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1.
Gene ; 723: 143986, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323309

RESUMO

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Accumulating evidence shows that microRNAs play important roles in diabetic kidney. However, the potential role of MicroRNA-544 (miR-544) in DN remains unclear. In this study, we explored the role of miR-544 on inflammation and fibrosis in diabetic kidney using db/db mice. Renal expression of miR-544 was decreased in mice, companied by increased the expression of FASN. The dual luciferase assay confirmed FASN as a direct target of miR-544. Over-expression of miR-544 significantly ameliorated renal injury, mesangial matrix and renal fibrosis. In addition, over-expression of miR-544 significantly attenuated inflammatory cells infiltration and IL-1, IL-6, TNF- and iNOS production in DN. Furthermore, miR-544 over-expression inhibited the activation of NF-kB signal pathway in DN. In conclusion, our finding demonstrated that miR-544 attenuates diabetic renal injury via suppressing glomerulosclerosis and inflammation by targeting FASN, suggesting that miR-544 might have therapeutic potential for the treatment of DN.


Assuntos
Citocinas/metabolismo , Nefropatias Diabéticas/genética , Ácido Graxo Sintase Tipo I/genética , MicroRNAs/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Regiões 3' não Traduzidas , Animais , Nefropatias Diabéticas/imunologia , Modelos Animais de Doenças , Regulação para Baixo , Células HEK293 , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Camundongos , NF-kappa B/metabolismo , Receptores para Leptina/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
2.
Toxicol Lett ; 318: 1-11, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31618665

RESUMO

Triptolide (TP), a principal bioactive component extracted from traditional Chinese medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted wide attention of its therapeutic effects on inflammation and autoimmune diseases. However, the therapeutic application of TP is hindered by severe cardiomyocyte toxicity and narrow therapeutic window. We previously identified that the p53 was an indispensable contributor in TP-induced myocardial injury. p53 has an inhibitory effect on IKKß-NF-κB pathway that regulates glucose transporters (GLUT) expression. Based on these evidences, we speculate that p53 mediates TP-disturbed glucose uptake by blocking IKKß-NF-κB signaling. This study focused on the effect of TP on cardiac glucose uptake and the role of p53 in glucose metabolism in cardiomyocytes, and p53 -/- mice. TP treatment depressed glucose consumption and ATP production resulting in myocardial damage. Incubation with ATP (5 mM) remarkably decreased the cellular damage. Immunoblotting and immunofluorescence identified that TP suppressed glucose uptake by restricting IKKß-NF-κB signaling activation, GLUT1 and GLUT4 expression. p53 inhibition alleviated the cell damage and the compromise of glucose uptake. Mechanistically, p53 antagonist PFTα abolished TP-induced the inhibition of IKKß, IκBα phosphorylation, p65 nuclear translocation, and GLUT1, GLUT4 expression. Consistently, in acute heart injury models, p53 deficiency upregulated IKKß-NF-κB activation and GLUT1, GLUT4 protein levels which was also indicated as amelioration of heart histological injury after 1.2 mg kg-1 TP administration. The present findings indicate that TP-induced p53 overactivation suppresses glucose uptake by inhibiting IKKß-NF-κB pathway and downregulating NF-κB-dependent GLUT1 and GLUT4 expression.


Assuntos
Diterpenos/toxicidade , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Quinase I-kappa B/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Fenantrenos/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Compostos de Epóxi/toxicidade , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/patologia , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
3.
J Photochem Photobiol B ; 201: 111657, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31706085

RESUMO

Parkinson's disease (PD) is a general neurodegenerative disorder which largely has an effect on the society of the aged populations. PD is distinguishedwith loss of dopaminergic (DA) neurons in the substantia nigra. The exceptional properties of gold nanoparticles (AuNPs) have fascinated great attention in biomedical applications. In this present study, we explored theprospective beneficial effects of AuNPs synthesized from Cinnamomum verum on PD. PD rat models were established through MPTP injection treatment and AuNPs was administered. Administration of AuNPs reduces effect of MPTP-induced oxidative stress and motor abnormalities observed in PD rats. In addition ELISA analysis demonstrated that AuNPs treatment significantly attenuates Tumor Necrosis Factor-α (TNF-α), Interleukin-1ß (IL-1ß) and Interleukin-6 (IL-6) expression levels. Consequently, we investigated TLR/NF-κB pathway to examine the function of AuNPs on MPTP- induced PD rats. We found that AuNPs suppressed the alterations in the pathway of TLR/NF-κB associated molecules in MPTP stimulated PD rats. Hence, our results suggest that AuNPs attenuates MPTP introduced motor disorders, oxidative stress, activated inflammatory cytokines and activated TLR/NF-κB signaling in PD rats. In conclusion, AuNPs ease PD symptoms by the inhibition of TLR/NF-κB signaling pathway and recommend promise approach in the treatment of neurodegenerative diseases such as PD.


Assuntos
Cinnamomum zeylanicum/química , Ouro/química , Intoxicação por MPTP/tratamento farmacológico , Nanopartículas Metálicas/uso terapêutico , Animais , Cinnamomum zeylanicum/metabolismo , Citocinas/metabolismo , Química Verde , Intoxicação por MPTP/patologia , Masculino , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismo
4.
J Environ Pathol Toxicol Oncol ; 38(3): 285-295, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679314

RESUMO

Psoriasis is an autoregulated immune and inflammation-based skin disease affecting approximately 3-4% of the worldwide population. Pinitol, conservatively used in ayurvedic medicine, has been shown to disclose an antiinflammatory effect, hold back the T-helper cells, and postpone cardiovascular diseases. In the present study we aimed to reveal the effect of D-pinitol on imiquimod (IMQ)-induced psoriasis-like skin inflammation in a mouse model via the nuclear factor-κB (NF-κB) pathway genes. In the current study, we found that D-pinitol ameliorated the skin abrasion and abridged epithelial thickness, inflammation numbers, and collagen-occupied regions in IMQ-induced psoriasis-like mice. The same results (epithelial thickness, inflammation numbers, and collagen-occupied regions) we achieved in dorsal skin regions. In addition, D-pinitol modified the lipid profile and antioxidant enzyme levels, which means that the IMQ-induced group showed elevated malondialdehyde when compared to D-pinitol. Downregulated expression of glutathione, superoxide dismutase, and catalase in the IMQ-induced group was incomparable with D-pinitol, control, and standard group. Additionally, inflammatory and NF-kB pathway gene levels in the psoriatic mouse skin, which includes tumor necrosis factor-α, interleukin [IL]-6, IL-17A, IL-23,TRAF3, NIK, IKKα, and RelB, were dramatically increased or decreased by treatment with D-pinitol. Histological and morphometric studies disclose the efficiency of D-pinitol. Finally, we found that D-pinitol reserved the TRAF3, NIK, IKKα, and RelB in the psoriatic skin, signifying that it restrains the commencement of NF-κB signaling pathways. The present results suggest that D-pinitol could prove to have tremendous preventive potential against the treatment and prevention of inflammatory disease.


Assuntos
Anti-Inflamatórios/farmacologia , Imiquimode/imunologia , Inflamação/tratamento farmacológico , Inositol/análogos & derivados , Psoríase/tratamento farmacológico , Animais , Inflamação/induzido quimicamente , Inflamação/imunologia , Inositol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Psoríase/imunologia
5.
J Chem Phys ; 151(17): 175101, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703512

RESUMO

Recently, a "mode-hopping" phenomenon has been observed in a NF-κB gene regulatory network with oscillatory tumor necrosis factor (TNF) inputs. It was suggested that noise facilitates the switch between different oscillation modes. However, the underlying mechanism of this noise-induced "cellular mode-hopping" behavior remains elusive. We employed a landscape and flux approach to study the stochastic dynamics and global stability of the NF-κB regulatory system. We used a truncated moment equation approach to calculate the probability distribution and potential landscape for gene regulatory systems. The potential landscape of the NF-κB system exhibits a "double ring valley" shape. Barrier heights from landscape topography provide quantitative measures of the global stability and transition feasibility of the double oscillation system. We found that the landscape and flux jointly govern the dynamical "mode-hopping" behavior of the NF-κB regulatory system. The landscape attracts the system into a "double ring valley," and the flux drives the system to move cyclically. As the external noise increases, relevant barrier heights decrease, and the flux increases. As the amplitude of the TNF input increases, the flux contribution, from the total driving force, increases and the system behavior changes from one to two cycles and ultimately to chaotic dynamics. Therefore, the probabilistic flux may provide an origin of chaotic behavior. We found that the height of the peak of the power spectrum of autocorrelation functions and phase coherence is correlated with barrier heights of the landscape and provides quantitative measures of global stability of the system under intrinsic fluctuations.


Assuntos
NF-kappa B/metabolismo , Fatores de Necrose Tumoral/genética , Difusão , Redes Reguladoras de Genes , Fatores de Necrose Tumoral/metabolismo
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 769-775, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750816

RESUMO

Objective To explore the functions and mechanisms of macrophages derived from PGRN gene knockout (PGRN-/- ) C57BL/6 mice in the invasion and migration of breast cancer cells. Methods Breast cancer cells were cultured in conditioned medium of macrophages derived from WT and PGRN-/- mice. TranswellTM assay and scratch assay were used to detect the invasion and migration ability of cancer cells. Western blot analysis was used to detect the expression of E-cadherin and N-cadherin in cancer cells. Cytokine array, real-time quantitative PCR and ELISA were performed to investigate the differences of cytokines secreted by macrophages derived from WT and PGRN-/- mice. Breast cancer cells were treated by the differentially expressed cytokine interleukin-6 (IL-6), and then the above methods were used to investigate its effect on cancer cells. Western blot analysis was used to verify the roles of NF-κB and JAK/STAT3 signaling pathways. Results The macrophages derived from PGRN-/- mice blocked NF-κB signaling pathway, reduced IL-6 secretion, and inhibited the invasion and migration of breast cancer cells. IL-6 activated JAK/STAT3 signaling pathway to promote the invasion and migration of breast cancer cells. Conclusion The macrophages derived from PGRN-/- mice can block the NF-κB and JAK/STAT3 signaling pathways, down-regulate IL-6 expression, and inhibit the invasion and migration of breast cancer cells.


Assuntos
Neoplasias da Mama/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Interleucina-6/imunologia , Macrófagos/imunologia , Transdução de Sinais , Animais , Neoplasias da Mama/imunologia , Caderinas , Movimento Celular , Meios de Cultivo Condicionados , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Invasividade Neoplásica , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas
7.
Anticancer Res ; 39(11): 5991-5998, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704824

RESUMO

BACKGROUND/AIM: This study aimed to discuss the effect and possible molecular mechanisms of Aurora-A/NF-ĸB signaling on the radiotherapy resistance of human docetaxel-resistant lung adenocarcinoma cells. MATERIALS AND METHODS: The human lung adenocarcinoma SPC-A1 and SPC-A1/DTX cell lines were utilized in the present study. The MTT assay measured the sensitivity of cells to radiotherapy. The tumor-initiating ability of the cells was detected in vitro by cloning assays. Apoptosis was quantified by flow cytometry. Real-time quantitative PCR and western blotting were used to detect the mRNA and protein expression of the Aurora-A/NF-ĸB, respectively. Tumors transplanted subcutaneously into nude mice were used to test the effect of Aurora-A on the in vivo sensitivity of the tumors to radiotherapy. RESULTS: The SPC-A1/DTX docetaxel-resistant lung adenocarcinoma cells were radio-resistant compared with the parental SPC-A1 cells. Up-regulated aurora-A was responsible for the in vitro radio-resistance of docetaxel-resistant SPC-A1/DTX cells. Nuclear transcription factor NF-ĸB was identified as a downstream target gene of Aurora-A in SPC-A1/DTX cells, and NF-ĸB also participated in the radio-resistance of SPC-A1/DTX cells regulated by Aurora-A. CONCLUSION: The Aurora-A/NF-ĸB pathway is association with radio-resistance of human lung adenocarcinoma docetaxel-resistant cells.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Aurora Quinase A/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Tolerância a Radiação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/radioterapia , Animais , Antineoplásicos/farmacologia , Apoptose , Aurora Quinase A/genética , Proliferação de Células , Docetaxel/farmacologia , Resistência a Múltiplos Medicamentos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Anticancer Res ; 39(11): 6135-6144, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704841

RESUMO

AIM: To investigate the effect of carnosine, an active compound of dietary beef, fish and chicken, on the regulation of cell adhesion and extravasation during metastasis. MATERIALS AND METHODS: Cell adhesion and extravasation abilities, and related regulating molecular mechanisms were analyzed in human colorectal cancer cells (HCT-116) and human umbilical vein cells (EA.hy926). RESULTS: Carnosine reduced the ability of HCT-116 cells to adhere to EA.hy926 cells. The expression levels of integrin-ß1 in HCT-116 cells, as well as of intercellular adhesion molecule-1 and E-selectin in EA.hy926 cells, were reduced after carnosine treatment. After EA.hy926 cells were treated with carnosine, phosphorylation of vascular endothelia-cadherin (VE-cadherin), protein levels of Ras homologous (RHO) and RHO-associated coiled-coil containing protein kinase, and levels of reactive oxygen species were reduced. After treating EA.hy926 cells with carnosine, phosphorylation of inhibitor of kappa B (IκB) and DNA binding activity of nuclear factor-κB (NF-κB) were reduced. CONCLUSION: Carnosine inhibits metastatic cell adhesion and extravasation by suppressing NF-κB signaling activation.


Assuntos
Carnosina/farmacologia , Adesão Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Células Tumorais Cultivadas
9.
Anticancer Res ; 39(11): 6165-6173, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704844

RESUMO

AIM: To improve survival in patients with glucocorticoid-resistant T-cell acute lymphoblastic leukemia (T-ALL), it is critical to develop new therapeutic strategies to overcome steroid resistance. MATERIALS AND METHODS: Biochemical and molecular methodologies were used to evaluate whether tissue transglutaminase (TG2) confers steroid resistance in T-ALL. RESULTS: T-ALL cells were found to express elevated levels of TG2. Models of steroid-adapted subclones of T-ALL cell lines which were notably less sensitive to steroids than the parental cells. The steroid-adapted subclones showed increased TG2 expression and nuclear factor-κB (NF-κB) activity compared to T-ALL parental cells. Inhibition of TG2 suppressed steroid resistance and improved steroid cytotoxicity in steroid-adapted subclones of T-ALL in association with reduced NF-κB activity. CONCLUSION: TG2 may serve as a new target to overcome steroid resistance in T-ALL.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prednisolona/farmacologia , Transglutaminases/metabolismo , Diferenciação Celular , Proteínas de Ligação ao GTP/antagonistas & inibidores , Humanos , NF-kappa B/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia , Transdução de Sinais , Transglutaminases/antagonistas & inibidores , Células Tumorais Cultivadas
10.
Life Sci ; 236: 116917, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614149

RESUMO

AIMS: To investigate the underlying mechanism by which glioblastoma (GBM) cells gain temozolomide (TMZ) resistance and to clarify novel therapeutic targets and new prognostic biomarkers for GBM. MAIN METHODS: A genome-wide hierarchical bi-clustering based on previously published microarray databases identified Nuclear Factor I A (NFIA) as one of the most significantly upregulated genes correlated to TMZ resistance in GBM. Then, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, Western blotting and in vivo xenograft models with artificially induced TMZ-resistant U87 cells. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of NFIA in glioma patients. Last, luciferase reporter assay was performed to study the transcriptional regulation of NFIA on the nuclear factor κb (NF-kB) pathway. KEY FINDINGS: NFIA was correlated with TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated with adverse outcomes of glioma patients, especially in GBM patients. Moreover, NFIA contributed to the acquired TMZ resistance of GBM cells, while suppression of NFIA via lentivirus reduced cell proliferation, tumorigenesis and resistance to TMZ of GBM. Additionally, NFIA promoted transcription activity that regulated the expression of NF-kB. Last, NFIA induced phosphorylation of NF-kB p65 at serine 536, thus inducing TMZ resistance in GBM cells. Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to acquired TMZ resistance in GBM. SIGNIFICANCE: Abnormally activated NFIA-NF-kB signaling was strongly correlated with acquired TMZ resistance and poor prognosis in GBM, and it could be a new therapeutic target for TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , NF-kappa B/metabolismo , Fatores de Transcrição NFI/metabolismo , Temozolomida/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Nus , NF-kappa B/genética , Fatores de Transcrição NFI/genética , Prognóstico , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1424-1430, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607293

RESUMO

OBJECTIVE: To investigate the relationship of miR-140 expression level with the therapeutic effect of decitabine, and to explore whether the molecular mechanism is dependent on the regulation of TLR4 expression. METHODS: Forty-seven patients with acute myeloid leukaemia (AML) were enrolled in our study and divided into decitabine combination treatment group (22 cases) and traditional treatment group (25 cases). The clinical efficacy was compared between these two groups. Real-time PCR was used to determine the plasma level of miR-140 in AML patients. Decitabine, miR-140 mimic and miR140 inhibitor were used to treat AML HL-60 cells in vitro, the real-time PCR and Western blot were used to detect the expressions of miR-140, TLR4 and NF-κB at both mRNA and protein levels. RESULTS: Compared with traditional treatment group, decitabine combination treatment group showed more significant clinical efficacy. Plasma miR-140 level in both 2 treatment groups both decreased, but the plasma miR-140 level was higher in decitabine combination treatment group as compared with traditional treatment group. Experiment in vitro showed that 0.3 µmol/L decitabine significantly inhibited the HL-60 cell proliferation accompanied by up-regulation of miR-140 expression and down-regulation of expression of TLR4 and NF-κB. These effects induced by decitabine were partly reversed by pretreating the cells with 200 nmol/L miR-140 inhibitor. CONCLUSION: Decitabine-induced up-regulation of miR-140 expression may be related with its chemotherapeutic effects, and miR-140/TLR4/NF-κB pathway may partly mediate the pharmacologic action of decitabine.


Assuntos
Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Regulação para Baixo , Células HL-60 , Humanos , MicroRNAs , NF-kappa B
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1449-1454, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607297

RESUMO

OBJECTIVE: To analyze and investigate the expression levels of HES1, C-MYC and NF-kB in peripheral blood of patients with T cell acute lymphoblastic leukemia (T-ALL) and their significance. METHODS: Sixty patients with T-ALL and 60 patients with acute myelogenous leukemia (AML) diagnosed in our hospital from June 2012 to March 2015 were enrolled in T-ALL group and AML group, respectively. Another 30 healthy people were enrolled in the control group. Peripheral blood was collected to detect the expression levels of HES1, C-MYC and NF-kB by RT-PCR. The general data and the expression of HES1, C-MYC and NF-kB in peripheral blood were compared among the patients with different type of leukemia, cytogenetical types and different prognosis. RESULTS: There was no significant difference in baseline data, such as age and sex among the 3 groups (P>0.05). The Hb level, WBC and Plt count, BM blast cell ratio in T-ALL and AML groups all were significantly higher than those in control group (P<0.01), but there were no statistical difference in above-mentioned indicators between T-ALL and AML groups (P>0.05). The expression levels of HES1, C-MYC and NF-kB in peripheral blood among 3 groups were significantly differenct (P<0.01), the expressions levels of HES1, C-MYC and NF-kB in T-ALL and AML groups were significantly higher than those in control were significantly group (P<0.01), moreover, the expression levels of above-mentional indicators in T-ALL groups were significantly higher than than those in AML group (P<0.01). The expression levels of HES1, C-MYC and NF-kB iin T-ALL patients with poor prognosis were significantly higher than those in T-ALL patients with favorable prognosis (P<0.01); the expression levels of HES1, C-MYC and NF-kB in peripheral blood of patients with different theraptic efficacy were follow: complete remission group<partial remission group<no remission group (P<0.01). CONCLUSION: The HES1, C-MYC and NF-kB are highly expressed in peripheral blood of the patients with T-ALL, moreover, the expression levels maybe different, because of the cytogenetic, and theraptic efficacy.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia Mieloide Aguda , NF-kappa B , Indução de Remissão , Linfócitos T , Fatores de Transcrição HES-1
13.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 311-316, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631595

RESUMO

Objective: To investigate the anti-tumor effect of bortezomib on extranodal natural killer/T cell lymphoma, nasal type (ENKTL). Methods: SNK-6 cells were treated with different mass concentrations of bortezomib (0, 1, 2, 4, 5, 6 ng/mL) for 24, 48, 72 h, and different concentrations of nuclear factor-kappa B (NF-κB) signaling pathway inhibitor BAY11-7082 (0, 1, 2, 2.5, 5, 10, 20 µmol/L) for 24 h respectively, then the cell viability was measured by CCK8 kit and the half inhibitory concentration (IC 50) was calculated. SNK-6 cells were treated with 30µmol/L Z-VAD-FMK (Pan-caspase inhibitor)+3ng/mL bortezomib, and 5, 10 µmol/L BAY11-7082+3 ng/mL bortezomib for 24 h respectively, then the cell viability was measured by CCK8 kit. After treatment of SNK-6 cells with different mass concentrations of bortezomib for 24 h, apoptosis was detected by AnnexinⅤ/PI flow cytometry; the expression of apoptosis-related protein Caspase-3, poly ADP-ribose polymerase (PARP) and Bcl-2 and NF-κB signaling pathway key proteins P65 and P100/P52 were detected by Western blot. Results: Bortezomib inhibited the proliferation of SNK-6 cells in a dose-dependent manner ( P<0.05), and IC 50( (2.87±0.06) ng/mL) at 24 h was lower than that at 48 h and 72 h ( P<0.05). BAY11-7082 also inhibited the proliferation of SNK-6 cells with an IC 50= (9.73±0.36) µmol/L at 24 h. The combination treatment indicated that Z-VAD-FMK could attenuate the inhibitory effect of bortezomib on the proliferation of SNK-6 cells ( P<0.05), while BAY11-7082 could enhance the inhibitory effect of bortezomib on the proliferation of SNK-6 cells ( P<0.05). After treatment of SNK-6 cells with bortezomib for 24 h, apoptosis-related protein Caspase-3 cleavage, PARP activation, and Bcl-2 cleavage; NF-κB signaling pathway-related protein P65 phosphorylation level decreased, and P52 decreased. Conclusion: Bortezomib inhibits ENKTL cells proliferation by inhibiting NF-κB signaling pathway and induces apoptosis of ENKTL cells via mitochondria-mediated caspase pathway.


Assuntos
Apoptose , Bortezomib/farmacologia , Linfoma Extranodal de Células T-NK/patologia , NF-kappa B , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Nitrilos/farmacologia , Sulfonas/farmacologia
14.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 334-338, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631599

RESUMO

Objective: To study the mechanism of renal injury in Lepr db/ db mice with the leptin receptor homozygous deficiency. Methods: Ten male of 28-week-old Lepr db/+ mice with leptin receptor heterozygous deficiency were selected as control group and ten male Lepr db/ db mice with leptin receptor homozygous deficiency were used in this study. After fasting for 8 hours, the body mass, fasting blood glucose (FBG) and glycosylated hemoglobulin (HbA1c) of the mice were measured. Blood of the mice was obtained from femoral artery before euthanasia. Serum creatinine (CRE), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione (GSH) and malonaldehyde (MDA) were detected by corresponding kits, and serum interleukin-1ß (IL-1ß), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA) method. The kidney was taken for pathological observation. The expression levels of nuclear factor E2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) in renal were analyzed by Western blot. The mitochondria of renal was isolated by the corresponding kit. Meanwhile, the expression level of lipoic acid synthase (LIAS) in renal mitochondria was measured by Western blot. Results: The body mass, FPG, HbA1c, CRE and BUN levels of the Lepr db/ db mice were significantly increased in comparison with the Lepr db/+ mice ( P<0.05). Compared with the Lepr db/+ mice, the Lepr db/ db mice renal exhibited glomerular hypertrophy, thickened basement membrane and capillary wall, the mesangial matrix expansion and mesangial cell hyperplasia. Compared with the Lepr db/+ mice, the serum level of GSH in the Lepr db/ db mice was decreased significantly ( P<0.05). The levels of MDA and concentrations of MCP-1, IL-1ß and TNF-α in serum of the Lepr db/ db mice were higher than those of the Lepr db/+ mice ( P<0.05). Compared with the Lepr db/+ mice, the expression of LIAS and Nrf2 protein in the Lepr db/ db mice renal were decreased ( P<0.05), while the expression of NF-κB protein was increased ( P<0.05). Conclusion: LIAS, Nrf2 and NF-κB might play significant roles through regulation of oxidative stress and inflammation in the renal injury of Lepr db/ db mice.


Assuntos
Rim/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Receptores para Leptina/genética , Sulfurtransferases/metabolismo , Animais , Masculino , Camundongos , Camundongos Knockout , Estresse Oxidativo
15.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(8): 702-706, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31638567

RESUMO

Objective To analyze the changes and correlation between inflammation and Klotho expression in kidney tissue of mice with acute kidney injury (AKI) induced by cisplatin, and to explore the role and possible mechanism of Klotho in AKI induced by cisplatin. Methods Eighteen male C57BL/6 mice were randomly divided into 0-day group, 1-day group and 3-day group with 6 mice in each group. The mice were killed at 0, 1 and 3 days after a single intraperitoneal injection of 25 mg/kg of cisplatin, and the serum and kidney tissues were collected. The content of serum creatinine (Scr) and blood urea nitrogen (BUN) were measured by biochemical analyzer, and the pathological changes of kidney tissues were observed by HE staining. Neutrophil gelatinase-associated lipocalin (NGAL), tumor necrosis factor α (TNF-α), NLR family pyrin domain containing 3 (NLRP3), Klotho, signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), nuclear factor-kappa B (NF-κB), phosphorylated NF-kappa B (p-NF-κB) were detected by Western blot analysis. Spearman rank correlation test was used to analyze the correlations. Results The content of serum Scr and BUN in 1-day and 3-day groups were significantly higher than those in 0-day group, and inflammatory cell infiltration, renal tubular epithelial cell exfoliation, edema and accumulation of cell fragments were seen in 1-day and 3-day groups. In the 3-day group, the content of NGAL, TNF-α, NLRP3, p-STAT3, STAT3, p-NF-κB and NF-κB proteins in renal tissues significantly increased, and the expression of TNF-α, p-STAT3 and STAT3 increased in a time-dependent manner. The expression of Klotho decreased in a time-dependent manner in the 1-day and 3-day groups, and the expression of NGAL, TNF-α, NLRP3, p-STAT3, and p-NF-κB were significantly negatively correlated with the expression of Klotho. Conclusion The activation of STAT3/NF-κB pathway by Klotho is involved in the regulation of the occurrence and development of AKI induced by cisplatin in mice.


Assuntos
Lesão Renal Aguda , Cisplatino , Regulação da Expressão Gênica , Glucuronidase , Rim , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/fisiopatologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Glucuronidase/genética , Rim/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Distribuição Aleatória
16.
Anticancer Res ; 39(10): 5403-5415, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570435

RESUMO

BACKGROUND/AIM: Tubugi-1 is a more stable and accessible synthetic counterpart of natural tubulysins. This study aimed to evaluate its cytotoxic potential against anaplastic human melanoma cells. MATERIALS AND METHODS: The viability of A-375 cells was determined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assay. The type of cell death and proliferative rate were investigated using flow cytometry and fluorescent microscopy, while the molecular background was evaluated by western blot. RESULTS: Tubugi-1 reduced the viability of A-375 cells, inducing massive micronucleation, followed by augmented expression of inhibitor of nuclear factor-κB and caspase-2, typical of a mitotic catastrophe. Disturbed proliferation and G2M block with prominent caspase activity, weakened the expression of B-cell lymphoma 2 and B-cell lymphoma 2-associated X transient up-regulation, coexisted with intensive autophagy. Specific inhibition of autophagy by chloroquine resulted in conversion from mitotic catastrophe to rapid apoptosis. CONCLUSION: Multilevel anticancer action of tubugi-1 is extended by co-application of an autophagy inhibitor, giving a new dimension in further preclinical advancement of this potential agent.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Citotoxinas/farmacologia , Melanoma/tratamento farmacológico , Caspase 2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Melanoma/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
17.
Brain Nerve ; 71(10): 1039-1051, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588048

RESUMO

Dementia is a leading cause of death in many countries. Late-onset Alzheimer's disease (LOAD) is the most common form of dementia, with approximately 35 million affected people. LOAD shows a high heritability (h2) of 58-79%. Clarifying the genetic architecture of LOAD could contribute to precision medicine. In recent years, large-scale genome-wide association studies (GWASs) and their meta-analyses with a large sample size have elucidated the disease-susceptible genes and disease-causing pathways. To date, meta-analyses of GWASs in the Caucasian population have successfully identified approximately 40 LOAD risk loci. The gene set and disease pathway analysis obtained from the results of GWASs suggested biological mechanisms involving brain immune function, lipid-related processes, tau binding proteins, and degradation of amyloid precursor proteins in the pathogenesis of LOAD. Furthermore, the exome sequencing analysis in Japanese individuals with LOAD also revealed a rare variant with a large effect of SHARPIN in LOAD susceptibility, and the variant protein possibly affects the immune response through aberrant cellular localization, which may result in attenuated NF-κB activity in the brain. These findings could provide biological and pharmaceutical approaches in precision medicine for LOAD.


Assuntos
Doença de Alzheimer/genética , Patrimônio Genético , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Humanos , NF-kappa B/metabolismo , Ubiquitinas/genética , Proteínas tau/metabolismo
18.
Int J Nanomedicine ; 14: 7191-7213, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564873

RESUMO

Background: Diosmin showed poor water solubility and low bioavailability. Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles were successfully used to improve the drugs solubility and bioavailability. Coating of PLGA nanoparticles with chitosan can ameliorate their gastric retention and cellular uptake. Methodology: PLGA nanoparticles of diosmin were prepared using different drug and polymer amounts. Nanoparticles were selected based on entrapment efficiency% (EE%) and particle size measurements to be coated with chitosan. The selected nanoparticles either uncoated or coated were evaluated regarding morphology, ζ-potential, solid-state characterization, in vitro release, storage stability, and mucoadhesion. The anti-ulcer activity (AA) against ethanol-induced ulcer in rats was assessed through macroscopical evaluation, histopathological examination, immunohistochemical localization of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transmission electron microscopic examination of gastric tissues compared to free diosmin (100 mg/kg) and positive control. Results: Based on EE% and particle size measurements, the selected nanoparticles, either uncoated or coated with 0.1% w/v chitosan, were based on 1:15 drug-PLGA weight ratio and 20 mg diosmin employing methylene chloride as an organic phase. Examination by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed nanoscopic spherical particles. Drug encapsulation within the selected nanoparticles was suggested by Fourier transform-infrared, differential scanning calorimetry (DSC) and X-ray diffractometry results. Chitosan-coated nanoparticles were more stable against size enlargement probably due to the higher ζ-potential. Only coated nanoparticles showed gastric retention as revealed by SEM examination of stomach and duodenum. The superior AA of coated nanoparticles was confirmed by significant reduction in average mucosal damage, the majority of histopathological changes and NF-κB expression in gastric tissue when compared to positive control, diosmin and uncoated nanoparticles as well as insignificant difference relative to normal control. Coated nanoparticles preserved the normal ultrastructure of the gastric mucosa as revealed by TEM examination. Conclusion: The optimized chitosan-coated PLGA nanoparticles can be represented as a potential oral drug delivery system of diosmin.


Assuntos
Antiulcerosos/uso terapêutico , Quitosana/química , Diosmina/uso terapêutico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Estômago/patologia , Úlcera/tratamento farmacológico , Adesividade , Animais , Antiulcerosos/farmacologia , Varredura Diferencial de Calorimetria , Diosmina/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Duodeno/efeitos dos fármacos , Duodeno/patologia , Duodeno/ultraestrutura , Mucosa Gástrica/patologia , Mucosa Gástrica/ultraestrutura , Cinética , Masculino , Muco/química , NF-kappa B/metabolismo , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Estômago/efeitos dos fármacos , Estômago/ultraestrutura , Úlcera/patologia , Difração de Raios X
19.
Medicine (Baltimore) ; 98(40): e17126, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577702

RESUMO

BACKGROUND: The aim of this study was to investigate the role of n-acetyl cysteine (NAC) in the lipopolysaccharide (LPS)-mediated induction of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) synthesis by human periodontal ligament fibroblast cells (hPDLFs). In addition, we aimed to determine the involvement of the nuclear factor-kappa B (NF-κB) pathway in any changes in IL-1ß and TNF-α expression observed in response to LPS and NAC. METHODS: HPDLFs were obtained by primary culture. The culture medium used in this experiment was Dulbecco's Modified Eagle Medium (DMEM low-glucose). Cells were stimulated with various concentrations of NAC or LPS. Cell proliferation was measured at various time-points with the cell Counting Kit 8 (CCK-8) assay. mRNA levels of IL-1ß and TNF-α were determined by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Protein levels of IL-1ß and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). Protein and mRNA expression levels of NF-κB were measured by western blot and RT-qPCR. RESULTS: The results showed that LPS treatment in hPDLFs induced mRNA and protein expression of IL-1ß, TNF-α, and NF-κB. However, these effects were eliminated by pretreatment with NAC. Pretreatment with both NAC (1 mmol/L) and BAY11-7082 (10 µmol/L) significantly inhibited the NF-κB activity induced by LPS. CONCLUSION: NAC inhibits the LPS-mediated synthesis of tumor TNF-α and IL-1ß in hPDLFs, through the NF-κB pathway.


Assuntos
Acetilcisteína/farmacologia , Fibroblastos/efeitos dos fármacos , Interleucina-1beta/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Fibroblastos/metabolismo , Humanos , Interleucina-1beta/biossíntese , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Ligamento Periodontal , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
20.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3423-3428, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602904

RESUMO

To investigate the effect of triptolide on cognitive dysfunction in vascular dementia rats and its effect on SIRT1/NF-κB pathway,fifty healthy male Sprague-Dawley rats were randomly divided into 5 groups: Sham operation group( Sham group),vascular dementia model group( 2 VO group),triptolide intraperitoneal injection group( TR group),triptolide intraperitoneal injection + EX527 intracerebroventricular administration group( T+E group),EX527 intracerebroventricular administration group( EX527 group). After 4 weeks of modeling,Morris water maze test and object recognition test were used to evaluate the learning and memory ability of rats. The morphological changes of hippocampus in each group were observed in brain tissue. The chemical colorimetry was used to detect the activities of SOD and MDA in hippocampus. IL-6 and TNF-α levels were detected by ELISA. Western blot was used to detect the expression of SIRT1,NF-κB,IκBα and caspase 3 in hippocampus. The results showed that compared with the Sham group,the learning and memory ability of the vascular dementia model rats was reduced,the SOD activity in the hippocampus was decreased,the MDA activity and IL-6 level were increased,the neuronal degeneration changed significantly,the expression of SIRT1 and IκBα was decreased and the expression of caspase 3 and NF-κB was significantly increased. After intervention by triptolide,the level of oxidative stress and the degenerative changes in hippocampus were significantly slowed down. The expression of SIRT1 and IκBα protein was increased and the expression of caspase 3 and NF-κB was significantly decreased. While,after intervention by triptolide and EX527,the expression of SIRT1 was decreased,the levels of oxidative stress and neuronal degeneration in the hippocampus were aggravated,and the learning and memory ability was reduced. The results showed that triptolide could improve cognitive impairment in vascular dementia rats and its mechanism may be related to SIRT1/NF-κB signaling pathway.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Diterpenos/farmacologia , NF-kappa B/metabolismo , Fenantrenos/farmacologia , Transdução de Sinais , Sirtuína 1/metabolismo , Animais , Compostos de Epóxi/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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