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BACKGROUND: Oxidative stress injury is an important pathological factor of premature ovarian failure (POF). Salidroside, extracted from the Chinese herb-Rhodiola rosea, has advantages in antioxidant characteristics. However, their therapeutic efficacy and mechanisms in POF have not been explored. PURPOSE: This study aims to assess the therapeutic effects of salidroside in chemotherapy-induced ovarian failure rats. METHODS: A POF rat model was established by injection of cyclophosphamide, followed by treatment with salidroside. The therapeutic effect of salidroside was evaluated based on hormone levels, follicle count, and reproductive ability. Oxidative stress injury was assessed by the detection of SOD enzyme activity and MDA levels. Differential gene expression of Keap1, Nrf2, HMOX1, NQO1, AMH, BMP15, and GDF9, were identified by qRTPCR. The protein expression of Keap1, Nrf2, P53, and Bcl-2 were detected by western blot. RESULTS: Salidroside treatment markedly restored FSH, E2, and AMH hormone secretion levels, reduced follicular atresia, and increased antral follicle numbers in POF rats. In addition, salidroside improves fertility in POF rats, activates the Nrf2 signaling pathway, and reduces the level of oxidative stress. The recovery function of high dose salidroside (50 mg/kg) in a reproductive assay was significantly improved than that of lower dose salidroside (25 mg/kg). Meanwhile, the safety evaluation of salidroside treatment in rats showed that salidroside was safe for POF rats at doses of 25-50 mg/kg. CONCLUSIONS: Salidroside therapy improved premature ovarian failure significantly through antioxidant function and activating Nrf2 signaling.
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Glucosídeos , Fenóis , Insuficiência Ovariana Primária , Humanos , Ratos , Feminino , Animais , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/patologia , Proteína 1 Associada a ECH Semelhante a Kelch , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Fator 2 Relacionado a NF-E2 , Atresia Folicular , Ciclofosfamida/efeitos adversos , HormôniosRESUMO
BACKGROUND: Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications in cancer cells are dynamic and reversible and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of breast cancer cell proliferation and metabolism through m6A methylation in the Hippo pathway. METHODS: A combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal a map of m6A modifications in breast cancer tissues and cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis to identify the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells. The expression and biological functions of m6A proteins were confirmed in breast cancer cells in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway was affected by m6A regulation of LATS1 in breast cancer cells. RESULTS: We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. CONCLUSIONS: In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.
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Neoplasias da Mama , Humanos , Feminino , Metilação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Fatores de Transcrição/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismoRESUMO
BACKGROUND: Acquired aplastic anemia (AA) is a life-threatening disease associated with an imbalance in Th17/Treg cells. Regulating this balance may be an effective treatment approach for AA. Rhodiola rosea has shown efficacy in AA treatment, but its mechanisms remain unclear. PURPOSE: We investigated salidroside's effect (a component of Rhodiola rosea) on Th17/Treg balance in adult AA patients and a mouse model. METHODS: HIF-1α mRNA and protein levels were measured in AA patients' peripheral blood. Flow cytometry, qRT-PCR, and WB analyzed salidroside's impact on T cell differentiation, Th17 cells, Treg cells, STAT3, HIF-1α, and RORγt expression. ELISA measured hematopoietic growth factors in mouse serum. RESULTS: AA patients exhibited elevated HIF-1α levels. Salidroside improved hematopoietic function, increasing blood cell count and enhancing bone marrow. Salidroside induced SCF, TPO, and IL-3 expression while inhibiting IL-2 in mice. Salidroside reduced STAT3, HIF-1α, RORγt, and IL-17a, while increasing FoxP3 expression, correcting the Th17/Treg imbalance in vitro and in vivo. CONCLUSION: Salidroside has potential as a novel AA treatment by correcting the Th17/Treg imbalance through the STAT3/HIF-1α/RORγt pathway.
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Anemia Aplástica , Glucosídeos , Linfócitos T Reguladores , Animais , Camundongos , Anemia Aplástica/tratamento farmacológico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Humanos , Fator de Transcrição STAT3 , Subunidade alfa do Fator 1 Induzível por Hipóxia , Células Th17RESUMO
UDP-GlcNAc is a sugar substrate necessary for the O-GlcNAcylation of proteins. SLC35B4 is one of the nucleotide sugar transporters that transport UDP-GlcNAc and UDP-xylose into the endoplasmic reticulum and Golgi apparatus for glycosylation. The roles of SLC35B4 in hepatocellular carcinoma (HCC) tumorigenesis remain unknown. We find that the expression levels of SLC35B4 are higher in HCC tissues than adjacent non-tumor tissues. SLC35B4 is important for the proliferation and tumorigenesis of HCC cells. Mechanistically, SLC35B4 is important for the O-GlcNAc modification of c-Myc and thus the stabilization of c-Myc, which is required for HCC tumorigenesis. Therefore, SLC35B4 is a promising therapeutic target for treating HCC.
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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. In recent decades, long non-coding RNAs (lncRNAs) have attracted increasing attention and have been reported to play important roles in human cancers, making them ideal candidates for precise disease assessment and treatment. Our previous study found that the loss of linc00261 was significantly correlated with the malignant biological behaviors of HCC, particularly MVI, and serves as an excellent independent prognostic factor for recurrence-free survival. In this study, our in-depth research demonstrated that linc00261 inhibits epithelial-mesenchymal transition (EMT) in liver cancer cells, thereby suppressing migration, invasion, and the formation of lung metastatic lesions. Moreover, linc00261 and its neighbor gene FOXA2 were positively correlated in HCC, the gain- and loss-of-function analyses indicated that linc00261 transcriptionally promotes the expression of FOXA2. Additionally, bioinformatic analysis and rescue assays confirmed that linc00261 partially suppresses migration, invasion, and EMT by upregulating FOXA2 expression. Molecular mechanism studies showed that linc00261 transcriptionally upregulates FOXA2 in cis by recruiting SMAD3. Finally, we identified EZH2 is responsible for linc00261 transcription repression via modulating trimethylation of H3K27 at Lys27 (H3K27Me3), both EZH2 and H3K27Me3 were negatively correlated with linc00261 expression in HCC. In conclusion, these findings demonstrated a crucial role of linc00261 in HCC metastasis, and that EZH2/linc00261/FOXA2 axis might reveal potential prognostic factors and be applied as therapeutic targets for HCC metastasis.
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BACKGROUND: Phosphatidylinositol-4-phosphate-binding protein GOLPH3L is overexpressed in human ductal carcinoma of the breast, and its expression levels correlate with the prognosis of breast cancer patients. However, the roles of GOLPH3L in breast tumorigenesis remain unclear. METHODS: We assessed the expression and biological function of GOLPH3L in breast cancer by combining bioinformatic prediction, metabolomics analysis and RNA-seq to determine the GOLPH3L-related pathways involved in tumorigenesis. Dual-luciferase reporter assay and coimmunoprecipitation (Co-IP) were used to explore the expression regulation mechanism of GOLPH3L. RESULTS: We demonstrated that knockdown of GOLPH3L in human breast cancer cells significantly suppressed their proliferation, survival, and migration and suppressed tumor growth in vivo, while overexpression of GOLPH3L promoted aggressive tumorigenic activities. We found that miRNA-1185-2-3p, the expression of which is decreased in human breast cancers and is inversely correlated with the prognosis of breast cancer patients, is directly involved in suppressing the expression of GOLPH3L. Metabolomics microarray analysis and transcriptome sequencing analysis revealed that GOLPH3L promotes central carbon metabolism in breast cancer by stabilizing the p53 suppressor SERPINE1. CONCLUSIONS: In summary, we discovered a miRNA-GOLPH3L-SERPINE1 pathway that plays important roles in the metabolism of breast cancer and provides new therapeutic targets for human breast cancer.
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Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , MicroRNAs/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Animais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Biologia Computacional , Modelos Animais de Doenças , Feminino , Genes Reporter , Humanos , Metabolômica/métodos , Camundongos , Prognóstico , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hydrogel-based material have been demonstrated promising potential for hemostasis. Herein, we prepared a composite hydrogel (CH-P 40%) by combining pectin and cellulose in ionic liquid. The superficial morphology of the CH-P 40% was explored by SEM; the internal chemical bonds, crystal form and thermal stability were determined via FTIR, XRD and thermogravimetric analysis, respectively. The biocompatibilities of the CH-P 40% hydrogel was evaluated by MTT, flow cytometry, and histological observation with H&E staining. Furthermore, the hemostatic effect was evaluated via the blood clotting index and mouse liver hemostatic model. The results showed that the CH-P 40% hydrogel exhibited a dense network structure and retained its chemical bonds, including the OH, CH, C=O, -CH2, CO, C1-H, and ß-glycosidic bonds. Simultaneously, the hydrogel retained the Cellulose I and II crystal structure and favorable thermal stability. Moreover, the proliferation rates of CH-P 40%-treated cells increased (P > 0.05), and there were no pathological lesions in the mouse organs, which suggests favorable biocompatibility. The results showed less bleeding in the hydrogel-treated liver wound within 3 min. Overall, the pectin-cellulose hydrogel is stable and possesses favorable biocompatibility and hemostatic ability, further highlighting that the composite hydrogel has the potential to be rapid hemostatic biomedical material.
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Aplastic anemia (AA) is a bone marrow failure disease. It is difficult to treat AA, and in addition, relapses are common because of its complex disease pathogenesis. Allogeneic bone marrow-derived mesenchymal stem cells (BMSCs) infusion is an effective and safe treatment option for the AA patients. However, it found that BMSCs infusion in AA patients is less than 30% effective. Therefore, the key to improve the efficacy of BMSCs treatment in these patients is to enhance their homing efficiency to the target sites. Studies have shown that stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays an important role in promoting BMSCs homing. In this study, human BMSCs were transduced with lentivirus stably expressing CXCR4-BMSCs. Transduced BMSCs resemble normal BMSCs in many ways. Migration ability of CXCR4-BMSCs toward SDF-1 was increased because of the overexpression of CXCR4. In the mice with bone marrow failure, the migration and colonization ability of CXCR4-BMSCs to the bone marrow was significantly improved as seen by IVIS imaging and FACS. The SDF-1 level in the bone marrow failure mice was significantly higher than in the normal mice. Thus, from our study, it is clear that after CXCR4-BMSCs were infused into mice with bone marrow failure, SDF-1 interacted with CXCR4 receptor, leading cells to migrate and colonize to bone marrow. Because of the high SDF-1 expression in mouse bone marrow and CXCR4 receptor expression in cells, BMSCs homing was increased.
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Medula Óssea/patologia , Hematopoese , Células-Tronco Mesenquimais/citologia , Receptores CXCR4/metabolismo , Receptores de Interleucina-8A/metabolismo , Adipogenia , Animais , Apoptose , Medula Óssea/diagnóstico por imagem , Ciclo Celular , Movimento Celular , Sobrevivência Celular , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , OsteogêneseRESUMO
The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.
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Processamento Alternativo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , RNA Helicases/genética , Idoso , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genes myc , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glicólise/fisiologia , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos SCID , Pessoa de Meia-Idade , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Regiões Promotoras Genéticas , RNA Helicases/metabolismo , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da TireoideRESUMO
PURPOSE: Micheliolide (MCL) is an effector compound of the flower which has been traditionally used to treat inflammation and cancer patients in oriental medicine. MCL has killing effects on several cancer and immune cells by modulating apoptosis, cell cycle, and metabolism. However, the detail of the mechanisms of anti-cancer activity remains to be elucidated and the effect on liver cancer cells is unknown. METHODS: Cell proliferation was determined by CCK8 and clone formation assay. The xenograft liver cancer model formed by injecting Huh7 cells into NUDE mice was used to evaluate the effects of MCL on liver cancer cells in vivo. We evaluated the stemness of cells with spheroid formation assay and flow cytometry assay. The apoptosis was determined by Annexin V assay. F-actin staining and ROS were performed to detect the impairment of the F-actin cytoskeleton and mitochondria. RESULTS: Here, we first show that MCL inhibits liver cancer cells both in vivo and in vitro by triggering apoptosis which was reduced by anti-oxidant, but not cell-cycle arrest. In addition, MCL induces mitochondrial ROS and caspase-3 activation. Also, we found that the aggregation of mitochondria and the perturbation of F-actin fibers in the MCL-treated liver cancer cells coincidently occurred before the induction of apoptosis and mitochondrial ROS. CONCLUSION: These results suggest that F-actin perturbation is involved in impaired mitochondria and apoptosis. Therefore, MCL can be a potent therapeutic reagent for liver cancer, primarily targeting the actin cytoskeleton.
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The tumor suppressor p53 is somatically mutated in half of all human cancers. Paradoxically, the wild-type p53 (WTp53) is often retained in certain human cancers, such as hepatocarcinoma (HCC). We discovered a physiological and oncogenic role of WTp53 in suppressing pyruvate-driven oxidative phosphorylation by inducing PUMA. PUMA inhibits mitochondrial pyruvate uptake by disrupting the oligomerization and function of mitochondrial pyruvate carrier (MPC) through PUMA-MPC interaction, which depends on IκB kinase-mediated phosphorylation of PUMA at Ser96/106. High expression levels of PUMA are correlated with decreased mitochondrial pyruvate uptake and increased glycolysis in HCCs and poor prognosis of HCC patients. These findings are instrumental for cancer drug discovery aiming at activating WTp53 or restoring WTp53 activity to p53 mutants.
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Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Neoplasias Hepáticas/metabolismo , Fosforilação Oxidativa , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Animais , Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Glicólise , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Quinase I-kappa B/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas/genética , Ácido Pirúvico/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
With a high incidence and high mortality rate, ovarian cancer presents a challenge for clinical practice. It is thus extremely urgent to investigate new diagnosis and therapy methods for the treatment of ovarian cancer. Ternary copper-based chalcogenide nanomaterials are attractive owing to their near infrared (NIR) response for cancer theranostic fields. However, improving the theranostic efficiency of these nanomaterials is challenging. Herein, CuS-MnS2 nano-flowers were easily synthesized and under NIR irradiation exhibited a relatively high photothermal conversion efficiency of 67.5% and a simultaneous reactive oxygen species (ROS) generation effect. Owing to these outstanding photothermal/photodynamic effects, excellent tumor ablation results could be achieved by the combined use of CuS-MnS2 nano-flowers and 808 nm NIR laser treatments. The main anticancer mechanism of CuS-MnS2 nano-flowers + NIR was likely necroptosis. In addition, the nano-flowers showed remarkable contrast enhancement according to magnetic resonance imaging (MRI). These CuS-MnS2 nano-flowers could thus serve as a promising multifunctional nanotheranostic agent for MRI and as a photothermal/photodynamic cancer therapy agent through necroptosis.
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Cobre , Hipertermia Induzida , Imageamento por Ressonância Magnética , Compostos de Manganês , Nanopartículas , Necroptose/efeitos dos fármacos , Neoplasias Experimentais , Neoplasias Ovarianas , Fototerapia , Sulfetos , Células A549 , Animais , Cobre/química , Cobre/farmacologia , Feminino , Humanos , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/terapia , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Sulfetos/química , Sulfetos/farmacologiaRESUMO
Previous studies have demonstrated that asiatic acid (AA), the major component of Centella asiatica, is able to meditate cytotoxic and anticancer effects on various types of carcinoma cells. In order to investigate the molecular mechanism that underlies the antitumor effect of AA, the present study investigated the effects of AA on proliferation, migration and apoptosis of SW480 and HCT116 colon cancer cells. Viability and changes in cell morphology in the cells were assessed by MTT assay and transmission electron microscopy, respectively. Colony formation analysis was used to observe proliferation of the single cell, and migratory ability of the cells was assessed by performing Transwell migration assay. Hoechst 33342 nuclear staining and flow cytometry were used to assess apoptosis in colon carcinoma cells. The expression of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K signaling pathway and epithelial-mesenchymal transition (EMT) marker were analyzed by western blotting. The present study revealed that proliferation and migration of colon carcinoma cells were inhibited by AA in a dose-dependent and time-dependent manner. Numerous apoptotic bodies were observed, and G2/M and S phase progression were delayed in colon cancer cells treated with AA, but not in the control group. A number of phosphorylated proteins, including PI3K, Akt (Ser473), mTOR, ribosomal protein S6 kinase (p70S6K) downregulated, while the expression of Pdcd4 was upregulated following treatment with AA. Additionally, AA affects expression of EMT markers in a dose-dependent manner. On the basis of these results, it was concluded that AA inhibited proliferation, migration and induced apoptosis of colon cancer cells by regulating Pdcd4 via the PI3K/Akt/mTOR/p70S6K signaling pathway. These observations suggest that AA may be a potential therapeutic agent for the treatment of colon carcinoma.
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The mechanisms underlying immunomodulatory ability of mesenchymal stromal cells (MSCs) remain unknown. Recently, studies suggested that the immunomodulatory activity of MSCs is largely mediated by paracrine factors. Among which, exosome is considered to play a major role in the communication between MSCs and target tissue. The aim of our study is to investigate the effect of MSCs-derived exosome on peripheral blood mononuclear cells (PBMCs), especially T cells. We find that the MSCs-derived exosome extracted from healthy donors' bone marrow suppressed the secretion of pro-inflammatory factor TNF-α and IL-1ß, but increased the concentration of anti-inflammatory factor TGF-ß during in vitro culture. In addition, exosome may induce conversion of T helper type 1 (Th1) into T helper type 2 (Th2) cells and reduced potential of T cells to differentiate into interleukin 17-producing effector T cells (Th17). Moreover, the level of regulatory T cells (Treg) and cytotoxic T lymphocyte-associated protein 4 were also increased. These results suggested that MSC-derived exosome possesses the immunomodulatory properties. However, it showed no effects on the proliferation of PBMCs or CD3+ T cells, but increases the apoptosis of them. In addition, indoleamine 2, 3-dioxygenase (IDO) was previously shown to mediate the immunoregulation of MSCs, which was increased in PBMCs co-cultured with MSCs. In our study, IDO showed no significant changes in PBMCs exposed to MSCs-derived exosome. We conclude that exosome and MSCs might differ in their immune-modulating activities and mechanisms.
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Micropartículas Derivadas de Células/imunologia , Exossomos/imunologia , Células-Tronco Mesenquimais/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Apoptose , Antígeno CTLA-4/metabolismo , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Humanos , Imunomodulação , Ativação Linfocitária , Comunicação Parácrina , Equilíbrio Th1-Th2RESUMO
The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factorα (TNFα) increased the level of vascular cell adhesion molecule1 (VCAM1) expression in a dosedependent manner. The nuclear factor-κB (NF-κB), extracellular signalregulated kinase (ERK) and cJun Nterminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM1 expression induced by TNFα at the mRNA and protein levels (P<0.05). TNFα augmented the activation of NFκB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NFκB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-α-induced VCAM-1 expression, which is potentially mediated by the NFκB, ERK and JNK signaling pathways.
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MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Antracenos/farmacologia , Biomarcadores , Butadienos/farmacologia , Adesão Celular , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunofenotipagem , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Nitrilas/farmacologia , Fosforilação , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
The influence of the TNF-α -308 G>A polymorphism on bone marrow failure syndrome susceptibility is unclear. We have conducted a meta-analysis of all relevant published studies. We searched PubMed, Chinese Biomedical Literature and China National Knowledge Infrastructure databases up to February 2015. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to assess the strength of associations. Eleven case-control studies with a total sample size of 909 cases and 1803 controls were eligible to assess the association between the TNF-α -308 G>A polymorphism and susceptibility to bone marrow failure syndrome. Overall, the TNF-α -308 G>A polymorphism was significantly associated with an increased risk of bone marrow failure syndrome in any genetic model. In stratified analysis by disease type, there was a significant association between the TNF-α -308 G>A polymorphism and increased risk of aplastic anemia but no significant association with myelodysplastic syndrome (AA vs. GG: OR=2.23, 95% CI=1.23-4.05, P=0.006; recessive model: OR=3.52, 95% CI=1.30-9.53, P=0.010). In subgroup analysis by ethnicity, there were significant associations between the TNF-α -308 G>A polymorphism and increased risk of bone marrow failure syndrome for Caucasians in two models, but not in Asian populations (AA vs. GG: OR=2.66, 95% CI=1.36-5.21, P=0.003; recessive model: OR=2.68, 95% CI=1.37-5.24, P=0.002). In conclusion, our meta-analysis suggests that the TNF-α -308 G>A polymorphism may contribute to the risk of bone marrow failure syndrome, particularly among Caucasian and aplastic anemia patients. Further investigations are needed to clarify the role of the TNF-α -308 G>A polymorphism in bone marrow failure syndrome.
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Anemia Aplástica/genética , Hemoglobinúria Paroxística/genética , Fator de Necrose Tumoral alfa/genética , Anemia Aplástica/etnologia , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Estudos de Associação Genética , Predisposição Genética para Doença , Hemoglobinúria Paroxística/etnologia , Humanos , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
BACKGROUND: Nestin is associated with neoplastic transformation. However, the mechanisms by which nestin contributes regarding invasion and malignancy of gastric adenocarcinoma (GAC) remain unknown. Recent studies have shown that the epithelial-mesenchymal transition (EMT) is important in invasion and migration of cancer cells. In the present study, we aimed to investigate the expression of nestin and its correlation with EMT-related proteins in GAC. MATERIALS AND METHODS: The expression of nestin and EMT-related proteins was examined in GAC specimens and cell lines by immunohistochemistry and Western blotting. Clinicopathological features and survival outcomes were retrospectively analyzed. RESULTS: Positive nestin immunostaining was most obviously detected in the cytoplasm, nucleus or both cytoplasm and nucleus of tumor cells in 19.2% (24/125) of GAC tissues, which was significantly higher than that in normal gastric mucosa tissues (1.7%, 1/60) (p=0.001). Nestin expression was closely related to several clinicopathological factors and EMT-related proteins (E-cadherin, vimentin and Snail) and displayed a poor prognosis. Interestingly, simultaneous cytoplasmic and nuclear nestin expression correlated with EMT-related proteins (E-cadherin, vimentin and Snail) (p<0.05) and lymph node metastasis (p=0.041) and a shorter survival time (p<0.05), but this was not the case with cytoplasmic or nuclear nestin expression. CONCLUSIONS: Nestin, particularly expression in both cytoplasm and nucleus, might be involved in regulating EMT and malignant progression in GAC, with potential as an unfavorable indicator in tumor diagnosis and a target for clinical therapy.