RESUMO
BACKGROUND: The association of hypertension and depression with mortality has not been fully understood. We aimed to explore the possible independent or joint association of hypertension and depression with mortality. Their interaction effects on mortality and possible mediating role were also investigated. METHODS: Associations of hypertension, depression, and their interaction with all-cause and cardiovascular disease (CVD) mortality were evaluated using multivariate Cox proportional hazards regression models. The mediation analysis was conducted with a Sobel test. RESULTS: A total of 35152 participants were included in the final analysis. Hypertension and depression were independently associated with increased risk of all-cause and CVD mortality. The co-existence of hypertension and depression resulted in a 1.7-fold [95% confidence interval (CI): 1.3-2.1] increase in all-cause mortality and a 2.3-fold (95% CI: 1.4-3.7) increase in CVD mortality compared to those with neither of them. Hypertension and depression showed no significant multiplicative (P for interaction, 0.587) and additive interaction (P for relative excess risk of interaction, 0.243; P for Interaction on additive scale, 0.654) on all-cause mortality, as well as on CVD mortality. Depression did not mediate the relationship between hypertension and all-cause (Z=1.704, P=0.088) and CVD mortality (Z=1.547, P=0.122). Hypertension did not mediate the relationship between all-cause and CVD mortality as well. CONCLUSION: Hypertension and depression were related to all-cause and CVD mortality independently and the co-existence of them increased the risk of mortality. However, there is no interaction effect of them on mortality, and hypertension or depression did not mediate the association of each other with mortality.
Assuntos
Doenças Cardiovasculares , Hipertensão , Humanos , Depressão/complicações , Hipertensão/complicações , Risco , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
Recent studies have found that the acetaldehyde dehydrogenase 1A3 (ALDH1A3) gene is a marker of glioma stem cells. A total of 115 brain glioma specimens were collected and classified into grade I-IV, while non-tumor brain tissue specimens, taken from 12 patients of vascular malformation surgery, were used as control. ALDH1A3 gene promoter methylation in glioma tissues was detected by pyrosequencing, while immunohistochemistry and western blot were used to detect ALDH1A3 protein expressions in different grades of glioma tissues and normal brain tissues. The expression of ALDH1A3 in the glioma cell line U87 was detected by quantitative real-time polymerase chain reaction and RNA-Seq technology was applied to investigate differentially expressed genes before and after silencing the ALDH1A3 gene. Among the 115 glioma tissue specimens, 50 (43.48%) showed low and 65 (56.52%) high expression of ALDH1A3, but no expression was detected in the control. Univariate and multivariate COX regression analyses showed that the patient's tumor pathological grade, the methylation status of ALDH1A3 promoter, and the expression of ALDH1A3 protein were risk factors for progression-free survival (PFS) and overall survival (OS) (all P < 0.05) and the OS of mice with silenced ALDH1A3 in a glioma nude mouse model was prolonged. U87 experiments revealed that ALDH1A3 expression had significant effects on apoptosis, proliferation, cell cycle, mitochondrial membrane potential, glucose consumption, lactate production, invasion ability, and expression of the pyruvate kinase M2 (PKM2) and hexokinase 2 (HK2) in glioma cells. ALDH1A3 protein expression is a marker for poor PFS and OS in glioma patients.
Assuntos
Aldeído Oxirredutases/metabolismo , Neoplasias Encefálicas/mortalidade , Regulação Neoplásica da Expressão Gênica , Glioma/mortalidade , Glucose/metabolismo , Ácido Láctico/metabolismo , Adolescente , Adulto , Aldeído Oxirredutases/genética , Animais , Apoptose , Biomarcadores Tumorais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Ciclo Celular , Proliferação de Células , Progressão da Doença , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of 4-aryl-5-aminoalkyl-thiazole-2-amines were designed and synthesized, and their inhibitory activity on ROCK II was screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives had certain ROCK II inhibitory activities. Compound 10l showed ROCK II inhibitory activity with IC50 value of 20 nM.
Assuntos
Aminas/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Quinases Associadas a rho/metabolismoRESUMO
Pretubulysin is a bio-precursor of highly toxic tetrapeptide tubulysins. Although pretubulysin has a much simpler chemical structure, it has similar anti-mitotic potency. A series of 2-amino-thiazole-4-carboxamides were designed and synthesized based on the structure of cemadotin. These are all novel compounds and their structures are characterized by 1H-NMR, 13C-NMR, and high resolution (HR)MS. The antitumor activities of these compounds were screened using the methyl thiazolyl tetrazolium colorimetric (MTT) cell viability method in MCF7 (breast cancer) and NCI-H1650 (lung cancer) cells. All the synthesized compounds 6a-n showed moderate anti-proliferation activities. Compounds 6m exhibited antitumor activity with the IC50 value of 0.47 and 1.1 µM in MCF7 and NCI-H1650 cells, respectively.
Assuntos
Amidas/síntese química , Antineoplásicos/síntese química , Tiazóis/síntese química , Amidas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Oligopeptídeos , Tiazóis/farmacologiaRESUMO
Microglia mediated neuroinflammation is known to cause various neurodegenerative and neurological ailments. Tannic acid is a natural polyphenol which has been reported to possess antioxidant, anti-inflammatory, anticarcinogenic, antimutagenic, antitumor, and antimicrobial activities. As there are no reports till date on the anti-neuroinflammatory effects of tannic acid, this study was conducted to analyze the possible mechanism and pathway involved in the prevention of neuroinflammation by tannic acid in BV2 microglial cells. BV2 microglial cells were pretreated with tannic acid (10, 25, and 50 µM/mL) and induced with lipopolysaccharide (LPS; 1 µM/mL) to assess the production of reactive oxygen species (ROS), nitric oxide (NO), prostaglandin E2 (PGE2), pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α), and nuclear factor-kappa B (NF-κB) protein expressions through western blotting. The results showed that LPS significantly activated the BV2 cells via toll-like receptor 4 to induce elevated productions of ROS, NO, PGE2, IL-6, and IL-1ß. However, tannic acid was able to reverse all the neuroinflammatory effects of LPS-induced BV2 cells in a dose-dependent manner. Collectively, the anti-inflammatory effects of tannic acid on LPS-induced BV2 microglial cells are attributed to the inhibition of ROS formation and the suppression of NF-κB pathway activation. Tannic acid could be a potential therapeutic agent for the treatment of neurological related disorders.
Assuntos
Anti-Inflamatórios/farmacologia , Microglia/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Taninos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Dinoprostona/metabolismo , Lipopolissacarídeos , Camundongos , Microglia/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Background: Endoscopic transnasal optic canal decompression is widely used in the treatment of traumatic optic neuropathy (TON) following head and craniofacial trauma. Intraoperative hemorrhage is a catastrophic surgical complication during optic canal decompression. Case description: We present two cases of patients with TON who suffered unexpected intra-operative massive bleeding during endoscopic transnasal optic canal decompression. After intraoperative hemostasis was achieved, emergent cerebral angiograms demonstrated the formation of internal carotid pseudoaneurysms, which were immediately embolized with coils combined with or without Onyx with balloon assistance. One of these cases was also complicated by a postoperative cerebrospinal fluid leak, which failed to be treated with lumbar drainage but was successfully repaired with endoscopic transnasal surgery. Conclusion: The intra-operative rupture of ICA pseudoaneurysm is a rare but catastrophic complication in TON patients. Intraoperative massive bleeding indicates rupture of ICA pseudoaneurysm. Postoperative emergency angiography and endovascular therapy should be arranged to evaluate and repair the cerebral vascular injury. Endoscopic trans-nasal surgery repairing CSF leaks resistant to lumbar drainage could be efficient and safe following pseudoaneurysm embolization.
RESUMO
To explore the potential role of circular RNAs (circRNAs) in children developing very early-onset schizophrenia (VEOS). Total RNA was extracted from the plasma samples of 10 VEOS patients and eight healthy controls. Expression profiles of circRNAs, micro RNAs (miRNAs), and messenger RNAs (mRNAs) were analyzed using RNA-seq. The interaction networks between miRNAs and targets were predicted using the miRanda tool. A differentially expressed circRNA-miRNA-mRNA (ceRNA) network was further constructed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the target mRNAs in the ceRNA network were performed to predict the potential functions of their host genes. The patient group and the control group were also compared on the regulatory patterns of circRNAs on mRNAs. 1934 circRNAs were identified from the samples and reported for the first time in schizophrenia. The circRNA expression levels were lower in the VEOS group than in the healthy control group, and 1889 circRNAs were expressed only in the control group. Differential expression analysis (i.e., log2fold change > 1.5, p 0.05) identified 235 circRNAs (1 up-regulated, 234 down-regulated), 11 miRNAs (7 up-regulated, 4 down-regulated), and 2,308 mRNAs (1906 up-regulated, 402 down-regulated) respectively. In VEOS, a ceRNA network with 10 down-regulated circRNA targets, 6 up-regulated miRNAs, and 47 down-regulated mRNAs was constructed. The target genes were involved in the membrane, the signal transduction, and the cytoskeleton and transport pathways. Finally, different expression correlation patterns of circRNA and mRNA in the network were observed between the patient group and the control group. The current research is the first to reveal the differentially expressed circRNAs in the plasma of VEOS patients. A circRNA-miRNA-mRNA network was also conducted in this study. It may be implied that the circRNAs in this network are potential diagnostic biomarkers for VEOS and they play an important role in the onset and development of VEOS symptoms.
RESUMO
BACKGROUND: The association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) with depression has been investigated extensively while the results were conflicting. We aim to investigate whether NLR, PLR, and MLR are associated with depression, as well as to explore the potential non-linear relationship between them. METHODS: This cross-sectional study was conducted based on representative samples of US adults from the National Health and Nutrition Examination Survey 2005-06 to 2017-18. Major depression was defined as a 9-item Patient Health Questionnaire of 10 or more. Multivariable logistic regression models were used to calculate the odds ratio of depression in relation to NLR, PLR, and MLR with the first quartile of their values as the reference. Restricted cubic splines (RCS) were added to the regression model to estimate the non-linear relationship between NLR, PLR, or MLR and depression. RESULTS: A total of 34,324 participants were included in the study and 3009 of them were diagnosed with major depression. Only PLR was significantly associated with depression after adjustment of all covariates in the multivariable logistic regression analysis. RCS showed that NLR was significantly associated with depression after adjustment of all covariates and NLR, PLR, and MLR were associated with depression in a non-linear manner. LIMITATIONS: The cross-sectional design did not imply any causal inferences. CONCLUSION: NLR and PLR were associated with depression after adjustment of potential confounders in a non-linear manner. Prospective studies might be needed to further reveal the non-linear relationships.
Assuntos
Monócitos , Neutrófilos , Adulto , Plaquetas , Estudos Transversais , Depressão , Humanos , Contagem de Linfócitos , Linfócitos , Inquéritos Nutricionais , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Pretubulysin, a biosynthetic precursor of the tubulysins, shows potent biological activity in a variety of tumor cell lines. Although there are several total synthesis routes to tubulysin and pretubulysin reported, the commercialization still has been hampered due to the complexity of the structure. To find structurally simpler pretubulysin analogs, a series of 2-(3-(methylamino)propyl)thiazole-4-carboxamides are designed and synthesized, and their anticancer activities are screened using MCF-7 (breast cancer), and NCI-H157 (lung cancer) cell lines. Taxol (IC50 = 0.01 µM) and pretubulysin are used as the control. Compounds 8c (IC50 = 0.05 µM, MCF-7; 0.09 µM, NCI-H157) and 8h (IC50 = 0.01 µM, MCF-7; 0.02 µM, NCI-H157) exhibited certain antitumor activities comparable to those of Taxol. The urea analogs of pretubulysin might represent a promising scaffold for the further development of novel antitumor drugs.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Oligopeptídeos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/química , Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Paclitaxel/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Nuclear Receptor Subfamily 5 Group A Member 2 (NR5A2, LRH-1) is an oncogene in a wide range of cancer types. Bioinformatics analysis on glioblastoma multiforme (GBM) tumors has revealed that the miR-139-5p-NR5A2 axis may be putatively regulated by the long non-coding RNA (lncRNA) RP3-439F8.1. This led us to hypothesize the existence of a RP3-439F8.1-miR-139-5p-NR5A2 regulatory axis in GBM cells. METHODS: Gene expression analysis was performed in GBM tumor samples and normal controls from our hospital, the Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) cohort, and the Gene Expression Omnibus (GEO) database (GSE7696). Cell proliferation, apoptosis, Matrigel Transwell, colony formation, and cell cycle assays were performed in T98 G and U251 cells in vitro. An orthotopic U251 xenograft murine model was employed to test the effects of RP3-439F8.1 knockdown in vivo. RESULTS: NR5A2 was upregulated in the three independent GBM tumor cohorts. In vitro, NR5A2 overexpression enhanced GBM cell proliferation, colony formation, invasiveness, and G0-G1 cell cycle phase shift via co-activating ß-catenin/TCF4 signaling, with no apparent effect upon apoptosis. In contrast, RP3-439F8.1 knockdown produced the opposite effects. RP3-439F8.1 knockdown reduced tumor progression in vivo, increasing overall survival in model mice. Further in vitro experiments revealed that RP3-439F8.1 acts as a competing endogenous RNA (ceRNA) to regulate NR5A2 by sponging the microRNA miR-139-5p. These findings were clinically validated by a positive correlation between RP3-439F8.1 and NR5A2 and a negative correlation between RP3-439F8.1 and miR-139-5p in GBM tumors. CONCLUSIONS: Our study supports a tumorigenic role for RP3-439F8.1 in GBM through the RP3-439F8.1/miR-139-5p/NR5A2 axis.
Assuntos
Neoplasias Encefálicas/metabolismo , Proliferação de Células , Glioblastoma/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Bases de Dados Genéticas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais , Carga Tumoral , Regulação para CimaRESUMO
A series of urea-based ROCK2 inhibitors were design and synthesized. The inhibitory activity on ROCK2 was screened by enzyme-linked immunosorbent assay (ELISA). The study results showed that the urea derivatives exhibited certain ROCK2 inhibitory activity. The most potent compound 10p showed ROCK2 inhibitory activity with the IC50 value of 0.03 µM. A preliminary structure-activity relationship was then summarized. The molecular docking studies showed that further optimization needs to conduct to obtain more potent ROCK inhibitors.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ureia/química , Quinases Associadas a rho/antagonistas & inibidores , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaio de Imunoadsorção Enzimática , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , Quinases Associadas a rho/química , Quinases Associadas a rho/metabolismoRESUMO
Rho-associated kinases (ROCK) are a class of serine/threonine kinases that play important roles in various biological processes. ROCK are becoming attractive targets for drug designing. A novel scaffold was designed according to molecular hybridization strategy, then a series of 4-aryl-5-aminomethyl-thiazole-2-amines were synthesized, and their inhibitory activities on ROCK were screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives displayed certain ROCK II inhibitory activities. The IC50 value of the most potent compound 4v was found to be 20 nM. The preliminary structure-activity-relationship investigation showed that compounds with 4-pyridine substitution were generally found to be more potent than compounds with 3-pyridine substitution. The molecular docking studies indicated that more optimization work needs to conduct to obtain more potent ROCK inhibitors.
RESUMO
Gonadotroph pituitary adenomas (GPAs) constitute approximately 15-40% of pituitary tumors. Some GPAs can be highly infiltrative, making full surgical resection challenging and increasing the risk of recurrence. The transcriptional co-activator Mastermind-Like Domain Containing 1 (MAMLD1, CXorf6, F18) is involved in regulating signaling pathways important in pituitary tumorigenesis, including the Notch signaling pathway. However, MAMLD1's role in GPA remains unknown. GPA biopsies were collected from 96 patients following surgery, who were monitored until tumor recurrence. GPA tissue was used for immunohistochemistry. The murine GPA cell lines αT3 and LßT2 were used for in vitro experiments. Lentiviral constructs were employed for MAMLD1 knockdown (KD) and dominant negative (DN) mutant experiments. Quantitative real-time PCR (qPCR) and Western blotting of MAMLD1 and Notch2 were performed. MTT and Transwell assays were used to quantify proliferation and migration, respectively. An αT3 xenograft model was established in athymic nude mice followed by fluorescent IHC of xenograft tumors. MAMLD1 and Notch2 levels correlated positively with aggressive GPAs. Increased MAMLD1 levels correlated with shortened recurrence-free survival (RFS) in aggressive GPA patients. Moreover, MAMLD1 expression independently affected patient RFS according to multivariate Cox regression. In vitro, MAMLD1 KD in the murine GPA cell lines attenuated their proliferation and migration and Notch2 expression. Additionally, DN MAMLD1L210X lowered their proliferative and migratory capacity. MAMLD1 KD suppressed tumor growth and Notch2 expression in murine xenografts. MAMLD1 may serve as a predictor of GPA patient outcome and may also be leveraged as a possible therapeutic target for aggressive GPA tumors.
Assuntos
Adenoma/patologia , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Hipofisárias/patologia , Fatores de Transcrição/metabolismo , Animais , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Gonadotrofos/metabolismo , Xenoenxertos , Humanos , Masculino , CamundongosRESUMO
An amphiphilic dimeric-podophyllotoxin (PODO) phospholipid was synthesized to assemble into liposomes as a combination of prodrug and nanocarrier. The results have demonstrated that the cell membrane-like delivery system possessed an improved cellular uptake and favorable antitumor efficacy with reduced side-effects. This strategy provides a new effective platform in drug delivery for cancer chemotherapy.