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1.
FEBS J ; 290(3): 692-711, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-35882390

RESUMEN

5-Bromodeoxyuridine (BrdU), a thymidine analogue, is an interesting reagent that modulates various biological phenomena. BrdU, upon incorporation into DNA, causes destabilized nucleosome positioning which leads to changes in heterochromatin organization and gene expression in cells. We have previously shown that BrdU effectively induces cellular senescence, a phenomenon of irreversible growth arrest in mammalian cells. Identification of the mechanism of action of BrdU would provide a novel insight into the molecular mechanisms of cellular senescence. Here, we showed that a basic domain in the histone H2B N-terminal tail, termed the HBR (histone H2B repression) domain, is involved in the action of BrdU. Notably, deletion of the HBR domain causes destabilized nucleosome positioning and derepression of gene expression, as does BrdU. We also showed that the genes up-regulated by BrdU significantly overlapped with those by deletion of the HBR domain, the result of which suggested that BrdU and deletion of the HBR domain act in a similar way. Furthermore, we showed that decreased HBR domain function induced cellular senescence or facilitated the induction of cellular senescence. These findings indicated that the HBR domain is crucially involved in the action of BrdU, and also suggested that disordered nucleosome organization may be involved in the induction of cellular senescence.


Asunto(s)
Histonas , Nucleosomas , Animales , Histonas/genética , Histonas/metabolismo , Bromodesoxiuridina/farmacología , ADN/metabolismo , Senescencia Celular/genética , Mamíferos/metabolismo
2.
Exp Cell Res ; 390(1): 111927, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32126237

RESUMEN

Cellular senescence is a phenomenon of irreversible growth arrest of mammalian somatic cells. Senescent cells increase the production of secretory proteins such as inflammatory cytokines, a phenomenon termed senescence-associated secretory phenotype (SASP). SASP is known to have profound effects on organismal health and aging; however, the molecular mechanisms of SASP are not precisely understood. In our previous studies, we have shown that senescent cells show decreased function of lamin B receptor (LBR), a nuclear membrane protein that regulates heterochromatin organization. Here we examined the implication of LBR in the regulation of SASP because senescent cells show altered heterochromatin organization, which would affect gene expression. We found that knock-down of LBR up-regulated the expression of the SASP factors such as IL-6, IL-8, and MMP1 in HeLa cells, even though cellular senescence was not induced by LBR knock-down. Conversely, enforced expression of LBR suppressed their up-regulated expression in senescent cells induced by excess thymidine. Further, our gene expression profile analysis also showed that many secretory proteins were up-regulated by LBR knock-down. We then analyzed the regulatory mechanisms of the expression of SASP factors by LBR, and found that the promoters of these SASP factors associated with LBR in normally growing cells, but dissociated from it in senescent cells. Additionally, we found that enforced expression of LBR decreased the generation of cytoplasmic DNA, which could be involved in SASP, in senescent cells. These findings suggested that LBR would play crucial roles in the regulation of SASP.


Asunto(s)
Senescencia Celular , Receptores Citoplasmáticos y Nucleares/genética , Vías Secretoras , Células Cultivadas , Células HeLa , Heterocromatina/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Fenotipo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptor de Lamina B
3.
J Cosmet Dermatol ; 19(11): 3083-3090, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32125089

RESUMEN

BACKGROUND: Cellular senescence, a phenomenon of irreversible growth arrest of mammalian cells, is involved in various age-related phenomena in organisms. Hair follicle dermal papilla (DP) cells play important roles in the regulation of hair growth and loss. AIMS: We examined the implication of cellular senescence of DP cells in androgenetic alopecia (AGA), the most common form of male hair loss, and searched for the compounds that have a beneficial effect on the prevention of AGA. PATIENTS/METHODS: Expression of the 5α-reductase type II (SRD5A2) gene, which plays a key role in the development of AGA, was examined by quantitative RT-PCR and Western blotting analysis in DP cells. Besides, DP cells were cultured with the extracts of herbs used in traditional Ayurvedic medicine to search for the compounds that have a beneficial effect on the growth of DP cells. RESULTS: We found that expression of the SRD5A2 was up-regulated in senescent DP cells. We also found that the herbal extract of Plumbago zeylanica (root) enhanced the growth of DP cells and down-regulated the expression of SRD5A2 in DP cells. Further, plumbagin, an ingredient of P zeylanica, would be responsible for the above effects of P zeylanica. CONCLUSION: These results suggested the possibility that senescent DP cells may have a role in the development of AGA through up-regulating SRD5A2 expression, and the P zeylanica extract and plumbagin may suppress its development through enhancing the growth of DP cells and down-regulating SRD5A2 expression in DP cells.


Asunto(s)
Folículo Piloso , Plumbaginaceae , Animales , Colestenona 5 alfa-Reductasa/genética , Regulación hacia Abajo , Masculino , Extractos Vegetales/farmacología
4.
FEBS Open Bio ; 10(2): 237-250, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31825172

RESUMEN

Cellular senescence is a terminal growth arrest phenomenon in mammalian cells. Coordinated regulation of protein synthesis and degradation is required to maintain protein homeostasis in cells; however, senescent cells exhibit decreased activity of the proteasome, a major cellular proteolytic machinery, with an accumulation of proteins. Indeed, we showed that MG132, a proteasome inhibitor, induced cellular senescence through an accumulation of proteins in human cells. We then investigated the mechanisms of cellular senescence induced by protein accumulation by treating cells with MG132. We found that lamin B receptor (LBR), a nuclear membrane protein that regulates heterochromatin organization, was mislocalized and down-regulated in cells on treatment with MG132. Importantly, enforced expression of LBR suppressed cellular senescence induced by MG132. We also showed that LBR was involved in the regulation of chromatin organization in senescent cells, and that endoplasmic reticulum stress and autophagy were likely to be involved in the mislocalization and down-regulation of LBR. These findings indicate that decreased LBR function was responsible for the induction of cellular senescence by MG132, and thus suggest that protein accumulation caused by inhibition of the proteasome induced cellular senescence probably through chromatin dysregulation in human cells.


Asunto(s)
Senescencia Celular/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Línea Celular Tumoral , Senescencia Celular/fisiología , Cromatina , Citoplasma , Células HeLa , Humanos , Lamina Tipo B/metabolismo , Leupeptinas/farmacología , Proteínas de la Membrana , Complejo de la Endopetidasa Proteasomal/genética , Receptores Citoplasmáticos y Nucleares/genética , Receptor de Lamina B
5.
J Integr Med ; 17(2): 141-146, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30709781

RESUMEN

OBJECTIVE: Keratinocytes are the predominant cell type in the epidermis and play key roles in epidermal function. Thus, identification of the compounds that regulate the growth of keratinocytes is of importance. Here we searched for such compounds from the herbs used in traditional medicine Ayurveda. METHODS: Human keratinocytes were cultured in the presence or absence of the herbal extracts for 2 weeks; the effect of the extracts on cell growth was determined by staining the cells with Coomassie brilliant blue. To detect the compounds that regulate the growth of keratinocytes, the herbal extracts were subjected to high-performance liquid chromatography (HPLC). RESULTS: We found that the extract of Emblica officinalis enhanced the growth of keratinocytes in culture. Further, we fractionated the extract of E. officinalis using HPLC and identified the fractions responsible for the enhanced growth of keratinocytes. CONCLUSION: The extract of E. officinalis enhanced the growth of human keratinocytes in culture. E. officinalis contains the compounds that would be beneficial for human skin health because enhanced growth of keratinocytes would promote wound healing.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Sustancias de Crecimiento/farmacología , Queratinocitos/efectos de los fármacos , Phyllanthus emblica/química , Extractos Vegetales/farmacología , Cromatografía Líquida de Alta Presión , Sustancias de Crecimiento/análisis , Humanos , Queratinocitos/citología , Extractos Vegetales/análisis
6.
Mech Ageing Dev ; 178: 25-32, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30615890

RESUMEN

Cellular senescence is a phenomenon of irreversible growth arrest in mammalian somatic cells in culture. Various stresses induce cellular senescence and indeed, we have found that excess thymidine effectively induces cellular senescence in human cells. Further, many reports indicate the implication of chromatin proteins in cellular senescence. Here we analysed the role of lamin B receptor (LBR), a nuclear envelope protein that regulates heterochromatin organization, in cellular senescence induced by excess thymidine. We then found that the LBR protein was down-regulated and showed aberrant localization in cells upon induction of cellular senescence by excess thymidine. Additionally, we also found that knock-down of LBR facilitated the induction of cellular senescence by excess thymidine in cancerous HeLa cells, and importantly, it induced cellular senescence in normal human diploid fibroblast TIG-7 cells. These results suggested that decreased LBR function is involved in the induction of cellular senescence in human cells.


Asunto(s)
Senescencia Celular/fisiología , Receptores Citoplasmáticos y Nucleares/metabolismo , Bromodesoxiuridina/farmacología , Senescencia Celular/genética , Daño del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Células HeLa , Heterocromatina/metabolismo , Humanos , Lamina Tipo B/metabolismo , Membrana Nuclear/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Timidina/farmacología , Receptor de Lamina B
7.
Biochem Cell Biol ; 95(4): 517-523, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28380310

RESUMEN

Enforced expression of GNG11, G-protein subunit γ 11, induces cellular senescence in normal human diploid fibroblasts. We here examined the effect of the expression of GNG11 on the growth of immortalized human cell lines, and found that it suppressed the growth of SUSM-1 cells, but not of HeLa cells. We then compared these two cell lines to understand the molecular basis for the action of GNG11. We found that expression of GNG11 induced the generation of reactive oxygen species (ROS) and abnormal nuclear morphology in SUSM-1 cells but not in HeLa cells. Increased ROS generation by GNG11 would likely be caused by the down-regulation of the antioxidant enzymes in SUSM-1 cells. We also found that SUSM-1 cells, even under normal culture conditions, showed higher levels of ROS and higher incidence of abnormal nuclear morphology than HeLa cells, and that abnormal nuclear morphology was relevant to the increased ROS generation in SUSM-1 cells. Thus, SUSM-1 and HeLa cells showed differences in the regulation of ROS and nuclear morphology, which might account for their different responses to the expression of GNG11. Thus, SUSM-1 cells may provide a unique system to study the regulatory relationship between ROS generation, nuclear morphology, and G-protein signaling.


Asunto(s)
Núcleo Celular/metabolismo , Núcleo Celular/patología , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular , Células Cultivadas , Células HeLa , Humanos
8.
Curr Genet ; 63(5): 895-907, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28289833

RESUMEN

Oxygen is essential for aerobic organisms but causes cytotoxicity probably through the generation of reactive oxygen species (ROS). In this study, we screened for the genes that regulate oxidative stress in the yeast Saccharomyces cerevisiae, and found that expression of CTH2/TIS11 caused an increased resistance to ROS. CTH2 is up-regulated upon iron starvation and functions to remodel metabolism to adapt to iron starvation. We showed here that increased resistance to ROS by CTH2 would likely be caused by the decreased ROS production due to the decreased activity of mitochondrial respiration, which observation is consistent with the fact that CTH2 down-regulates the mitochondrial respiratory proteins. We also found that expression of CTH1, a paralog of CTH2, also caused an increased resistance to ROS. This finding supported the above view, because mitochondrial respiratory proteins are the common targets of CTH1 and CTH2. We further showed that supplementation of iron in medium augmented the growth of S. cerevisiae under oxidative stress, and expression of CTH2 and supplementation of iron collectively enhanced its growth under oxidative stress. Since CTH2 is regulated by iron, these findings suggested that iron played crucial roles in the regulation of oxidative stress in S. cerevisiae.


Asunto(s)
Hierro/metabolismo , Estrés Oxidativo , Saccharomyces cerevisiae/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias/genética , Mitocondrias/metabolismo , Modelos Biológicos , Especies Reactivas de Oxígeno/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tristetraprolina/genética , Tristetraprolina/metabolismo
9.
J Biosci ; 41(4): 569-575, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27966480

RESUMEN

Ayurveda is a holistic medical system of traditional medicine, and Triphala is one of the most popular formulations in Ayurveda. Triphala is composed of three kinds of herb, Terminalia chebula, Terminalia bellirica, and Emblica officinalis. Since Triphala is shown to exhibit a protective activity against ionizing radiation in mice, we investigated its activity in HeLa cells. We found that Triphala showed the protective effects against X-radiation and bleomycin, both of which generate DNA strand breaks, in HeLa cells. Further, Triphala efficiently eliminated reactive oxygen species (ROS) in HeLa cells. Thus, the antioxidant activity of Triphala would likely play a role in its protective actions against X-radiation and bleomycin because both agents damage DNA through the generation of ROS. These observations suggested that the radioprotective activity of Triphala can be, at least partly, studied with the cells cultured in vitro. The simple bioassay system with human cultured cells would facilitate the understanding of the molecular basis for the beneficial effects of Triphala.


Asunto(s)
Antioxidantes/administración & dosificación , Medicina Ayurvédica , Extractos Vegetales/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/química , Bleomicina/efectos adversos , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Células HeLa , Humanos , Ratones , Phyllanthus emblica/química , Extractos Vegetales/química , Terminalia/química , Rayos X
10.
J Integr Med ; 14(6): 473-479, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27854199

RESUMEN

OBJECTIVE: Chronic exposure to ultraviolet (UV) radiation induces skin photoaging (premature skin aging). UV irradiation generates reactive oxygen species (ROS), which are shown to play a pivotal role in skin photoaging. Ayurveda is a holistic traditional medical system, and Chyawanprash is one of the most popular formulations in Ayurveda. Since maintenance of the function and appearance of skin is important, we examined whether Chyawanprash has a protective effect on skin photoaging. METHODS: To examine the effect of Chyawanprash on skin photoaging, hairless mice were administered with Chyawanprash in drinking water for 3 weeks, and then repeatedly exposed to ultraviolet light B (UVB) irradiation (225 or 450 mJ/cm2) to induce skin photoaging. To further examine the function of Chyawanprash, its effects were examined in cells cultured in vitro. Chyawanprash was added in culture medium, and examined for the effect on the growth of human keratinocytes, and for the ability to eliminate ROS which generated by paraquat (50 µmol/L) in HeLa cells. RESULTS: UVB irradiation caused symptoms such as rough skin, erythema, and edema on the skin in hairless mice, but administration of Chyawanprash relieved these symptoms. Further, Chyawanprash significantly suppressed epidermal thickening, a typical marker of skin photoaging, in mice. We then analyzed the effect of Chyawanprash in human cells in culture, and found that Chyawanprash enhanced the growth of human keratinocytes, and efficiently eliminated ROS, which are causally involved in skin photoaging, in HeLa cells. CONCLUSION: These findings suggested that Chyawanprash may have beneficial effects on slowing skin photoaging.


Asunto(s)
Medicina Ayurvédica , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Preparaciones de Plantas/farmacología , Envejecimiento de la Piel/efectos de los fármacos , Piel/efectos de los fármacos , Rayos Ultravioleta/efectos adversos , Animales , Femenino , Fibroblastos/metabolismo , Células HeLa , Humanos , Queratinocitos/efectos de los fármacos , Ratones Pelados , Paraquat , Especies Reactivas de Oxígeno/metabolismo , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación
11.
Exp Cell Res ; 346(2): 216-23, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27443255

RESUMEN

DNA damage response is crucially involved in cellular senescence. We have previously shown that excess thymidine, which stalls DNA replication forks, induces cellular senescence in human cells, and ERK1/2 play a key role in the induction of it. In this study, we found that Chk1 and ERK1/2 were activated to promote cell survival upon addition of excess thymidine. Knockdown of ERK1/2 activated Chk1, and conversely, knockdown of Chk1 activated ERK1/2, which observations suggested a mechanism for compensatory activation of Chk1 and ERK1/2 in the absence of ERK1/2 and Chk1, respectively. We also found that Chk1 functioned mainly at the onset of cellular senescence, and on the other hand, ERK1/2 functioned for a more extended period to induce cellular senescence. Our findings suggested that Chk1 and ERK1/2 were activated to promote cell survival upon addition of excess thymidine, but prolonged activation of ERK1/2 led to cellular senescence. This implies a pleiotropic effect of ERK1/2 in cellular senescence induced by excess thymidine.


Asunto(s)
Senescencia Celular/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Timidina/farmacología , Western Blotting , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Quinasa de Punto de Control 2/metabolismo , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Unión Proteica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factores de Tiempo
12.
Exp Cell Res ; 345(2): 239-46, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27339653

RESUMEN

Mammalian cells, when treated with sub-lethal doses of genotoxic stresses, slow down DNA synthesis but continue protein synthesis. Thus, these cells show an accumulation of proteins and undergo unbalanced growth. In the previous studies, we have shown that HeLa cells treated with excess thymidine or camptothecin undergo unbalanced growth, and prolonged unbalanced growth causes induction of cellular senescence, which is suppressed by restriction of protein synthesis or inhibition of ERK-signaling. In this study, we found that restriction of protein synthesis, inhibition of ERK-signaling, and elimination of reactive oxygen species showed a combinatorial effect on suppression of cellular senescence induced by excess thymidine or camptothecin. Of these, restriction of protein synthesis most effectively suppressed cellular senescence. Importantly, a similar combinatorial effect was observed in replicative senescence in normal human diploid fibroblasts. Our findings suggested that various stresses were cumulatively involved in cellular senescence, and suppression of cellular senescence was improved by combining the treatments that reduce the stresses.


Asunto(s)
Senescencia Celular , Sistema de Señalización de MAP Quinasas , Biosíntesis de Proteínas , Especies Reactivas de Oxígeno/metabolismo , Antioxidantes/farmacología , Butadienos/farmacología , Camptotecina/farmacología , Tamaño de la Célula/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Cicloheximida/farmacología , Daño del ADN , Células HeLa , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Nitrilos/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Timidina/farmacología
13.
Biochem Biophys Res Commun ; 473(4): 1078-1083, 2016 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-27059139

RESUMEN

5-Bromodeoxyuridine (BrdU), a thymidine analogue, induces cellular senescence in mammalian cells. BrdU induces cellular senescence probably through the regulation of chromatin because BrdU destabilizes or disrupts nucleosome positioning and decondenses heterochromatin. Since heterochromatin is tethered to the nuclear periphery through the interaction with the nuclear envelope proteins, we examined the localization of the several nuclear envelope proteins such as lamins, lamin-interacting proteins, nuclear pore complex proteins, and nuclear transport proteins in senescent cells. We have shown here that lamin B receptor (LBR) showed a change in localization in both BrdU-induced and replicative senescent cells.


Asunto(s)
Senescencia Celular/fisiología , Laminas/metabolismo , Membrana Nuclear/metabolismo , Membrana Nuclear/ultraestructura , Receptores Citoplasmáticos y Nucleares/metabolismo , Bromodesoxiuridina/farmacología , Células HeLa , Humanos , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismo , Distribución Tisular/efectos de los fármacos , Receptor de Lamina B
14.
Sci Rep ; 6: 18722, 2016 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-26729469

RESUMEN

Cellular senescence or its equivalence is induced by treatment of cells with an appropriate inducer of senescence in various cell types. Mild restriction of cytoplasmic protein synthesis prevented induction of all aspects of cellular senescence in normal and tumor-derived human cells. It allowed the cells to continuously grow with no sign of senescent features in the presence of various inducers. It also delayed replicative senescence in normal human fibroblasts. Moreover, it allowed for growth of the cells that had entered a senescent state. When adult worms of the nematode C. elegans were grown under protein-restricted conditions, their average and maximal lifespans were significantly extended. These results suggest that accumulation of cytoplasmic proteins due to imbalance in macromolecule synthesis is a fundamental cause of cellular senescence.


Asunto(s)
Envejecimiento , Caenorhabditis elegans/fisiología , Senescencia Celular , Biosíntesis de Proteínas , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular , Tamaño de la Célula/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Cicloheximida/farmacología , Humanos , Longevidad/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos
15.
Mol Cell Biochem ; 411(1-2): 117-25, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26463993

RESUMEN

Cell swelling and retardation in DNA replication are always observed in senescent cells. When DNA replication is slowed down with RNA and protein syntheses unchanged in proliferating cells, it causes a phenomenon known as unbalanced growth. The purpose of this study is to assess the role of cell swelling in unbalanced growth in terms of senescence and investigate the mechanism underlying this phenomenon. We tried to induce cell swelling with minimum damage to cells in this study. We perturbed the osmoregulatory functions to induce cell swelling under hypotonic and hypertonic conditions in normal human fibroblasts. Addition of excess NaCl was found to induce significant cell and nuclear swelling in dose- and time-dependent manners. Excess NaCl immediately retarded DNA replication, accumulated cells at G1 phase of the cell cycle, and eventually deprived division potential of the cells. Such cells showed typical senescent cell shape followed by expression of the typical senescence-associated genes. Excess NaCl also activated ERK1/2, p38, and JNK of the mitogen activated protein kinase family. Addition of U0126, an inhibitor of ERK1/2, prevented appearance of senescent features induced by excess NaCl. These results suggest that hypertonic conditions induce cell swelling due to unbalanced growth, thereby leading to cellular senescence.


Asunto(s)
Senescencia Celular/efectos de los fármacos , Cloruro de Sodio/administración & dosificación , Línea Celular Transformada , Humanos , Cloruro de Sodio/farmacología
16.
Biosci Biotechnol Biochem ; 78(12): 2022-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25198914

RESUMEN

Sublethal doses of surfactants as exemplified by NP-40 clearly induce premature senescence in normal human cells. To understand molecular basis for this phenomenon, we tried to suppress it with use of various inhibitors. An inhibitor of p38 of the MAPK family almost completely suppressed growth arrest and morphological changes induced by surfactants; however, other inhibitors tested had no effect. Oleic acid, a weak inducer of premature senescence, was found to suppress the effect of NP-40. Fluorescein-labeled oleic acid rapidly bound to the cell surface, and this binding was clearly blocked by pre-treatment with surfactants, suggesting that surfactants and oleic acid compete for binding to the cell surface. Moderate concentrations of cycloheximide, an inhibitor of protein synthesis, also suppressed the senescent features induced by NP-40. These results suggest that surfactants activate p38 signaling pathway by binding to the cell surface, and induce cellular senescence.


Asunto(s)
Fibroblastos/efectos de los fármacos , Imidazoles/farmacología , Queratinocitos/efectos de los fármacos , Octoxinol/farmacología , Polietilenglicoles/farmacología , Piridinas/farmacología , Tensoactivos/farmacología , Unión Competitiva , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Cicloheximida/farmacología , Fibroblastos/citología , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Genes Reporteros , Células HeLa , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Ácido Oléico/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Transducción de Señal , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
17.
Biochem Biophys Res Commun ; 425(4): 897-901, 2012 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-22902634

RESUMEN

Excess thymidine induces unbalanced growth by delaying DNA replication and subsequently induces senescence in every human cell type. Our previous studies with use of inhibitors suggested that ERK1/2 has a major role in these processes. Here we directly assessed the roles of ERK1 and ERK2 in unbalanced growth induced by excess thymidine. Knockdown of ERK2 and ERK1 by vector-based RNA interference prevented loss of colony forming ability and appearance of senescence markers induced by excess thymidine in HeLa and TIG-7 cells, respectively. Such cells continued growing in the presence of excess thymidine. Double knockdown of ERK1 and ERK2 did not improve the effects of single knockdowns of ERK1 and ERK2 in either cell types. These results demonstrate that ERK1 or ERK2 has a major role in manifestation of unbalanced growth in human cells.


Asunto(s)
Senescencia Celular/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Timidina/metabolismo , División Celular/genética , División Celular/fisiología , Senescencia Celular/genética , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Sistema de Señalización de MAP Quinasas/genética , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Fosforilación , Interferencia de ARN
18.
Biochem Biophys Res Commun ; 420(3): 552-7, 2012 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-22445755

RESUMEN

Oxygen is essential for animals, but high concentrations of oxygen are toxic to them probably because of an increase in reactive oxygen species (ROS). Many genes are involved in the regulation of ROS, but they largely remain to be identified. To identify these genes, we employed the nematode Caenorhabditis elegans as a model organism, and systematically screened for genes that, when down-regulated by RNAi, lead to an increased sensitivity to ROS. We examined approximately 2400 genes on linkage group I and found that knock-down of 9 genes which participate in various cellular functions led to an increased sensitivity to ROS. This finding suggests an implication of a variety of cellular processes in the regulation of oxidative stress.


Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Regulación de la Expresión Génica/fisiología , Estrés Oxidativo/genética , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/fisiología , Regulación hacia Abajo , Regulación de la Expresión Génica/efectos de los fármacos , Pruebas Genéticas , Carbonilación Proteica , Interferencia de ARN , Especies Reactivas de Oxígeno/farmacología
19.
Genes Cells ; 16(10): 1022-34, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21895890

RESUMEN

rad-8 is an interesting mutant that shows increased sensitivities to UV radiation and reactive oxygen species in the nematode Caenorhabditis elegans. In this study, we have characterized rad-8 and have found that rad-8 showed several phenotypes of mitochondrial dysfunction such as a decreased activity of the respiratory chain, increased generation of superoxide anions, increased oxidative damage, increased apoptosis, and abnormal mitochondrial structure. Our genetic analysis has also indicated that rad-8 has a causative mutation in the F56H1.6 gene, which encodes a mitochondrial dehydrogenase/reductase. The functional role of RAD-8 may be evolutionarily conserved because expression of the putative human homologue RTN4IP/NIMP in rad-8 rescued the increased sensitivity to oxygen in rad-8. These results suggest that RAD-8 plays an important role in oxygen metabolism in mitochondria in higher eukaryotes.


Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Genes Mitocondriales , Mitocondrias/enzimología , Mutación/genética , Estrés Oxidativo , Oxidorreductasas/genética , Secuencia de Aminoácidos , Animales , Apoptosis/genética , Caenorhabditis elegans/enzimología , Clonación Molecular , Transporte de Electrón/fisiología , Expresión Génica , Regulación de la Expresión Génica , Masculino , Mitocondrias/genética , Mitocondrias/ultraestructura , Datos de Secuencia Molecular , Oxidorreductasas/metabolismo , Alineación de Secuencia
20.
Biosci Biotechnol Biochem ; 75(7): 1395-8, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21737914

RESUMEN

We evaluated the cytotoxicity of surfactants in human cells. Synthetic surfactants showed different cytotoxicity levels depending on their structures. The cytotoxicity of commercial washing products was determined mainly by the contents of surfactants. All of them induced premature senescence in normal cells, but not in tumor-derived or immortalized cells, under sublethal conditions. Residual surfactants might be a risk factor for skin aging.


Asunto(s)
Senescencia Celular/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Piel/efectos de los fármacos , Piel/patología , Tensoactivos/toxicidad , Línea Celular , Colagenasas/efectos de los fármacos , Colagenasas/metabolismo , Fibronectinas/efectos de los fármacos , Fibronectinas/metabolismo , Humanos , Inhibidor 1 de Activador Plasminogénico/metabolismo , Tensoactivos/administración & dosificación
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