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1.
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
2.
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
3.
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
4.
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
5.
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
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 , Granulinas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Invasividade Neoplásica , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas
7.
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
8.
Zhongguo Zhong Yao Za Zhi ; 44(14): 2947-2952, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602838

RESUMO

The aim of this paper was to discuss the protective effect and mechanism of Acanthopanax senticosus polysaccharides( ASPs) on immunological liver injury caused by conanavalin A( Con A). BALB/c mice were randomly divided into seven groups: control group,model group( Con A),low-,medium-,and high-dose( 36. 25,72. 5,145 mg·kg~(-1)) ASPs groups,bifendate( 200 mg·kg~(-1),positive drug) group and pyrrolidinedithiocarbamate( PDTC,NF-κB inhibitor,200 mg·kg~(-1)) group. ASPs groups and bifendate group were given with corresponding drugs by ig administration once daily for 7 d. Control group,model group and PDTC group were given with normal saline by ig administration once daily for 7 d. After the last ig administration,PDTC was given in DTC group by iv administration( 200 mg·kg~(-1)); 0. 5 h after that,Con A( 20 mg·kg~(-1)) was injected via the tail vein to induce immunological liver injury in all the mice except normal control group. The mice were killed 8 h later and their liver tissues were collected for histopathological examination. The contents of nitric oxide( NO),superoxide dismutase( SOD),malondialdehyde( MDA),reduced glutathione( GSHPX),interleukin( IL-1ß) and tumor necrosis factor( TNF-α) in liver tissues were detected by kit assay. Western blot method was used to detect TNF-α,intercellular cell adhesion molecule-1( ICAM-1),inducible nitric oxide synthase( i NOS) and nuclear factor( NF-κB) protein expression in liver tissues. As compared with model group,ASPs not only could reduce the activity of MDA,NO,IL-1ß and TNF-α,but also increase the content of GSH-PX and SOD; at the same time,the protein expression levels of TNF-α,ICAM-1,i NOS and NF-κB were reduced in liver tissues; in addition,inflammatory cell infiltration was alleviated,hepatocyte cytoplasm was loose and swollen,and nuclear condensation and staining were improved. ASPs has a protective effect on immunological liver injury,and the mechanism may be associated with regulating secretion of inflammatory cytokines and the expression of adhesion factor through NF-κB signaling pathway.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Citocinas/metabolismo , Eleutherococcus/química , Polissacarídeos/farmacologia , Animais , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Peptídeos Cíclicos , Distribuição Aleatória , Transdução de Sinais
9.
Zhongguo Zhong Yao Za Zhi ; 44(14): 2966-2971, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602841

RESUMO

To study the effects of saikosaponin b2( SS-b2) on inflammatory factors and energy metabolism against lipopolysaccharide/galactosamine( LPS/Gal N) induced acute liver injury in mice. Mice were randomly divided into normal group( equal amount of normal saline),model group( 100 g·kg~(-1) LPS and 400 mg·kg~(-1) Gal N),low,medium,high dose group of SS-b2( SS-b25,10,20 mg·kg~(-1)·d-1) and positive control group( dexamethasone,10 mg·kg~(-1)). All of the groups except for the normal group were treated with LPS/Gal N though intraperitoneally injection to establish the acute liver injury model. The organ indexes were calculated. The levels of serum transaminases( ALT and AST) and the activities of ATPase( Na+-K+-ATPase,Ca2+-Mg2+-ATPase) in liver were detected. The activity of tumor necrosis factor-α( TNF-α),interleukin-1ß( IL-1ß) and interleukin-6( IL-6) were determined by the enzyme-linked immunosorbent assay( ELISA). The contents of lactate dehydrogenase( LDH) in liver were determined by micro-enzyme method. HE staining was used to observe the histopathological changes of the liver. Histochemical method was used to investigate the protein expression of liver lactate dehydrogenase-A( LDH-A). The protein expressions of Sirt-6 and NF-κB in the liver were detected by Western blot. According to the results,compared with the model group,there were significant changes in organ indexes in the high-dose group of SS-b2( P<0. 05). The level of ALT,AST,TNF-α,IL-1ß,IL-6 and the activities of LDH in serum of mice with liver injury were significantly reduced in the medium and high dose groups of SS-b2( P<0. 01). With the increase of the concentration of SS-b2,the range of hepatic lesions and the damage in mice decreased. The activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in liver of mice were significantly enhanced in each dose group( P<0. 01). The expression of NF-κB in liver tissues was significantly down-regulated in the medium and high dose group( P<0. 01). Meanwhile,the expression of Sirt-6 protein in the liver of mice with acute liver injury was significantly increased in each dose group( P<0. 01).In summary,SS-b2 has a significant protective effect on LPS/Gal N-induced acute liver injury in mice,which may be related to the down-regulation of NF-κB protein expression and up-regulation of Sirt-6 protein expression to improve inflammatory injury and energy metabolism.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Metabolismo Energético , Inflamação/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Citocinas/metabolismo , Galactosamina , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Ácido Oleanólico/farmacologia , Distribuição Aleatória , Sirtuínas/metabolismo
10.
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
11.
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
12.
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
13.
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
14.
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
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.
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
17.
Cell Physiol Biochem ; 53(3): 518-531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502430

RESUMO

BACKGROUND/AIMS: Liver regeneration is induced by S1P and accompanied with an increase in hepatic Na+/K+ ATPase activity, suggesting a potential modulatory role of the sphingolipid on the ATPase activity. The ability of S1P to alter the ATPase activity was confirmed in a previous work which showed a time dependent effect, with an inhibition appearing at 15min and a stimulation at two hours. The aim of this work was to investigate if FTY720-P, an analogue of S1P used in the treatment of multiple sclerosis, exerts a similar effect at 2 hours. METHODS: HepG2 cells were treated with FTY720-P for two hours and the activity of the Na+/K+ ATPase was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of ouabain. The involvement of NF-κB in the pathway was investigated by determining changes in the protein expression of IκB. RESULTS: FTY720-P induced a 2.5-fold increase in the activity of the Na+/K+ ATPase which was maintained in the presence of JTE-013, a specific blocker of S1PR2, but disappeared completely in presence of CAY 10444, a specific S1PR3 antagonist. The involvement of S1PR3 was supported by the stimulation observed with Cym5541, a S1PR3 agonist. FTY720-P increased the expression of COX2, and reduced that of IκB. Its effect was not manifested in presence of indomethacin, a COX inhibitor, or in presence of an NF-κB inhibitor. Exogenous PGE2 induced a significant stimulatory effect. Inhibiting PKC and ERK with respectively calphostin C and PD98059 abolished the effect of FTY720-P on the ATPase and on IκB, but not that of exogenous PGE2 indicating that the two kinases are upstream of NF-κB and PGE2. The PKC activator PMA increased the activity of the Na+/K+ ATPase as well as the expression of phopho-ERK, inferring that PKC is upstream of ERK. CONCLUSION: It was concluded that FTY720-P stimulates the Na+/K+ ATPase via PGE2 by activating sequentially S1PR3, PKC, ERK, NF-κB. The latter enhances COX-2 expression leading to PGE2 release.


Assuntos
Dinoprostona/metabolismo , Organofosfatos/farmacologia , Receptores de Lisoesfingolipídeo/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Esfingosina/análogos & derivados , Western Blotting , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/farmacologia
18.
Life Sci ; 235: 116824, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476305

RESUMO

AIMS: Leflunomide is a disease modifying anti-rheumatic drug (DMARD) beneficial in refractory cases of rheumatoid arthritis. Since leflunomide approval, hepatotoxicity and instructions of liver function monitoring have been recommended. The current work aimed to explore the possible role of inflammation in leflunomide-induced hepatotoxicity with a focus on the TLR4-mediated stimulation of PI3K/mTOR/NFκB pathway. MAIN METHODS: Forty-eight male albino mice were allocated into four different groups (n; 12 mice/group). Group (i): normal mice, Group (ii-iv) mice received escalating dosed/s of leflunomide (2.5, 5 or 10 mg/kg, p.o.) every 48 h for eight weeks. At the end of the study, mice were sacrificed, and blood samples were collected for determination of liver enzymes. Liver samples were collected; (1) formalin-fixed for histologic examination, (2) frozen for PI3K and mTOR genes PCR assays. KEY FINDINGS: Results indicated a significant elevation of liver enzymes in leflunomide-treated mice (10 mg/kg); AST and ALT activities were 218.17 ±â€¯6.83 U/L and 99.83 ±â€¯9.82 U/L versus 130.5 ±â€¯12.79 U/L and 44.72 ±â€¯3.58 U/L in the vehicle group. Additionally, histopathological examination revealed higher necro-inflammatory scores in leflunomide-treated mice. Immunohistochemistry indicated dose-dependent increased staining of TLR4 and caspase 3. Furthermore, leflunomide-treated mice (5 or 10 mg/kg) showed greater staining for NFκB compared to vehicle control. RT-PCR results revealed upregulations in genes expressing PI3K and mTOR by leflunomide. SIGNIFICANCE: The current study highlights the possible role of TLR4-PI3K/mTOR/NFκB in the pathogenesis of leflunomide-induced hepatic injury. A better understanding of mechanisms of leflunomide-induced hepatotoxicity may be of translational implication for the predictive, preventive and therapeutic purposes.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Leflunomida/efeitos adversos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Caspase 3/metabolismo , Relação Dose-Resposta a Droga , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
19.
Life Sci ; 235: 116823, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476307

RESUMO

AIMS: Advanced glycation end products (AGEs) trigger intracellular reactive oxygen species (ROS) generation, activation of receptor for AGEs (RAGE) expression/functionality and RAGE-associated signalling pathways which influence the diabetic-cum-atherosclerotic complications, whereas, the atherosclerosis progression is greatly influenced by hepatic ß-Hydroxy-ß-methyl-glutaryl-Co-A reductase (HMG-R) activity. The present report was premeditated to uncover the regulatory role of HMG-R inhibitors and ezetimibe (EZ) in attenuating the LDL-AGEs-induced pathogenicity via targeting cellular-ROS and RAGE-associated signalling in HEK-293 cells. MAIN METHODS: The MTT assay was used to assess either the cytotoxic or cytoprotective impact of each HMG-R inhibitors, EZ, and LDL-AGEs, whereas, quantification of ROS was performed by DCFDA method. The qRT-PCR was used to detect the mRNA level of RAGE, neuropilin-1 (NRP-1) and other RAGE-associated genes like MMP-2, NF-κB, and TGFß-1. KEY FINDINGS: The HMG-R inhibitors do not exert any cytotoxicity in HEK-293 cells, whereas, and LDL-AGEs negatively affected the cell viability of HEK-293 cells. However, viability of LDL-AGEs-treated HEK-293was markedly retained after simultaneous treatment with our test inhibitors. Further, DCFDA staining showed that LDL-AGEs-induced ROS was also suppressed upon treatment with our test inhibitors in HEK-293 cells. qRT-PCR analysis reflected that these inhibitors suppress the RAGE, NF-κB, TGFß-1, and MMP-2 expression, whereas, the NRP-1 was up-regulated by these compounds in LDL-AGEs-exposed HEK-293 cells. SIGNIFICANCE: The above pharmacological effects signify that HMG-R inhibitors and EZ (alone or in combination) may implied in the treatment of AGEs-induced oxidative stress and tissue damage in diabetic complications via targeting intracellular-ROS, NRP-1 functionality and RAGE-associated genes i.e. NF-κB, TGFß-1, and MMP-2.


Assuntos
Ezetimiba/farmacologia , Produtos Finais de Glicação Avançada/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas LDL/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Anticolesterolemiantes/farmacologia , Apoptose , Complicações do Diabetes/tratamento farmacológico , Células HEK293 , Humanos , NF-kappa B/metabolismo
20.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 443-451, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484604

RESUMO

Objective To analyze the differences in biological functions between bone marrow(BM)-derived CD106 +mesenchymal stem cells(MSCs)and the CD106 - subgroup. Methods The MSCs from normal BM were isolated and expanded.The subgroups of CD106 + and CD106 -MSCs were sorted.The cell proliferation and adhesion functions,chemotactic activities,adipogenic and osteogenic potentials,senescence,and senescence protein 21(p21)were detected.The capacity of translocation into nucleus of nuclear factor-kappa B(NF-κB)when stimulated by tumor necrosis factor(TNF-α)was measured. Results The proliferative ability was higher in CD106 +MSCs than that in CD106 -MSCs.In 48 hours,the value of optical density(OD)was significantly higher in CD106 +MSCs than that in CD106 - subgroup(1.004±0.028 vs. 0.659±0.023,t=3.946,P=0.0225).In 72 hours,this phenomenon was even more pronounced(2.574±0.089 vs. 1.590±0.074,t=11.240,P=0.0000).The adhesive capacity of CD106 +MSCs was significantly stronger than that of CD106 - subgroup(0.648±0.018 vs. 0.418±0.023,t=7.869,P=0.0002).Besides,the metastasis ability of CD106 +MSCs were significantly stronger than that of CD106 - subgroup(114.500±4.481 vs.71.000±4.435,t=6.900,P=0.0005).The CD106 +MSCs had signifcnatly lower proportions of senescent cells.The expression of aging protein p21 in CD106 +MSCs was significantly lower than that in CD106 -MSCs [(17.560±1.421)% vs.(45.800±2.569)%,t=9.618,P=0.0000].Furthermore,there were no visible pigmenting cells after ß-galactosidase staining in CD106 +MSCs subgroup.However,in CD106 -MSCs,some colored green cells were detected.The rate of NF-κB translocation into nucleus after stimulated by TNF-α was significantly higher in CD106 +MSCs than CD106 - MSCs [(37.780±3.268)% vs.(7.30±1.25)%,t=8.713,P=0.0001]. Conclusion Bone marrow-derived CD106 +MSCs possess more powerful biological functions than CD106 -MSCs.


Assuntos
Células da Medula Óssea/citologia , Células-Tronco Mesenquimais/citologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adesão Celular , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , NF-kappa B/metabolismo , Transporte Proteico , Fator de Necrose Tumoral alfa/farmacologia
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