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1.
COPD ; 20(1): 109-118, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-36882376

RESUMEN

Aberrant communication in alveolar epithelium is a major feature of inflammatory response for the airway remodeling leading to chronic obstructive pulmonary disease (COPD). In this study, we investigated the effect of protein transduction domains (PTD) conjugated Basic Fibroblast Growth Factor (FGF2) (PTD-FGF2) in response to cigarette smoke extract (CSE) in MLE-12 cells and porcine pancreatic elastase (PPE)-induced emphysematous mice. When PPE-induced mice were intraperitoneally treated with 0.1-0.5 mg/kg PTD-FGF2 or FGF2, the linear intercept, infiltration of inflammatory cells into alveoli and pro-inflammatory cytokines were significantly decreased. In western blot analysis, phosphorylated protein levels of c-Jun N-terminal Kinase 1/2 (JNK1/2), extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinases (MAPK) were decreased in PPE-induced mice treated PTD-FGF2. In MLE-12 cells, PTD-FGF2 treatment decreased reactive oxygen species (ROS) production and further decreased Interleukin-6 (IL-6) and IL-1b cytokines in response to CSE. In addition, phosphorylated protein levels of ERK1/2, JNK1/2 and p38 MAPK were reduced. We next determined microRNA expression in the isolated exosomes of MLE-12 cells. In reverse transcription-polymerase chain reaction (RT-PCR) analysis, level of let-7c miRNA was significantly increased while levels of miR-9 and miR-155 were decreased in response to CSE. These data suggest that PTD-FGF2 treatment plays a protective role in regulation of let-7c, miR-9 and miR-155 miRNA expressions and MAPK signaling pathways in CSE-induced MLE-12 cells and PPE-induced emphysematous mice.


Asunto(s)
Enfisema , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Animales , Ratones , Porcinos , Elastasa Pancreática , Factor 2 de Crecimiento de Fibroblastos/genética , Células Epiteliales Alveolares , Enfisema Pulmonar/inducido químicamente , Citocinas/genética
2.
FASEB J ; 31(5): 2076-2089, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28148566

RESUMEN

The receptor for advanced glycan end products (RAGE) has been identified as a susceptibility gene for chronic obstructive pulmonary disease (COPD) in genome-wide association studies (GWASs). However, less is known about how RAGE is involved in the pathogenesis of COPD. To determine the molecular mechanism by which RAGE influences COPD in experimental COPD models, we investigated the efficacy of the RAGE-specific antagonist FPS-ZM1 administration in in vivo and in vitro COPD models. We injected elastase intratracheally and the RAGE antagonist FPS-ZM1 in mice, and the infiltrated inflammatory cells and cytokines were assessed by ELISA. Cellular expression of RAGE was determined in protein, serum, and bronchoalveolar lavage fluid of mice and lungs and serum of human donors and patients with COPD. Downstream damage-associated molecular pattern (DAMP) pathway activation in vivo and in vitro and in patients with COPD was assessed by immunofluorescence staining, Western blot analysis, and ELISA. The expression of membrane RAGE in initiating the inflammatory response and of soluble RAGE acting as a decoy were associated with up-regulation of the DAMP-related signaling pathway via Nrf2. FPS-ZM1 administration significantly reversed emphysema in the lung of mice. Moreover, FPS-ZM1 treatment significantly reduced lung inflammation in Nrf2+/+ , but not in Nrf2-/- mice. Thus, our data indicate for the first time that RAGE inhibition has an essential protective role in COPD. Our observation of RAGE inhibition provided novel insight into its potential as a therapeutic target in emphysema/COPD.-Lee, H., Park, J.-R., Kim, W. J., Sundar, I. K., Rahman, I., Park, S.-M., Yang. S.-R. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signaling.


Asunto(s)
Elastasa Pancreática/farmacología , Enfisema Pulmonar/metabolismo , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Animales , Citocinas/metabolismo , Humanos , Pulmón/metabolismo , Ratones Endogámicos C57BL , Enfisema Pulmonar/inducido químicamente , Regulación hacia Arriba
3.
Clin Exp Pharmacol Physiol ; 43(9): 808-17, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27218229

RESUMEN

This study investigated the alteration of voltage-dependent K(+) (Kv) channels in mesenteric arterial smooth muscle cells from control (Long-Evans Tokushima Otsuka [LETO]) and diabetic (Otsuka Long-Evans Tokushima Fatty [OLETF]) rats during the early and chronic phases of diabetes. We demonstrated alterations in the mesenteric Kv channels during the early and chronic phase of diabetes using the patch-clamp technique, the arterial tone measurement system, and RT-PCR in Long-Evans Tokushima (LETO; for control) and Otsuka Long-Evans Tokushima Fatty (OLETF; for diabetes) type 2 diabetic model rats. In the early phase of diabetes, the amplitude of mesenteric Kv currents induced by depolarizing pulses was greater in OLETF rats than in LETO rats. The contractile response of the mesenteric artery induced by the Kv inhibitor, 4-aminopyridine (4-AP), was also greater in OLETF rats. The expression of most Kv subtypes- including Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv1.6, Kv2.1, Kv3.2, Kv4.1, Kv4.3, Kv5.1, Kv6.2, Kv8.1, Kv9.3, and Kv10.1-were increased in mesenteric arterial smooth muscle from OLETF rats compared with LETO rats. However, in the chronic phase of diabetes, the Kv current amplitude did not differ between LETO and OLETF rats. In addition, the 4-AP-induced contractile response of the mesenteric artery and the expression of Kv subtypes did not differ between the two groups. The increased Kv current amplitude and Kv channel-related contractile response were attributable to the increase in Kv channel expression during the early phase of diabetes. The increased Kv current amplitude and Kv channel-related contractile response were reversed during the chronic phase of diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Arterias Mesentéricas/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismo , Enfermedad Aguda , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Enfermedad Crónica , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Regulación de la Expresión Génica/efectos de los fármacos , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiopatología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Ratas , Vasoconstricción/efectos de los fármacos
4.
PLoS Pathog ; 9(10): e1003646, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24098117

RESUMEN

Thioredoxin-interacting protein (TXNIP) has multiple functions, including tumor suppression and involvement in cell proliferation and apoptosis. However, its role in the inflammatory process remains unclear. In this report, we demonstrate that Txnip⁻/⁻ mice are significantly more susceptible to lipopolysaccharide (LPS)-induced endotoxic shock. In response to LPS, Txnip⁻/⁻ macrophages produced significantly higher levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS), and an iNOS inhibitor rescued Txnip⁻/⁻ mice from endotoxic shock-induced death, demonstrating that NO is a major factor in TXNIP-mediated endotoxic shock. This susceptibility phenotype of Txnip⁻/⁻ mice occurred despite reduced IL-1ß secretion due to increased S-nitrosylation of NLRP3 compared to wild-type controls. Taken together, these data demonstrate that TXNIP is a novel molecule that links NO synthesis and NLRP3 inflammasome activation during endotoxic shock.


Asunto(s)
Proteínas Portadoras/metabolismo , Inflamasomas/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Choque Séptico/metabolismo , Tiorredoxinas/metabolismo , Animales , Proteínas Portadoras/genética , Inflamasomas/genética , Lipopolisacáridos/toxicidad , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Óxido Nítrico/genética , Óxido Nítrico Sintasa de Tipo II/genética , Choque Séptico/inducido químicamente , Choque Séptico/genética , Tiorredoxinas/genética
5.
Cell Tissue Bank ; 16(2): 209-18, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25163610

RESUMEN

Recent studies have reported that stem cells can be isolated from a wide range of tissues including bone marrow, fatty tissue, adipose tissue and placenta. Moreover, several studies also suggest that skin dermis could serve as a source of stem cells, but are of unclear phenotype. Therefore, we isolated and investigated to determine the potential of stem cell within human skin dermis. We isolated cells from human dermis, termed here as human dermis-derived mesenchymal stem cells (hDMSCs) which is able to be isolated by using explants culture method. Our method has an advantage over the enzymatic method as it is easier, less expensive and less cell damage. hDMSCs were maintained in basal culture media and proliferation potential was measured. hDMSCs were highly proliferative and successfully expanded with no additional growth factor. In addition, hDMSCs revealed normal karyotype and expressed high levels of CD90, CD73 and CD105 while did not express the surface markers for CD34, CD45 and HLA-DR. Also, we confirmed that hDMSCs possess the capacity to differentiate into multiple lineage including adipocyte, osteocyte, chondrocyte and precursor of hepatocyte lineage. Considering these results, we suggest that hDMSCs might be a valuable source of stem cells and could potentially be a useful source of clinical application.


Asunto(s)
Adipocitos/citología , Tejido Adiposo/citología , Diferenciación Celular/fisiología , Separación Celular , Dermis/citología , Células Madre Mesenquimatosas/citología , Técnicas de Cultivo de Célula/métodos , Proliferación Celular , Separación Celular/métodos , Condrocitos/citología , Humanos , Fenotipo , Células Madre/citología
6.
Cancer Sci ; 103(7): 1280-9, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22494103

RESUMEN

High dysadherin expression has been recognized as a biological predictor of metastasis and poor prognosis for many different cancer types; however, the molecular mechanisms of how dysadherin affects cancer progression are still poorly understood. In this study, we examined whether AKT signaling could link dysadherin expression with downstream events that promote the metastatic potential of human breast cancer cells. Immunohistochemical analysis of breast cancer tissues showed that dysadherin expression was highly associated with elevated expression of phospho-AKT. The introduction of dysadherin cDNA into BT-474, MCF-7 and T-47D breast cancer cell lines enhanced their levels of AKT phosphorylation, while knockdown of dysadherin in MDA-MB-231 and Hs578T breast cancer cell lines suppressed AKT phosphorylation. Treatment with the AKT inhibitor triciribine suppressed dysadherin-mediated pro-metastatic effects, including epithelial-mesenchymal transition, cell motility and drug resistance. These findings suggest that dysadherin might contribute to breast cancer progression through AKT activation.


Asunto(s)
Movimiento Celular , Glicoproteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular , Femenino , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica , Humanos , Immunoblotting , Canales Iónicos , Células MCF-7 , Glicoproteínas de Membrana/genética , Proteínas de Microfilamentos , Proteínas de Neoplasias/genética , Paclitaxel/farmacología , Fosforilación , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleósidos/farmacología
7.
Biochem Biophys Res Commun ; 425(2): 436-42, 2012 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-22846569

RESUMEN

Breast cancer is the leading cause of deaths from cancer in women. Cancer recurrence is the most common cause of mortality in breast cancer patients. The cancer stem cell (CSC) hypothesis proposes that CSCs are the center of cancer development and recurrence. Targeting CSCs, in combination with standard chemotherapy, may prevent cancer recurrence and improve long-term survival. Stem cells can be enriched in non-adherent sphere cultures. To identify molecular targets in breast CSCs, we evaluated the transcription levels of stem cell-related genes in 4T1 mouse mammary cancer cells grown as spheres or in a monolayer culture. The most differentially expressed gene was found to be wingless-type MMTV integration site family member 1 (Wnt1) in the 4T1 sphere culture. Functionally, knockdown of Wnt1 in breast cancer cell lines suppressed the in vitro properties of the stem-like cells, including their sphere-forming ability and ALDH activity, whereas the addition of recombinant Wnt1 to breast cancer cell lines enhanced the in vitro properties of these stem-like cells. In addition, knockdown of Wnt1 in 4T1 cells affected the properties of the stem-like cells in vivo, including their tumorigenic potential and tumor initiation ability. Collectively, these results suggest that Wnt1 expression may give rise to the properties of CSCs in breast tumors. Therefore, targeting Wnt1-associated signaling proteins may provide an effective therapeutic approach for the treatment of advanced breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Transformación Celular Neoplásica/metabolismo , Células Madre Neoplásicas/metabolismo , Proteína Wnt1/antagonistas & inhibidores , Animales , Neoplasias de la Mama/genética , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Células Madre Neoplásicas/patología , Proteína Wnt1/biosíntesis , Proteína Wnt1/genética
8.
Exp Mol Med ; 54(9): 1524-1535, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36117220

RESUMEN

Follicle-stimulating hormone (FSH) promotes the production and secretion of estrogen, which in turn stimulates the growth and maturation of ovarian follicles. Therefore, consecutive FSH treatment to induce ovarian hyperstimulation (superovulation) is still considered the most cost-effective option for the majority of assisted reproductive technologies (ARTs). However, a relatively high cancellation rate and subsequent low pregnancy outcomes (approximately 15%) are the most challenging aspects of this FSH-based ART. Currently, the main cause for this low implantation rate of FSH-based ART has not yet been revealed. Therefore, we hypothesized that these high cancellation rates with FSH-based superovulation protocols might be associated with the harmful effects of consecutive FSH treatment. Importantly, several recent studies have revealed that tissue-resident stem cell deficiency can significantly reduce cyclic endometrial regeneration and subsequently decrease the pregnancy outcome. In this context, we investigated whether FSH treatment could directly inhibit endometrial stem cell functions and consequently suppress endometrial regeneration. Consistent with our hypothesis, our results revealed for the first time that FSH could inhibit various regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, and multilineage differentiation capacities, via the PI3K/Akt and ERK1/2 signaling pathways both in vitro and in vivo.


Asunto(s)
Hormona Folículo Estimulante , Proteínas Relacionadas con la Folistatina , Estrógenos/farmacología , Femenino , Fertilización In Vitro/métodos , Hormona Folículo Estimulante/farmacología , Humanos , Fosfatidilinositol 3-Quinasas , Embarazo , Proteínas Proto-Oncogénicas c-akt , Células Madre
9.
Cell Death Dis ; 13(7): 605, 2022 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-35831270

RESUMEN

Luteinizing hormone (LH) stimulates the synthesis and secretion of the key steroid hormone estrogen, which subsequently promotes ovarian follicular growth and development. Therefore, the administration of exogenous LH to achieve superovulation (multiple ovulations) and an LH surge is commonly used as the most effective therapeutic option in a majority of in vitro fertilization (IVF) clinics. However, a relatively low pregnancy rate (between 20% and 35%) is one of the most challenging aspects of LH-based infertility treatment. Furthermore, the major cause of this low pregnancy rate in LH-based infertility treatment remains unidentified. Recent studies have shown that endometrial stem cell loss or deficiency can significantly decrease tissue regeneration ability during the menstrual cycle and reduce endometrial receptivity. In this context, we postulated that the low pregnancy rates following LH-based ovarian hyperactivation may be the result of the adverse effects of consecutive exogenous LH administration on endometrial stem cells. To the best of our knowledge, this study revealed for the first time that in addition to its previously reported roles in stimulating ovarian functions through the pituitary-gonadal axis, LH brings about the extragonadal suppression of various tissue regeneration-associated functions in endometrial stem cells, such as self-renewal, migration ability, multilineage differentiation potential, and pluripotency/stemness, by inhibiting pro-survival Akt and ERK1/2 signaling pathways in vitro and in vivo, and as a consequence, it decreases the endometrial receptivity.


Asunto(s)
Infertilidad , Hormona Luteinizante , Endometrio/metabolismo , Estradiol/farmacología , Femenino , Fertilización In Vitro , Hormona Folículo Estimulante/metabolismo , Humanos , Hormona Luteinizante/farmacología , Embarazo , Células Madre/metabolismo
10.
J Hepatol ; 54(1): 122-31, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20952084

RESUMEN

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is associated with a high potential for metastasis and disease recurrence, even after surgical resection. The cancer stem cell (CSC) hypothesis proposes that CSCs are responsible for chemo-resistance, recurrence, and metastasis. Dysadherin is a prognostic indicator of metastasis and poor survival in many different cancer types. In this study, we investigated the possible link between dysadherin and CSC in HCC. METHODS: We analyzed the functional implications of dysadherin on cancer stemness by modification of the dysadherin gene in HCC cell lines. RESULTS: The transfection of dysadherin cDNA into the liver cancer cell line PLC/PRF/5 enhanced the properties of CSCs, including anti-apoptosis, their sphere-forming ability, side population phenotype, and tumor initiation ability in vivo. Furthermore, knockdown of dysadherin in the liver cancer cell line SK-Hep1 suppressed its stem cell-like properties. CONCLUSIONS: These results show that dysadherin give rise to properties of CSC in HCC. Therefore, these findings suggest that dysadherin may be a potential molecular prognostic marker of HCC and may aid in the development of more effective therapies.


Asunto(s)
Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/fisiopatología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/fisiopatología , Glicoproteínas de Membrana/fisiología , Proteínas de Neoplasias/fisiología , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/fisiología , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/fisiología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Canales Iónicos , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas de Microfilamentos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Pronóstico , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Esferoides Celulares , Transfección , Ensayo de Tumor de Célula Madre
11.
Artículo en Inglés | MEDLINE | ID: mdl-33197991

RESUMEN

PURPOSE: This study aimed to evaluate the level of professional ethics awareness and medical ethics competency in order to assess the potential need for ethics items to be included on the Korean Dental Hygienist Licensing Examination. METHODS: In total, 358 clinical dental hygienists and dental hygiene students completed a structured questionnaire to evaluate their level of ethical awareness and medical ethics competency. The sub-factors of medical ethics were classified into relationships with patients, medical and social relations, and individual specialized fields. RESULTS: Only 32.1% of participants indicated that they had taken a course on professional ethics in the university curriculum, but 95.2% of respondents considered professional ethics to be important. The overall score for medical ethics competency was average (3.37 out of 5). The score for relationships with patients was 3.75 points, followed by medical and social relations (3.19 points) and individual specialized fields (3.16 points). The level of professional ethics awareness was higher among participants who had taken a course on professional ethics than among those who had not done so or who did not remember whether they had done so. CONCLUSION: Dental hygienists were aware of the importance of professional ethics, but their medical ethics competency was moderate. Therefore, medical ethics should be treated as a required subject in the university curriculum, and medical ethics competency evaluations should be strengthened by adding ethics items to the Korean Dental Hygienist Licensing Examination.


Asunto(s)
Higienistas Dentales , Higiene Bucal , Ética Médica , Ética Profesional , Humanos , República de Corea , Estudiantes
12.
Growth Factors ; 27(6): 425-37, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19919531

RESUMEN

It has widely been reported that basic fibroblast growth factor (bFGF) promotes proliferation of human stem cells and contributes to the maintenance of their self-renewal capability through repeated replications. In contrast to embryonic stem cells (ESCs), the effects of growth factors on adult stem cells are poorly understood. In human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs), bFGF is associated with an increased number of proliferating cells. Furthermore, expression levels of ESC markers were increased after treatment with bFGF. bFGF also increased the expression of FGFR, which in turn increased expression of insulin-like growth factor (IGFs). Since IGFs exert autocrine and paracrine effects on stem cells, bFGF-mediated release of IGFs from hUCB-MSCs might enhance FGFR1 and IGF1R expression in neighboring cells. These receptors could subsequently regulate the effects of bFGF and IGFs in adult stem cells. These results suggest that positive feedback regulation of bFGF and IGFs leads to proliferation of hUCB-MSCs.


Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/farmacología , Regulación de la Expresión Génica , Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células Madre Multipotentes/efectos de los fármacos , Adulto , Diferenciación Celular/efectos de los fármacos , Proliferación Celular , Células Cultivadas , Femenino , Sangre Fetal , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/genética , Células Madre Multipotentes/citología , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/efectos de los fármacos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo
13.
Cytotherapy ; 11(3): 289-98, 1 p following 298, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19308770

RESUMEN

BACKGROUND AIMS: Mesenchymal stromal cells (MSC) have been studied intensively in regenerative medicine. However, their therapeutic potential against tumor formation and cancer metastasis is still unclear. The effects of transplantation of MSCs in early-stage of carcinogenesis, should be evaluated. METHODS: MSC isolated from human umbilical cord blood (UCB) and adipose tissue (AD) were transplanted in a mouse cancer metastasis model. The effects of MSC on tumor growth and metastasis were analyzed. The effects of transplantation of MSC into the mouse model at very early stage carcinogenesis were also evaluated. RESULTS: Human MSC reduced lung metastasis and inhibited the growth of human breast cancer cells by inducing apoptosis. In addition, transplantation of both UCB and AD MSC into a cancer model with no detectable clinical symptoms did not appear to promote tumor growth or metastasis. CONCLUSIONS: We evaluated the effect of MSC derived from human UCB and AD tissue in a tumor model. Our findings may help to elucidate the interaction between cancer cells and MSC, as well as the application of MSC to clinical trials.


Asunto(s)
Neoplasias de la Mama/terapia , Neoplasias Pulmonares/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Tejido Adiposo/citología , Animales , Antígenos de Diferenciación/metabolismo , Apoptosis , Neoplasias de la Mama/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Femenino , Sangre Fetal/citología , Humanos , Neoplasias Pulmonares/secundario , Células Madre Mesenquimatosas/citología , Ratones , Ratones SCID , Trasplante de Neoplasias , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Embarazo , Ensayo de Tumor de Célula Madre
14.
In Vitro Cell Dev Biol Anim ; 54(7): 505-512, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29869056

RESUMEN

L-carnosine, a dipeptide of the amino acids ß-alanine and histidine, is found in various tissues, such as the central nervous system and skeletal muscles. Recently, L-carnosine has been reported to possess anti-tumor activity; however, the molecular mechanism underlying its activity in colorectal cancer is still unknown. Therefore, we investigated the effect of L-carnosine using a human colorectal cancer cell line, HCT116. Treatment with L-carnosine (0, 100, or 200 mM) for 24 h gradually reduced cellular proliferation according to immunochemistry and 7-aminoactinomycin D (7-AAD) analyses and induced G0/G1 phase arrest. In the RT-PCR analysis, L-carnosine decreased the mRNA levels of cell cycle-related genes in HCT116 cells. In the Western blot analysis, levels of the cyclin D1, BAX/Bcl-2, cleaved caspase-3, p21, and p53 proteins were significantly increased in cells treated with L-carnosine. We next determined whether STAT1/NF-κB pathway is involved in regulation of cell cycle arrest- and cell death-associated gene in HCT116. The L-carnosine treatment significantly inhibited the phosphorylation of STAT1 on Tyr701 and NF-κB p65 on Ser276 and Ser536, and then, we exogenously blocked the NF-κB phosphorylation using Bay 11-7082. Based on our findings, L-carnosine induces cell cycle arrest and apoptosis in human colorectal cancer cells by suppressing of NF-κB/STAT1 signaling.


Asunto(s)
Apoptosis/efectos de los fármacos , Carnosina/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , FN-kappa B/metabolismo , Factor de Transcripción STAT1/metabolismo , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fase G1/efectos de los fármacos , Células HCT116 , Humanos , Modelos Biológicos , Fosforilación/efectos de los fármacos , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo
15.
J Tissue Eng Regen Med ; 12(7): 1646-1657, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29763986

RESUMEN

There is lack of researches on effects of intravenously injected mesenchymal stem cells (MSCs) against transient cerebral ischemia (TCI). We investigated the disruption of the neurovascular unit (NVU), which comprises the blood-brain barrier and examined entry of human dermis-derived MSCs (hDMSCs) into the damaged hippocampal CA1 area in a gerbil model of TCI and their subsequent effects on neuroprotection and cognitive function. Impairments of neurons and blood-brain barrier were examined by immunohistochemistry, electron microscopy, and Evans blue and immunoglobulin G leakage. Neuronal death was observed in pyramidal neurons 5-day postischemia. NVU were structurally damaged; in particular, astrocyte end-feet were severely damaged from 2-day post-TCI and immunoglobulin G leaked out of the CA1 area 2 days after 5 min of TCI; however, Evans blue extravasation was not observed. On the basis of the results of NVU damages, ischemic gerbils received PKH2-transfected hDMSCs 3 times at early times (3 hr, 2, and 5 days) after TCI, and fluorescence imaging was used to detect hDMSCs in the tissue. PKH2-transfected hDMSCs were not found in the CA1 from immediate time to 8 days after injection, although they were detected in the liver. Furthermore, hDMSCs transplantation did not protect CA1 pyramidal neurons and did not improve cognitive impairment. Intravenously transplanted hDMSCs did not migrate to the damaged CA1 area induced by TCI. These findings suggest no neuroprotection and cognitive improvement by intravenous hDMSCs transplantation after 5 min of TCI.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Dermis/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Células Piramidales/metabolismo , Animales , Compuestos de Bifenilo , Barrera Hematoencefálica/lesiones , Barrera Hematoencefálica/patología , Isquemia Encefálica/patología , Isquemia Encefálica/terapia , Dermis/patología , Modelos Animales de Enfermedad , Gerbillinae , Xenoinjertos , Humanos , Masculino , Células Madre Mesenquimatosas/patología , Células Piramidales/patología , Pirimidinas , Tetrazoles
16.
PLoS One ; 12(11): e0185134, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29091708

RESUMEN

Chronic alcohol consumption causes alcohol-induced lipogenesis and promotes hepatic injury by preventing the oxidation of hepatocellular fatty acids through the suppression of the activation of AMP-activated protein kinase (AMPK). HIMH0021, an active flavonoid compound, which is a component of the Acer tegmentosum extract, has been shown to protect against liver damage caused by alcohol consumption. Therefore, in this study, we aimed to determine whether HIMH0021 could regulate alcoholic fatty liver and liver injury in mice. Oral administration of 10 days of Lieber-DeCarli ethanol plus a single binge of 30% ethanol (chronic-plus-binge model) induced steatosis and liver injury and inflammation in mice, which appears similar to the condition observed in human patients with alcohol-related diseases. HIMH0021, which was isolated from the active methanol extract of A. tegmentosum, inhibited alcohol-induced steatosis and attenuated the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during hepatocellular alcohol metabolism, both of which promote lipogenesis as well as liver inflammation. Treatment with HIMH0021 conferred protection against lipogenesis and liver injury, inhibited the expression of cytochrome P4502E1, and increased serum adiponectin levels in the mice subjected to chronic-plus-binge feeding. Furthermore, in hepatocytes, HIMH0021 activated fatty acid oxidation by activating pAMPK, which comprises pACC and CPT1a. These findings suggested that HIMH0021 could be used to target a TNFα-related pathway for treating patients with alcoholic hepatitis.


Asunto(s)
Etanol/toxicidad , Hígado Graso/prevención & control , Flavonas/farmacología , Glicósidos/farmacología , Hígado/efectos de los fármacos , Adenilato Quinasa/metabolismo , Adiponectina/metabolismo , Animales , Conducta Alimentaria , Metabolismo de los Lípidos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo
17.
Oncotarget ; 7(36): 58405-58417, 2016 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-27517151

RESUMEN

The tripeptide-copper complex glycyl-l-histidyl-l-lysine-Cu (II) (GHK-Cu) is involved in wound healing and tissue remodeling. Although GHK-Cu exhibits anti-aging and tissue renewing properties, its roles in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are still unknown. Therefore, we examined the effects of GHK-Cu in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro and ALI in mice in vivo. GHK-Cu treatment reduced reactive oxygen species (ROS) production, increased superoxide dismutase (SOD) activity while decreased TNF-α and IL-6 production through the suppression of NF-κB p65 and p38 MAPK signaling in vitro and in vivo model of ALI. Moreover, GHK-Cu attenuated LPS-induced lung histological alterations, suppressed the infiltration of inflammatory cells into the lung parenchyma in LPS-induced ALI in mice. Taken together, these findings demonstrate that GHK-Cu possesses a protective effect in LPS-induced ALI by inhibiting excessive inflammatory responses; accordingly it may represent a novel therapeutic approach for ALI/ARDS.


Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Oligopéptidos/química , Factor de Transcripción ReIA/metabolismo , Lesión Pulmonar Aguda/metabolismo , Animales , Antioxidantes/metabolismo , Proliferación Celular , Sistema Inmunológico , Inflamación , Lipopolisacáridos , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Permeabilidad , Peroxidasa/metabolismo , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Superóxido Dismutasa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
18.
In Vitro Cell Dev Biol Anim ; 52(5): 545-54, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27059327

RESUMEN

Mesenchymal stem cells (MSCs) can be isolated from various tissues including bone marrow, adipose tissue, skin dermis, and umbilical Wharton's jelly as well as injured tissues. MSCs possess the capacity for self-renewal and the potential for differentiation into adipogenic, osteogenic, and chondrogenic lineages. However, the characteristics of MSCs in injured tissues, such as achondroplasia (ACH), are not well known. In this study, we isolated MSCs from human subcutaneous adipose (ACH-SAMSCs) tissue and circumjacent human adipose tissue of the cartilage (ACH-CAMSCs) from a patient with ACH. We then analyzed the characterization of ACH-SAMSCs and ACH-CAMSCs, compared with normal human dermis-derived MSCs (hDMSCs). In flow cytometry analysis, the isolated ACH-MSCs expressed low levels of CD73, CD90, and CD105, compared with hDMSCs. Moreover, both ACH- SAMSCs and ACH-CAMSCs had constitutionally overactive fibroblast growth factor receptor 3 (FGFR3) and exhibited significantly reduced osteogenic differentiation, compared to enhanced adipogenic differentiation. The activity of extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 mitogen-activated protein kinases (p38 MAPK) was increased in ACH-MSCs. In addition, the efficacy of osteogenic differentiation was slightly restored in osteogenic differentiation medium with MAPKs inhibitors. These results suggest that they play essential roles in MSC differentiation toward adipogenesis in ACH pathology. In conclusion, the identification of the characteristics of ACH-MSCs and the favoring of adipogenic differentiation via the FGFR3/MAPK axis might help to elucidate the pathogenic mechanisms relevant to other skeletal diseases and could provide targets for therapeutic interventions.


Asunto(s)
Acondroplasia/patología , Tejido Adiposo/patología , Células Madre Mesenquimatosas/fisiología , Acondroplasia/genética , Adipogénesis , Diferenciación Celular , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Sistema de Señalización de MAP Quinasas , Células Madre Mesenquimatosas/patología , Persona de Mediana Edad , Mutación , Osteogénesis , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética
19.
Toxicol Lett ; 240(1): 140-8, 2016 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-26546778

RESUMEN

Cigarette smoking is the major aetiologic factor in chronic obstructive pulmonary disease (COPD). Lung fibroblasts are key participants in the maintenance of the extracellular matrix within the lung parenchyma. However, it still remains unknown how pulmonary fibroblasts are affected by cigarette smoking. Therefore, in this study, we isolated lung fibroblasts from mice and determined the apoptotic mechanism in response to cigarette smoke extract (CSE). When the lung fibroblasts were exposed to CSE, the generation of ROS was increased as shown by H2-DCFDA staining and Flow Cytometry. By immunocytochemistry, Ki67 expressing cells gradually decreased in a dose-dependent manner. The nitrite concentration in the supernatants increased, while the SOD activity and GSH recycling decreased in response to CSE. CSE increased the mRNA levels of TNF-α and COX-2, and the secretory proteins TNF-α and IL-6 increased as measured by ELISA. We next determined whether this inflammatory process is associated with the Bax/Bcl-2 apoptosis pathway. The Bax/Bcl-2 mRNA ratio increased, and cleaved caspase-3 protein was activated in the lung fibroblasts treated with CSE. Moreover, CSE induced the phosphorylation of STAT1 at Tyr701/Ser727 and increased the activation of ERK1/2, p38, and JNK in the MAPK pathway. Taken together, these data suggest that CSE-mediated inflammation alters the redox regulation via the MAPK-STAT1 pathway, leading to intrinsic apoptosis of lung fibroblasts.


Asunto(s)
Apoptosis/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Pulmón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fumar/efectos adversos , Animales , Caspasa 3/genética , Caspasa 3/metabolismo , Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Glutatión/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmón/citología , Pulmón/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , Óxido Nítrico/metabolismo , Fosforilación , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
20.
Oxid Med Cell Longev ; 2015: 486263, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26273422

RESUMEN

MSCs have become an emerging cell source with their immune modulation, high proliferation rate, and differentiation potential; indeed, they have been challenged in clinical trials. Recently, it has shown that ROS play a dual role as both deleterious and beneficial species depending on their concentration in MSCs. Various environmental stresses-induced excessive production of ROS triggers cellular senescence and abnormal differentiation on MSCs. Moreover, MSCs have been suggested to participate in the treatment of ALI/ARDS and COPD as a major cause of high morbidity and mortality. Therapeutic mechanisms of MSCs in the treatment of ARDS/COPD were focused on cell engraftment and paracrine action. However, ROS-mediated therapeutic mechanisms of MSCs still remain largely unknown. Here, we review the key factors associated with cell cycle and chromatin remodeling to accelerate or delay the MSC aging process. In addition, the enhanced ROS production and its associated pathophysiological pathways will be discussed along with the MSC senescence process. Furthermore, the present review highlights how the excessive amount of ROS-mediated oxidative stress might interfere with homeostasis of lungs and residual lung cells in the pathogenesis of ALI/ARDS and COPD.


Asunto(s)
Enfermedades Pulmonares/genética , Enfermedades Pulmonares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Senescencia Celular , Humanos , Células Madre Mesenquimatosas/citología
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