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Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase-activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.
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Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteína Forkhead Box O1/metabolismo , Histona Desacetilases/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Proteína Forkhead Box O1/genética , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Repressoras/genética , Sequências de Repetição em Tandem , Células Tumorais Cultivadas , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: The overall outcome of patients with refractory AML (rAML) remains poor. Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as the only curative therapy, it is routinely recommended only for patients after remission with salvage chemotherapy. OBJECTIVE: In this study, we evaluated the impact of salvage chemotherapy or allo-HSCT on the overall outcome in rAML. METHODS: We collected the clinical data of 220 patients from 4 medical centers and performed retrospective analysis of prognosis factors, including salvage chemotherapy, intensity of chemotherapy, and allo-HSCT. RESULTS: A total of 29 patients received allo-HSCT directly without salvage chemotherapy, 26 patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) after transplantation and 4-year leukemia-free survival (LFS) and overall survival (OS) were 45.0 ± 10.7 and 51.0 ± 10.6%, respectively. Another 191 patients received salvage chemotherapy and 81 (42.2%) achieved CR or CRi. Thirty-four patients among them underwent subsequent allo-HSCT with 4-year LFS and OS of 46.0 ± 8.8 and 46.2 ± 9.0%. The 4-year LFS and OS in 26 patients who failed to obtain CR or CRi but received allo-HSCT with active disease were 32.9 ± 10.0 and 36.9 ± 10.8%, respectively. For patients who received salvage chemotherapy but not allo-HSCT, few of them became long-term survivors. In multivariate analysis, salvage chemotherapy and the intensity of chemotherapy failed to have significant impact on both OS and LFS. Allo-HSCT was the only prognostic factor for improved OS and LFS in multivariate analysis. CONCLUSIONS: These results indicate the benefit of allo-HSCT in patients with rAML and direct allo-HSCT without salvage chemotherapy could be treatment option.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/terapia , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação/métodosRESUMO
Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation. Valproic acid (VPA) was described as a histone deacetylase inhibitor that had anti-inflammatory effects and reduced the production of proinflammatory cytokines in experimental autoimmune disease models. Using well-characterized mouse models of MHC-mismatched transplantation, we studied the effects of VPA on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of VPA significantly attenuated the clinical severity of GVHD, the histopathology of GVHD-involved organs, and the overall mortality from GVHD. VPA downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on GVHD was regulatory T cell independent. The effect of VPA was related to its ability to directly reduce the activity of Akt, an important regulator of T cell immune responses. Importantly, when mice received lethal doses of host-type acute leukemia cells, administration of VPA did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a unique role for VPA as a histone deacetylase inhibitor in reducing the donor CD4(+) T cells that contribute to GVHD, which may provide a strategy to reduce GVHD while preserving the GVL effect.
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Doença Enxerto-Hospedeiro/etiologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Ácido Valproico/farmacologia , Animais , Transplante de Medula Óssea/efeitos adversos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/citologia , Células Th1/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Transplante Homólogo , Ácido Valproico/administração & dosagemRESUMO
Verticillium wilt causes massive annual losses of cotton yield, but the mechanism of cotton resistance to Verticillium dahliae is complex and poorly understood. In this study, a comparative proteomic analysis was performed in resistant cotton (Gossypium barbadense cv7124) on infection with V. dahliae. A total of 188 differentially expressed proteins were identified by mass spectrometry (MALDI-TOF/TOF) analysis and could be classified into 17 biological processes based on Gene Ontology annotation. Most of these proteins were implicated in stimulus response, cellular processes and metabolic processes. Based on the proteomic analysis, several genes involved in secondary metabolism, reactive oxygen burst and phytohormone signaling pathways were identified for further physiological and molecular analysis. The roles of the corresponding genes were further characterized by employing virus-induced gene silencing (VIGS). Based on the results, we suggest that the production of gossypol is sufficient to affect the cotton resistance to V. dahliae. Silencing of GbCAD1, a key enzyme involving in gossypol biosynthesis, compromised cotton resistance to V. dahliae. Reactive oxygen species and salicylic acid signaling may be also implicated as regulators in cotton responsive to V. dahliae according to the analysis of GbSSI2, an important regulator in the crosstalk between salicylic acid and jasmonic acid signal pathways. Moreover, brassinosteroids and jasmonic acid signaling may play essential roles in the cotton disease resistance to V. dahliae. The brassinosteroids signaling was activated in cotton on inoculation with V. dahliae and the disease resistance of cotton was enhanced after exogenous application of brassinolide. Meanwhile, jasmonic acid signaling was also activated in cotton after inoculation with V. dahliae and brassinolide application. These data provide highlights in the molecular basis of cotton resistance to V. dahliae.
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Brassinosteroides/metabolismo , Ciclopentanos/metabolismo , Regulação da Expressão Gênica de Plantas , Gossypium/metabolismo , Gossipol/metabolismo , Oxilipinas/metabolismo , Doenças das Plantas/imunologia , Proteínas de Plantas/imunologia , Esteroides Heterocíclicos/metabolismo , Verticillium/fisiologia , Brassinosteroides/farmacologia , Resistência à Doença , Eletroforese em Gel Bidimensional , Inativação Gênica , Gossypium/genética , Gossypium/imunologia , Gossypium/microbiologia , Interações Hospedeiro-Patógeno , Doenças das Plantas/microbiologia , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/genética , Proteômica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ácido Salicílico/metabolismo , Transdução de Sinais , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Esteroides Heterocíclicos/farmacologia , Verticillium/patogenicidadeRESUMO
To prepare myclobutanil molecularly imprinted polymer, a method was established for the choice of the appropriate functional monomer and its dosage. UV spectra was applied to study the combination form, the effect intensity, the optimal concentration ratio and the numbers of binding sites between myclobutanil and methyl acrylic acid (MAA) or acrylamide (AM) functional monomer. The results showed that hydrogen-bonding interaction could be formed between myclobutanil and methyl acrylic acid (MAA) or acrylamide (AM) functional monomer. The pi electron of the triazole ring conjugated double bond in my clobutanil could transit to pi* conjugate antibonding orbital when it absorbed energy. The formation of hydrogen bond could make pi-->pi* absorption band transit. Maximum absorption wavelength produced red shift with the increase in the functional monomer concentration in the system. The research revealed that the optimal concentration ratios between myclobutanil and the two monomers were c(M):c(MAA) = 1:4, c(M):c(AM) = 1:2. Myclobutanil and the both the functional monomers had the bonding ability, and strong bonding force. The prepared molecularly imprinted polymer using AM as a functional monomer had better stability and specificity of recognition for myclobutanil.
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OBJECTIVE: To investigate the mechanism of induction of ferroptosis by brazilin in breast cancer cells. METHODS: Breast cancer 4T1 cells were divided into 6 groups: control, brazilin 1/2 half maximal inhibitory concentration (IC50), IC50, 2×IC50, erastin (10 µg/mL) and capecitabine (10 µg/mL) groups. The effect of brazilin on the proliferation of 4T1 cells was detected by cell counting kit-8 assay, and the treatment dose of brazilin was screened. The effect of brazilin on the mitochondrial morphology of 4T1 cells, and the mitochondrial damage was evaluated under electron microscopy. The levels of Fe2+, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and glutathione peroxidase 4 (GPX4) were estimated using various detection kits. The invasion and migration abilities of 4T1 cells were detected by scratch assay and transwell assay. The expressions levels of tumor protein p53, solute carrier family 7 member 11 (SLC7A11), GPX4 and acyl-CoA synthetase long-chain family member 4 (ACSL4) proteins were quantified by Western blot assay. RESULTS: Compared to the control group, the 10 (1/2 IC50), 20 (IC50) and 40 (2×IC50) µg/mL brazilin, erastin, and capecitabine groups showed a significant decrease in the cell survival rate, invasion and migration abilities, GSH, SLC7A11 and GPX4 protein expression levels, and mitochondrial volume and ridge (P<0.05), and a significant increase in the mitochondria membrane density, Fe2+, ROS and MDA levels, and p53 and ACSL4 protein expression levels (P<0.05). CONCLUSIONS: Brazilin actuated ferroptosis in breast cancer cells, and the underlying mechanism is mainly associated with the p53/SLC7A11/GPX4 signaling pathway.
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Background: Serum carbohydrate antigen 50 (CA50) is an auxiliary diagnostic marker for various solid tumors, but it remains unclear whether CA50 in pleural fluid can assist in the diagnosis of malignant pleural effusion (MPE). This study aimed to evaluate the diagnostic accuracy of pleural fluid CA50 for MPE in pleural effusion patients with undetermined causes. Methods: This study prospectively recruited pleural effusion patients with undetermined causes who visited the Affiliated Hospital of Inner Mongolia Medical University between September 2018 and July 2021. We measured pleural fluid CA50 level with an electrochemiluminescence assay. We analyzed the diagnostic accuracy of CA50 and carcinoembryonic antigen (CEA) for MPE with the receiver operating characteristic (ROC) curve. The net benefits of CA50 and CEA were analyzed using the decision curve analysis (DCA). Results: We enrolled 66 MPEs and 87 benign pleural effusions (BPEs). MPE patients had significantly higher CA50 and CEA than BPE patients. The area under the ROC curve (AUC) of CA50 was 0.72 (95% CI: 0.63-0.80). CA50 had a sensitivity of 0.30 (95% CI: 0.19-0.41) and a specificity of 1.00 (95% CI: 1.00-1.00) at the threshold of 15 IU/mL. The decision curve of CA50 was above the reference line at the calculated risk probability of between 0.30 and 1.00. Venn diagram indicated that some patients with low CEA (<50 or <150 ng/mL) and/or negative cytology can be identified by positive CA50 (>15 IU/mL). Conclusions: Pleural fluid CA50 has moderate accuracy and net benefit for detecting MPE. CA50 >15 IU/mL can be used to diagnose MPE. The combination of CA50 and CEA improves the diagnostic sensitivity for MPE.
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Background: Serum pro-gastrin releasing peptide (proGRP) is a well-recognized diagnostic marker for small cell lung cancer (SCLC). Pleural effusion is common in patients with advanced SCLC. The diagnostic accuracy of pleural proGRP for malignant pleural effusion (MPE) has not yet been established. This study aimed to evaluate the diagnostic accuracy of pleural proGRP for MPE. Methods: We prospectively recruited patients with undiagnosed pleural effusions from two centers (Hohhot and Changshu). An electrochemiluminescence immunoassay was used to detect pleural fluid proGRP. The diagnostic accuracy of proGRP for MPE was evaluated using a receiver operating characteristic (ROC) curve. Results: In both the Hohhot (n=153) and Changshu (n=58) cohorts, pleural proGRP in MPE patients did not significantly differ from that in patients with benign pleural effusions (BPEs) (Hohhot, P=0.91; Changshu, P=0.12). In the Hohhot and Changshu cohorts, the areas under the curves (AUCs) of proGRP were 0.51 [95% confidence interval (CI): 0.41-0.60] and 0.62 (95% CI: 0.47-0.77), respectively. However, patients with SCLC-induced MPE had significantly higher proGRP levels than those with BPE and other types of MPE (P=0.001 for both). In the pooled cohort, the AUC of proGRP for SCLC-induced MPE was 0.90 (95% CI: 0.78-1.00, P=0.001). At a threshold of 40 pg/mL, proGRP had a sensitivity of 1.00 (95% CI: 0.61-1.00) and specificity of 0.59 (95% CI: 0.52-0.66). The positive likelihood ratio was 2.61 (95% CI: 1.99-3.41), and the negative likelihood ratio was 0. Conclusions: Pleural proGRP has no diagnostic value for MPE, but has high diagnostic accuracy for SCLC-induced MPE. In patients with proGRP levels <40 pg/mL, MPE secondary to SCLC can be excluded.
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INTRODUCTION: Pleural effusion is common in clinical practice, and its differential diagnosis remains challenging for clinicians. This study investigates the diagnostic value of apolipoprotein E (apoE) in patients with undetermined pleural effusion. METHODS: This prospective, double-blind study enrolled 152 patients with undiagnosed pleural effusion. Their pleural fluid apoE levels were measured, and a receiver operating characteristics (ROC) curve was used to evaluate the diagnostic accuracy of apoE. Decision curve analysis (DCA) was used to assess apoE's net benefit. Subgroup analyses were performed to investigate the effect of age on the diagnostic accuracy of apoE. RESULTS: Among the included participants, 23 had heart failure (HF). HF patients had the lowest apoE level among pleural effusion patients. The area under the curve (AUC) of apoE for HF was 0.79 (95%CI: 0.69-0.89). At the threshold of 40 mg/L, the sensitivity and specificity of apoE were 0.96 (95%CI: 0.87-1.00) and 0.33 (95%CI: 0.25-0.42), respectively. The decision curve for apoE was above reference lines. The AUC of apoE decreased in older patients. CONCLUSION: Pleural fluid apoE has moderate diagnostic value for HF and has net benefits in patients with undiagnosed pleural effusion. The diagnostic accuracy of apoE decreases with age.
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Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with standard myeloablative conditioning regimens such as fludarabine (Flu) and busulfan (Bu) remains a major concern in patients with myeloid malignancies. A low relapse rate has been reported when thiotepa or melphalan (Mel) is added to Flu-Bu, but at a possible increased risk of nonrelapse mortality (NRM). Here we evaluated the outcomes of 100 patients (70 with acute myeloid leukemia, 23 with myelodysplastic syndrome, 4 with chronic myelomonocytic leukemia, and 3 with granulocytic sarcoma) who underwent their first allo-HSCT after a moderate-dose FBM conditioning regimen consisting of Flu 150 mg/m2, Bu 6.4 mg/kg, and Mel 140 mg/m2 (n = 69), with Mel 100 mg/m2 for patients age >55 years and/or with a Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) ≥3 (n = 31). Donors were HLA-matched siblings (n = 19), matched unrelated donors (n = 4), and haploidentical donors (n = 77). The majority of patients (88%) had an intermediate or high Disease Risk Index. Out of 96 evaluable patients, 94 achieved neutrophil engraftment and had full donor chimerism on day +30 post-transplantation. After a median follow-up of 468 days (range, 55 to 1039 days), only 4 patients relapsed, with a 2-year cumulative incidence of relapse (CIR) of 5.3% ± 3.6%. The 100-day and 2-year NRM were 6.8% ± 4.4% and 12.3% ± 3.6%, respectively. At the last follow-up, the 2-year disease-free survival (DFS) and overall survival (OS) were 82.4% ± 4.2% and 80.3% ± 6.0%, respectively. Comparing the transplantation outcomes between patients receiving Mel 100 mg/m2 and those receiving Mel 140 mg/m2, showed no significant differences in NRM and CIR between the 2 groups and similar 2-year DFS and OS in the 2 groups, although the Mel 100 group had a higher median age (58 years versus 42 years; P < .001) and a higher percentage of patients with an HCT-CI ≥3 (P = .005). In the total cohort, the sole independent factor associated with transplantation outcomes was HCT-CI ≥3, which correlated with higher NRM and inferior DFS and OS. Our study suggests that moderate-intensity FBM conditioning is feasible for patients with myeloid malignancies, with a low relapse rate without increased NRM. A lower Mel dose of 100 mg/m2 maintained the low risk of relapse without excess NRM in older adults. However, the FBM regimen should be used with caution in patients with high-risk HCT-CI (≥3).
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Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Idoso , Humanos , Pessoa de Meia-Idade , Bussulfano/uso terapêutico , Incidência , Leucemia Mieloide Aguda/tratamento farmacológico , Melfalan/uso terapêutico , Recidiva , AdultoRESUMO
Introduction: Post-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and relapsefree survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations. Methods: Therefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Sixtyseven patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen. Results: The median follow-up was 521 (range, 10~991) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 14.9±4.4%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 2-yearchronic GVHD and moderate-to-severe chronic GVHD were 25.4±5.4% and 11.9±4%, respectively. The non-relapse mortality at day+100 and 2year were 7.5±3.2% and 9.0±3.5%, respectively. The cumulative incidence of relapse at 2year was 16±6.4%. The 2-year probability of DFS and OS were 73.8% (95%CI, 61.5~88.4%) and 72.5% (95% CI, 57.1~92.1%), respectively. The 2-year GRFS was estimated as 63.6% (95%CI, 50.6~80%). Discussion: Our results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting.
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BACKGROUND: Corosolic acid is a pentacyclic triterpene acid with hypoglycemic, anti-inflammatory, and anti-cancer effects. However, its potential targets in hepatocellular carcinoma (HCC) are unknown, hindering clinical utilization. METHODS: Differentially expressed proteins of the Bel-7404 cell line were identified with tandem mass tag analysis and differentially expressed genes (DEGs) of an HCC TCGA dataset using bioinformatics. Gene functions and pathways were inferred using the DAVID database. Online databases were used to establish P4HA2 expression in HCC (GEPIA2) and its relationship with patient survival (UALCAN and The Human Protein Atlas), the association between P4HA2 expression and immune cell infiltration (TIMER2), and DNA methylation of the P4HA2 gene (MethSurv). Cell proliferation, cell cycle, and cell death were assessed with PI and SYTOX-Green staining, CCK-8, and colony formation assays. Protein expression levels were detected by Western blotting. RESULTS: A total of 44 differentially expressed proteins and 4498 DEGs were identified. Four genes whose proteins were also found in the differential protein profile but with opposing expressions were selected as candidate targets. The candidate gene prolyl 4-hydroxylase subunit alpha 2 (P4HA2) was recognized as the only potential target due to its high expression in public datasets, association with poor patient survival, and relation to immune cell infiltration in HCC tissues. Moreover, the DNA methylation status in 4 CpG islands of the P4HA2 gene correlated with a poor prognosis. Furthermore, corosolic acid treatment inhibited the proliferation of HCC cell lines Bel-7404 and HepG2 in a dose-dependent manner, caused G2/M phase cell cycle arrest, and promoted cell death. In addition, the treatment reduced P4HA2 protein levels. CONCLUSION: Our results indicate that P4HA2 is a potential target of corosolic acid. Thus, they contribute to understanding molecular changes in HCC after corosolic acid treatment and facilitate finding new treatment regimens.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Triterpenos , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Triterpenos/farmacologia , Farmacologia em RedeRESUMO
HLA-C*06:02:102 differs from HLA-C*06:02:01:01 by one nucleotide in exon 2.
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Antígenos HLA-C , Nucleotídeos , Humanos , Antígenos HLA-C/genética , Alelos , Análise de Sequência de DNA , ChinaRESUMO
OBJECTIVE: To identify specific Chinese medicines (CM) that may benefit patients with primary liver cancer (PLC), and to explore the mechanism of action of these medicines. METHODS: In this retrospective, singlecenter study, prescription information from PLC patients was used in combination with Traditional Chinese Medicine Inheritance Supports System to identify the specific core drugs. A system pharmacology approach was employed to explore the mechanism of action of these medicines. RESULTS: Taking CM more than 6 months was significantly associated with improved survival outcomes. In total, 77 putative targets and 116 bioactive ingredients of the core drugs were identified and included in the analysis (P<0.05). A total of 1,036 gene ontology terms were found to be enriched in PLC. A total of 75 pathways identified from Kyoto Encyclopedia of Genes and Genomes were also enriched in this disease, including fluid shear stress, interleukin-17 signaling, signaling between advanced glycan end products and their receptors, cellular senescence, tumor necrosis factor signaling, p53 signaling, cell cycle signaling, steroid hormone biosynthesis, T-helper 17 cell differentiation, and metabolism of xenobiotics by cytochrome. Docking studies suggested that the ingredients in the core drugs exert therapeutic effects in PLC by modulating c-Jun and interleukin-6. CONCLUSIONS: Receiving CM for 6 months or more improves survival for the patients with PLC. The core drugs that really benefit for PLC patients likely regulates the tumor microenvironment and tumor itself.
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Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Mineração de Dados , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Medicina Tradicional Chinesa , Farmacologia em Rede , Estudos Retrospectivos , Microambiente TumoralRESUMO
Background and Objective: Green tea is a popular beverage worldwide and has numerous health-promoting properties. Accumulating evidence indicates that green tea has preventive and therapeutic effects on lung cancer. This study aimed to investigate the association between green tea consumption and lung cancer. Methods: We performed a narrative review to summarized the association between green tea consumption and lung cancer. Key Content and Findings: Green tea consumption is known to decrease lung cancer risk in the general population, as indicated by meta-analyses of observational studies. Two active components of green tea, theabrownin and (-)-epigallocatechin gallate (EGCG), mediate the antitumor activity of green tea. Theabrownin promotes apoptosis, induces cell cycle arrest, and inhibits the migration, clone formation, and proliferation of lung cancer cell lines in vitro and in vivo. EGCG inhibits lung cancer cell proliferation and promotes apoptosis, agenesis, and epithelial-mesenchymal transition (EMT). In addition, EGCG sensitizes lung cancer cells to cisplatin and tyrosine kinase inhibitors (TKIs). The possible molecular mechanisms underlying the antitumor activity of EGCG and theabrownin were reviewed. Conclusions: Observational studies have indicated that green tea has preventive effects on lung cancer. In vitro and animal studies have indicated that green tea has therapeutic effects on lung cancer. Further clinical trials are needed to illustrate the therapeutic effects of green tea or its active components (i.e., theabrownin, EGCG) on lung cancer.
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BACKGROUND: We report a rare case of a large congenital hemangioma (CH) in the maxillofacial region in a female neonate that caused thrombocytopenia and heart failure. With close multidisciplinary collaboration, the congenital hemangioma was successfully resected with good results. CASE SUMMARY: The patient was delivered at gestational age of 36 wk by cesarean section due to cephalopelvic disproportion and lack of onset of labor (birth weight: 2630 g). A right-sided facial tumor was detected in the fetus during routine antenatal ultrasound examination of the mother at 32 wk of gestation. Physical examination revealed a 7 cm × 7 cm × 3 cm hard, dull purple-colored mass on the right maxillofacial region. The mass was tense and had prominent surface telangiectasias. Laboratory investigations revealed reduced hemoglobin and platelet count, and increased activated partial thromboplastin time, prothrombin time, and thrombin time. International normalized ratio, fibrin degradation products, and D-Dimer levels were significantly increased. Thromboelastography showed increased alpha angle, mean amplitude, and the clot formation speed. Thyroid-stimulating hormone level was significantly elevated. The patient was administered prednisone, propranolol, euthyrox, vitamin K1, milrinone, and digoxin. After operation, cefepime was administered for anti-infection and propranolol was prescribed at discharge. CONCLUSION: We report a rare case of CH in the right maxillofacial region causing thrombocytopenia and heart failure.
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Objective: To investigate the molecular mechanisms of Gupi Xiaoji decoction on apoptosis of human hepatoma cells HepG2. Methods: HepG2 cells were divided into 4 groups: control group (Control), blank serum group (Blank), Gupi Xiaoji Yin serum group (GPXJY) and cisplatin group (Positive). Eight duplicate holes were set in each group. After treated with Gupi Xiaoji Decoction-containing serum or cisplatin for 24 hours, the cell viability, the number of viable cells, the state of apoptosis, the cell cycle and the mitochondrial membrane potential were detected, and the level of lipid peroxidation (MDA) and glycolysis rate of the cells were detected. The expressions of apoptotic Bax, Bcl-2, and Caspase-3 proteins, and the contents of triacylglycerol (TG), cholesterol (TC), pyruvate and glucose in the cell supernatant were detected. Results: Compared with the control group, in the GPXJY group, the inhibition rate was increased (Pï¼0.05), the number of cells was decreased, the number of apoptosis-positive cells was increased (Pï¼0.01), the number of cells in the G1 phase was increased significantly (Pï¼0.05), and the cell membrane potential was decreased (Pï¼0.05,Pï¼0.01), the glycolytic function was inhibited significantly, the MDA level was increased, the expressions of Bax and Caspase-3 in the GPXJY group were increased, and the expression of Bcl-2 was decreased (Pï¼0.05, Pï¼0.01). In cell supernatant, the TC, TG and glucose contents were decreased significantly, and the pyruvate content was increased significantly (Pï¼0.05,Pï¼0.01). Conclusion: Gupi Xiaoji Decoction can induce apoptosis of HepG2 cells and may play a role in energy metabolism.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Caspase 3/metabolismo , Cisplatino , Medicamentos de Ervas Chinesas , Glucose , Células Hep G2 , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piruvatos , Proteína X Associada a bcl-2/metabolismoRESUMO
Background: As a key regulator of metabolic pathways, long non-coding RNA (lncRNA) has received much attention for its relationship with reprogrammed fatty acid metabolism (FAM). This study aimed to investigate the role of the FAM-related lncRNAs in the prognostic management of patients with lung adenocarcinoma (LUAD) using bioinformatics analysis techniques. Methods: We obtained LUAD-related transcriptomic data and clinical information from The Cancer Genome Atlas (TCGA) database. The lncRNA risk models associated with FMA were constructed by single-sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network (WGCNA), differential expression analysis, overlap analysis, and Cox regression analysis. Kaplan-Meier (K-M) and receiver operating characteristic (ROC) curves were utilized to assess the predictive validity of the risk model. Gene set variation analysis (GSVA) revealed molecular mechanisms associated with the risk model. ssGSEA and microenvironment cell populations-counter (MCP-counter) demonstrated the immune landscape of LUAD patients. The relationships between lncRNAs, miRNAs, and mRNAs were predicted by using LncBase v.2 and miRTarBase. The lncRNA-miRNA-mRNA regulatory network was visualized with Cytoscape v3.4.0. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed using DAVID v6.8. Quantitative real-time fluorescence PCR (qRT-PCR) was performed to verify the expression levels of the prognostic lncRNAs. Results: We identified 249 differentially expressed FMA-related lncRNAs in TCGA-LUAD, six of which were used to construct a risk model with appreciable predictive power. GSVA results suggested that the risk model may be involved in regulating fatty acid synthesis/metabolism, gene repair, and immune/inflammatory responses in the LUAD process. Immune landscape analysis demonstrated a lower abundance of immune cells in the high-risk group of patients associated with poor prognosis. Moreover, we predicted 279 competing endogenous RNA (ceRNA) mechanisms for 6 prognostic lncRNAs with 39 miRNAs and 201 mRNAs. Functional enrichment analysis indicated that the ceRNA network may be involved in the process of LUAD by participating in genomic transcription, influencing the cell cycle, and regulating tissue and organogenesis. In vitro experiments showed that prognostic lncRNA CTA-384D8.35, lncRNA RP5-1059L7.1, and lncRNA Z83851.4 were significantly upregulated in LUAD primary tumor tissues, while lncRNA RP11-401P9.4, lncRNA CTA-384D8.35, and lncRNA RP11-259K15.2 were expressed at higher levels in paraneoplastic tissues. Conclusion: In summary, the prognostic factors identified in this study can be used as potential biomarkers for clinical applications. ceRNA network construction provides a new vision for the study of LUAD pathogenesis.
RESUMO
Folic acid-O-carboxymethyl chitosan ultrasmall superparamagnetic iron oxide nanoparticles (FA-OCMCS-USPIO-NPs) are a novel molecular targeting MR contrast agent. This paper reperts the pharmacokinetics and magnetic resonance response characteristics of FA-OCMCS-USPIO-NPs in normal rats and mice, and discussed its distributing regularity in animals, providing basis for tumor targeting imaging. O-phenanthroline method was used to determine iron content in rats' plasma and mice's organs following high and low doses of nanoparticles injected through tail vein, and the blood concentration-time curve was drawn, the calculated t1/2 of two groups were greater than 7 h. The results of tissue distribution showed that only a small part of nanoparticles were swallowed by the liver and spleen, while none in the heart, lung and kidney. At the same times, the phagocytosis of nanoparticles did not change with the dose. The results of MRI showed that renal excretion occurred 4 hours after injection, and signal to noise ratio (SNR) of liver and kidney returned to normal levels 24 hours after injection. There were no nanoparticles in the lungs. So a part of nanoparticles escaped from phagocytosis of liver and spleen, and it owned lower toxicity and longer half-life. indicated its use for tumor-targeting imaging. All of these indicated its use for tumor-targeting imaging.
Assuntos
Quitosana/análogos & derivados , Meios de Contraste/farmacocinética , Compostos Férricos/farmacocinética , Ácido Fólico/farmacocinética , Nanopartículas de Magnetita/química , Animais , Área Sob a Curva , Quitosana/administração & dosagem , Quitosana/química , Quitosana/farmacocinética , Meios de Contraste/administração & dosagem , Meios de Contraste/química , Relação Dose-Resposta a Droga , Portadores de Fármacos , Compostos Férricos/administração & dosagem , Compostos Férricos/química , Ácido Fólico/administração & dosagem , Ácido Fólico/química , Injeções Intravenosas , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/administração & dosagem , Masculino , Camundongos , Nanopartículas , Tamanho da Partícula , Fagocitose , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
As a new soil amendment strategy, the effects of biochar application on soil microbial community have been reported in literature, but little information is available on the response of nitrogen-related microbial communities to biochar application in the reclaimed soil from coal-mining area. Through an outdoor pot experiment with reclaimed soil from coal-mining area of Huaibei, the effects of biochar and biochar compound fertilizer on nitrifier and denitrifier communities were investigated by real time PCR (qPCR) and terminal-restricted fragment length polymorphism (T-RFLP). There were five treatments: control (CK), NPK fertilizer (CF), biochar compound fertili-zer (BF), 2% biochar and NPK fertilizer (LB), 4% biochar and NPK fertilizer (HB). Results showed that compared with the CK, the treatments CF, BF, LB and HB significantly increased the abundance of ammonia oxidizing archaea (AOA), ammonia oxidizing bacteria (AOB), nirK and nirS genes of denitrifier. Compared with the CF treatment, BF, LB and HB significantly increased the abundance of AOB and nirK genes by 42.9%-82.1% and 33.5%-62.7%, respectively. Results of redundancy analysis showed that soil organic carbon, pH, NH4+-N and available potassium significantly affected AOB community structure, while soil organic carbon concentration, pH and NO3--N concentration significantly altered nirK-denitrifier community structure. Therefore, the application of biochar and biochar compound fertilizer could improve soil quality of the reclaimed soil from coal-mining area, and increase the abundances of nitrifier and denitrifier and alter community structure of AOB and nirK-denitrifier.