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1.
Theranostics ; 11(16): 8112-8128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335983

RESUMO

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas/genética , Humanos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
2.
Pak J Pharm Sci ; 34(2): 561-565, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34275830

RESUMO

This study was aimed to investigate differences in antioxidant and anti-inflammatory effects of propofol at two commonly used dosing schedules on morbidly obese patients. Twenty-two morbidly obese patients were randomly divided into two groups, namely, TBW (dosing based on total body weight) and LBW (dosing based on lean body weight) groups. Three biomarkers, i.e. superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) were measured as indicators of the level of oxidation stress reaction. Pro-inflammatory cytokines including Interleukin-6 (IL-6) and Interleukin-8 (IL-8) were used to describe the degree of inflammation. Plasma levels of SOD, MDA and NO were increased and reached a peak value 0.5h after anesthesia induction, but the increase was smaller in the LBW group compared with the TBW group. Besides, plasma concentrations of IL-6 and IL-8 were also increased and attained a peak level 0.5h after anesthesia induction, but the increase was higher in the TBW group compared with the LBW group. The LBW-based dosing of propofol had more potent antioxidant and anti-inflammatory effects than the TBW-based dosing during anesthesia induction period on morbidly obese patients. This study provided a dosing recommendation of propofol for morbidly obese patients.

3.
Sci Rep ; 11(1): 13556, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193895

RESUMO

Alternanthera philoxeroides (Martius) is an infamous invasive alien plant that is widely distributed in aquatic and terrestrial habitats. To investigate the vegetative reproduction, growth, survival strategy, and the function of leaves in fragment of A. philoxeroides under different water conditions, two water control experiments were conducted with different leaf treatments: (1) water control with stolon fragments, and (2) water control with plants. The water control was subjected to five levels: I 30% soil water content, II 70% soil water content, III 97% soil water content, IV water depth of 5 cm, and V water depth of 10 cm in combination with the two leaf treatments, fragments with two leaves and fragments without leaves. Based on the results, A. philoxeroides produced a significantly higher stem length, node number, leaf number, stem biomass, leaf biomass, and total biomass in the 97% soil water content and in treatments with leaves. Additionally, the stem mass ratio increased and the root mass ratio decreased with the increase of the water content. In Exp. 1, the survival rate was the highest in the 97% water content and was 0 in the 30% water content. Therefore, the leaves of stolon fragments contribute to the vegetative reproduction and growth of A. philoxeroides. In response to different water conditions, A. philoxeroides adopts different strategies according to the resource reserves by itself, which are conducive to its survival and widespread occurrence.


Assuntos
Amaranthaceae/crescimento & desenvolvimento , Folhas de Planta/crescimento & desenvolvimento , Plântula/crescimento & desenvolvimento , Solo , Água/metabolismo , Espécies Introduzidas
4.
Front Microbiol ; 12: 620322, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163438

RESUMO

Objective: Gasdermin D (GSDMD), controlling pyroptosis in cells, has multiple physiological functions. The diagnostic role of GSDMD in pleural effusion (PE) remains unknown. Methods: Sandwich ELISA kits that we developed were applied to measure the level of GSDMD for 335 patients with a definite cause of PE, including transudative PE, tuberculous pleural effusion (TPE), parapneumonic pleural effusion (PPE), and malignant pleural effusion (MPE). The diagnostic accuracy of Light's criteria vs. the new marker GSDMD was performed. Clinical follow-up of 40 cases of PPE was conducted and divided into efficacy and non-efficacy groups according to the therapeutic outcome. Nucleated cells (NCs) in PE were isolated and further infected with bacteria to verify the cell source of GSDMD. Results: The diagnostic accuracy of GSDMD for the diagnosis of PE were 96% (sensitivity) and 94% (specificity). The receiver operating characteristic (ROC) curve indicated that GSDMD can be an efficient biomarker for the differential diagnosis of transudative PE and other groups (all AUC > 0.973). Noteworthily, the highest AUC belonged to tuberculosis diagnosis of 0.990, and the cut-off value was 18.40 ng/mL. Moreover, the same cut-off value of PPE and MPE was 9.35 ng/mL. The combination of GSDMD, adenosine deaminase (ADA), and lactate dehydrogenase (LDH) will further improve the diagnostic efficiency especially between TPE and PPE (AUC = 0.968). The AUC of GSDMD change at day 4, which could predict the therapeutic effect at an early stage, was 0.945 (P < 0.0001). Interestingly, bacterial infection experiments further confirm that the pleural fluid GSDMD was expressed and secreted mainly by the NCs. Conclusion: GSDMD and its combination are candidates as a potentially novel biomarker not only to separate PEs early and effectively, but also monitor disease progression.

5.
Front Psychiatry ; 12: 544746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149464

RESUMO

Objective: Auditory verbal hallucinations (AVH), with unclear mechanisms, cause extreme distresses to schizophrenia patients. Deficits of inhibitory top-down control may be linked to AVH. Therefore, in this study, we focused on inhibitory top-down control in schizophrenia patients with AVH. Method: The present study recruited 40 schizophrenia patients, including 20 AVH patients and 20 non-AVH patients, and 23 healthy controls. We employed event-related potentials to investigate the N2 and P3 amplitude and latency differences among these participants during a Go/NoGo task. Results: Relative to healthy controls, the two patient groups observed longer reaction time (RT) and reduced accuracy. The two patient groups had smaller NoGo P3 amplitude than the healthy controls, and the AVH patients showed smaller NoGo P3 amplitude than the non-AVH patients. In all the groups, the parietal area showed smaller NoGo P3 than frontal and central areas. However, no significant difference was found in N2 and Go P3 amplitude between the three groups. Conclusions: AVH patients might have worse inhibitory top-down control, which might be involved in the occurrence of AVH. Hopefully, our results could enhance understanding of the pathology of AVH.

6.
Nucleic Acids Res ; 49(10): 5916-5924, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33978763

RESUMO

k-Turns are widespread key architectural elements that occur in many classes of RNA molecules. We have shown previously that their folding properties (whether or not they fold into their tightly kinked structure on addition of metal ions) and conformation depend on their local sequence, and we have elucidated a series of rules for prediction of these properties from sequence. In this work, we have expanded the rules for prediction of folding properties, and then applied the full set to predict the folding and conformation of four probable k-turns we have identified amongst 224 structured RNA species found in bacterial intergenenic regions by the Breaker lab (1). We have analyzed the ion-dependence of folding of the four k-turns using fluorescence resonance energy transfer, and determined the conformation of two of them using X-ray crystallography. We find that the experimental data fully conform to both the predicted folding and conformational properties. We conclude that our folding rules are robust, and can be applied to new k-turns of unknown characteristics with confidence.


Assuntos
Íons/química , Metais/química , Conformação de Ácido Nucleico , RNA/química , Actinomyces/química , Actinomyces/genética , Cristalografia por Raios X , Transferência Ressonante de Energia de Fluorescência , Haloarcula marismortui/química , Haloarcula marismortui/genética , Magnésio/química , Modelos Moleculares , Dobramento de RNA , RNA de Cadeia Dupla/química
7.
Mol Ther Methods Clin Dev ; 20: 615-624, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33718512

RESUMO

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Chinese and other Southeast Asians. We aimed to explore the precise mechanism for NESG1 in NPC for understanding the pathogenesis of NPC. Transwell, Boyden assays, and wounding healing were respectively performed for cell metastasis. The microRNA (miRNA) microarray and luciferase reporter assays were designed to clarify NESG1-modulated miRNAs and miR-1254-targeted protein. Western blotting assays examined the pathways regulated by miR-1254, the (Hepatoma-Derived Growth Factor) HDGF/DDX5 complex, and NESG1. The chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and co-immunoprecipitation (coIP) assays were used to explore the DNA-protein complex and protein-protein complex. NESG1 suppressed NPC migration and invasion via Wnt/ß-catenin signaling. Further, miR-1254 was confirmed as a positive downstream modulator of NESG1 reducing metastatic abilities of NPC cells in vivo and in vitro. Transduction of HDGF significantly restored cell migration and invasion ability in miR-1254-overexpressing NPC cells. In clinical samples, miR-1254 expression was negatively correlated with HDGF and positively correlated with NESG1 expression. miR-1254 acts as an independent prognostic factor for NPC, which was induced by NESG1 to suppress NPC metastasis via inactivating Wnt/ß-catenin pathway and its downstream EMT signals.

8.
Sci Rep ; 10(1): 15385, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958884

RESUMO

The nucleosome is the basic structural repeating unit of chromatin. DNA damage and cell apoptosis release nucleosomes into the blood circulatory system, and increased levels of circulating nucleosomes have been observed to be related to inflammation and autoimmune diseases. However, how circulating nucleosomes trigger immune responses has not been fully elucidated. cGAS (cGMP-AMP synthase) is a recently discovered pattern recognition receptor that senses cytoplasmic double-stranded DNA (dsDNA). In this study, we employed in vitro reconstituted nucleosomes to examine whether extracellular nucleosomes can gain access to the cytoplasm of mammalian cells to induce immune responses by activating cGAS. We showed that nucleosomes can be taken up by various mammalian cells. Additionally, we found that in vitro reconstituted mononucleosomes and oligonucleosomes can be recognized by cGAS. Compared to dsDNA, nucleosomes exhibit higher binding affinities to cGAS but considerably lower potency in cGAS activation. Incubation of monocytic cells with reconstituted nucleosomes leads to limited production of type I interferons and proinflammatory cytokines via a cGAS-dependent mechanism. This proof-of-concept study reveals the cGAS-dependent immunogenicity of nucleosomes and highlights the potential roles of circulating nucleosomes in autoimmune diseases, inflammation, and antitumour immunity.


Assuntos
Imunidade Inata/imunologia , Nucleossomos/imunologia , Nucleotidiltransferases/metabolismo , Monofosfato de Adenosina/metabolismo , Animais , Apoptose , Linhagem Celular , Cromatina/metabolismo , GMP Cíclico/metabolismo , Citocinas/metabolismo , Citosol/metabolismo , DNA/metabolismo , Dano ao DNA , Vesículas Extracelulares/imunologia , Células HeLa , Células Hep G2 , Humanos , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Nucleossomos/metabolismo , Nucleotidiltransferases/imunologia , Transdução de Sinais/genética , Células THP-1
9.
Front Psychiatry ; 11: 765, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903707

RESUMO

Schizophrenia is a holergasia with unclear mechanism and high heterogeneity. Auditory verbal hallucination (AVH) study might help in understanding schizophrenia from the perspective of individual symptoms. This study aimed to investigate the activities of the resting-state networks (RSN) in the electroencephalogram (EEG) and mismatch negativity (MMN) in task-related state of schizophrenia patients with AVH. We recruited 30 schizophrenia patients without any medication for more than 4 weeks (15 AVH patients and 15 Non-AVH patients) and 15 healthy controls. We recorded the EEG data of the participants in the resting-state for 7 min and the event-related potential (ERP) data under an auditory oddball paradigm. In the resting-state EEG network, AVH patients exhibited a higher clustering coefficient than Non-AVH patients and healthy controls on delta and beta bands and a shorter characteristic path length than Non-AVH patients and healthy controls on all frequency bands. For ERP data, AVH patients showed a lower MMN amplitude than healthy controls (p = 0.017) and Non-AVH patients (p = 0.033). What's more, MMN amplitude was positively correlated with clustering coefficient, and negatively correlated with characteristic path length on delta, theta, beta and gamma band in AVH patients. Our results indicate that AVH patients showed a hyper-activity in resting-state and may have impaired higher-order auditory expectations in the task-related state than healthy controls and Non-AVH patients. And it seems reasonable to conclude that the formation of AVH may occupy certain brain resources and compete for brain resources with external auditory stimuli.

10.
Biomed Pharmacother ; 123: 109780, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31901550

RESUMO

FAM83A is part of an 8-member protein family of unknown function and is reported to be a cancer-promoting and treatment-resistance factor in several cancers. However, its role in hepatocellular carcinoma (HCC) remains unclear. Analysis of the Cancer Genome Atlas (TCGA) showed that FAM83A mRNA expression is upregulated in HCC, as are the protein expression levels in both HCC cell lines and tissues. Clinical data have demonstrated that high FAM83A expression is positively correlated with poor progression-free survival time, thus suggesting its cancer-promoting potential. Functional analyses showed that FAM83A overexpression promoted HCC cell migration and invasion in vitro and suppressed sorafenib sensitivity. Inhibiting FAM83A reversed these results. A pulmonary metastasis model further confirmed that FAM83A promoted HCC cell metastasis in vivo. Mechanistic analyses indicated that FAM83A activated the PI3K/AKT signaling pathway, its downstream c-JUN protein, and epithelial-to-mesenchymal transition (EMT)-related protein levels, including downregulation of E-cadherin and upregulation of Vimentin and N-cadherin. Interestingly, c-JUN induced FAM83A expression by directly binding to its promoter region and thus forming a positive-feedback loop for FAM83A/PI3K/AKT/c-JUN. In conclusion, we demonstrated that FAM83A, as a cancer-metastasis promoter, accelerates migration, invasion and metastasis by activating the PI3K/AKT/c-JUN pathway and inducing its self-expression via feedback, thus forming a FAM83A/PI3K/AKT/c-JUN positive-feedback loop to activate EMT signaling and finally promote HCC migration, invasion and metastasis.


Assuntos
Carcinoma Hepatocelular/patologia , Movimento Celular , Retroalimentação Fisiológica , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Retroalimentação Fisiológica/efeitos dos fármacos , Feminino , Inativação Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico
11.
BMC Anesthesiol ; 20(1): 21, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969113

RESUMO

BACKGROUND: This study was designed to examine whether severe aortic regurgitation will affect the pharmacodynamics (PD) and pharmacokinetics (PK) of cisatracurium during anesthetic induction. METHODS: A total of 32 patients were divided into two groups: the AR group (n = 16) and the control group (n = 16). Arterial blood samples were drawn before and at 1, 2, 4, 6, 8, 10, 16 and 20 min after intravenous injection of 0.15 mg/kg cisatracurium. TOF tests were applied to determine the onset time of maximal muscle relaxation. The concentration of cisatracurium in plasma was determined by high-performance liquid chromatography. RESULTS: The onset time to maximal neuromuscular block was prolonged from 2.07 ± 0.08 min to 4.03 ± 0.14 min, which indicated that the PD responses to cisatracurium were significantly delayed in the AR group (P < 0.05) compared to the control group. A conventional two-compartment PK model showed a higher plasma concentration of cisatracurium among the AR group with markedly reduced intercompartment transfer rate (K12 = 0.19 ± 0.02 and K21 = 0.11 ± 0.01 in the AR group vs. K12=0.26 ± 0.01 and K21 = 0.19 ± 0.01 in the control group, P < 0.01) compared to the control group. CONCLUSION: Backward blood flow during diastole in severe AR impaired distribution of cisatracurium from the central compartment to the peripheral compartment, which accounted for the lagged PD responses. Findings in this study underlie the importance of muscular blockade monitoring among patients with severe aortic regurgitation during anesthetic induction. REGISTRATION: Name of the registry: Abnormal Cisatracurium Pharmacodynamics and Pharmacokinetics among Patients with Severe Aortic Regurgitation during Anesthetic Induction. TRIAL REGISTRATION NUMBER: ChiCTR1800019654. Date of registration: November 20th 2018.


Assuntos
Insuficiência da Valva Aórtica/fisiopatologia , Atracúrio/análogos & derivados , Bloqueadores Neuromusculares/farmacologia , Insuficiência da Valva Aórtica/sangue , Atracúrio/sangue , Atracúrio/farmacocinética , Atracúrio/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bloqueadores Neuromusculares/sangue , Bloqueadores Neuromusculares/farmacocinética
12.
Medicine (Baltimore) ; 98(39): e16788, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574794

RESUMO

BACKGROUND: The aim of this study was to observe the effect and safety of Heyan Kuntai Capsule (HYKT) on glucose and lipid metabolism in patients with polycystic ovary syndrome (PCOS). METHODS: Hundred patients with PCOS were randomly divided into HYKT group (n = 50) and placebo groups (n = 50) in which the individuals were treated with HYKT and its placebo continuously for 6 months. Meanwhile, all participants received health education (such as exercise and diet). The primary outcomes were serum sex hormone levels, a series of blood lipid, fasting and postprandial 2 hours blood glucose. Body mass index (BMI), waist-hip ratio (WHR), insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and insulin-sensitive index (ISI) were also observed. In addition, adverse events were recorded to evaluate the drug safety. RESULTS: After treatment, the BMI and WHR of all the patients were decreased. The fasting and postprandial 2 hours blood glucose levels were significantly declined when treated with HYKT, which were not observed in the placebo group. Similarly, serum sex hormones including luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), and testosterone were lowered after treated with HYKT instead of the placebo. Besides, blood lipids outcomes such as total cholesterol, triglyceride, and low-density lipoprotein cholesterol, as well as insulin and HOMA-IR were decreased with significance in HYKT group when compared with those in the placebo group, whereas high-density lipoprotein cholesterol and ISI increased obviously. CONCLUSION: HYKT showed the effect on ameliorating the glucose and lipid metabolism disorder and improving insulin resistance and increase insulin sensitivity of PCOS patients, which is similar to insulin sensitizing agent.


Assuntos
Glicemia/metabolismo , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Lipídeos/sangue , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/tratamento farmacológico , Adolescente , Adulto , Índice de Massa Corporal , Método Duplo-Cego , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Insulina/sangue , Resistência à Insulina , Hormônio Luteinizante/sangue , Prolactina/sangue , Testosterona/sangue , Relação Cintura-Quadril , Adulto Jovem
13.
Sci Transl Med ; 11(510)2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534017

RESUMO

Transforming growth factor-ß1 (TGFß1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFß1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFß1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.


Assuntos
Nefropatias Diabéticas/genética , Transcrição Genética , Fator de Crescimento Transformador beta1/genética , Fator de Transcrição YY1/metabolismo , Animais , Sequência de Bases , DNA/metabolismo , Nefropatias Diabéticas/patologia , Progressão da Doença , Furanos/farmacologia , Furanos/uso terapêutico , Humanos , Lignanas/farmacologia , Lignanas/uso terapêutico , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
14.
Biosci Biotechnol Biochem ; 83(4): 675-683, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30570395

RESUMO

Ginkgo biloba, a natural biflavonoid isolated from Ginkgo biloba leaves, is reported to have strong anti-inflammatory and immunosuppressive properties. The aim of this study is to investigate the potential anti-inflammatory mechanisms of ginkgo flavonoids on cerebral ischemia/reperfusion (I/R) injury. Inflammatory-associated cytokines in cerebral ischemic hemispheres were determined by immunohistochemical staining, Western blot and enzyme-like immunosorbent assay (ELISA). Our results indicated that treatment with Ginkgetin significantly restored rat brain I/R-induced neurological deficit scores. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in Ginkgetin treatment group (100 mg/kg) also significantly reduced. The expression inflammation-related protein prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and interleukin-8 (IL-8) was also decreased in Ginkgetin treatment group. However, the expression of interleukin-10 (IL-10) was remarkably increased. Thus, this study demonstrates that Ginkgetin protects neurons from I/R-induced rat injury by down-regulating pro-inflammatory cytokines and blocking the TLR4/NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Biflavonoides/farmacologia , Isquemia Encefálica/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Ginkgo biloba/química , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Biflavonoides/isolamento & purificação , Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Dinoprostona/genética , Dinoprostona/imunologia , Modelos Animais de Doenças , Esquema de Medicação , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Masculino , NF-kappa B/genética , NF-kappa B/imunologia , Fármacos Neuroprotetores/isolamento & purificação , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
15.
EBioMedicine ; 36: 229-240, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30279141

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) signalling is critical in epithelial cancer development. Human rhomboid family-1 (RHBDF1) facilitates the secretion of TGFα, an EGFR ligand, in breast cancer; however, the underlying mechanism remains unclear. We evaluated the role for RHBDF1 in clathrin-coated vesicle (CCV)-dependent pro-TGFα membrane trafficking in breast cancer cells upon stimulation by G-protein coupled receptor (GPCR) agonists. METHODS: RHBDF1 was silenced in various breast cancer cells using shRNA. TGFα levels, subcellular localization, and secretion were evaluated using ELISA, immunofluorescent staining, and coimmunoprecipitation. Phosphorylation and expression of relevant proteins were measured by western blotting. RHBDF1-dependent cell viability and invasion were measured. FINDINGS: RHBDF1 mediates GPCR agonist-induced EGFR phosphorylation by promoting TGFα secretion in various types of breast cancer cells. RHBDF1 not only mediates ADAM17-dependent shedding of TGFα, but is essential in membrane trafficking of pro-TGFα. RHBDF1 silencing results in blocking of clathrin uncoating from CCV, a crucial step for the plasma membrane release of pro-TGFα. Interaction of RHBDF1 with auxilin-2, a CCV protein, determines the recruitment of HSC70 to CCV to facilitate clathrin uncoating. RHBDF1 function is required for the proliferation and mobility of breast cancer cells upon stimulation by Sphingosine 1 Phosphate (S1P), a GPCR agonist. We demonstrate a significant correlation between RHBDF1 overexpression and EGFR activation in breast cancer tissues. INTERPRETATION: RHBDF1 is an indispensable component of the protein trafficking machinery involved in GPCR-mediated EGFR transactivation, and is an attractive therapeutic target for cancer. FUND: National Natural Science Foundation of China (81,672,740 to ZSZ, 81,272,356 and 81,330,029 to LYL).


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Vesículas Revestidas por Clatrina/metabolismo , Proteínas de Membrana/metabolismo , Fator de Crescimento Transformador alfa/metabolismo , Proteína ADAM17/metabolismo , Auxilinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Receptores ErbB/metabolismo , Feminino , Proteínas de Choque Térmico HSC70/metabolismo , Humanos , Ligantes , Modelos Biológicos , Ligação Proteica , Transporte Proteico , RNA Interferente Pequeno/genética
16.
Biomed Pharmacother ; 106: 618-623, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29990851

RESUMO

This study aims to determine the pharmacodynamics (PD) effect (measured by cardiovascular depression) of propofol during anesthesia induction period on morbidly obese (MO) patients. Four hemodynamics indexes [i.e., three indexes about blood pressure and cardiac output (CO)] representing cardiovascular function were measured. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed by population analysis to obtain PD parameters. Two propofol dosing scalars, namely, dosing based on total body weight (TBW) or lean body weight (LBW), were used for MO subjects. The PD data were well described by a PK/PD model. Blood pressure and CO were rapidly decreased within one minute after intravenous injection of propofol (2 mg/kg). TBW group showed significantly lower blood pressure and CO values at and 1 min after propofol administration compared with the control group, whereas the control and LBW groups had similar PD profiles. In addition, the propofol EC50 value was significantly decreased in MO patients, whereas all other PD parameters were similar between control and MO subjects. This change indicated that propofol potency and/or sensitivity was increased in MO subjects. For MO patients, dosing of propofol based on LBW rather than TBW would be a safer choice due to a less cardiovascular depression effect.


Assuntos
Anestésicos Intravenosos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Cálculos da Dosagem de Medicamento , Modelos Biológicos , Obesidade Mórbida/fisiopatologia , Propofol/efeitos adversos , Adolescente , Adulto , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/farmacocinética , Índice de Massa Corporal , Peso Corporal , Feminino , Gastrectomia/métodos , Humanos , Infusões Intravenosas , Laparoscopia , Masculino , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/cirurgia , Segurança do Paciente , Propofol/administração & dosagem , Propofol/farmacocinética , Medição de Risco , Fatores de Risco , Adulto Jovem
17.
Trials ; 19(1): 314, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29880009

RESUMO

BACKGROUND: Endometriosis is a chronic gynecological disease that is characterized by the presence of endometrial tissue outside the uterine cavity. The main symptoms include dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. These symptoms impair the lives of most of the women suffering from the disease. Surgical resection of endometriotic lesions is an effective means of treating dysmenorrhea, but the risk of recurrence is high. Western medicine has limited use for treating it due to side effects and ineffectiveness. The purpose of this study is to verify the effectiveness and safety of acupuncture. METHODS/DESIGN: This trial will be carried out in four parts. A total of 106 eligible patients with pelvic pain related to endometriosis will be randomly assigned into two groups, in a 1:1 ratio, as the treatment group or the control group. The participants assigned to the treatment group will be treated with acupuncture treatment at Guanyuan (CV4), Sanyinjiao (SP6), Taichong (LR3), Zhaohai (KI6) and Qichong (ST30) while the control group will receive acupuncture at non-acupoints. The trial will include three menstrual cycles of treatment and three menstrual cycles of follow-up. The primary outcome is pelvic pain that will be assessed by means of a 10-cm visual analog scale (VAS). At each stage, we will evaluate the safety of the acupuncture treatment. DISCUSSION: The study will compare the effectiveness and safety of acupuncture with comfort needles on pelvic pain related to endometriosis in the hope of providing significant evidence for using acupuncture on pelvic pain related to endometriosis. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03125304 . Registered on 30 April 2017.


Assuntos
Terapia por Acupuntura , Endometriose/complicações , Dor Pélvica/terapia , Terapia por Acupuntura/efeitos adversos , Adulto , China , Endometriose/diagnóstico , Feminino , Humanos , Estudos Multicêntricos como Assunto , Medição da Dor , Dor Pélvica/diagnóstico , Dor Pélvica/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
18.
Reproduction ; 156(2): 133-144, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29844226

RESUMO

Peri-ovarian adipose tissue (POAT) is a kind of intra-abdominal white adipose tissue that is present surrounding the ovaries in rodents. Recent studies demonstrated that POAT-deficient mice displayed a phenotype of delayed antral follicular development, for which decreases in serum estrogen, serum FSH and FSHR levels were responsible. However, folliculogenesis is regulated by endocrine signals and also modulated by a number of locally produced intraovarian factors whose acts are both autocrine and paracrine. Here, we used a model of surgical removal of POAT unilaterally and contralateral ovaries as controls, as both were under the same endocrine control, to assess the paracrine effect of the POAT on folliculogenesis. Surgical removal of unilateral POAT resulted in delayed antral follicular development and the increased number of atretic follicles, accompanied by decreased levels of intraovarian adipokines and growth factors, lipid accumulation and steroidogenic enzyme expression. POAT-deficient ovaries displayed compensatory increased expressions of intraovarian genes, such as Vegf and Adpn for angiogenesis, Acc, Fasn, and Gapdh involved in lipogenesis and Fshr in response to FSH stimulation. Furthermore, we demonstrated that removal of POAT promoted follicular apoptosis, caused retention of cytoplasmic YAP and inhibited PTEN-AKT-mTOR activation. These alterations were observed only in the POAT-deficient ovaries but not in the contralateral ovaries (with POAT), which suggests that a paracrine interaction between POAT and ovaries is important for normal folliculogenesis.


Assuntos
Tecido Adiposo/fisiologia , Ovário/fisiologia , Adipocinas/metabolismo , Animais , Apoptose , Aromatase/metabolismo , Caspases/metabolismo , Feminino , Homeostase , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lipogênese , Camundongos , Receptores do FSH/metabolismo , Transdução de Sinais
19.
FASEB J ; 32(10): 5577-5586, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29727209

RESUMO

The human rhomboid family (RHBDF)1 gene is highly expressed in breast cancer under clinical conditions but not in normal mammary gland tissues. Silencing the RHBDF1 gene in breast cancer xenograft tumors leads to inhibition of tumor growth. We show in this study that artificially raising RHBDF1 protein levels in the mammary epithelial cells MCF-10A results in severe perturbations of the ability of the cells to form lumen-containing acini, either in 3-dimensional cell cultures or implanted in mouse mammary fat pads. Knocking down RHBDF1 with short hairpin (sh)RNA leads to restoration of acinus formation. Consistently, RHBDF1 overexpression gives rise to disordered distribution of polarity markers GM130 and laminin-5, which otherwise are located in apical and basal positions, respectively, in the acini. Further investigations reveal that RHBDF1 directly binds to Par6a, a component of a protein complex consisting of partitioning-defective scaffold protein (Par)6, Par3, renin-angiotensin system-related C3 botulinum toxin substrate (Rac)1, and cell-division cycle (Cdc)42, which is structurally critical to the formation of apicobasal polarity. RHBDF1 binding to Par6a results in collapse of the protein complex and thus disruption of polarity formation. Since early stages of breast cancer are characterized by the loss of mammary gland epithelial cell polarity, our findings indicate that perturbations of apicobasal polarity by high levels of RHBDF1 is a significant attribute in the development of breast neoplasia.-Peng, X.-M., Gao, S., Deng, H.-T., Cai, H.-X., Zhou, Z., Xiang, R., Zhang, Q.-Z., Li, L.-Y. Perturbation of epithelial apicobasal polarity by rhomboid family-1 gene overexpression.


Assuntos
Neoplasias da Mama/metabolismo , Polaridade Celular , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glândulas Mamárias Humanas/metabolismo , Proteínas de Membrana/biossíntese , Proteínas de Neoplasias/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Autoantígenos/biossíntese , Autoantígenos/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Humanos , Glândulas Mamárias Humanas/patologia , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética
20.
Sci Rep ; 7: 43826, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28262788

RESUMO

The ability to propagate via small diaspores is crucial for the invasion of a clone plant that does not reproduce sexually in its introduced range. We investigated the effects of node and internode adjacent mode, fragment type, burial orientation and position of the node in relation to the soil surface on the sprouting and growth of alligator weed (Alternanthera philoxeroides (Martius) Griseb.). All the factors had effects and interaction effects on the sprouting rate and growth. As a whole fragment in all treatments, the fragments with basal node buried upward on the soil surface, exhibited the best above-ground growth and root growth. The one-node fragment with basal node buried downward above the soil surface and upward under the soil surface significantly decreased the above-ground growth and root growth compared to that of the two-node fragment. Therefore, the one-node fragments were more affected by environmental conditions than the two-node fragments. The results indicated that reducing the number of nodes of a fragment and burying the node under the soil or orienting it downward above the soil surface could be applied to control the invasion of alligator weed.


Assuntos
Amaranthaceae/crescimento & desenvolvimento , Raízes de Plantas/crescimento & desenvolvimento , Caules de Planta/crescimento & desenvolvimento , Solo , Amaranthaceae/anatomia & histologia , Análise de Variância , Biomassa , Raízes de Plantas/anatomia & histologia , Brotos de Planta/anatomia & histologia , Brotos de Planta/crescimento & desenvolvimento , Caules de Planta/anatomia & histologia
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