RESUMO
The NLRP3 inflammasome serves as a host defense mechanism against various pathogens, but there is growing evidence linking its activation in sterile condition to diverse inflammatory diseases. Therefore, the identification of specific inhibitors that target NLRP3 inflammasome activation is meaningful and important for novel therapies for NLRP3 inflammasome-associated diseases. In this study, we identified a chemical compound, namely ODZ10117 (ODZ), that showed NLRP3 inflammasome-targeting anti-inflammatory effects during the screening of a chemical library for anti-inflammatory activity. Although ODZ was initially discovered as a STAT3 inhibitor, here we found it also has inhibitory activity on NLRP3 inflammasome activation. ODZ inhibited the cleavage of caspase-1 and IL-1ß-induced canonical NLRP3 inflammasome triggers, but had no effect on those induced by AIM2 or NLRC4 triggers. Mechanistically, ODZ impairs NLRP3 inflammasome activation through the inhibition of NLRP3-NEK7 interaction that is required for inflammasome formation. Moreover, the results obtained from the in silico docking experiment suggested that ODZ targets NLRP3 protein, which provides evidence for the specificity of ODZ to the NLRP3 inflammasome. Furthermore, ODZ administration significantly reduced MSU-induced IL-1ß release and the mortality rate of mice with LPS-induced sepsis. Collectively, these results demonstrate a novel effect of ODZ10117 in regulating NLRP3 inflammasome activation both in vitro and in vivo, making it a promising candidate for the treatment of NLRP3-inflammasome-associated immune disorders and cancer.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Caspase 1/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
Phospholipase C gamma 1 (PLCγ1) plays an oncogenic role in several cancers, alongside its usual physiological roles. Despite studies aimed at identifying the effect of PLCγ1 on tumors, the pathogenic role of PLCγ1 in the tumorigenesis and development of hepatocellular carcinoma (HCC) remains unknown. To investigate the function of PLCγ1 in HCC, we generated hepatocyte-specific PLCγ1 conditional knockout (PLCγ1f/f ; Alb-Cre) mice and induced HCC with diethylnitrosamine (DEN). Here, we identified that hepatocyte-specific PLCγ1 deletion effectively prevented DEN-induced HCC in mice. PLCγ1f/f ; Alb-Cre mice showed reduced tumor burden and tumor progression, as well as a decreased incidence of HCC and less marked proliferative and inflammatory responses. We also showed that oncogenic phenotypes such as repressed apoptosis, and promoted proliferation, cell cycle progression and migration, were induced by PLCγ1. In terms of molecular mechanism, PLCγ1 regulated the activation of signal transducer and activator of transcription 3 (STAT3) signaling. Moreover, PLCγ1 expression is elevated in human HCC and correlates with a poor prognosis in patients with HCC. Our results suggest that PLCγ1 promotes the pathogenic progression of HCC, and PLCγ1/STAT3 axis was identified as a potential therapeutic target pathway for HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Camundongos , Animais , Fator de Transcrição STAT3/genética , Carcinoma Hepatocelular/induzido quimicamente , Dietilnitrosamina/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Fosfolipase C gama/genética , Proliferação de Células , Carcinogênese/genéticaRESUMO
Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.
Assuntos
Antígeno B7-H1 , Neoplasias da Mama , Antígeno B7-H1/metabolismo , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
The resistance of highly aggressive glioblastoma multiforme (GBM) to chemotherapy is a major clinical problem resulting in a poor prognosis. GBM contains a rare population of self-renewing cancer stem cells (CSCs) that proliferate, spurring the growth of new tumors, and evade chemotherapy. In cancer, major vault protein (MVP) is thought to contribute to drug resistance. However, the role of MVP as CSCs marker remains unknown and whether MVP could sensitize GBM cells to Temozolomide (TMZ) also is unclear. We found that sensitivity to TMZ was suppressed by significantly increasing the MVP expression in GBM cells with TMZ resistance. Also, MVP was associated with the expression of other multidrug-resistant proteins in tumorsphere of TMZ-resistant GBM cell, and was highly co-expressed with CSC markers in tumorsphere culture. On the other hands, knockdown of MVP resulted in reduced sphere formation and invasive capacity. Moreover, high expression of MVP was associated with tumor malignancy and survival rate in glioblastoma patients. Our study describes that MVP is a potentially novel maker for glioblastoma stem cells and may be useful as a target for preventing TMZ resistance in GBM patients.
RESUMO
Gain- or loss-of-function mutations in Janus kinase 3 (JAK3) contribute to the pathogenesis of various haematopoietic malignancies and immune disorders, suggesting that aberrant JAK3 signalling is an attractive therapeutic target to treat these disorders. In this study, we performed structure-based computational database screening using the 3D structure of the JAK3 kinase domain and the National Cancer Institute diversity set and identified tubulosine as a novel JAK3 inhibitor. Tubulosine directly blocked the catalytic activity of JAK3 by selective interacting with the JAK3 kinase domain. Consistently, tubulosine potently inhibited persistently activated and interleukin-2-dependent JAK3, and JAK3-mediated downstream targets. Importantly, it did not affect the activity of other JAK family members, particularly prolactin-induced JAK2/signal transducer and activator of transcription 5 and interferon alpha-induced JAK1-TYK2/STAT1. Tubulosine specifically decreased survival and proliferation of cancer cells, in which persistently active JAK3 is expressed, by inducing apoptotic and necrotic/autophagic cell death without affecting other oncogenic signalling. Collectively, tubulosine is a potential small-molecule compound that selectively inhibits JAK3 activity, suggesting that it may serve as a promising therapeutic candidate for treating disorders caused by aberrant activation of JAK3 signalling.
Assuntos
Trifosfato de Adenosina/metabolismo , Emetina/análogos & derivados , Janus Quinase 3/antagonistas & inibidores , Transdução de Sinais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Emetina/química , Emetina/farmacologia , Humanos , Janus Quinase 3/metabolismo , Modelos Biológicos , Necrose , Oncogenes , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Although prostate cancer is clinically manageable during the early stages of progression, metastatic progression severely compromises the prognosis and leads to mortality. Constitutive activation of STAT3 has been connected to prostate cancer malignancy, and abolishing the STAT3 activity may diminish tumor growth and metastasis. However, its suppressor genes and pathways have not been well established. In this study, we show that promyelocytic leukemia zinc finger (PLZF) has a putative tumor-suppressor function in prostate cancer by inhibiting phosphorylation of STAT3. Compared with a benign prostate, high-grade prostate cancer patient tissue was negatively correlated with PLZF expression. PLZF depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, we demonstrated a novel role of PLZF as the transcriptional regulator of the tyrosine phosphatase SHP-1 that inhibits the oncogenic JAKs-STAT3 pathway. These results suggest that the collapse of PLZF expression by the CCL3 derived from fibroblasts accelerates the cell migration and invasion properties of prostate cancer cells. Our results suggest that increasing PLZF could be an attractive strategy for suppressing prostate cancer metastasis as well as for tumor growth.
RESUMO
Constitutively activated STAT3 plays an essential role in the initiation, progression, maintenance, malignancy, and drug resistance of cancer, including glioblastoma, suggesting that STAT3 is a potential therapeutic target for cancer therapy. We recently identified ODZ10117 as a small molecule inhibitor of STAT3 and suggested that it may have an effective therapeutic utility for the STAT3-targeted cancer therapy. Here, we demonstrated the therapeutic efficacy of ODZ10117 in glioblastoma by targeting STAT3. ODZ10117 inhibited migration and invasion and induced apoptotic cell death by targeting STAT3 in glioblastoma cells and patient-derived primary glioblastoma cells. In addition, ODZ10117 suppressed stem cell properties in glioma stem cells (GSCs). Finally, the administration of ODZ10117 showed significant therapeutic efficacy in mouse xenograft models of GSCs and glioblastoma cells. Collectively, ODZ10117 is a promising therapeutic candidate for glioblastoma by targeting STAT3.
Assuntos
Glioblastoma/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioblastoma/mortalidade , Humanos , Camundongos , Fator de Transcrição STAT3/uso terapêutico , Análise de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cancer stem-like cells (CSCs) can generate solid tumors through the properties of stem cells such as self-renewal and differentiation and they cause drug resistance, metastasis and recurrence. Therefore, establishing CSC lines is necessary to conduct various studies such as on the identification of CSC origin and specific targeted therapies. In this study, we stimulated NIH3T3 fibroblasts to exhibit the characteristics of CSCs using the whole protein lysates of B16F10 melanoma cells. As a result, we induced colony formation that displayed self-renewal and differentiation capacities through anchorage-independent culture and re-attached culture. Moreover, colonies showed drug resistance by being maintained in the G0/G1 state. Colonies expressed various CSC markers and displayed high-level drug efflux capacity. Additionally, colonies clearly demonstrated tumorigenic ability by forming a solid tumor in vivo. These results show that proteins of cancer cells could transform normal cells into CSCs by increasing expression of CSC markers. This study argues the tremendous importance of the extracellular microenvironmental effect on the generation of CSCs. It also provides a simple experimental method for deriving CSCs that could be based on the development of targeted therapy techniques.
Assuntos
Fibroblastos/citologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Células-Tronco Neoplásicas/citologia , Animais , Técnicas de Cultura de Células , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Fibroblastos/metabolismo , Fibroblastos/patologia , Camundongos , Células NIH 3T3 , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células Tumorais Cultivadas , Microambiente TumoralRESUMO
Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that regulates cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and immune responses. Aberrant STAT3 activation triggers tumor progression through oncogenic gene expression in numerous human cancers, leading to promote tumor malignancy. On the contrary, STAT3 activation in immune cells cause elevation of immunosuppressive factors. Accumulating evidence suggests that the tumor microenvironment closely interacts with the STAT3 signaling pathway. So, targeting STAT3 may improve tumor progression, and anti-cancer immune response. In this review, we summarized the role of STAT3 in cancer and the tumor microenvironment, and present inhibitors of STAT3 signaling cascades. [BMB Reports 2019; 52(7): 415-423].
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Antineoplásicos/química , Humanos , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral/efeitos dos fármacosRESUMO
Gravitational forces can impose physical stresses on the human body as it functions to maintain homeostasis. It has been reported that astronauts exposed to microgravity experience altered biological functions and many subsequent studies on the effects of microgravity have therefore been conducted. However, the anticancer mechanisms of simulated microgravity remain unclear. We previously showed that the proliferation of human Hodgkin's lymphoma (HL) cells was inhibited when these cells were cultured in time-averaged simulated microgravity (taSMG). In the present study, we investigated whether taSMG produced an anticancer effect. Exposure of human HL cells to taSMG for 2 days increased their reactive oxygen species (ROS) production and NADPH oxidase family gene expression, while mitochondrial mass, ATPase, ATP synthase, and intracellular ATP levels were decreased. Furthermore, human HL cells exposed to taSMG underwent autophagy via AMPK/Akt/mTOR and MAPK pathway modulation; such autophagy was inhibited by the ROS scavenger N-acetylcysteine (NAC). These results suggest an innovative therapeutic approach to HL that is markedly different from conventional chemotherapy and radiotherapy.
Assuntos
Autofagia/fisiologia , Doença de Hodgkin/terapia , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Simulação de Ausência de Peso , Acetilcisteína/farmacologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/patologia , Humanos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico/efeitos dos fármacosRESUMO
Cathepsin L of cancer cells has been shown to play an important role in degradation of extracellular matrix for metastasis. In order to reduce cell invasion, cathepsin L propeptide-like proteins which are classified as the I29 family in the MEROPS peptidase database were characterized from Calotropis procera R. Br., rich in cysteine protease. Of 19 candidates, the cloned and expressed recombinant SnuCalCp03-propeptide (rSnuCalCp03-propeptide) showed a low nanomolar Ki value of 2.3 ± 0.2 nM against cathepsin L. A significant inhibition of tumor cell invasion was observed with H1975, HT29, MDA-BM-231, PANC1, and PC3 with a 76, 67, 67, 63, and 79% reduction, respectively, in invasion observed in the presence of 400 nM of the rSnuCalCp03-propeptide. In addition, thermal and pH study showed rSnuCalCp03-propeptide consisting of secondary structures was stable at a broad range of temperatures (30-70 °C) and pH (2-10, except for 5 which is close to the isoelectric point of 5.2).
Assuntos
Calotropis/química , Catepsina L/metabolismo , Clonagem Molecular , Precursores Enzimáticos/metabolismo , Catepsina L/química , Catepsina L/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Precursores Enzimáticos/química , Precursores Enzimáticos/genética , Humanos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Mesenchymal stem cells (MSCs) have been suggested as a primary candidate for cell therapy applications because they have self-renewal and differentiation capabilities. Although they can be expanded in ex vivo system, clinical application of these cells is still limited because they survive poorly and undergo senescence or apoptosis when transplanted and exposed to environmental factors such as oxidative stress. Thus, reducing oxidative stress is expected to improve the efficacy of MSC therapy. The milk protein lactoferrin is a multifunctional iron-binding glycoprotein that plays various roles, including reduction of oxidative stress. Thus, we explored the effect of lactoferrin on oxidative stress-induced senescence and apoptosis of human MSCs (hMSCs). Measurement of reactive oxygen species (ROS) revealed that lactoferrin inhibited the production of hydrogen peroxide-induced intracellular ROS, suggesting lactoferrin as a good candidate as an antioxidant in hMSCs. Pretreatment of lactoferrin suppressed hydrogen peroxide-induced senescence of hMSCs. In addition, lactoferrin reduced hydrogen peroxide-induced apoptosis via inhibition of caspase-3 and Akt activation. These results demonstrate that lactoferrin can be a promising factor to protect hMSCs from oxidative stress-induced senescence and apoptosis, thus increasing the efficacy of MSC therapy.
Assuntos
Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Lactoferrina/farmacologia , Células-Tronco Mesenquimais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/metabolismo , Caspase 3/efeitos dos fármacos , Sobrevivência Celular , Humanos , Peróxido de Hidrogênio/farmacologia , Proteínas de Ligação ao Ferro/fisiologia , Proteína Oncogênica v-akt/efeitos dos fármacos , Substâncias Protetoras , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Gravity is omnipresent on Earth; however, humans in space, such as astronauts at the International Space Station, experience microgravity. Long-term exposure to microgravity is considered to elicit physiological changes, such as muscle atrophy, in the human body. In addition, certain types of cancer cells demonstrate inhibited proliferation under condition of time-averaged simulated microgravity (taSMG). However, the response of human Hodgkin's lymphoma cancer cells to reduced gravity, and the associated physiological changes in these cells, have not been elucidated. METHODS: In this study, the proliferation of human Hodgkin's lymphoma cancer cells (L-540 and HDLM-2) under taSMG condition (<10-3 G, 1 G is defined as 9.8 m/s2) was studied using a 3D clinostat. Normal human dermal fibroblast (HDF) was proliferated in the same condition as a control group. For the development of 3D clinostat, two motors were used to actuate the frames. Electrical wires for power supply and communication were connected via slip ring. For symmetrical path of gravitational vector, optimal angular velocities of the motors were found using simulation results. Under the condition of taSMG implemented by the 3D clinostat, proliferation of the cells was observed for 3 days. RESULTS: The results indicated that proliferation of these cancer cells was significantly (p < 0.0005) inhibited under taSMG, whereas proliferation of normal HDF cells was not affected. CONCLUSIONS: Findings in this study could be significantly valuable in developing novel strategies for selective killing of cancer cells such as lymphoma.
Assuntos
Proliferação de Células , Doença de Hodgkin/patologia , Doença de Hodgkin/fisiopatologia , Simulação de Ausência de Peso/instrumentação , Simulação de Ausência de Peso/métodos , Ausência de Peso , Apoptose , Reatores Biológicos , Linhagem Celular Tumoral , Desenho de Equipamento , Análise de Falha de Equipamento , Humanos , RotaçãoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng is one of the most well-known medicinal herbs in Korea and China, which has been used for treatment and prevention of cancer, obesity, diabetes, and cardiovascular diseases. Ginsenosides are the major components of P. ginseng, having a wide range of pharmacological activities. Among the ginsenosides, protopanaxadiol (PPD)-types reportedly have potent anti-cancer effects. Rh2 is PPD-type ginsenoside, and two stereoisomeric forms of Rh2 as 20(S)- and 20(R)-Rh2 were selectively isolated recently. AIM OF THE STUDY: The biological activities of Rh2 ginsenosides are known to depend on their differences in stereochemistry. Colorectal cancer (CRC) is one of the most lethal neoplasm, and cancer-related death is usually associated with metastasis to other organs. We aimed this study to investigate whether 20(S)- and 20(R)-Rh2 can suppress tumor invasion in human CRC cells. MATERIALS AND METHODS: 20(S)- and 20(R)-Rh2 were isolated from the roots of ginseng. Human CRC cells were incubated with 20(S)- or 20(R)-Rh2 in the presence or absence of interleukin-6. An MTT assay was used to measure cell viability. Western blot and quantitative real-time PCR analyses were performed to determine levels of expression and phosphorylation. An invasion assay was performed using a Boyden chamber system with the Matrigel-coated membrane to measure cancer cell invasion. RESULTS: 20(S)- and 20(R)-Rh2 showed differential cytotoxic activity. Only 20(S)-Rh2 decreased cancer cell viability. Additionally, 20(S)-Rh2 effectively inhibited IL-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of matrix metalloproteinases (MMPs), including MMP-1, -2, and -9, resulting in inhibition of cancer cell invasion. Interestingly, these pharmacological activities of 20(S)-Rh2 were more potent than those of 20(R)-Rh2. Furthermore, combination treatment showed that 20(S)-Rh2 enhanced the sensitization of doxorubicin-treated anti-cancer activities in CRC cells. CONCLUSION: Our results demonstrated that ginsenoside 20(S)-Rh2 has therapeutic potential for the treatment with CRC and may be valuable as a combination partner with more classic chemotherapeutic agents, such as doxorubicin, to treat CRC.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Ginsenosídeos/farmacologia , Interleucina-6/antagonistas & inibidores , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/metabolismo , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Ginsenosídeos/uso terapêutico , Humanos , Interleucina-6/fisiologia , Metaloproteinases da Matriz/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
T-cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathologic immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite that multiple pharmacologic properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4(+) T-cell subsets by regulating the expression and production of T-cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited TCR-mediated Akt and NF-κB signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as 2,4,6-trinitrochlorobenzene-induced contact and atopic dermatitis and IL-23-induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4(+) T cell differentiation and overall immune responses.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dermatite Alérgica de Contato/imunologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Imunomodulação/efeitos dos fármacos , Animais , Biópsia por Agulha , Diferenciação Celular/imunologia , Células Cultivadas , Dermatite Alérgica de Contato/tratamento farmacológico , Dermatite Alérgica de Contato/patologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Imuno-Histoquímica , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Sensibilidade e Especificidade , Subpopulações de Linfócitos T/imunologiaRESUMO
Exposure of the skin to ultraviolet radiation can cause skin damage with various pathological changes including inflammation. In the present study, we identified the skin-protective activity of 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (pentagalloyl glucose, PGG) in ultraviolet B (UVB) radiation-induced human dermal fibroblasts and mouse skin. PGG exhibited antioxidant activity with regard to intracellular reactive oxygen species (ROS) generation as well as ROS and reactive nitrogen species (RNS) scavenging. Furthermore, PGG exhibited anti-inflammatory activity, inhibiting the activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, resulting in inhibition of the expression of pro-inflammatory mediators. Topical application of PGG followed by chronic exposure to UVB radiation in the dorsal skin of hairless mice resulted in a significant decrease in the progression of inflammatory skin damages, leading to inhibited activation of NF-κB signaling and expression of pro-inflammatory mediators. The present study demonstrated that PGG protected from skin damage induced by UVB radiation, and thus, may be a potential candidate for the prevention of environmental stimuli-induced inflammatory skin damage.
Assuntos
Taninos Hidrolisáveis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Radiodermite/prevenção & controle , Pele/efeitos dos fármacos , Protetores Solares/farmacologia , Raios Ultravioleta/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Pelados , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiaçãoRESUMO
Anti-tumor activity of the proteins from Gecko (GP) on cervical cancer cells, and its signaling mechanisms were assessed by viable cell counting, propidium iodide (PI) staining, and Western blot analysis. GP induced the cell death of HeLa cells in a dose-dependent manner while it did not affect the viability of normal cells. Western blot analysis showed that GP decreased the activation of Akt, and co-administration of GP and Akt inhibitors synergistically exerted anti-tumor activities on HeLa cells, suggesting the involvement of PI3-kinase/Akt pathway in GP-induced cell death of the cancer cells. Indeed, the cytotoxic effect of GP against HeLa cells was inhibited by overexpression of constituvely active form of Akt in HeLa cells. The candidates of the functional proteins in GP were analyzed by Mass-spectrum. Taken together, our results suggest that GP elicits anti-tumor activity against HeLa cells by inhibition of PI3-kinase/Akt pathway.