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OBJECTIVE: Regulatory T cells (Tregs) induce immune tolerance in patients after organ transplantation. Various immunosuppressors can affect Tregs function through different mechanisms. PD-1 and TIGIT are important receptors on Tregs surface. Here, we investigated the effects of Tacrolimus and mycophenolate mofetil (MMF) on the inhibitory function of Tregs and explored the regulatory mechanism in patients after liver transplantation. METHODS: Thirty patients that underwent a liver transplant and 15 healthy people were enrolled. Fifteen patients received Tacrolimus only, and 15 received a combination of Tacrolimus and MMF. Tregs and effector T cells (Teffs) were isolated using magnetic beads and were mixed at different ratios of 0:1, 1:4, 1:2 and 1:1. An inhibition assay was performed by adding anti-PD-1 and anti-TIGIT when the mixture ratio was 1:1. The Tregs inhibition rate was determined and the levels of IFN-γ and TNF-α were measured. RESULTS: As the ratios of Tregs to Teffs in the mixture increased, the Tregs inhibition rate increased and the levels of IFN-γ and TNF-α decreased. At each mixture ratio, Tacrolimus + MMF group had the highest Tregs inhibition rate compared to Tacrolimus and control group. At the specific mixture ratio of 1:1, the addition of both anti- PD-1 and anti-TIGIT led to lower Tregs inhibition rate and higher IFN-γ and TNF-α levels in all three groups as opposed to the addition of each antibody separately. Additionally, both the decrease in the Tregs inhibition rate and the increase in the IFN-γ and TNF-α levels were the most for Tacrolimus + MMF group among all cases, either adding antibodies alone or mixed. CONCLUSION: Tacrolimus and MMF enhanced the function of Tregs by synergistically affecting PD-1 and TIGIT in liver transplant patients.
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Trasplante de Hígado/tendencias , Ácido Micofenólico/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores Inmunológicos/antagonistas & inhibidores , Linfocitos T Reguladores/efectos de los fármacos , Tacrolimus/administración & dosificación , Adulto , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Context: Recent studies have shown that a combination treatment of mycophenolate mofetil (MMF) and tacrolimus (FK506) may be an option for organ transplantation patients. Objective: In this study, we detected the effects of FK506 and MMF on the expressions of regulatory T cells (Tregs) and co-inhibitory receptors on Tregs in peripheral blood mononuclear cells (PBMC) of patients with stable phase after liver transplantation. Materials and methods: A total of 35 patients with stable stage after 6 months of liver transplantation were divided into two groups including 20 patients were treated with FK506 monotherapy (FK506 group), and 15 patients with FK506 and MMF combination (FK506 + MMF group). 15 healthy subjects were served as the control. Results: It is found that percentages of CD3+, CD3+CD4+ and CD3+CD8+ T cells in FK506 group are lowered compared to the control group but they are elevated in FK506 + MMF group. Amount of CD4+CD25+CD127low/-Treg cells in CD3+ CD4+T cells in FK506 + MMF group was higher than that in FK506 group and control group. The expressions of co-inhibitory receptors (CTLA-4, PD-1, Tim-3, LAG-3 and TIGIT) on Tregs in FK506 + MMF group were significant higher than those in the FK506 group and control group. The levels of the relative cytokines (TGF-ß and IL-10) in FK506 group are down-regulated compared to the control group. Conclusion: The application of FK506 combined with MMF may be superior to FK506 monotherapy for the patients to further induce the immune tolerance after liver transplantation.
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Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Trasplante de Hígado , Ácido Micofenólico/administración & dosificación , Linfocitos T Reguladores/inmunología , Tacrolimus/administración & dosificación , Tolerancia al Trasplante/efectos de los fármacos , Adulto , Aloinjertos , Antígenos CD/inmunología , Linfocitos T CD8-positivos/inmunología , Quimioterapia Combinada , Femenino , Humanos , Interleucina-10/inmunología , Masculino , Persona de Mediana Edad , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
OBJECTIVE: To study the difference in expression of TOPK/PBK in lymph nodes between children with malignant lymphoma and those with reactive lymphoid hyperplasia. METHODS: Eighty children with malignant lymphoma and twenty children with reactive lymphoid hyperplasia were enrolled as subjects. Immunohistochemistry was used to determine the expression of TOPK/PBK in all the subjects. The expression of TOPK/PBK was compared between the two groups. RESULTS: The TOPK/PBK-positivity rate was significantly higher in children with malignant lymphoma than in those with reactive lymphoid hyperplasia (P<0.05). There was no significant difference in the TOPK/PBK-positivity rate between the children with Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). There were significant differences in the TOPK/PBK-positivity rate among children with different pathological types of NHL (P<0.05): the children with lymphoblastic lymphoma showed the highest TOPK/PBK-positivity rate and those with mature B-cell lymphoma and mature T/NK-cell lymphoma had a similar TOPK/PBK-positivity rate. CONCLUSIONS: The expression of TOPK/PBK is up-regulated in the lymph nodes of children with malignant lymphoma. The expression level of TOPK/PBK may be related to the pathological type of NHL.
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Linfoma/enzimología , Quinasas de Proteína Quinasa Activadas por Mitógenos/análisis , Seudolinfoma/enzimología , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Ganglios Linfáticos/enzimologíaRESUMEN
A two-year-old girl was admitted due to repeated yellowing of the skin and sclera for 2 years and had no other specific symptoms or signs. The use of phenobarbital could relieve the symptoms of jaundice. Multiple examinations showed increased indirect bilirubin levels, and the results of aminotransferases and liver imaging were normal. There was no evidence of hemolysis. The analysis of UGT1A1 gene in her family found that this child had double homozygous mutation of c.211G>A(G71R) and c.1456T>G(Y486D), which had been reported as the pathogenic mutation for Gilbert syndrome. Her parents carried double heterozygous mutation of G71R and Y486D and had no symptom of jaundice. The child was diagnosed as having Gilbert syndrome. It is concluded that as for patients with unconjugated hyperbilirubinemia which cannot be explained by liver damage and hemolysis, their family history should be investigated in detail and gene analysis should be performed as early as possible, in order to identify congenital bilirubin metabolic disorders.
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Enfermedad de Gilbert/diagnóstico , Glucuronosiltransferasa/genética , Mutación , Preescolar , Femenino , Humanos , Esclerótica/patología , Piel/patologíaRESUMEN
Purpose: To investigate the predictive value of hemoglobin (Hb) to red blood cell distribution width (RDW) (Hb/RDW) ratio in combination with serum sodium for major adverse cardiovascular events (MACE) in elderly acute heart failure patients with preserved ejection fraction at 30 days after discharge. Methods: 130 elderly acute heart failure patients with preserved ejection fraction were enrolled and followed up at 30 days after discharge. They were classified into the MACE group (n=11) and none-MACE group (n=119). On the day of admission, clinical baseline characteristics were measured and results from laboratory tests were gathered. The correlation and predictive value of Hb/RDW and serum sodium with the occurrence of MACE at 30 days after discharge in acute heart failure patients with preserved ejection fraction in the elderly were analyzed. Results: Spearman correlation analysis showed that the occurrence of MACE was negatively correlated with Hb/RDW, serum sodium (r=-0.209, r=0.291, p<0.05) and Hb/RDW (OR=0.484, 95% CI:0.254, 0.922), serum sodium (OR=0.779, 95% CI:0.646,0.939) were independent risk factors (p<0.05) analyzed by multifactorial logistic. Receiver operating characteristic curves (ROC) analysis showed that the area under the curve (AUC) for the prediction of MACE by Hb/RDW was 0.73, with an optimal threshold of 9.28, sensitivity 81.80%, specificity 70.60%, positive predictive value (PPV) 20.50%, negative predictive value (NPV) 97.70%; the AUC of serum sodium for predicting the occurrence of MACE was 0.76, with an optimal threshold of 140.35 mmol/L, sensitivity 90.90%, specificity 57.10%, PPV 16.40%, NPV 98.60%; and the AUC of Hb/RDW combined serum sodium to predict the occurrence of MACE was 0.83, with sensitivity 90.90%, specificity 78.20%, PPV 27.80% and NPV 98.90%. Conclusion: Hb/RDW and serum sodium had negative correlation with MACE and were independent risk factors of 30-day MACE; Hb/RDW combined with serum sodium can predict 30-day MACE occurrence in elderly acute heart failure patients with preserved ejection fraction.
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Background: This investigation evaluated the prognostic significance of the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), and introduced a combined NLR-PLR score to evaluate the correlation between NLR-PLR score and hepatocellular carcinoma (HCC) recurrence. Material/Methods: We enrolled 110 patients who underwent orthotopic liver transplantation (LT) for HCC. The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were assessed, and appropriate cut-off values were established. The NLR-PLR score ranged from 0 to 2 as follows: score of 2, high NLR (≥3.37) and high PLR (≥105.96); score of 1, either high NLR or high PLR; score of 0, neither high NLR nor high PLR. Results: The median overall survival (OS) of patients with NLR-PLR score of 0, 1 and 2 was 27, 26.5, and 6 months, respectively. The median OS of patients with NLR-PLR score of 2 was shorter than those with 0 (P < 0.001) and 1 (P < 0.001). The median disease-free survival (DFS) time of patients with NLR-PLR score of 0, 1 and 2 was 24.5, 24, and 6 months, The median DFS of patients with NLR-PLR score of 2 was shorter than those with 0 (P = 0.001) and 1 (P = 0.015). Multivariate analysis showed that NLR-PLR score was an independent risk factor for prognosis and survival. Conclusion: NLR, PLR and NLR-PLR score can predict the long-term survival of patients, and NLR-PLR score, having more predictive value than NLR and PLR alone is an independent risk factor for patient survival. more predictive value than NLR and PLR alone.
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Oxaliplatin has been included as a basal drug in various chemotherapy regimens for colorectal cancer (CRC), a global health concern. However, acquired resistance to oxaliplatin affects the prognosis. This study aimed to determine whether the consumption of a KD increases the sensitivity of CRC cells to oxaliplatin via the inhibition of a classical stem cell marker, Krupple-like factor 5 (KLF5). KLF5 functions as a transcription factor for the leukemia inhibitory factor (LIF) and directly binds to its promoter region. LIF upregulation induces dephosphorylation of metal regulatory transcription factor 1 (MTF1), which is recruited to the promoter area of Ferroportin (FPN1), the only cellular iron exporter. FPN1 upregulation reduces the labile iron pool (LIP) and ferroptosis in CRC cells. KLF5 knockdown inhibits the LIF/MTF1/FPN1 axis and induces iron overload, thereby conferring sensitivity to oxaliplatin to CRC cells. KD mimicked KLF5 silencing and sensitized CRC cells to oxaliplatin via a similar mechanism. Thus, potential correlations were observed among ketogenesis, stemness, and iron homeostasis. This finding can be used to formulate a new strategy for overcoming oxaliplatin resistance in patients with CRC.
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Proteínas de Transporte de Catión , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Homeostasis , Hierro , Factores de Transcripción de Tipo Kruppel , Factor Inhibidor de Leucemia , Oxaliplatino , Humanos , Oxaliplatino/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Hierro/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Homeostasis/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Factor Inhibidor de Leucemia/metabolismo , Factor Inhibidor de Leucemia/genética , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacología , AnimalesRESUMEN
BACKGROUND: Circular RNAs (circRNAs) are identified as important regulators in human diseases, including keloid. The purpose of this study is to reveal the role and molecular mechanism of circSLC8A1 in keloid formation. METHODS: Expression of circSLC8A1, microRNA (miR)-181a-5p, and hypoxia inducible factor 1 alpha inhibitor (HIF1AN) were detected by quantitative real-time PCR. Protein expression of extracellular matrix (ECM) deposition markers and HIF1AN was detected by western blot analysis. Furthermore, the interaction between miR-181a-5p and circSLC8A1 or HIF1AN was confirmed by dual-luciferase reporter assay, RIP assay and RNA pull-down assay. RESULTS: Expression of circSLC8A1 was downregulated in keloid tissues and HKFs. Overexpression of circSLC8A1 suppressed HKFs proliferation, migration, ECM deposition, and promoted apoptosis. MiR-181a-5p is targeted by circSLC8A1, and its mimic reversed the effect of circSLC8A1 on the biological function of HKFs. HIF1AN was a target of miR-181a-5p, and it was positively regulated by circSLC8A1. Knockdown of HIF1AN also reversed the negatively regulation of circSLC8A1 on the biological functions of HKFs. CONCLUSION: Our data showed that circSLC8A1 regulates the miR-181a-5p/HIF1AN axis to restrain HKFs biological functions, confirming that circSLC8A1 might serve as a novel therapeutic target for keloids.
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Quemaduras , Queloide , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Queloide/metabolismo , Proliferación Celular/genética , Quemaduras/metabolismo , Fibroblastos/patología , Apoptosis/genética , Matriz Extracelular/metabolismo , Oxigenasas de Función Mixta/metabolismo , Proteínas Represoras/metabolismoRESUMEN
Background: Hepatocellular carcinoma (HCC) relapse is the main reason for the poor prognosis of HCC after Liver transplantation (LT). This study aimed to explore the molecular mechanisms and immune repertoire profiles of HCC relapse. Material and Methods: RNA-seq of blood samples from patients with normal (n=12) and HCC relapse (n=6) after LT was performed to identify differentially expressed genes (DEGs) and key signalling pathways. The DEGs and immune genes were further analyzed by bioinformatics. TRUST4 was used to analyze the differences in the immune repertoire between the two groups. Another 11 blood samples from patients with HCC who had received LT were collected for RT-qPCR verification of key genes. Results: A total of 131 upregulated and 157 downregulated genes were identified using RNA-seq, and GO enrichment analysis revealed that the top 15 pathways were immune-related. The PPI network identified 10 key genes. Immune infiltration analysis revealed a significant difference in the five immune cell types between the two groups. A total of 83 intersecting genes were obtained by intersecting DEGs and immune genes. 6 key genes, including MX1, ISG15, OAS1, PRF1, SPP1, and THBS1 were obtained according to the intersection of DEGs, PPI network top 10 genes and immune intersecting genes. Immune repertoire analysis showed that the usage frequency of variable (V) and joining (J) genes in the normal group was higher than that in the relapse group. RT-qPCR validation showed that the expression levels of key genes were consistent with the RNA-seq results. Conclusion: Our study identified key pathways and genes that could help determine whether transplant recipients are more prone to HCC relapse. Immune repertoire analysis revealed a difference in the usage frequency of VJ genes between the normal and relapse groups, providing a research direction for immunotherapy in patients with HCC relapse after liver transplantation.
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Glioblastomas (GBMs) are the brain tumors with the highest malignancy and poorest prognoses. GBM is characterized by high heterogeneity and resistance to drug treatment. Organoids are 3-dimensional cultures that are constructed in vitro and comprise cell types highly similar to those in organs or tissues in vivo, thus simulating specific structures and physiological functions of organs. Organoids have been technically developed into an advanced ex vivo disease model used in basic and preclinical research on tumors. Brain organoids, which simulate the brain microenvironment while preserving tumor heterogeneity, have been used to predict patients' therapeutic responses to antitumor drugs, thus enabling a breakthrough in glioma research. GBM organoids provide an effective supplementary model that reflects human tumors' biological characteristics and functions in vitro more directly and accurately than traditional experimental models. Therefore, GBM organoids are widely applicable in disease mechanism research, drug development and screening, and glioma precision treatments. This review focuses on the development of various GBM organoid models and their applications in identifying new individualized therapies against drug-resistant GBM.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/patología , Antineoplásicos/farmacología , Neoplasias Encefálicas/patología , Glioma/patología , Organoides/metabolismo , Organoides/patología , Microambiente TumoralRESUMEN
BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) has been limited by resistance. The level of O-6-methylguanine-DNA methyltransferase (MGMT) and intrinsic DNA damage repair factors are important for the TMZ response in patients. Here, we reported a novel compound, called EPIC-0307, that increased TMZ sensitivity by inhibiting specific DNA damage repair proteins and MGMT expression. METHODS: EPIC-0307 was derived by molecular docking screening. RNA immunoprecipitation (RIP), and chromatin immunoprecipitation by RNA (ChIRP) assays were used to verify the blocking effect. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) assays were performed to explore the mechanism of EPIC-0307. A series of in vivo and in vitro experiments were designed to evaluate the efficacy of EPIC-0307 in sensitizing GBM cells to TMZ. RESULTS: EPIC-0307 selectively disrupted the binding of PRADX to EZH2 and upregulated the expression of P21 and PUMA, leading to cell cycle arrest and apoptosis in GBM cells. EPIC-0307 exhibited a synergistic inhibitory effect on GBM when combined with TMZ by downregulating TMZ-induced DNA damage repair responses and epigenetically silencing MGMT expression through modulating the recruitment of ATF3-pSTAT3-HDAC1 regulatory complex to the MGMT promoter. EPIC-0307 demonstrated significant efficacy in suppressing the tumorigenesis of GBM cells, restoring TMZ sensitivity. CONCLUSION: This study identified a potential small-molecule inhibitor (SMI) EPIC-0307 that selectively disrupted the PRADX-EZH2 interaction to upregulate expressions of tumor suppressor genes, thereby exerting its antitumor effects on GBM cells. EPIC-0307 treatment also increased the chemotherapeutic efficacy of TMZ by epigenetically downregulating DNA repair-associate genes and MGMT expression in GBM cells.
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Glioblastoma , Humanos , Temozolomida/uso terapéutico , Glioblastoma/patología , Antineoplásicos Alquilantes/uso terapéutico , Simulación del Acoplamiento Molecular , Reparación del ADN , Enzimas Reparadoras del ADN/genética , O(6)-Metilguanina-ADN Metiltransferasa/genética , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , O(6)-Metilguanina-ADN Metiltransferasa/farmacología , Metilasas de Modificación del ADN/genética , ARN/farmacología , ARN/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
The glioma tumor microenvironment plays a crucial role in the development, occurrence, and treatment of gliomas. Glioma-associated macrophages (GAMs) are the most widely infiltrated immune cells in the tumor microenvironment (TME) and one of the major cell populations that exert immune functions. GAMs typically originate from two cell types-brain-resident microglia (BRM) and bone marrow-derived monocytes (BMDM), depending on a variety of cytokines for recruitment and activation. GAMs mainly contain two functionally and morphologically distinct activation types- classically activated M1 macrophages (antitumor/immunostimulatory) and alternatively activated M2 macrophages (protumor/immunosuppressive). GAMs have been shown to affect multiple biological functions of gliomas, including promoting tumor growth and invasion, angiogenesis, energy metabolism, and treatment resistance. Both M1 and M2 macrophages are highly plastic and can polarize or interconvert under various malignant conditions. As the relationship between GAMs and gliomas has become more apparent, GAMs have long been one of the promising targets for glioma therapy, and many studies have demonstrated the therapeutic potential of this target. Here, we review the origin and activation of GAMs in gliomas, how they regulate tumor development and response to therapies, and current glioma therapeutic strategies targeting GAMs.
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Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Macrófagos , Microglía , Citocinas/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: miR-29a plays a vital role in AS, but the relationship between the miR-29a-targeted PI3K signaling pathway and AS remains unclear. Therefore, this study was carried out. METHODS: Gene expression profiles from the GEO database containing AS samples were analyzed. ApoE-/- mice and RAW264.7 cells were treated with miR-29a negative control (NC), miR-29a mimic and miR-29a inhibitor to establish the AS model. Then MOVAT staining, TEM, Western blotting, and immunofluorescence staining were adopted for testing target proteins. RESULTS: DEGs were identified from GSE137578, GSE132651, GSE113969, GSE43292, and GSE97210 datasets. It was found that there were targeted binding sites between miR-29a and PIK3CA. Besides, GO and KEGG analysis demonstrated that autophagy was an enriched pathway in AS. Later, PPI network was depicted, and hub genes were then determined. The results revealed that miR-29a suppressed the areas of plaques and lesional macrophages, but had no impact on VSMCs. TEM results showed the organelles pyknosis of lesional macrophages damaged morphological changes. Furthermore, miR-29a amplified the M2-like macrophages but suppressed the polarization of M1-like macrophages in atherosclerotic plaques. According to mouse and RAW 264.7 cell experiments, miR-29a significantly inhibited the protein expressions of PI3K, p-PI3K, p-AKT, and p-mTOR, which were consistent with the increased expressions of autophagy-related proteins, Beclin 1 and LC3II. However, the miR-29a suppression exhibited the contrary results. CONCLUSION: MiR-29a elevation induces the increase of autophagy by down-regulating the PI3K/AKT/mTOR pathway in the progression of AS, indicating that miR-29a is a novel therapeutic strategy for AS.
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Aterosclerosis , MicroARNs , Placa Aterosclerótica , Animales , Aterosclerosis/metabolismo , Autofagia/genética , Macrófagos/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Placa Aterosclerótica/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Glioblastoma multiform (GBM) is the most frequent type of malignant brain tumor with a poor prognosis. After optimal surgery, radiotherapy plus temozolomide (TMZ) is the standard treatment for GBM patients. However, the development of TMZ resistance limits its efficacy in GBM management. Runt Related Transcription Factor 1 (RUNX1) and microRNAs have been implicated in drug resistance of TMZ in GBM. In this study, we revealed the underlying mechanism of TMZ resistance and identified miR-128-3p/RUNX1 axis as a novel target for TMZ resistance in GBM. RUNX1 expression was significantly upregulated in GBM tissues as compared to normal tissues, and its expression was even higher in recurrent GBM tissues and TMZ-resistant GBM cells. RUNX1 depletion inhibited the viability, proliferation, migration, invasion and TMZ resistance of GBM cells, which could be rescued by RUNX1 overexpression. We further identified miR-128-3p as a tumor-suppressor whose overexpression restored the sensitivity of TMZ in GBM cells. miR-128-3p negatively regulated RUNX1 and subsequently downregulated multidrug resistance-associated protein 1 (MRP1). Together, the present study indicates that RUNX1 confers TMZ resistance in GBM by upregulating MRP1, which is negatively regulated by miR-128-3p. Targeting miR-128-3p/RUNX1/MRP1 axis provides a potential strategy to overcome TMZ resistance in GBM.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Resistencia a Antineoplásicos/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , MicroARNs/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Temozolomida/uso terapéutico , Regulación hacia Arriba/genética , Adulto , Anciano , Secuencia de Bases , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Invasividad Neoplásica , Pronóstico , Temozolomida/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: To observe the effects of resveratrol on body composition in adult catch-up growth rats and to explore the possible mechanism. METHODS: Eight-week-old male SD rats were randomly divided into 6 groups: normal controls for 4 weeks (NC4) group, caloric restriction for 4 weeks (R4) group, calorie restriction meanwhile resveratrol treatment for 4 weeks (R4E) group, normal controls for 12 weeks (NC12) group, catch-up growth (CUG) group and catch-up growth meanwhile resveratrol treatment for 8 weeks (CUGE) group. At the end of the four-week and twelve-week experimental period, the body weight, muscle and fat content of trunk and whole body, the ratio of trunk to whole body fat were detected, and at the end of twelve-week experimental period, the expression of SIRT1 in skeletal muscle and epididymal adipose tissue, and the expression of PPARγ in epididymal adipose tissue were detected. RESULTS: Compared with NC12 group, the fat content of trunk and whole body and trunk to whole body fat ratio in CUG group were increased significantly, along with the expression of PPARγ in epididymal adipose tissue was increased significantly (Pï¼0.05), while the muscle content of trunk and whole body, the expression of SIRT1 in skeletal muscle and epididymal adipose tissue in CUG group were decreased significantly compared with NC12 group (Pï¼0.05 or Pï¼0.01); compared with CUG group, oral administration of resveratrol distinctly reduced the body fat content and trunk to whole body fat ratio in the CUGE groups, and the expression of PPARγ in epididymal adipose tissue of CUGE group was also significantly decreased (Pï¼0.05). Meanwhile, the muscle content and the expression of SIRT1 in skeletal muscle and epididymal adipose tissue in CUGE group were significantly increased compared with the CUG group (Pï¼0.05). CONCLUSION: Resveratrol can decrease body fat content, increase muscle content and improve abdominal fat accumulation in adult catch-up growth rats, and its mechanism may be associated with increasing SIRT1 expression in skeletal muscle and visceral adipose tissue, decreasing PPARγ expression in visceral adipose tissue.
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Composición Corporal/efectos de los fármacos , Resveratrol/farmacología , Tejido Adiposo , Animales , Restricción Calórica , Grasa Intraabdominal , Masculino , Músculo Esquelético , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , Sirtuina 1/metabolismoRESUMEN
The aim of the present study was to investigate the characteristics and progression of intestinal injury at the anhepatic phase in portal hypertensive rats. A total of 120 healthy male Wistar rats were purchased, with 15 rats in the normal control group and 105 rats were assigned to establish a prehepatic portal hypertension model. The 105 model rats were further divided into seven treatment groups following ischemia-reperfusion. Meanwhile, portal vein pressure, the area of lower esophageal mucosal vein, endotoxin levels in portal vein blood and the level of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Morphology changes of the intestine were observed using optical microscopy and transmission electron microscopy. A portal hypertension rat model was successfully established. Furthermore, endotoxin, MDA and SOD level reached a peak at 12-24 h following reperfusion and then decreased gradually to normal levels at 1 week following reperfusion. However, cytological damage did not recover to preoperative level within 1 week. These findings suggest that intestinal injury was most severe within 12-24 h following ischemia-reperfusion and most indicators recovered to almost normal levels. Therefore, further study on the intestinal mucosal damage is required, with the aim to reduce the production of intestinal endotoxin.
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A series of novel 1-anilino-4-(arylsulfanylmethyl)phthalazines were designed and synthesized. The structures of all the compounds were confirmed by IR, 1H-NMR, elemental analysis and MS. The analogues 1-(3-chloro-4-fluoroanilino)-4-(3,4- difluorophenylthio-methyl)phthalazine (12) and 1-(4-fluoro-3-trifluoromethylanilino)-4- (3,4-difluorophenyl-thiomethyl)phthalazine (13) showed higher activity than a cisplatin control when tested in vitro against two different cancer cell lines using the microculture tetrazolium method (MTT) method.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ftalazinas/síntesis química , Ftalazinas/farmacología , Antineoplásicos/química , Benzofuranos/síntesis química , Benzofuranos/farmacología , Línea Celular Tumoral , Fibrosarcoma/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ftalazinas/químicaRESUMEN
OBJECTIVE: To investigate the effect of miR-25 on the proliferation of human cervical carcinoma HeLa cells and its association with reversion-inducing cysteine-rich protein with Kazal motifs (RECK). METHODS: The recombinant plasmids of pcDNATM6.2-GW-pre-miR-25, pmirGLO-RECK-WT, pmirGLO-RECK-MT and anti-miR-25 were constructed, and their transfection efficiencies into HeLa cells were identified by real-time quantitative PCR (qRT-PCR). The potential proliferation-stimulating function of miR-25 was analyzed by MTT assay in HeLa cells. Furthermore, the target effect of miR-25 on the RECK was determined by dual-luciferase reporter assay system, qRT-PCR and Western blotting. RESULTS: Sequence analysis demonstrated that the recombinant plasmids of pcDNATM6.2-GW-pre-miR-25 and pmirGLO-RECK-WT, pmirGLO-RECK-MT were successfully constructed, and qRT-PCR revealed that the transfection efficiencies of pre-miR-25 and anti-miR-25 were desirable in HeLa cells. MTT assay showed that miR-25 over-expression promoted the proliferation of HeLa cells. In addition, the luciferase activity was significantly reduced in HeLa cells cotransfected with pre-miR-25 and RECK-WT. The qRT-PCR and Western blotting indicated that the expression level of RECK was up-regulated in HeLa cells transfected with anti-miR-25 at the transcriptional and posttranscriptional levels. CONCLUSION: miR-25 could promote cell proliferation by targeting RECK in HeLa cells.
Asunto(s)
Carcinoma/genética , Proliferación Celular , Proteínas Ligadas a GPI/metabolismo , MicroARNs/metabolismo , Neoplasias del Cuello Uterino/genética , Secuencia de Bases , Carcinoma/metabolismo , Carcinoma/patología , Carcinoma/fisiopatología , Movimiento Celular , Femenino , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Células HeLa , Humanos , MicroARNs/genética , Datos de Secuencia Molecular , Invasividad Neoplásica , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/fisiopatologíaRESUMEN
PURPOSE: To evaluate bone regeneration in defects at titanium implants with nHA/BG coating in conjunction with Bio-Oss. METHODS: Four mandibular premolars were extracted in 6 Beagle dogs. After 3 months, buccal dehiscence-type defects (2.25 mm×3 mm×4 mm) were surgically created following implant site. The three treatment modalities were randomly allocated: nHA/BG implant/Bio-Oss, nHA/BG implant/blood clot, and mHA implant/Bio-Oss. After 8 and 16 weeks, the dogs were sacrificed respectively. A histomorphometric analysis was performed. The data was analyzed with SPSS 13.0 software package for Student's t test and ANOVA. RESULTS: At 8- and 16-week, nHA/BG implant group revealed comparable mean BIC (30% to 18% versus 61% to 53%). However, mHA implant/Bio-Oss group revealed significantly lower mean BIC (21% versus 46%) values than nHA/BG implant/Bio-Oss group.A significant difference was observed for the mean BIC and RA values at 8-week between nHA/BG implant/Bio-Oss group and mHA implant/Bio-Oss group. CONCLUSIONS: It is concluded that the application of Bio-Oss graft did not seem to interfere with the nHA/BG coating activity, but ensured a stabilization of the newly formed bone for defects.