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The heightened prevalence and accelerated progression of periodontitis in individuals with diabetes is primarily attributed to inflammatory responses in human periodontal ligament cells (HPDLCs). This study is aimed at delineating the regulatory mechanism of nucleotide-binding oligomerization domain-like receptors (NLRs) in mediating inflammation incited by muramyl dipeptide (MDP) in HPDLCs, under the influence of advanced glycation end products (AGEs), metabolic by-products associated with diabetes. We performed RNA-seq in HPDLCs induced by AGEs treatment and delineated activation markers for the receptor of AGEs (RAGE). It showed that advanced glycation end products modulate inflammatory responses in HPDLCs by activating NLRP1 and NLRP3 inflammasomes, which are further regulated through the NF-κB signaling pathway. Furthermore, AGEs synergize with NOD2, NLRP1, and NLRP3 inflammasomes to augment MDP-induced inflammation significantly.
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Diabetes Mellitus , NF-kappa B , Humanos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Ligamento Periodontal/metabolismo , Transdução de Sinais , Inflamação , Produtos Finais de Glicação Avançada/farmacologiaRESUMO
BACKGROUND & AIMS: Dysregulation of microRNA (miRNA) expression in various cancers and their vital roles in malignant progression of cancers are well investigated. Our previous studies have analysed miRNAs that promote malignant progression in hepatocellular carcinoma (HCC); this study aims to systematically elucidate the mechanism of metastasis suppressor miRNAs in HCC. METHODS: High-throughput RNA sequencing was used to identify anti-metastatic miRNAs. The relative expression levels of miRNAs were confirmed by qRT-PCR. The biological functions of miRNAs were detected in vitro and in vivo. Circulating tumour cells (CTCs) were enriched from blood samples of HCC patients and cultured by three-dimensional (3D) system. Kaplan-Meier and Cox regression were used to analyse the value of potential target mRNAs on overall survival. RESULTS: miR-2392 was significantly down-regulated in HCC. Overexpression of miR-2392 suppressed proliferation, clonogenicity, mobility, spheroid formation and maintenance of cancer stem cells (CSC)-like characteristics in HCC cells. CTCs from HCC patients with lower serum miR-2392 level had stronger cell spheroid formation ability. A negative correlation between the content of miR-2392 in serum and the number of CTC spheroids had been found. We identified Jagged2 (JAG2) as a direct target of miR-2392. miR-2392 inhibited the expression of JAG2 by targeting 3'-UTR of JAG2. Down-regulation of JAG2 inhibited the overexpression effects of miR-2392 in vitro and in vivo. JAG2 is highly expressed in HCC and is closely related to poor prognosis and survival of patients. CONCLUSIONS: miR-2392 may play a role as a tumour suppressor to guide the individualized precise treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Jagged-2/genética , Proteína Jagged-2/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismoRESUMO
Tumor microenvironment (TME) is a critical determinant for hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) are main interstitial cells in TME and play a vital role in early intrahepatic invasion and metastasis of HCC. The potential mechanism on the interactions between HSCs and HCC cells remains unclear. In this study, the effects of extracellular vesicles (EVs)-derived OncomiRs that mediate communication between HCC cells and cancer-associated hepatic stellate cells (caHSCs) and remold TME were investigated. The results found that the HCC cells-released EVs contained more various OncomiRs, which could activate HSCs (LX2 cells) and transform them to caHSCs, the caHSCs in turn exerted promotion effects on HCC cells through HSCs-released EVs. To further simulate the effects of OncomiRs in EVs on construction of pro-metastatic TME, a group of OncomiRs, miR-21, miR-221 and miR-151 was transfected into HCC cells and LX2 cells. These microRNAs in the EVs from OncomiRs-enhanced cells were demonstrated to have oncogenic effects on HCC cells by upregulating the activities of protein kinase B (AKT)/extracellular signal-regulated kinase (ERK) signal pathways. Equivalent results were also found in HCC xenografted tumor models. The findings suggested that the OncomiR secretion and transference by cancer cells-released EVs can mediate the communication between HCC cells and HSCs. HCC cells and caHSCs, as well as their secreted EVs, jointly construct a pro-metastatic TME suitable for invasion and metastasis of cancer cells, all these TME components form a positive feedback loop to promote HCC progression and metastasis.
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Carcinoma Hepatocelular/genética , Comunicação Celular/genética , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , Microambiente Tumoral/genética , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Progressão da Doença , Vesículas Extracelulares/metabolismo , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/patologia , Humanos , Fígado/citologia , Fígado/patologia , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Invasividade Neoplásica/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Lithium, one of the few effective treatments for bipolar depression (BPD), has been hypothesized to work by enhancing serotonergic transmission. Despite preclinical evidence, it is unknown whether lithium acts via the serotonergic system. Here we examined the potential of serotonin transporter (5-HTT) or serotonin 1A receptor (5-HT1A) pre-treatment binding to predict lithium treatment response and remission. We hypothesized that lower pre-treatment 5-HTT and higher pre-treatment 5-HT1A binding would predict better clinical response. Additional analyses investigated group differences between BPD and healthy controls and the relationship between change in binding pre- to post-treatment and clinical response. Twenty-seven medication-free patients with BPD currently in a depressive episode received positron emission tomography (PET) scans using 5-HTT tracer [11C]DASB, a subset also received a PET scan using 5-HT1A tracer [11C]-CUMI-101 before and after 8 weeks of lithium monotherapy. Metabolite-corrected arterial input functions were used to estimate binding potential, proportional to receptor availability. Fourteen patients with BPD with both [11C]DASB and [11C]-CUMI-101 pre-treatment scans and 8 weeks of post-treatment clinical scores were included in the prediction analysis examining the potential of either pre-treatment 5-HTT or 5-HT1A or the combination of both to predict post-treatment clinical scores. RESULTS: We found lower pre-treatment 5-HTT binding (p = 0.003) and lower 5-HT1A binding (p = 0.035) were both significantly associated with improved clinical response. Pre-treatment 5-HTT predicted remission with 71% accuracy (77% specificity, 60% sensitivity), while 5-HT1A binding was able to predict remission with 85% accuracy (87% sensitivity, 80% specificity). The combined prediction analysis using both 5-HTT and 5-HT1A was able to predict remission with 84.6% accuracy (87.5% specificity, 60% sensitivity). Additional analyses BPD and controls pre- or post-treatment, and the change in binding were not significant and unrelated to treatment response (p > 0.05). CONCLUSIONS: Our findings suggest that while lithium may not act directly via 5-HTT or 5-HT1A to ameliorate depressive symptoms, pre-treatment binding may be a potential biomarker for successful treatment of BPD with lithium. CLINICAL TRIAL REGISTRATION: PET and MRI Brain Imaging of Bipolar Disorder Identifier: NCT01880957; URL: https://clinicaltrials.gov/ct2/show/NCT01880957.
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Transtorno Bipolar , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Humanos , Lítio/uso terapêutico , Tomografia por Emissão de Pósitrons , Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
CD147 is highly expressed in hepatocellular carcinoma (HCC) and associated with the invasion and metastasis of HCC. The efficacy of I131 -metuximab (I131 -mab), a newly developed agent that targets CD147, as a radio-immunotherapy for local HCC, has been validated in clinical practice. However, the synergistic anticancer activity and molecular mechanism of different conjugated components within I131 -mab remain unclear. In this study, the cytological experiments proved that I131 -mab inhibited the proliferation and invasion of HCC cells. Mechanically, this inhibition effect was mainly mediated by the antibody component part of I131 -mab, which could reverse the epithelial-mesenchymal transition of HCC cells partially by suppressing the phosphorylation of VEGFR-2. The inhibitory effect of I131 on HCC cell proliferation and invasion is limited, whereas, when combined with metuximab, I131 significantly enhanced the sensitivity of HCC cells to CD147-mab and consequently reinforced the anticancer effects of CD147-mab, suggesting that the two components of I131 -mab exerted synergistic anti-HCC capability. Furthermore, the experiments using SMMC-7721 human HCC xenografts in athymic nude mice showed that I131 -mab and CD147-mab significantly inhibited the growth of xenograft tumors and that I131 -mab was more effective than CD147-mab. In conclusion, our results elucidated the mechanism underlying the anti-HCC effects of I131 -mab and provided a theoretical foundation for the clinical application of I131 -mab.
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Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Células Tumorais Cultivadas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Costunolide (CE) and dehydrocostuslactone (DE) are derived from many species of medicinal plants, such as Saussurea lappa Decne and Laurus nobilis L. They have been reported for their wide spectrum of biological effects, including anti-inflammatory, anticancer, antiviral, antimicrobial, antifungal, antioxidant, antidiabetic, antiulcer, and anthelmintic activities. In recent years, they have caused extensive interest in researchers due to their potential anti-cancer activities for various types of cancer, and their anti-cancer mechanisms, including causing cell cycle arrest, inducing apoptosis and differentiation, promoting the aggregation of microtubule protein, inhibiting the activity of telomerase, inhibiting metastasis and invasion, reversing multidrug resistance, restraining angiogenesis has been studied. This review will summarize anti-cancer activities and associated molecular mechanisms of these two compounds for the purpose of promoting their research and application.
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Antineoplásicos/farmacologia , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , HumanosRESUMO
OBJECTIVE: This study aimed to establish a prognostic model for clinical T1N0M1 (cT1N0M1) lung adenocarcinoma patients to evaluate the prognosis of patients in terms of overall survival (OS) rate and cancer-specific survival (CSS) rate. METHODS: Data of patients with metastatic lung adenocarcinoma from 2010 to 2016 were collected from the Surveillance, Epidemiology and End Results database. Multivariate Cox regression analysis was conducted to identify relevant prognostic factors and used to develop nomograms. The receiver operating characteristic (ROC) curve and calibration curve are used to evaluate the predictive ability of the nomograms. RESULTS: A total of 45610 patients were finally included in this study. The OS and CSS nomograms were constructed by same clinical indicators such as age (<60 years or ≥60 years), sex (female or male), race (white, black, or others), surgery, radiation, chemotherapy, and the number of metastatic sites, based on the results of statistical Cox analysis. From the perspective of OS and CSS, surgery contributed the most to the prognosis. The ROC curve analysis showed that the survival nomograms could accurately predict OS and CSS. According to the points obtained from the nomograms, survival was estimated by the Kaplan-Meier method, then cT1N0M1 patients were divided into three groups: low-risk group, intermediate-risk group, and high-risk group, and the OS ( P â <â 0.001) and CSS ( P â <â 0.001) were significantly different among the three groups. CONCLUSION: The nomograms and risk stratification model provide a convenient and reliable tool for individualized evaluation and clinical decision-making of patients with cT1N0M1 lung adenocarcinoma.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Nomogramas , Projetos de Pesquisa , Tomada de Decisão Clínica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Prognóstico , Programa de SEERRESUMO
BACKGROUND: Microsatellite instability (MSI) and mismatch repair (MMR) detection is valuable in assessing prognosis and treatment options. However, the conventional detection methods such as immunohistochemistry (IHC) are limited by not fully consistent results as well as a long turnaround time. TrueMark™ MSI Assay is a novel solution for MSI analysis, but lack of research support in the Chinese colorectal cancer (CRC) patients. MATERIALS AND METHODS: 60 dMMR and 60 pMMR CRC samples identified by IHC were collected and their MSI status were detected using TrueMark™ MSI assay with an expanded panel of 13 markers. The overall performance and diagnostic concordance between TrueMark™ MSI test and MMR IHC analysis were assessed and analyzed. RESULTS: According to the TrueMark™ test, 55 out of the 120 (45.8 %) CRCs were identified as MSI-high (MSI-H) with an instability at ≥ 4/13 markers. Compared with the MMR IHC analysis, an overall percent agreement of 94.2 % and a Kappa of 0.883 were achieved. For the seven inconsistent samples, tumor mutation burden analysis was performed and the results supported the diagnosis by TrueMark™ test. To confirm the robustness of the above findings, a validation was performed in an independent cohort comprising 51 consecutive CRCs. Furthermore, an optimized panel composed of NR-21, NR-24, NR-27, ABI-16, ABI-17 and ABI-20B was developed by multivariate logistic regression model, and showed 100 % agreement with the 13-marker panel for MSI detection in both the derivation and validation sets. CONCLUSION: TrueMark™ MSI provides a fast, reliable and highly automated solution to MSI detection in Chinese CRC patients, and the new 6-marker panel we established shows promise deserving further evaluation.
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Neoplasias Colorretais , Instabilidade de Microssatélites , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , China , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/diagnóstico , Reparo de Erro de Pareamento de DNA/genética , População do Leste Asiático , Imuno-Histoquímica/métodosRESUMO
RATIONALE: Severe congenital neutropenia (SCN) is a rare and heterogeneous genetic disease. By describing the diagnosis and treatment of a child with SCN and periodontitis, this case provides a reference for the oral health management of a child with SCN and periodontitis. PATIENT CONCERNS: We describe a boy with clinical manifestations of oral bleeding, neutropenia, recurrent fever, and other recurrent infections. The absolute neutrophil count (ANC) was <0.50â ×â 109/L most of the time. Morphological examination of bone marrow cells showed active granulocyte hyperplasia and dysmaturation. DIAGNOSES: According to the clinical manifestations, hematological examination and gene detection results, the child was diagnosed as SCN with chronic periodontitis. INTERVENTIONS: Periodontal treatment was performed after informed consent was obtained from the child guardian. These included supragingival and subgingival cleaning, hydrogen peroxide and saline irrigation, placement of iodoglycerin in the gingival sulcus, and oral hygiene instruction. Hematopoietic stem cell transplantation (HSCT) was performed later. OUTCOMES: One month after initial periodontal treatment, oral hygiene was well maintained and gingival swelling had subsided. Probing depth (PD) index on periodontal probing and bleeding was significantly reduced. However, there was no significant change in blood routine and other indicators before and after periodontal treatment. CONCLUSION: Once SCN is diagnosed, individualized treatment plans can be developed according to the characteristics of the disease and its impact on oral health, which can effectively control the interaction between SCN and periodontal disease and reduce the occurrence of serious infection.
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Síndrome Congênita de Insuficiência da Medula Óssea , Neutropenia , Humanos , Masculino , Neutropenia/congênito , Neutropenia/terapia , Neutropenia/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Criança , Saúde Bucal , Periodontite Crônica/terapia , Periodontite Crônica/complicações , Periodontite Crônica/diagnóstico , Higiene Bucal , Transplante de Células-Tronco Hematopoéticas/métodos , Periodontite/terapia , Periodontite/complicaçõesRESUMO
Toxoplasmosis, a zoonotic parasitic disease caused by Toxoplasma gondii (T. gondii), is prevalent worldwide. The fact should be emphasized that a considerable proportion of individuals infected with T. gondii may remain asymptomatic; nevertheless, the condition can have severe implications for pregnant women or immunocompromised individuals. The current treatment of toxoplasmosis primarily relies on medication; however, traditional anti-toxoplasmosis drugs exhibit significant limitations in terms of efficacy, side effects, and drug resistance. The life cycles of T. gondii are characterized by distinct stages and its body morphology goes through dynamic alterations during the growth cycle that are intricately governed by a wide array of post-translational modifications (PTMs). Ubiquitin (Ub) signaling and ubiquitin-like (Ubl) signaling are two crucial post-translational modification pathways within cells, regulating protein function, localization, stability, or interactions by attaching Ub or ubiquitin-like proteins (Ubls) to target proteins. While these signaling mechanisms share some functional similarities, they have distinct regulatory mechanisms and effects. T. gondii possesses both Ub and Ubls and plays a significant role in regulating the parasite's life cycle and maintaining its morphology through PTMs of substrate proteins. Investigating the role and mechanism of protein ubiquitination in T. gondii will provide valuable insights for preventing and treating toxoplasmosis. This review explores the distinctive characteristics of Ub and Ubl signaling in T. gondii, with the aim of inspiring research ideas for the identification of safer and more effective drug targets against toxoplasmosis.
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Transdução de Sinais , Toxoplasma , Toxoplasmose , Ubiquitina , Toxoplasma/metabolismo , Toxoplasma/fisiologia , Toxoplasma/efeitos dos fármacos , Ubiquitina/metabolismo , Humanos , Toxoplasmose/parasitologia , Toxoplasmose/tratamento farmacológico , Toxoplasmose/metabolismo , Animais , Proteínas de Protozoários/metabolismo , Ubiquitinação , Processamento de Proteína Pós-Traducional , Ubiquitinas/metabolismo , Estágios do Ciclo de VidaRESUMO
Background: Toxoplasmosis caused by Toxoplasma gondii is a globally distributed zoonosis. Most infections appear asymptomatic in immunocompetent individuals, but toxoplasmosis can be fatal in fetuses and immunocompromised adults. There is an urgent need to research and develop effective and low-toxicity anti-T. gondii drugs because of some defects in current clinical anti-T. gondii drugs, such as limited efficacy, serious side effects and drug resistance. Methods: In this study, 152 autophagy related compounds were evaluated as anti-T. gondii drugs. The activity of ß-galactosidase assay based on luminescence was used to determine the inhibitory effect on parasite growth. At the same time, MTS assay was used to further detect the effects of compounds with over 60% inhibition rate on host cell viability. The invasion, intracellular proliferation, egress and gliding abilities of T. gondii were tested to assess the inhibitory effect of the chosen drugs on the distinct steps of the T. gondii lysis cycle. Results: The results showed that a total of 38 compounds inhibited parasite growth by more than 60%. After excluding the compounds affecting host cell activity, CGI-1746 and JH-II-127 were considered for drug reuse and further characterized. Both CGI-1746 and JH-II-127 inhibited tachyzoite growth by 60%, with IC50 values of 14.58 ± 1.52 and 5.88 ± 0.23 µM, respectively. TD50 values were 154.20 ± 20.15 and 76.39 ± 14.32 µM, respectively. Further research found that these two compounds significantly inhibited the intracellular proliferation of tachyzoites. Summarize the results, we demonstrated that CGI-1746 inhibited the invasion, egress and especially the gliding abilities of parasites, which is essential for the successful invasion of host cells, while JH-II-127 did not affect the invasion and gliding ability, but seriously damaged the morphology of mitochondria which may be related to the damage of mitochondrial electron transport chain. Discussion: Taken together, these findings suggest that both CGI-1746 and JH-II-127 could be potentially repurposed as anti-T. gondii drugs, lays the groundwork for future therapeutic strategies.
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Toxoplasma , Toxoplasmose , Adulto , Animais , Humanos , Toxoplasmose/tratamento farmacológico , Toxoplasmose/parasitologia , Zoonoses , Proliferação de CélulasRESUMO
[This corrects the article DOI: 10.3389/fcimb.2023.1145824.].
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BACKGROUND AND AIM: The proline rich mitotic checkpoint control factor (PRCC) is involved in the splicing process of pre-mRNA. This study aims to elucidate PRCC molecular function, regulatory mechanism and diagnostic value in hepatocellular carcinoma (HCC). METHODS: The tissue microarray and serum samples from HCC patients were used to investigate the clinical value of PRCC. The biological function and molecular mechanism of PRCC were demonstrated by cell biology, biochemical and animal experiments. The relationship between PRCC and intratumoral heterogeneity (ITH) was analyzed by bioinformatics. RESULTS: PRCC was highly expressed in HCC tissues and related to the poor prognosis of HCC patients, its contents were elevated in the preoperative sera of HCC patients. PRCC exhibited high application potential as a substitute or adjuvant of alpha-fetoprotein (AFP) for clinical diagnosis of HCC. It had no significant effect on the proliferation of cancer cells, but could inhibit spheroid formation and metastasis of HCC cells in vitro and in vivo. The high ectopic expression of PRCC made cancer cells insensitive to DNA damage, and enhanced the heterogeneity of HCC cells by inhibiting the JNK/ATM/ATR/ATF2 axis. The HCC patients with high PRCC expression had high ITH, which corresponded to a short overall survival in patients. CONCLUSIONS: PRCC has high application potential as a substitute or adjuvant of AFP for clinical diagnosis of HCC. The high ectopic expression of PRCC not only caused HCC cells to resist to cell death induced by DNA damage, but also endowed cancer cells with numerous DNA mutations to become increasingly heterogeneous, finally leading to a poor prognosis in HCC patients. These data suggested PRCC could be a promising therapeutic target in HCC patients.
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BACKGROUND: Smaller hippocampal volumes are reported in adults with major depressive disorder (MDD) and in reported childhood abuse. The hippocampus is a complex structure with distinct functional subfields. We sought to examine the effect of MDD diagnosis and childhood abuse on hippocampal subfields. METHODS: Forty-one MDD participants (17 reported abuse and 24 did not) and 46 healthy volunteers (HV) (2 reported abuse) underwent T1- weighted structural magnetic resonance imaging (MRI) and clinical characterization in a retrospective design. A subfield segmentation program was used to measure the whole and subfield hippocampal volumes. Linear mixed-effects models were fitted for group comparisons. RESULTS: No main effect of diagnosis interaction effect between diagnosis and subfield region was observed. However, a comparison of abused MDD vs. HVs showed a group by region interaction. A significant interaction between childhood abuse and region was observed. Effects were confined to the left side of the brain, and post hoc, exploratory region-specific tests indicated smaller left CA1 volume in abused MDD compared with non-abused MDD. In addition, smaller amygdala volume was found in all MDD compared with HVs. LIMITATIONS: We did not have a sample of healthy volunteers with reported childhood abuse. CONCLUSIONS: The diagnosis of pure MDD may not be sufficient to exert effects on hippocampal volumes, indicating the importance of taking into account childhood trauma in studies on psychopathological mechanisms. Left CA1 might be the hippocampal subfield most relevant to reported childhood abuse. Smaller amygdala volume may be related to MDD diagnosis independent of childhood abuse.
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Transtorno Depressivo Maior , Delitos Sexuais , Adulto , Criança , Depressão , Transtorno Depressivo Maior/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Tamanho do Órgão , Projetos Piloto , Estudos RetrospectivosRESUMO
Importance: A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. Objective: To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. Design, Setting, and Participants: This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. Intervention: Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. Main Outcomes and Measures: Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. Results: A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose (t36 = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36 = 2.25; P = .03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response (t33 = -2.400; P = .02; slope estimate, -9.85 [95% CI, -18.2 to -1.50]). Although GABA levels correlated with Glx (t33 = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382 to 0.638]), GABA response did not correlate with antidepressant effect. When both ketamine dose and Glx response were included in a mediation analysis model, ketamine dose was no longer associated with antidepressant effect, indicating that Glx response mediated the relationship. Adverse effects were related to blood levels in men only (t5 = 2.606; P = .048; estimated slope, 0.093 [95% CI, 0.001 to 0.186]), but Glx and GABA response were not related to adverse effects. Conclusions and Relevance: In this study, intravenous ketamine dose and blood levels correlated positively with antidepressant response. The Glx response correlated inversely with ketamine dose and with antidepressant effect. Future studies are needed to determine whether the relationship between Glx level and antidepressant effect is due to glutamate or glutamine. Trial Registration: ClinicalTrials.gov Identifier: NCT01558063.
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Antidepressivos/administração & dosagem , Transtorno Depressivo Maior , Ácido Glutâmico/metabolismo , Ketamina/administração & dosagem , Ácido gama-Aminobutírico/metabolismo , Adulto , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Ketamina/efeitos adversos , Ketamina/farmacocinética , Ketamina/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismoRESUMO
Structural brain deficits are linked to risk for suicidal behavior. However, there is disagreement about the nature of these deficits, probably due to the heterogeneity of suicidal behavior in terms of the suicidal act's lethality. We hypothesized that individuals with major depressive disorder (MDD) and history of more lethal suicide attempts would have lower gray matter volume (GMV) of the prefrontal regions and insula compared with MDD lower-lethality attempters and MDD non-attempters. We collected structural MRI scans on 91 individuals with MDD; 11 with history of higher-lethality suicide attempts, 14 with lower-lethality attempts, and 66 were non-attempters. Differences in GMV between these three groups were examined using both regions-of-interest (ROI) and brain-wide voxel-based morphometry (VBM) analyses. Both ROI and VBM analyses showed that higher-lethality suicide attempters have greater GMV of the prefrontal cortical regions and insula, compared with the other two groups. Although this contrasts with our hypothesis, the observed larger prefrontal cortex GMV in higher-lethality suicide attempters may underlie the set of attributes observed previously in this suicidal subgroup, including enhanced suicide attempt planning, greater response inhibition, and delayed reward capabilities. Future studies should further examine the role of these brain regions in relation to suicidal intent and planning.
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Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/psicologia , Substância Cinzenta/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Ideação Suicida , Tentativa de Suicídio/psicologia , Adolescente , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Recompensa , Adulto JovemRESUMO
Protein phosphatase 2, regulatory subunit B (B56), alpha isoform (PPP2R5A) is one of the regulatory subunits of the protein phosphatase 2A (PP2A), which is a major member of protein serine/threonine phosphatases in cells. PPP2R5A can regulate the cellular location, substrate specification and protein phosphatase function of PP2A, through which PPP2R5A plays an important role in many cellular activities. It has been reported that PPP2R5A relates with many diseases including some kinds of cancers, but the related mechanisms have a lot remaining to be discovered or demonstrated. This review arms to summarize PPP2R5A and its relationships with the occurrence and progression of tumors, helping us to further understand its significance in the prevention, early diagnosis, targeted therapy and prognosis improvement of tumors.
Assuntos
Fenômenos Fisiológicos Celulares , Neoplasias/metabolismo , Proteína Fosfatase 2/metabolismo , Transdução de Sinais , Animais , Humanos , Ativação Linfocitária , Mitose , Modelos Biológicos , Neoplasias/diagnóstico , Neoplasias/terapia , FosforilaçãoRESUMO
Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death which needs novel drugs to improve patient outcome. Survivin overexpresses in HCC and contributes to HCC malignant progression. In this study, we established a Survivin-targeted drug screening platform, a cell model HepG2-Sur5P-EGFP-Sur3U stably transfected with lentivirus carrying an EGFP expression cassette, in which the EGFP expression was regulated by the upstream Survivin promoter and downstream Survivin 3'-UTR. By using this platform, we screened and easily identified one of matrine derivatives, WM-127, from hundreds of matrine derivatives. WM-127 was demonstrated to be a strong Survivin inhibitor that inhibited cell proliferation, induced cell cycle arrest and apoptosis of HCC cells, and suppressed the growth of HCC xenografted tumors in nude mice, suggesting that WM-127 might be a promising drug for HCC treatment. WM-127 exhibited less cytotoxicity in normal cells. Mechanistic studies showed that WM-127 suppressed the activity of Survivin/ß-catenin pathway and the expression of Bax to induce cell cycle arrest and apoptosis. Taken together, we constructed an economical, practical, efficient and convenient cell platform for screening the Survivin-targeted drugs from the enormous diversity of chemicals or factors, which would be a potential tool for antitumor drug research and development.
Assuntos
Alcaloides/administração & dosagem , Alcaloides/síntese química , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Survivina/antagonistas & inibidores , Alcaloides/química , Alcaloides/farmacologia , Animais , Carcinoma Hepatocelular/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The octamer-binding transcription factor 4 (OCT4) can promote cancer proliferation and metastasis. Esophageal carcinoma (ECC) harbors different quantities of OCT4-positive cancer cells. These cells are highly malignant and prone to metastasis; however, the mechanism remains unknown. In this study, we found that OCT4 enhances vascular endothelial growth factor C (VEGF-C) promoter activity to promote VEGF-C expression and activates VEGF receptor 3 (VEGFR-3) in ECC cells, thereby inducing cancer cell epithelial-mesenchymal transition (EMT). Studies using xenograft models showed that OCT4 promoted xenograft growth and intraperitoneal implantation metastasis of ECC cells. Downregulation of OCT4 expression could inhibit cancer metastasis. OCT4- and VEGF-C-positive ECC presented more malignant biological behaviors and the corresponding patients exhibited a poor prognosis. The study confirmed that the OCT4/VEGF-C/VEGFR-3/EMT signaling plays a role in the progression of ECC. Understanding of how OCT4 regulates EMT and how ECC metastasis occurs will provide useful targets for the biological treatment of ECC.