhibited. These findings demonstrate that EGCG has the potential to inhibit UVB-induced oxidative stress-mediated phosphorylation of MAPK signaling pathways, suggesting that EGCG could be useful in attenuation of oxidative stress-mediated and MAPK-caused skin disorders in humans.


Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Catequina/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno , Queratinócitos/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Estresse Oxidativo/fisiologia , Estresse Oxidativo/efeitos da radiação , Ácido Ascórbico/farmacologia , Western Blotting , Células Epidérmicas , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Queratinócitos/efeitos dos fármacos , MAP Quinase Quinase 4 , Proteína Quinase 3 Ativada por Mitógeno , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oxidantes/farmacologia , Fosforilação , Raios Ultravioleta , Proteínas Quinases p38 Ativadas por Mitógeno
6.
J Photochem Photobiol B ; 63(1-3): 61-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11684452

RESUMO

Because of its accessibility the human skin is constantly exposed to solar ultraviolet (UV) radiation. It is increasingly appreciated that exposure of the mammalian skin to UV plays a causal and decisive role in acute and chronic skin damage including the development of skin cancer. UV exposure causes sunburn, pigmentation, hyperplasia, immunosuppression, DNA damage, photoaging and photocarcinogenesis. To cope with constant environmental damage the skin possesses elaborate enzymatic detoxification systems. This paper briefly focuses on the effect of solar radiation, particularly UV spectrum, on detoxification pathways in the skin. Specifically the effect of solar radiation on cytochrome P450, glutathione, superoxide dismutase, glutathione peroxidase, catalase, glutathione-S-transferase and ceruloplasmin has been discussed.


Assuntos
Pele/enzimologia , Pele/efeitos da radiação , Animais , Enzimas/metabolismo , Humanos , Inativação Metabólica , Atividade Solar , Raios Ultravioleta/efeitos adversos
7.
Biochem Biophys Res Commun ; 288(3): 579-85, 2001 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-11676482

RESUMO

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, nuts, many other fruits, and red wine, is a potent antioxidant with anti-inflammatory and cancer-preventive properties. The mechanism(s) by which resveratrol imparts cancer chemopreventive effects has not been clearly defined. Earlier, we have shown that resveratrol treatment results in an induction of the cyclin kinase inhibitor WAF1/CIP1/p21 which, by inhibiting cyclin (E, D1, and D2) and cyclin-dependent kinases (cdk2, cdk4, and cdk6), results in a G0/G1-phase arrest followed by apoptosis of A431 human epidermoid carcinoma cells (Ahmad et al., Clin. Cancer Res. 7, 1466-1473, 2001). Retinoblastoma (pRb) and the E2F family of transcription factors are important proteins, which regulate the progression of the cell cycle at and near the G1-->S phase transition. Here we provide evidence for the involvement of the pRb-E2F/DP pathway as an important contributor of resveratrol-mediated cell cycle arrest and apoptosis. Immunoblot analysis demonstrated that resveratrol treatment of A431 cells results in a dose- as well as time-dependent decrease in the hyperphosphorylated form of pRb with a relative increase in hypophosphorylated pRb. This response was accompanied by downregulation of protein expression of all five E2F ( 1 - 5 ) family members of transcription factors studied and their heterodimeric partners DP1 and DP2. This suggests that resveratrol causes a downregulation of hyperphosphorylated pRb protein with a relative increase in hypophosphorylated pRb that, in turn, compromises with the availability of free E2F. We suggest that this series of events results in a stoppage of the cell cycle progression at the G1-->S phase transition thereby leading to a G0/G1 arrest and subsequent apoptotic cell death. To our knowledge, this is the first study showing the involvement of the pRb-E2F/DP pathway as a mechanism of the cancer-chemopreventive effects of resveratrol.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Fase G1/efeitos dos fármacos , Proteína do Retinoblastoma/metabolismo , Estilbenos/farmacologia , Fatores de Transcrição/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Fatores de Transcrição E2F , Fator de Transcrição E2F1 , Fase G1/fisiologia , Humanos , Resveratrol , Proteína do Retinoblastoma/efeitos dos fármacos , Fatores de Transcrição/efeitos dos fármacos , Células Tumorais Cultivadas
8.
Biochem Biophys Res Commun ; 287(4): 914-20, 2001 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-11573952

RESUMO

Agents that are capable of inducing selective apoptosis of cancer cells are receiving considerable attention in developing novel cancer-preventive approaches. In the present study, employing normal human prostate epithelial cells (NHPE), virally transformed normal human prostate epithelial cells (PZ-HPV-7), and human prostate adenocarcinoma (CA-HPV-10) cells, we evaluated the growth-inhibitory effects of apigenin, a flavonoid abundantly present in fruits and vegetables. Apigenin treatment to NHPE and PZ-HPV-7 resulted in almost similar growth inhibitory responses of low magnitude. In sharp contrast, apigenin treatment resulted in a significant decrease in cell viability of CA-HPV-10 cells. Similar selective growth inhibitory effects were also observed for human epidermoid carcinoma A431 cells compared to normal human epidermal keratinocytes. Apigenin treatment resulted in significant apoptosis of CA-HPV-10 cells as evident from (i) DNA ladder assay, (ii) fluorescence microscopy, and (iii) TUNEL assay, whereas the NHPE and PZ-HPV-7 cells did not undergo apoptosis but showed exclusive necrotic staining only at a high dose of 40 microM. Apigenin (1-10 microM) also resulted in a dose-dependent G2-M phase cell cycle arrest of CA-HPV-10 cells but not of PZ-HPV-7 cells. The growth-inhibitory and apoptotic potential of apigenin was also observed in a variety of prostate carcinoma cells representing different stage and androgen responsiveness. Apigenin may be developed as a promising chemopreventive and/or chemotherapeutic agent against prostate cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Flavonoides/farmacologia , Próstata/citologia , Neoplasias da Próstata/patologia , Adenocarcinoma/patologia , Apigenina , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Viral , DNA/metabolismo , Fragmentação do DNA , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Flavonoides/química , Citometria de Fluxo , Humanos , Marcação In Situ das Extremidades Cortadas , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Masculino , Microscopia de Fluorescência , Próstata/efeitos dos fármacos , Células Tumorais Cultivadas
9.
Clin Cancer Res ; 7(5): 1466-73, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11350919

RESUMO

Resveratrol (trans-3,4',5,-trihydroxystilbene), a phytoalexin found in grapes, nuts, fruits, and red wine, is a potent antioxidant with cancer-preventive properties. The mechanism by which resveratrol imparts cancer chemopreventive effects is not clearly defined. Here, we demonstrate that resveratrol, via modulations in cyclin-dependent kinase (cdk) inhibitor-cyclin-cdk machinery, results in a G(1)-phase arrest of the cell cycle followed by apoptosis of human epidermoid carcinoma (A431) cells. Resveratrol treatment (1-50 microM for 24 h) of A431 cells resulted in a dose-dependent (a) inhibition of cell growth as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, (b) G(1)-phase arrest of the cell cycle as shown by DNA cell cycle analysis, and (c) induction of apoptosis as assessed by ELISA. The immunoblot analysis revealed that resveratrol treatment causes a dose- and time-dependent (a) induction of WAF1/p21; (b) decrease in the protein expressions of cyclin D1, cyclin D2, and cyclin E; and (c) decrease in the protein expressions of cdk2, cdk4, and cdk6. Resveratrol treatment was also found to result in a dose- and time-dependent decrease in kinase activities associated with all of the cdks examined. Taken together, our study suggests that resveratrol treatment of the cells causes an induction of WAF1/p21 that inhibits cyclin D1/D2-cdk6, cyclin D1/D2-cdk4, and cyclin E-cdk2 complexes, thereby imposing an artificial checkpoint at the G(1)-->S transition of the cell cycle. This series of events results in a G(1)-phase arrest of the cell cycle, which is an irreversible process that ultimately results in the apoptotic death of cancer cells. To our knowledge, this is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of cancer cells by resveratrol.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose , Quinases relacionadas a CDC2 e CDC28 , Carcinoma de Células Escamosas/patologia , Ciclinas/fisiologia , Fase G1/efeitos dos fármacos , Proteínas Proto-Oncogênicas , Estilbenos/farmacologia , Divisão Celular/efeitos dos fármacos , Ciclina D1/antagonistas & inibidores , Ciclina D2 , Ciclina E/antagonistas & inibidores , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21 , Quinases Ciclina-Dependentes/antagonistas & inibidores , Ciclinas/antagonistas & inibidores , Humanos , Fosfotransferases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Resveratrol , Células Tumorais Cultivadas
10.
Carcinogenesis ; 22(2): 287-94, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11181450

RESUMO

The use of naturally occurring botanicals with substantial antioxidant activity to afford protection to human skin against UV damage is receiving increasing attention. The green tea constituent (-)-epigallocatechin-3-gallate (EGCG) is a potent antioxidant and has shown remarkable preventive effects against photocarcinogenesis and phototoxicity in mouse models. In this study we have investigated the effects of topical application of EGCG, the major polyphenol present in green tea, to human skin before UV irradiation on UV-induced markers of oxidative stress and antioxidant enzymes. Using immunohistochemistry and analytical enzyme assays, we found that application of EGCG (mg/cm(2) skin) before a single UV exposure of 4x minimal erythema dose (MED) markedly decreases UV-induced production of hydrogen peroxide (68-90%, P < 0.025-0.005) and nitric oxide (30-100%, P < 0.025-0.005) in both epidermis and dermis in a time-dependent manner. EGCG pretreatment also inhibits UV-induced infiltration of inflammatory leukocytes, particularly CD11b(+) cells (a surface marker of monocytes/macrophages and neutrophils), into the skin, which are considered to be the major producers of reactive oxygen species. EGCG treatment was also found to inhibit UV-induced epidermal lipid peroxidation at each time point studied (41-84%, P < 0.05). A single UV exposure of 4x MED to human skin was found to increase catalase activity (109-145%) and decrease glutathione peroxidase (GPx) activity (36-54%) and total glutathione (GSH) level (13-36%) at different time points studied. Pretreatment with EGCG was found to restore the UV-induced decrease in GSH level and afforded protection to the antioxidant enzyme GPx. Further studies are warranted to study the preventive effects of EGCG against multiple exposures to UV light of human skin.


Assuntos
Catequina/análogos & derivados , Catequina/farmacologia , Sequestradores de Radicais Livres/farmacologia , Estresse Oxidativo/efeitos da radiação , Radiodermite/prevenção & controle , Pele/efeitos dos fármacos , Chá/química , Raios Ultravioleta/efeitos adversos , Adulto , Catalase/metabolismo , Catequina/isolamento & purificação , Feminino , Sequestradores de Radicais Livres/isolamento & purificação , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Técnicas Imunoenzimáticas , Leucócitos/metabolismo , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Radiodermite/etiologia , Radiodermite/metabolismo , Pele/metabolismo , Pele/efeitos da radiação , Fatores de Tempo
11.
Toxicol Lett ; 117(1-2): 53-60, 2000 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-11033233

RESUMO

Chrysotile, an important commercial variety of asbestos, is known to cause oxidative stress by enhancing production of hydrogen peroxide (H(2)O(2)) and thiobarbituric acid reactive substances (TBARS), depleting glutathione (GSH) and altering levels of GSH redox system enzymes. N-acetyl L-cysteine (NAC), a compound that increases GSH levels, protects cells against chrysotile toxicity. In the present study, rats were exposed intratracheally to a single dose (5 mg/rat) of chrysotile. This was followed by a daily dose of NAC 50 mg/kg. b. wt., i.p. At 1, 4, 8 and 16 days post chrysotile exposure lung lavage fluid was collected to determine H(2)O(2) generation, TBARS production, GSH level and its redox system enzymes activities. A significant decrease in H(2)O(2) and TBARS, an increase in GSH content and its redox system enzymes was observed in chrysotile+NAC animals in comparison to chrysotile-exposed animals. In this preliminary study it appears that NAC may be protecting cells against oxidative damage. This protection may be due to its ability to maintain intracellular GSH/oxidative scavenging capability.


Assuntos
Acetilcisteína/farmacologia , Asbestos Serpentinas/toxicidade , Sequestradores de Radicais Livres/farmacologia , Oxidantes/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Contagem de Células , Feminino , Glucosefosfato Desidrogenase/efeitos dos fármacos , Glucosefosfato Desidrogenase/metabolismo , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Glutationa Redutase/efeitos dos fármacos , Glutationa Redutase/metabolismo , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos Alveolares/citologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Ratos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
12.
Toxicol Lett ; 106(1): 31-9, 1999 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-10378448

RESUMO

A significant depletion in the content of glutathione (GSH) and alteration in GSH redox system enzymes were observed in the lung of chrysotile-exposed animals (5 mg) during different developmental stages of asbestosis. In the alveolar macrophages (AM) of exposed animals, the depletion in GSH started from day 1 and reached a maximum at day 16, whereas in lung tissue the maximum depletion was observed when fibrosis has matured. It appears that cellular GSH depletion triggers oxidative stress in the system as observed from increased thiobarbituric acid reactive substance (TBARS) production and alteration in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PD) and glutathione S-transferase (GST), the enzymes regulating oxidative tone. The depletion in GSH was also observed in red blood cells (RBC) of the exposed animals reaching a maximum when fibrosis matured. Thus the observed depletion in GSH, ascorbic acid and alteration in GSH redox system enzymes may be involved in fibrosis and carcinogenesis induced by chrysotile.


Assuntos
Asbestos Serpentinas/toxicidade , Asbestose/etiologia , Glutationa/metabolismo , Animais , Asbestose/metabolismo , Ácido Ascórbico/metabolismo , Feminino , Peroxidação de Lipídeos , Ratos
13.
Crit Rev Toxicol ; 29(6): 543-68, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10628776

RESUMO

Glutathione (GSH) is a ubiquitous intracellular thiol present in all tissues, including lung. Besides maintaining cellular integrity by creating a reduced environment, GSH has multiple functions, including detoxification of xenobiotics, synthesis of proteins, nucleic acids, and leukotrienes. Present in high concentrations in bronchoalveolar lavage fluid (BALF), GSH provides protection to the lung from oxidative injury induced by different endogenous or exogenous pulmonary toxicants. Its depletion in the lung has been associated with the increased risk of lung damage and disease. The redox system of GSH consists of primary and secondary antioxidants, including glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and glucose 6-phosphate dehydrogenase (G6PD). Alterations in the activities of these enzymes may reflect reduced cellular defense and may serve as surrogate markers of many lung diseases. As GSH is also involved in the regulation of expression of protooncogenes and apoptosis (programmed cell death), the development of diseases such as cancer and human immune deficiency may be affected by depleting or elevating cellular GSH levels. Exogenous delivery of GSH or its precursor N-acetyl cysteine (NAC) is being used as chemotherapeutic approach.


Assuntos
Antioxidantes/farmacologia , Glutationa/farmacologia , Pneumopatias/induzido quimicamente , Estresse Oxidativo , Regulação da Expressão Gênica , Genes fos/genética , Genes jun/genética , Glutationa/biossíntese , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Humanos , Pneumopatias/enzimologia , Pneumopatias/fisiopatologia , Oxirredução , Xenobióticos/efeitos adversos
14.
Toxicol Lett ; 99(3): 175-82, 1998 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-9862283

RESUMO

The cytotoxic and oxidative responses of crocidolite and chrysotile asbestos fibers and ultrafine titanium dioxide (UF-TiO2) particles were measured in alveolar macrophages (AM) and peripheral red blood cells (RBC) of rat after 30 days with a single intratracheal exposure (5 mg). The following responses were observed one month after fiber/particle instillation: (1) AM population increased; (2) lactate dehydrogenase and acid phosphatase activities in cell free lung lavage fluid increased; (3) substances that react with hydrogen peroxide or thiobarbituric acid were elevated in both AM and peripheral RBC; (4) glutathione peroxidase, glutathione reductase, and catalase were altered in both AM and peripheral RBC; (5) glutathione and ascorbic acid decreased in both AM and peripheral RBC. A significant difference from negative controls was noted in all responses of the two fiber-exposed groups, and in most responses of the UF-TiO2-exposed group. The level of responses to the three test substances suggested a decreasing order of toxicity, with crocidolite > chrysotile > UF-TiO2.


Assuntos
Poeira/efeitos adversos , Eritrócitos/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Fibras Minerais/toxicidade , Aerossóis , Animais , Asbesto Crocidolita/toxicidade , Asbestos Serpentinas/toxicidade , Líquido da Lavagem Broncoalveolar , Carcinógenos/toxicidade , Eritrócitos/enzimologia , Eritrócitos/metabolismo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/metabolismo , Tamanho da Partícula , Ratos , Espécies Reativas de Oxigênio/metabolismo , Titânio/toxicidade
15.
J Appl Toxicol ; 18(5): 307-12, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9804429

RESUMO

In order to understand the pulmonary toxicity of ultrafine titanium dioxide (UF-TiO2) particles, various biochemical and chemical parameters were assayed in rat alveolar macrophages (AMs) and cell-free lavage fluid. Single intratracheal exposure of UF-TiO2 (2 mg per rat) caused cytotoxicity to pulmonary AMs. An increase in the population of AMs could be observed, followed by increased activities of lactate dehydrogenase and acid phosphatase in cell-free lavage fluid. In addition, AMs showed an adaptive response because the activities of glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione S-transferase were increased in these cells. However, this enhancement of antioxidant enzymes could not diminish the enhanced lipid peroxidation and increased rate of hydrogen peroxide generation. The level of glutathione remained decreased in UF-TiO2-exposed rat AMs. The data suggest that the induction of antioxidant enzymes by these cells for self-protection is not sufficient to cope against the toxic action of UF-TiO2, which may lead to oxidative stress.


Assuntos
Corantes/toxicidade , Macrófagos Alveolares/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Titânio/toxicidade , Animais , Feminino , Glutationa Transferase/metabolismo , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos , Estresse Oxidativo , Tamanho da Partícula , Ratos
16.
Toxicology ; 95(1-3): 135-40, 1995 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-7529952

RESUMO

Single exposure of rats to hexachlorocyclohexane (100 mg/kg) did not cause any significant change in phosphoinositide levels in rat erythrocyte membrane and cerebrum (fore brain) 2 or 24 h after exposure. However, the phosphoinositide turnover and generation of second messengers from phosphoinositides were increased in the treated erythrocyte membranes as judged from a marked increase in the incorporation of [2-3H]inositol into phosphoinositides 24 h after the treatment. A significant decrease in phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) was observed in the erythrocyte membrane and cerebrum of rats repeatedly exposed to the pesticide for 3 or 6 months. This drastic reduction in phosphoinositide levels suggests adverse effects on vital membrane and cell functions modulated by phosphoinositides.


Assuntos
Membrana Eritrocítica/metabolismo , Hexaclorocicloexano/toxicidade , Fosfatidilinositóis/metabolismo , Prosencéfalo/metabolismo , Animais , Membrana Eritrocítica/efeitos dos fármacos , Feminino , Prosencéfalo/efeitos dos fármacos , Ratos
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