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1.
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
2.
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
3.
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
4.
J Agric Food Chem ; 67(37): 10321-10329, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31419115

RESUMO

Pterostilbene (PTS) is a phenolic compound with diverse pharmacologic activities. However, its potential for inhibiting obesity-related colorectal cancer (CRC) remains unclear. Our study evaluated the mechanism of inhibitory effects of PTS on adipocyte conditioned-medium (aCM)-induced malignant transformation in HT-29 colorectal adenocarcinoma cells. The results demonstrated that PTS could downregulate the expression of aCM-induced fatty acid-binding protein 5 (FABP5) and prometastatic factors such as vascular endothelial growth factor, matrix metalloproteinase-2 (MMP2), MMP9, and extracellular tumor necrosis factor α via inhibiting aCM-induced nuclear factor-kappa B (NF-κB), ß-catenin, and peroxisome proliferator-activated receptor γ (PPAR-γ). Moreover, PTS can suppress aCM-stimulated phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases 1/2 (JNK 1/2) signaling pathways activation that are upstream of NF-κB, ß-catenin, and PPAR-γ. Therefore, we suggest that PTS could alleviate adiposity-induced metastasis in CRC via inhibiting cell migration through downregulating FABP5 gene expression.


Assuntos
Adipócitos/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/fisiopatologia , Meios de Cultivo Condicionados/química , Proteínas de Ligação a Ácido Graxo/metabolismo , Estilbenos/farmacologia , Células 3T3 , Animais , Linhagem Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Meios de Cultivo Condicionados/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Acta Cir Bras ; 34(6): e201900604, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31432995

RESUMO

PURPOSE: In view of the principal role of Toll-like receptor 4 (TLR4) in mediating sterile inflammatory response contributing to osteoarthritis (OA) pathogenesis, we used lipopolysaccharide (LPS), a known TLR4 activator, to clarify whether modulation of TLR4 contributed to the protective actions of intra-articular administration of curcumin in a classical rat OA model surgically induced by anterior cruciate ligament transection (ACLT). METHODS: The rats underwent ACLT and received 50µl of curcumin at the concentration of 1 mg mL-1 and 10 µg LPS by intra-articular injection once a week for 8 weeks. Morphological changes of the cartilage and synovial tissues were observed. Apoptotic chondrocytes were detected using TUNEL assay. The concentrations of IL-1ß and TNF-ɑ in synovial fluid were determined using ELISA kits. The mRNA and protein expression levels of TLR4 and NF-κB p65 were detected by real-time PCR and Western blotting, respectively. RESULTS: Intra-articular administration of curcumin significantly improved articular cartilage injury, suppressed synovial inflammation and down-regulated the overexpression of TLR4 and its downstream NF-κB caused by LPS-induced TLR4 activation in rat osteoarthritic knees. CONCLUSION: The data suggested that the inhibition of TLR4 signal might be an important mechanism underlying a protective effect of local curcumin administration on OA.


Assuntos
Ligamento Cruzado Anterior/cirurgia , Curcumina/farmacologia , Osteoartrite/prevenção & controle , Receptor 4 Toll-Like/metabolismo , Animais , Ligamento Cruzado Anterior/patologia , Western Blotting , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Injeções Intra-Articulares , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Masculino , NF-kappa B/metabolismo , Osteoartrite/induzido quimicamente , Osteoartrite/metabolismo , Reação em Cadeia da Polimerase , Ratos , Receptor 4 Toll-Like/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
6.
Acta Cir Bras ; 34(6): e201900609, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31433000

RESUMO

PURPOSE: The research is intended for clarification of the efficacy as well as the underlying mechanism of GSK-3ß inhibitors on the advancement of acute lung injuries in acute necrotizing pancreatitis (ANP) in rats. METHODS: Seventy-two rats were randomly divided into 6 groups: (1)ANP-vehicle; (2)ANP-TDZD-8;(3)ANP-SB216763;(4)Sham-vehicle;(5)Sham-TDZD-8;(6)Sham-SB216763; Blood biochemical test, histopathological examination and immunohistochemical analysis of rats pancreas and lung tissues were performed. The protein expression of GSK-3ß, phospho-GSK-3ß (Ser9), iNOS, ICAM-1, TNF-α, and IL-10 were detected in lung tissues by Western-blot. RESULTS: The outcomes revealed that the intervention of GSK-3ß inhibitors alleviated the pathological damage of pancreas and lung (P<0.01), reduced serum amylase, lipase, hydrothorax and lung Wet-to-Dry Ratio, attenuated serum concentrations of IL-1ß and IL-6 (P<0.01), inhibited the activation of NF-κB, and abated expression of iNOS, ICAM-1 and TNF-α protein, but up-regulated IL-10 expression in lung of ANP rats (P<0.01). The inflammatory response and various indicators in ANP-TDZD-8 groups were lower than those in ANP-SB216763 groups. CONCLUSIONS: Inhibition of GSK-3ß weakens acute lung injury related to ANP via the inhibitory function of NF-κB signaling pathway. Different kinds of GSK-3ß inhibitors have different effects to ANP acute lung injury.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Pancreatite Necrosante Aguda/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Masculino , NF-kappa B/metabolismo , Pancreatite Necrosante Aguda/patologia , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
7.
J Biol Regul Homeost Agents ; 33(4): 1051-1062, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392878

RESUMO

The development of electronic technology has attracted attention on the biological effects of electromagnetic fields (EMFs) and electromagnetic pulse (EMP). It remains controversial whether EMP irradiation is neurotoxic or beneficial for recovery from injuryies such as cerebral ischemia. Microglia is innate immune cells in the brain, exhibiting either neurotoxicity or neuroprotection effect during various central nervous system diseases, depending on their activation into a classical (M1) or alternative (M2) phenotype, respectively. The Toll-like receptor-4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear factor kappa B (NFκB) pathway is important for microglia activation. In this study, we investigated the effect of EMP on neuronal apoptosis and microglia polarization in vivo and in vitro, using an EMP of 400 kV/m and 1 hertz for 200 pulses. Short EMP irradiation (≤24 h) resulted in microglial conversion from the resting to the M1-type state, activation of the TLR4/MyD88/NFκB pathway, higher levels of inflammatory cytokines including interleukin (IL)-6, IL-1ß and tumor necrosis factor-α, as well as neuronal apoptosis induction. In contrast, long EMP irradiation (3 days) resulted in microglial activation into the M2-type, decreased apoptosis and inflammatory mediator production, and increased levels of the neuroprotective effectors IL-10, transforming growth factor beta, and brain-derived neurotrophic factor. EMP induces both neuronal damage and neuronal recovery by influencing the switch of M1/M2 polarization and the TLR4/MyD88/NFκB pathway.


Assuntos
Lesões Encefálicas/patologia , Polaridade Celular , Campos Eletromagnéticos/efeitos adversos , Microglia/citologia , Citocinas/metabolismo , Humanos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo
8.
Chem Biol Interact ; 311: 108777, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31376360

RESUMO

Nicorandil ameliorated doxorubicin-induced nephrotoxicity; this study aimed to show and explain the mechanism of this protection. A precise method was elucidated to study the effect of nicorandil on doxorubicin-induced nephrotoxicity in rats depending on the critical inflammation pathway TLR4/MAPK P38/NFκ-B. Adult male rats were subdivided into four groups. The 1st group was normal control, the 2nd group received nicorandil (3 mg/kg; p.o., for 4 weeks), the 3rd group received doxorubicin (2.6 mg/kg, i.p., twice per week for 4 weeks), and the fourth group was combination of doxorubicin and nicorandil for 4 weeks. Nephrotoxicity was assessed by biochemical tests through measuring Kidney function biomarkers such as [serum levels of urea, creatinine, albumin and total protein] besides renal kidney injury molecule-1 (KIM-1) and cystatin C], oxidative stress parameters such as [renal tissue malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase and nrf-2], mediators of inflammation such as [Toll like receptor 4 (TLR-4), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), p38 MAPK, Interleukin 1 beta (IL-1 ß), and Tumor necrosis factor alpha (TNF-α)] and markers of apoptosis [BAX and Bcl-2 in renal tissue]. Finally, our data were supported by histopathology examination. Nicorandil pretreatment resulted in a significant decrease in nephrotoxicity biomarkers, oxidative stress markers, inflammatory mediators and prevented apoptosis through decreasing BAX and increasing Bcl-2 in renal tissues. Nicorandil prevented all the histological alterations caused by doxorubicin. Nicorandil is a promising antidote against doxorubicin-induced nephrotoxicity by neutralizing all toxicity mechanisms caused by doxorubicin through normalizing inflammatory cascade of TLR4/MAPK P38/NFκ-B.


Assuntos
Doxorrubicina/toxicidade , Rim/efeitos dos fármacos , Nicorandil/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Nitrogênio da Ureia Sanguínea , Moléculas de Adesão Celular/sangue , Creatinina/sangue , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Rim/metabolismo , Rim/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Chem Biol Interact ; 311: 108786, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401087

RESUMO

Naturally occurring oleanolic acid (OA) possesses a hepatoprotective activity and ability to inhibit proliferation of human hepatocellular carcinoma cells. Both properties might be related to its anti-inflammatory activity. Its low bioavailability justifies the search for more hydrophilic OA derivatives. The aim of this study was the design and synthesis of four novel OA oxime derivatives conjugated with succinic acid at the C-3 position of oleanane skeleton structure and evaluation of their effect on NF-κB and STATs expression and activation in HepG2 cells. The expression of NF-κB and cyclooxygenase-2 (COX-2), STAT5A/B and STAT3 with its target genes: BAX, BCL-XL and MYC was evaluated after 24 h treatment with tested compounds. The comparison of the levels of cytosolic and nuclear NF-κB subunits p50, p65 and STATs proteins was used as the measure of their activation. The results pointed out the 3-succinyloxyiminoolean-12-en-28-oic acid morpholide (SMAM) as the most potent modulator of NF-κB and STAT3. SMAM significantly reduced the expression and activation of NF-κB as well as its nuclear protein level of p65 subunit. This compound also reduced the expression and activation of STAT3 and STAT5A/B. Combined effect of SMAM on these transcription factors resulted in reduced expression of COX-2, MYC and anti-apoptotic BCL-XL genes. Simultaneously, the increased expression of pro-apoptotic BAX gene was observed. In the cells treated with 3-succinyloxyiminoolean-12-en-28-oic acid (SMAA) the increased expression of BAX was also found. The effects of 3-succinyloxyiminoolean-12-en-28-oic acid benzyl ester (SMAEB) and 3-succinyloxyiminoolean-12-en-28-oic acid methyl ester (SMAEM) were moderate and ambiguous in relation to the tested factors. Moreover, the coordinated action of SMAM on NF-κB and STAT3 confirms their close association in HepG2 cells. We conclude that SMAM efficiently downregulates the key elements of signaling pathways involved in inflammatory driven HCC. Thus, may be considered as a potential chemopreventive or therapeutic agent in this type of cancer.


Assuntos
NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Oximas/farmacologia , Fatores de Transcrição STAT/metabolismo , Ácido Succínico/química , Carcinoma Hepatocelular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas , NF-kappa B/genética , Oximas/química , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição STAT/genética , Transcrição Genética/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
10.
Adv Exp Med Biol ; 1155: 857-867, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468452

RESUMO

We want to find the anti-neuroinflammatory action of the taurine derivative Glucose-Taurine Reduced (G-T-R). The anti-neuroinflammatory action by G-T-R were investigated in lipopolysaccharide (LPS)-induced BV2 microglia. G-T-R inhibited the production of nitric oxide and prostaglandin E2, and down-regulated the protein expression of inducible NO synthase and cyclooxygenase-2. In addition, G-T-R reduced the cytokines secretion such as tumor necrosis factor (TNF-α), interleukin (IL) -1ß and IL-6, in BV2 microglia treated with LPS. In addition, G-T-R dose-dependently decreased the activation of nuclear factor-kappa B. These findings confirmed the anti-neuroinflammatory activity of G-T-R, which may exert protective effects against neuroinflammatory-related diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Taurina/farmacologia , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Glucose , Lipopolissacarídeos , Camundongos , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/metabolismo
11.
Adv Exp Med Biol ; 1155: 989-999, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468462

RESUMO

In the present study, we investigated the regulation of inflammatory effects by glucose-taurine reduced (G-T-R), a taurine-carbohydrate derivative, on lipopolysaccharide (LPS)-induced RAW264.7 macrophages. The anti-inflammatory action of G-T-R revealed that this derivative markedly inhibited the nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW264.7 macrophages induced by LPS. Suppression of NO and PGE2 production was involved in the inhibitory action by G-T-R on the inducible nitric oxide synthase and cyclooxygenase-2 proteins expression. G-T-R decreased the production of a variety of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6. Moreover, G-T-R effectively suppressed the nuclear factor-kappa B (NF-κB) activation in LPS-stimulated RAW264.7 macrophages according to evaluation of the molecular inflammatory mechanisms. Thus, we suggest that G-T-R modulates several inflammatory pathways mediated by NF-κB activation, demonstrating its potential or preventing and treating inflammatory conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Taurina/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Glucose/farmacologia , Lipopolissacarídeos , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
12.
Adv Exp Med Biol ; 1155: 1001-1014, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468463

RESUMO

Batillaria multiformis (B. multiformis) belong to gastropods. They live generally in the sandpit of the lagoons and the estuaries of the intertidal zone. Most of them are distributed in Korea, Japan and China. In this study, we investigated the anti-inflammatory potential of B. multiformis water extracts (BMW). The results showed that the extracts significantly decreased the production of nitric oxide (NO) and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in LPS-induced RAW 264.7 macrophages. In addition, the extracts suppressed the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose dependent manner. Further investigation indicated that BMW suppressed phosphorylated c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase (ERK) and p38 through the MAPK signaling pathway and influenced the NF-κB signaling pathway by suppressing the IκBα degradation in LPS-induced RAW 264.7 macrophages.


Assuntos
Anti-Inflamatórios/farmacologia , Extratos Celulares/farmacologia , Gastrópodes/química , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Lipopolissacarídeos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Água
13.
Adv Exp Med Biol ; 1155: 1057-1067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468467

RESUMO

Ribose-taurine (Rib-T) suppressed the generation of inflammatory mediators and cytokines, such as nitric oxide (NO) and prostaglandin E2 (PGE2) through the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß induced by LPS was effectively blocked by Rib-T. Moreover, the anti-inflammatory actions of Rib-T were involved in its inhibitory effects against the nuclear translocation of nuclear factor-kappa B (NF-κB) p65, and NF-κB DNA-binding activity. These results suggest that the anti-inflammatory action of Rib-T is associated with NF-κB regulation.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Ribose/farmacologia , Taurina/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Inflamação , Lipopolissacarídeos , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Fator de Transcrição RelA
14.
Adv Exp Med Biol ; 1155: 1069-1081, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468468

RESUMO

Scallops belong to cosmopolitan family of bivalves which are found in any oceans. They are one of the most important marine fishery resources in the world. The shell, meat and pearl layer have a high utilization value and a lot of scallops are eaten as food. In this study, we established anti-inflammatory effect of Scallops water extract in lipopolysaccharide (LPS) stimulated RAW 264.7 mononuclear macrophage. Our results indicated that Scallop water extract effectively reduced the synthesis of nitric oxide (NO). In addition, Scallop water extract suppressed the reactive oxygen species (ROS) generation and the expression of IL-6 and TNF-α. Further investigation indicated that anti-inflammatory effect of Scallop water extract via suppressing downregulation of MAPK (JNK, p38 and ERK) and NF-κB signaling.


Assuntos
Anti-Inflamatórios/farmacologia , Extratos Celulares/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Pectinidae/química , Animais , Citocinas/metabolismo , Inflamação , Lipopolissacarídeos , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
15.
BMC Bioinformatics ; 20(1): 417, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409281

RESUMO

BACKGROUND: The development of high throughput sequencing techniques provides us with the possibilities to obtain large data sets, which capture the effect of dynamic perturbations on cellular processes. However, because of the dynamic nature of these processes, the analysis of the results is challenging. Therefore, there is a great need for bioinformatics tools that address this problem. RESULTS: Here we present DynOVis, a network visualization tool that can capture dynamic dose-over-time effects in biological networks. DynOVis is an integrated work frame of R packages and JavaScript libraries and offers a force-directed graph network style, involving multiple network analysis methods such as degree threshold, but more importantly, it allows for node expression animations as well as a frame-by-frame view of the dynamic exposure. Valuable biological information can be highlighted on the nodes in the network, by the integration of various databases within DynOVis. This information includes pathway-to-gene associations from ConsensusPathDB, disease-to-gene associations from the Comparative Toxicogenomics databases, as well as Entrez gene ID, gene symbol, gene synonyms and gene type from the NCBI database. CONCLUSIONS: DynOVis could be a useful tool to analyse biological networks which have a dynamic nature. It can visualize the dynamic perturbations in biological networks and allows the user to investigate the changes over time. The integrated data from various online databases makes it easy to identify the biological relevance of nodes in the network. With DynOVis we offer a service that is easy to use and does not require any bioinformatics skills to visualize a network.


Assuntos
Redes Reguladoras de Genes , Interface Usuário-Computador , Acetaminofen/farmacologia , Biologia Computacional/métodos , Bases de Dados Factuais , Humanos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
16.
J Agric Food Chem ; 67(35): 9727-9737, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31398034

RESUMO

The present study aimed to search for chicken abdominal fat deposition-related polymorphisms within RB1 and to provide functional evidence for significantly associated genetic variants. Association analyses showed that 11 single nucleotide polymorphisms (SNPs) in intron 17 of RB1, were significantly associated with both abdominal fat weight (P < 0.05) and abdominal fat percentage (P < 0.05). Functional analysis revealed that the A allele of g.32828A>G repressed the transcriptional efficiency of RB1 in vitro, through binding nuclear factor-kappa B (NF-KB) and SRY-related HMG box protein 2 (SOX2). Furthermore, RB1 mRNA expression levels in the abdominal fat tissue of individuals with the A/A genotype of g.32828A>G were lower than those of individuals with the G/G genotype. Collectively, we propose that the intronic SNP g.32828A>G of RB1 is an obesity-associated variant that directly affects binding with NF-KB and SOX2, leading to changes in RB1 expression which in turn may influence chicken abdominal fat deposition.


Assuntos
Adiposidade , Proteínas Aviárias/metabolismo , Galinhas/metabolismo , NF-kappa B/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Fatores de Transcrição SOX/metabolismo , Gordura Abdominal/metabolismo , Alelos , Animais , Proteínas Aviárias/genética , Sítios de Ligação , Galinhas/genética , Galinhas/crescimento & desenvolvimento , Íntrons , NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Fatores de Transcrição SOX/genética
17.
J Enzyme Inhib Med Chem ; 34(1): 1287-1297, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31288582

RESUMO

Inhibition of NF-κB signalling has been demonstrated as a therapeutic option in treating inflammatory diseases and cancers. Herein, we synthesized novel dissymmetric 3,5-bis(arylidene)-4-piperidones (BAPs, 83-102) and characterized fully. MTT and ELISA assay were performed to screen the anti-hepatoma and anti-inflammation properties. 96 showed the most potential bioactivity. 96 could promote HepG2 apoptosis through up-regulating the expression of C-Caspase-3 and Bax, down-regulating the expression of Bcl-2, while markedly inhibit LPS or TNF-α-induced activation of NF-κB through both inhibiting the phosphorylation of IκBα and p65, and preventing the p65 nuclear translocation to exhibit both anti-hepatoma and anti-inflammatory activities. Molecular docking verified that simulated 96 can effectively bond to the active site of Bcl-2 and NF-κB/p65 proteins. 96 inhibited xenografts growth by reducing the expression of TNF-α and Bcl-2 in the tumour tissue. This study suggested that 96 could be developed as a potential multifunctional agent for treatment of inflammatory diseases and cancers.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Inflamação/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , NF-kappa B/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular
18.
Zhongguo Zhong Yao Za Zhi ; 44(10): 2118-2123, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31355570

RESUMO

The aim of this paper was to investigate the mechanism and effect of psoralen and isopsoralen in the treatment of lipid accumulation in LO2 cells. Human LO2 cells nonalcoholic fatty liver models were established by using palmitic acid( PA). Then psoralen and isopsoralen were administered for intervention. Intracellular triglyceride( TG) and total cholesterol( TC) content,the cell supernatant alanine aminotransferase( ALT) and aspartate aminotransferase( AST) levels were determined by enzyme method. Cell supernatant proinflammatory cytokines( IL-6,TNF-α) and chemokines( IL-8,MCP-1) were determined by ELISA method. Western blot method was conducted to detect the protein expression of intracellular nuclear factor( NF-κB) p65 phosphorylation( p-p65),nonphosphorylated protein( p65),and transforming factor TGF-ß1. Result showed that as compared with the model group,intracellular TG and TC levels,the cell supernatant ALT and AST levels,proinflammatory cytokines and chemokines were decreased( P < 0. 01,P <0. 05); the p-p65/p65 ratio and TGF-ß1 protein expression were also significantly decreased( P< 0. 01,P< 0. 05) in psoralen intervention group. As compared with the model cells,intracellular TG content had no significant changes,but all the other indexes were reduced( P<0. 01,P<0. 05) in the cells of isopsoralen intervention group. Psoralen exhibited better effect than isopsoralen( P< 0. 01,P<0. 05). It is concluded that psoralen could improve the adipogenesis of LO2 cells induced by PA; both psoralen and isopsoralen are effective in ameliorating LO2 cells injury induced by PA,reducing inflammation via inhibiting the activation of NF-κB and down-regulating the expression of TGF-ß1.


Assuntos
Ficusina/farmacologia , Furocumarinas/farmacologia , Metabolismo dos Lipídeos , NF-kappa B/metabolismo , Linhagem Celular , Humanos , Hepatopatia Gordurosa não Alcoólica
19.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(6): 746-749, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31315735

RESUMO

OBJECTIVE: To investigate the protective effect of Polyphyllin I (PPI) on myocardial ischemia/reperfusion (I/R) injury in rats and its mechanism. METHODS: The 6-month-old Sprague-Dawley (SD) rats were divided into sham operation group (Sham group), I/R model group, and low, medium, high dose PPI groups according to the random number table method, with 10 in each group. The rat myocardial I/R model was prepared by ligating the left anterior descending branch of the coronary artery by 30 minutes and reperfusion by 120 minutes. Sham group was exposure to open chest without ligation. Low, medium, high dose PPI groups were injected with PPI 75, 150, 300 mg×kg-1×d-1 in front of the film for 4 weeks; dimethyl sulfoxide (DMSO) was gastric infused in the I/R model group. After the end of reperfusion, the myocardial infarction area (IA) was determined by triphenyltetrazole (TTC) and Evans blue (EB) staining; the apoptosis of myocardial cells was detected by TdT-mediated dUTP nick end labeling stain (TUNEL); the expressions of apoptosis related protein (Bax, Bcl-2), and cytoplasmic and nucleus expressions of P65 in nuclear factor-ΚB (NF-ΚB) signal pathway were detected by Western Blot. RESULTS: Compared with the Sham group, the myocardial IA was significantly increased in the I/R model group, the apoptosis rate of myocardial cells was significantly increased, the expression of Bcl-2 was significantly decreased, and the expression of Bax was significantly increased, and the intranuclear transfer of P65 was significantly increased. Compared with the I/R model group, low, medium and high dose PPI pretreatment could significantly reduce the myocardial IA [(21.6±0.9)%, (14.3±1.6)%, (15.0±0.8)% vs. (29.6±1.4)%], the apoptosis rate of myocardial cells was significantly decreased [(38.6±1.9)%, (24.3±2.6)%, (26.3±2.8)% vs. (56.8±2.4)%], the protein expression of Bcl-2 was significantly increased, while the protein expression of Bax was significantly decreased (Bcl-2/GAPDH: 0.24±0.07, 0.36±0.02, 0.34±0.09 vs. 0.13±0.04; Bax/GAPDH: 0.39±0.10, 0.21±0.08, 0.23±0.06 vs. 0.53±0.12); and P65 nuclear transfer was significantly decreased after middle and high dose PPI pretreatment [nuclear P65/Histone 3: 0.49±0.09, 0.51±0.06 vs. 0.83±0.11; cytoplasmic P65/GAPDH: 0.31±0.03, 0.30±0.05 vs. 0.22±0.07], with statistically significant differences (all P < 0.05). However, there was no significant difference in each index between the medium and high dose PPI groups (all P > 0.05). CONCLUSIONS: PPI alleviates myocardial I/R injury in rats via NF-ΚB signal pathway, and the PPI effect of 150 mg×kg-1×d-1 is most especially significant.


Assuntos
Diosgenina/análogos & derivados , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Apoptose , Diosgenina/metabolismo , Modelos Animais de Doenças , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
20.
Toxicol Lett ; 313: 130-136, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276767

RESUMO

We previously demonstrated that based on their potency, contact allergens differently modulate Blimp-1/NLRP12 expression in human keratinocytes, with the extreme allergen 2,4-dinitrochlorobenzene (DNCB) more rapidly upregulating Blimp-1, leading to downregulation of NLRP12, and to the production of interleukin-18 (IL-18). The purpose of this study was to further investigate the effects of DNCB and para-phenylenediamine (PPD) on the expression of the proteins of the inflammasome, namely NLRP3, ASC and caspase 1 by western blot analysis; to define the intracellular localization and co-localization of NLRP3 and NLPR12 by immunoprecipitation and immunohistochemistry; and to define the role of NF-κB in Blimp-1 induction by pharmacological inhibition. The human keratinocyte cell line NCTC2544 was used for all experiments. Dose and time course experiments were performed to evaluate the effect of the selected contact allergens on the parameters investigated. Results indicate, that consistent with previous finding, DNCB more rapidly (3 h) induces NLRP3, ASC protein expression and caspase-1 activation compared to PPD. Immunoprecipitation studies show the recruitment of ASC to the inflammasome following exposure to both allergens, while high level of NLRP12 and less ASC protein were found associated in control cells. By immunohistochemistry, we found increased NLRP3 expression following exposure to contact allergens, and observed a nuclear co-localization of the two proteins, indicating the NLRP12 likely acts preventing the cytosolic localization of NLRP3 and inflammasome assembly. Finally, contact allergen-induced Blimp-1 mRNA and protein expression can be completely blocked by inhibiting NF-κB activation, confirming the central role of NF-κB in contact allergen-induced keratinocyte activation.


Assuntos
Alérgenos/toxicidade , Dermatite Alérgica de Contato/etiologia , Dinitroclorobenzeno/toxicidade , Inflamassomos/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Queratinócitos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenilenodiaminas/toxicidade , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Linhagem Celular , Dermatite Alérgica de Contato/genética , Dermatite Alérgica de Contato/metabolismo , Relação Dose-Resposta a Droga , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fatores de Tempo
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