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1.
Life Sci ; 243: 117249, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926247

RESUMO

AIMS: Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive lymphoid malignancies, which remains incurable, thus warranting the development of new therapies. Our previous study determined that rafoxanide is very effective in treating multiple myeloma (MM). In the present study, we tried to evaluate the effects of rafoxanide on DLBCL, as well as the potential underlying molecular mechanisms. MAIN METHODS: We used CCK-8 assay and flow cytometry to assess cell viability and apoptosis. The proteins and pathways associated with apoptosis and proliferation were evaluated through western blot, and xenograft mice were used as the experimental animal model. We also used the TUNEL assay and immunofluorescence for further analyses. KEY FINDINGS: Treatment with different doses of rafoxanide significantly inhibited cell viability and apoptosis. Additionally, the compound induced cell cycle arrest, reduced mitochondrial membrane potential (Δψm), and stimulated reactive oxygen species (ROS) generation without the influence of normal peripheral blood monocytes (PBMCs). As expected, rafoxanide played a role in regulating these proteins and the PTEN/PI3K/AKT and JNK/c-Jun pathways. Furthermore, immunofluorescence and western blot results showed that rafoxanide upregulated H2AX phosphorylation and then inhibited DNA repair in DLBCL. In the xenograft mouse model, tumor volumes were reduced after intraperitoneal injection with rafoxanide. We also observed that TUNEL positive cells were remarkably increased in rafoxanide-treated tumor tissues. SIGNIFICANCE: These results collectively provide a novel choice to regular treatment for DLBCL patients with poor prognosis.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , MAP Quinase Quinase 4/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Rafoxanida/uso terapêutico , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Dano ao DNA , Humanos , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Gene ; 732: 144339, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31927008

RESUMO

OBJECTIVE: Previous studies have shown that follistatin-like protein 1 (FSTL1) is elevated in the synovial fluid of osteoarthritis and is associated with disease activity. The experiment was performed to stuy the effect and mechanism of FSTL1 on chondrocyte apoptosis in osteoarthritis. DESIGN: After the isolation of human normal and osteoarthritis (OA) chondrocytes, the expression of FSTL1 was detected by Q-PCR and western blot analyses. Chondrocytes were pre-transfected with FSTL1 overexpression plasmids then treated with SNP, and chondrocyte viability and apoptosis levels were detected by MTS and flow cytometry, respectively. Cartilage matrix gene expression was measured by Q-PCR and signal pathway-related proteins were assessed by western blot. RESULTS: The expression of FSTL1 in OA chondrocytes was markedly up-regulated compared with normal human chondrocytes (P < 0.05). The apoptosis rate of chondrocytes in the FSTL1 overexpression groups was highly elevated in the comparison with the negative control groups (P < 0.05). Additionally, FSTL1 potentiated protein abundances of MMP1, MMP3, MMP-9, and Bax as well as reduced Coll2a1 and Aggrecan and Bcl-2 expression. Furthermore, western blot results showed that the SAPK/JNK/Caspase3 signal pathway was significantly activated and the Ac-DEVD-FMK impaired FSTL1 induced chondrocyte apoptosis. CONCLUSION: FSTL1 promoted SNP-induced chondrocytes apoptosis by activating the SAPK/JNK/Caspase3 signal pathway.


Assuntos
Apoptose/fisiologia , Caspase 3/metabolismo , Condrócitos/citologia , Proteínas Relacionadas à Folistatina/fisiologia , MAP Quinase Quinase 4/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Óxido Nítrico/fisiologia , Transdução de Sinais/fisiologia , Idoso , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Proteínas Relacionadas à Folistatina/genética , Humanos , Pessoa de Meia-Idade , Osteoartrite/enzimologia , Osteoartrite/metabolismo , Osteoartrite/patologia , RNA Mensageiro/metabolismo
3.
Pak J Pharm Sci ; 32(3 Special): 1355-1359, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31551215

RESUMO

Mitogen-activated protein kinase (MAPK) cascades are important players in the cellular signal pathways, and the deregulation of MAPKs is involved in a variety of diseases, especially cardiovascular disorders. This study was designed to investigate the effects of quercetin on proliferation of cardiac fibroblasts, measured the secretion of Col I & Col III by ELISA and the expression of extra cellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) p38 by eastern blotting in cardiac fibroblasts challenged with angiotensin (Ang-II). Results showed that Ang-II significantly increased the DNA synthesis and collagen secretion. In contrast, quercetin reversed such effects and inhibited cardiac fibroblasts proliferation. Furthermore, reactive oxygen species (ROS) stimulated the phosphorylation of ERK, p38 and JNK, while pre-administration of quercetin significantly (P<0.05) reduced the phosphorylation. All these evidences revealed that quercetin inhibited the MAPK pathway activation via ROS.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miocárdio/patologia , Quercetina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Cardiotônicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Coração/efeitos dos fármacos , MAP Quinase Quinase 4/metabolismo , Miocárdio/metabolismo , Ratos Wistar
4.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547465

RESUMO

The aim is to explore the mechanism of the apoptosis signal-regulating kinase-1 (ASK-1) signaling pathway and the involvement of the thioredoxin (Trx) system during testicular ischemia reperfusion injury (tIRI) by using ASK-1 specific inhibitor, NQDI-1. Male Sprague-Dawley rats (n = 36, 250-300 g) were equally divided into 3 groups: sham, tIRI, and tIRI + NQDI-1 (10 mg/kg, i.p, pre-reperfusion). For tIRI induction, the testicular cord and artery were occluded for 1 h followed by 4 h of reperfusion. Histological analyses, protein immunoexpression, biochemical assays, and real-time PCR were used to evaluate spermatogenesis, ASK-1/Trx axis expression, enzyme activities, and relative mRNA expression, respectively. During tIRI, ipsilateral testes underwent oxidative stress indicated by low levels of superoxide dismutase (SOD) and Glutathione (GSH), increased oxidative damage to lipids and DNA, and spermatogenic damage. This was associated with induced mRNA expression of pro-apoptosis genes, downregulation of antiapoptosis genes, increased caspase 3 activity and activation of the ASK-1/JNK/p38/survivin apoptosis pathway. In parallel, the expression of Trx, Trx reductase were significantly reduced, while the expression of Trx interacting protein (TXNIP) and the NADP+/ nicotinamide Adenine Dinucleotide phosphate (NADPH) ratio were increased. These modulations were attenuated by NQDI-1 treatment. In conclusion, the Trx system is regulated by the ASK-1/Trx/TXNIP axis to maintain cellular redox homeostasis and is linked to tIRI-induced germ cell apoptosis via the ASK-1/JNK/p38/survivin apoptosis pathway.


Assuntos
Aporfinas/farmacologia , MAP Quinase Quinase Quinase 5/metabolismo , Quinolinas/farmacologia , Traumatismo por Reperfusão/metabolismo , Espermatozoides/metabolismo , Tiorredoxinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas de Ciclo Celular/metabolismo , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Survivina/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Eur J Appl Physiol ; 119(10): 2237-2253, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420735

RESUMO

PURPOSE: Stressful training with insufficient recovery can impair muscle performance. Expression of mitogen-activated protein kinases (MAPK) has been reported at rest following overreaching and overtraining. The acute myocellular exercise response to stressful training with insufficient recovery has not been investigated. We investigated MAPK, androgen, and glucocorticoid receptor phosphorylation following a period of stressful training. METHODS: Sixteen resistance-trained men were matched on barbell squat 1 repetition maximum strength and randomized into a group that performed normal training or stressful training with insufficient recovery. The control group (CON) performed three speed-squat training sessions on non-consecutive days, while the stressful training group (NFOR) performed 15 training sessions over 7.5 days. Resting and post-exercise skeletal muscle biopsies were obtained prior to (T1) and after the training period (T2). Samples were analyzed for total and phosphorylated androgen receptor (AR), glucocorticoid receptor (GR), and MAPKs (ERK, JNK, and p38). RESULTS: Total AR were down-regulated post-exercise at T2 in NFOR only. Phospho-AR at ser515 increased in both groups post-exercise at T1; however, ser515 only increased at T2 in NFOR. Phosphorylated ERK, JNK, and p38 increased post-exercise in CON and NFOR at T1 and T2. Post-exercise phospho-p38 was blunted in NFOR at T2 compared to T1. After the training intervention, resting phospho-p38 was higher in NFOR compared to T1. At T2, post-exercise phospho-GR at ser226 was lower compared to T1, and resting levels increased in NFOR. CONCLUSION: Steroid receptors are phosphorylated after acute resistance exercise, and in addition to MAPKs, are differentially regulated after stressful training with insufficient recovery.


Assuntos
Sistema de Sinalização das MAP Quinases , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Treinamento de Resistência/métodos , Estresse Fisiológico , Regulação para Baixo , Humanos , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Fosforilação , Receptores Androgênicos/genética , Receptores de Glucocorticoides/genética , Recuperação de Função Fisiológica , Treinamento de Resistência/efeitos adversos , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Arch Oral Biol ; 108: 104530, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31470141

RESUMO

OBJECTIVE: Periodontitis is an inflammatory disease of the supporting tissue around teeth commonly caused by gram-negative bacterial infections. Interleukin (IL)-1ß, a cytokine involved in host immune and inflammatory responses, is known to induce the activation of various intracellular signaling pathways. One of these signaling mechanisms involves the regulation of gene expression by activation of transcription factors (AP-1 and NF-κB). These transcription factors are controlled by mitogen-activated protein kinases (MAPKs), which increase cytokine and matrix metalloproteinase (MMP) expression. We examined the preventive effects of reversine, a 2,6-disubstituted purine derivative, on cytokine and MMP-3 expression in human gingival fibroblasts (HGFs) stimulated with IL-lß. STUDY DESIGN: Western blot analyses were performed to verify the activities of MAPK, p65, p50, and c-Jun and the expression of MMPs in IL-1ß-stimulated HGFs. Cytokine and MMP-3 expression in IL-1ß-stimulated HGFs was measured by real-time quantitative polymerase chain reaction. RESULTS: Reversine decreased the IL-1ß-induced expression of proinflammatory cytokines (IL-6 and IL-8) and MMP-3 in HGFs. Furthermore, the mechanism underlying the effects of reversine involved the suppression of IL-1ß-stimulated MAPK activation and AP-1 activation. CONCLUSION: Reversine inhibits IL-1ß-induced MMP and cytokine expression via inhibition of MAPK/AP-1 activation and ROS generation. Therefore, we suggest that reversine may be an effective therapeutic candidate for preventing periodontitis.


Assuntos
Gengiva/metabolismo , Interleucina-6 , Interleucina-8/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Morfolinas , Purinas , Fibroblastos/metabolismo , Humanos , Interleucina-1beta , Interleucina-6/metabolismo , MAP Quinase Quinase 4/metabolismo , Morfolinas/farmacologia , NF-kappa B , Periodontite/tratamento farmacológico , Periodontite/metabolismo , Purinas/farmacologia , Espécies Reativas de Oxigênio , Fator de Transcrição AP-1
7.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 445-449, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357761

RESUMO

Objective: To observe whether liraglutide protects HepG2 cells from lipotoxicity by affecting mitogen-activated protein kinase (MAPKs) pathway. Methods: HepG2 cells were induced with 400µmol/L palmitic acid, and cells were treated with a final concentration of 100 nmol/L liraglutide. In addition, JNK inhibitor (SP600125) and p38 MAPK inhibitor (SB203580) were added in advance, respectively. Apoptosis rate, malondialdehyde (MDA) content, and caspase3 activity were detected. Western blot was used to detect p38 mitogen-activated protein kinase (p38 MAPK), c-jun amino terminal kinase (JNK), cytochrome oxidase P450 2E1 (CYP2E1), glucose regulatory protein 78 (GRP78), activated caspase 3, B cell lymphoma associated Protein X (Bax), B cell lymphoma 2 (Bcl-2), and expression of C/EBP homologous protein (CHOP) protein. LSD or Dunnett's T3 test were used to compare the mean of multiple samples. Results: Palmitic acid increased the phosphorylation of p38 MAPK and JNK in HepG2 cells (P< 0.05). Furthermore, it increased the expression of GRP78, CHOP, CYP2E1, MDA, Bax, caspase3 and apoptosis rate, but inhibited the expression of Bcl-2 (Pvalue < 0.05). SP600125 and SB203580 had inhibited oxidative stress and apoptosis induced by palmitic acid (including CYP2E1, MDA, Bax, Bcl-2, caspase3, CHOP) (P< 0.05). The phosphorylation level of p38 MAPK and JNK was reduced with liraglutide and the expression of apoptosis-related proteins (Bax, Bcl-2, caspase3, CHOP) (P< 0.05) was regulated. There was no significant difference in the effect of liraglutide on apoptotic proteins (Bax, Bcl-2, caspase-3, CHOP) (P> 0.05) after pretreatment with those two inhibitors. Conclusion: Palmitic acid has strong lipotoxicity to HepG2 cells and induces apoptosis. Glucagon-like peptide-1 analogue, liraglutide may improve lipotoxicity of palmitic acid by mediating p38 MAPK and JNK pathways.


Assuntos
Apoptose , Carcinoma Hepatocelular , Liraglutida , Neoplasias Hepáticas , Ácido Palmítico , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/fisiopatologia , Células Hep G2 , Humanos , Liraglutida/farmacologia , Neoplasias Hepáticas/fisiopatologia , MAP Quinase Quinase 4/metabolismo , Ácido Palmítico/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Mediators Inflamm ; 2019: 3240713, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316298

RESUMO

Hepatic ischemia reperfusion (IR) injury (IRI) occurs during liver transplantation, hepatectomy, and hemorrhagic shock. Oleanolic acid (OA) is a natural compound with antioxidant and anti-inflammatory activity that has been used to treat liver disorders in clinical practice for several years. Here, we investigated the effects and underlying mechanisms of OA in hepatic IRI. A 60-minute partial (70%) hepatic, warm, ischemic reperfusion model was established in BALB/c mice, and two doses (30 and 60 mg/kg) of OA were administered intragastrically for 7 consecutive days prior to hepatic IR. Orbital blood and liver specimens were collected at 2, 8, and 24 h after IR. The results showed that OA preconditioning significantly alleviated hepatic injury, as evidenced by decreased alanine aminotransferase and aspartate aminotransferase levels; improved histology, inhibition of JNK phosphorylation, and high mobility group box 1 (HMGB1); and tumor necrosis factor-α downregulation in hepatic IR mice. OA upregulated Bcl-2 and downregulated caspase-3, caspase-9, Bax, Beclin 1, and LC3, which play crucial roles in the regulation of apoptosis and autophagy. These findings highlighted the protective effects of OA against hepatic IRI mediated by the inhibition of apoptosis and autophagy and the release of HMGB1, which acted as a late inflammatory mediator in hepatic IRI.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína HMGB1/metabolismo , Ácido Oleanólico/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Hepatectomia , Inflamação , Fígado/patologia , Transplante de Fígado , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Transdução de Sinais , Condicionamento Pré-Transplante , Fator de Necrose Tumoral alfa/metabolismo
9.
Acupunct Med ; 37(5): 312-318, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31219313

RESUMO

BACKGROUND: Acupuncture has been used to treat myofascial pain syndrome (MPS) for 2000 years in China, but its mechanisms are still not entirely clear. In the present study, we explored the effects of transcutaneous electrical acupuncture point stimulation (TEAS) at an Ashi acupuncture point on expression of phosphorylated c-Jun N-terminal kinase (p-JNK) in the dorsal root ganglion (DRG) using a rat model of MPS. METHODS: 32 rats were divided into four groups: normal, MPS, MPS+TEAS and MPS+sham- TEAS. MPS was produced by a blunt strike to the left vastus medialis combined with eccentric exercise for 8 weeks. Rats in the MPS+TEAS group received TEAS (6-9 mA, 2 Hz, 30 min) treatment at the Ashi acupuncture point for 2 weeks; rats in the MPS+sham -TEAS group had the same electrodes applied but received no stimulation. Paw withdrawal thermal latency (PWTL) was studied at baseline and on days 3, 7, 11 and 15 after treatment. Haematoxylin and eosin staining was used to examine for morphological changes in the left vastus medialis muscles; expression of p-JNK in the L3-L5 DRG was determined by immunofluorescence staining and western blotting after treatment. RESULTS: Compared with the normal group, PWTL decreased significantly (P<0.01) and the expression of p-JNK in the DRG increased in the MPS and MPS-sham-TEAS groups (P<0.01); compared with the MPS group, PWTL was increased significantly (P<0.01) and expression of p-JNK in the DRG was decreased in the MPS+TEAS group. However, when compared with the normal group, PWTL did not recover to baseline and expression of p-JNK was still higher. CONCLUSION: TEAS treatment may produce an analgesic effect, probably by inhibiting the expression of p-JNK in the DRG of rats with MPS.


Assuntos
Gânglios Espinais/metabolismo , MAP Quinase Quinase 4/metabolismo , Síndromes da Dor Miofascial/terapia , Estimulação Elétrica Nervosa Transcutânea , Pontos de Acupuntura , Terapia por Acupuntura , Animais , Humanos , MAP Quinase Quinase 4/genética , Masculino , Síndromes da Dor Miofascial/genética , Síndromes da Dor Miofascial/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley
10.
Int J Oncol ; 55(1): 21-34, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180559

RESUMO

Emerging studies have indicated that leucine­rich repeat kinase 2 (LRRK2) is associated with thyroid cancer (TC). The present study investigated the effect of LRRK2 on the cell cycle and apoptosis in TC, and examined the underlying mechanisms in vitro. To screen TC­associated differentially expressed genes, gene expression microarray analysis was conducted. Retrieval of pathways associated with TC from the Kyoto Encyclopedia of Genes and Genomes database indicated that the c­Jun N­terminal kinase (JNK) signaling pathway serves an essential role in TC. SW579, IHH­4, TFC­133, TPC­1 and Nthy­ori3­1 cell lines were used to screen cell lines with the highest and lowest LRRK2 expression for subsequent experiments. The two selected cell lines were transfected with pcDNA­LRRK2, or small interfering RNA against LRRK2 or SP600125 (a JNK inhibitor). Subsequently, flow cytometry, terminal deoxynucleotidyl transferase­mediated dUTP­biotin nick end labeling, a 5­ethynyl­2'­deoxyuridine assay and a scratch test was conducted to detect the cell cycle distribution, apoptosis, proliferation and migration, respectively, in each group. The LRRK2 gene was determined to be elevated in TC based on the microarray data of the GSE3678 dataset. The SW579 cell line was identified to exhibit the highest LRRK2 expression, while IHH­4 cells exhibited the lowest LRRK2 expression. LRRK2 silencing, through inhibiting the activation of the JNK signaling pathway, increased the expression levels of genes and proteins associated with cell cycle arrest and apoptosis in TC cells, promoted cell cycle arrest and apoptosis, and inhibited cell migration and proliferation in TC cells, indicating that LRRK2 repression could exert beneficial effects through the JNK signaling pathway on TC cells. These observations demonstrate that LRRK2 silencing promotes TC cell growth inhibition, and facilitates apoptosis and cell cycle arrest. The JNK signaling pathway may serve a crucial role in mediating the anti­carcinogenic activities of downregulated LRRK2 in TC.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/biossíntese , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Sistema de Sinalização das MAP Quinases , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/genética , Antracenos/farmacologia , Apoptose/fisiologia , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo , Ativação Enzimática , Humanos , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/metabolismo , Neoplasias da Glândula Tireoide/patologia , Transfecção
11.
Biofactors ; 45(5): 774-787, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31206890

RESUMO

Rosmarinic acid (RA) has a wide range of biological effects, including the antioxidation and antiaging. However, the detailed mechanisms remain unclear but highly attractive. Herein, RA promoted lifespan and motoricity in a dose-dependent manner, and reduced fat store without threatening fertility in Caenorhabditis elegans. In term of antioxidant efficacy, catalase activity, glutathione peroxidas activity, reduced glutathione content, and reduced glutathione/oxidized glutathione ratio were enhanced. And malondialdehyde content was diminished significantly. Moreover, RA increased survival under acute oxidative and thermal stress, and suppressed intestinal lipofuscin accumulation. So the improvement of lifespan mediated by RA could be related with its strong antioxidant properties. Furthermore, RA was absorbed by worms. Further research in pursuit of the mechanism showed that longevity induced by RA was involved with the genes sod-3, sod-5, ctl-1, daf-16, ins-18, skn-1, and sek-1, but was independent of subcellular localization of DAF-16. These findings indicated that RA had a potential for promoting healthy lifespan.


Assuntos
Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Cinamatos/farmacologia , Depsídeos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Catalase/genética , Catalase/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fertilidade/efeitos dos fármacos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Lipofuscina/metabolismo , Locomoção/efeitos dos fármacos , Longevidade/genética , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat/antagonistas & inibidores , Paraquat/farmacologia , Hormônios Peptídicos/genética , Hormônios Peptídicos/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
Life Sci ; 231: 116573, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207310

RESUMO

Hepatotoxicity is a common side effect encountered with tamoxifen (TAM) administration. Due to the great value of TAM in breast cancer treatment, hepato-protection is seriously recommended. AIMS: The present study investigated the hepato-protective effect of celecoxib (CX) against TAM-induced hepatotoxicity in rats. MAIN METHODS: Female rats were injected with TAM (45 mg/kg, i.p.) for 7 days and given CX (15 mg/kg, orally) 7 days before TAM injection, then continued for the following 7 days. KEY FINDINGS: Administration of CX for 14 days conferred significant hepatoprotection against TAM-induced hepatotoxicity indexed by decreased liver/body weight ratio, boosted cytoprotection and substantial reduction in serum LDH activity besides functional hepatic improvement; marked decrease in ALT, AST and ALP with significant elevation in serum albumin. Oxidant/antioxidants hemostasis was improved upon CX treatment with profound decrease in hepatic MDA content and elevation of GSH and SOD levels. Furthermore, hepatic content of NO decreased along with significant decrease in ASK-1, JNK and Bax levels as well as TNFα and caspase3 expression. Finally, CX administration resulted in obvious diminution of TAM-induced necrotic and apoptotic alterations. SIGNIFICANCE: Celecoxib might be used in combination with TAM in treatment protocol of breast to prevent liver injury induced by TAM and further clinical studies might be needed to approve this notion.


Assuntos
Celecoxib/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Tamoxifeno/farmacologia , Animais , Antineoplásicos Hormonais/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Interações de Medicamentos , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Fatores de Proteção , Ratos , Ratos Sprague-Dawley , Tamoxifeno/toxicidade
13.
Biol Pharm Bull ; 42(8): 1275-1281, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31155547

RESUMO

Polysaccharide is a key bioactive component of Schisandra chinensis and has significant pharmacological activities. The aim of this study was to evaluate the anti-diabetic effect of acidic polysaccharide from Schisandra chinensis (SCAP). Type 2 diabetic (T2D) rats were developed by giving a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), and administered orally with SCAP (25, 50 mg/kg) for 8 weeks. Fasting blood glucose (FBG), fasting insulin (FINS), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), malondialdehyde (MDA), and superoxide dismutase (SOD) in the rat's serum were measured. Oral glucose tolerance test (OGTT) and pathological changes of pancreas were observed. Furthermore, expressions of c-Jun N-terminal kinase (JNK), B-cell lymphoma 2-associated X protein (BAX), B-cell lymphoma 2 (Bcl-2), and Cleaved Caspase-3 in pancreatic islet were detected. The results showed that SCAP decreased FBG, TG, TC, LDL-C and MDA levels, increased insulin, HDL-C levels and SOD activity, improved the pathological changes in pancreatic islet. Furthermore, SCAP inhibited the up-regulation of phosphorylated JNK, BAX and Cleaved Caspase-3 proteins, and increased Bcl-2 protein expression. These data indicate that SCAP has a therapeutic effect in T2D rats, and the mechanism may be related to its protection against ß-cells apoptosis by regulating apoptosis-related proteins expression to alleviate the injury caused by the oxidative stress.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Polissacarídeos/farmacologia , Schisandra/química , Animais , Glicemia/efeitos dos fármacos , Caspase 3/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas/farmacologia , Jejum , Teste de Tolerância a Glucose , Insulina/sangue , Lipídeos/sangue , MAP Quinase Quinase 4/metabolismo , Masculino , Malondialdeído/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Estreptozocina , Superóxido Dismutase/metabolismo , Proteína X Associada a bcl-2/metabolismo
14.
Food Chem Toxicol ; 131: 110527, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31173817

RESUMO

Zearalenone (ZEA) can widely contaminate crops and agricultural products. The ingestion of ZEA-contaminated food or feed affects the integrity and functions of the intestines. In this study, we aimed to find the potential protective mechanism against ZEA ingestion. We found that ZEA induced cell death in IPEC-J2 cells. Meanwhile, the cytoprotective autophagy was activated in ZEA-treated cells. Further studies demonstrated that a p38/MAPK inhibitor down-regulated autophagy and increased cell death compared to those of the controls. Furthermore, ZEA could induce the accumulation of ROS, and eliminating ROS with NAC resulted in a decline in cell death, p38/MAPK phosphorylation, and the expression of LC3-II compared to those of ZEA-group. In addition, cytochrome P450 reductase (CYPOR) was significantly increased in ZEA-treated cells compared to that in the controls, and an inhibitor of CYPOR decreased ROS levels and mitigated cell death compared to those of the ZEA-group. More importantly, we found that blocking both p38/MAPK signalling and autophagy could enhance CYPOR expression and elevate ROS levels. Overall, our study indicated that the p38/MAPK pathway could activate protective autophagy in response to the CYPOR-dependent oxidative stress that was induced by ZEA in IPEC-J2 cells.


Assuntos
Autofagia/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Zearalenona/toxicidade , Acetilcisteína/farmacologia , Animais , Células Epiteliais/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Intestinos/efeitos dos fármacos , MAP Quinase Quinase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Suínos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
J Mol Neurosci ; 68(4): 647-657, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069661

RESUMO

The expression of homosynaptic long-term depression (LTD) governs the subsequent induction of long-term potentiation (LTP) at hippocampal synapses. This process, called metaplasticity, is associated with a transient increase in the levels of several kinases, such as extracellular signal-regulated protein kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and Akt kinase. It has been increasingly realized that the chemical changes in the hippocampus caused by hypothyroidism may be the key underlying causes of the learning deficits, memory loss, and impaired LTP associated with this disease. However, the functional role of thyroid hormones in the "plasticity of synaptic plasticity" has only begun to be elucidated. To address this issue, we sought to determine whether the administration of 6-n-propyl-2-thiouracil (PTU) alters the relationship between priming and the induction of subsequent LTP and related signaling molecules. The activation of ERK1/2, JNK, and Akt was measured in the hippocampus at least 95 min after priming onset. We found that priming stimulation at 5 Hz for 3 s negatively impacted the induction of LTP by subsequent tetanic stimulation in hypothyroid animals, as manifested by a more rapid decrease in the fEPSP slope and population spike amplitude. This phenomenon was accompanied by lower levels of phosphorylated Akt in the surgically removed hippocampus of the hypothyroid rats compared to the euthyroid rats. The metaplastic response and the expression of these proteins in the 1-Hz-primed hippocampus were not different between the two groups. These observations suggest that decreased PI3K/Akt signaling may be involved in the compromised metaplastic regulation of LTP observed in hypothyroidism, which may account for the learning difficulties/cognitive impairments associated with this condition.


Assuntos
Hipotireoidismo/metabolismo , Sistema de Sinalização das MAP Quinases , Plasticidade Neuronal , Animais , Potenciais Pós-Sinápticos Excitadores , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipotireoidismo/etiologia , Hipotireoidismo/fisiopatologia , MAP Quinase Quinase 4/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Propiltiouracila/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar
16.
J Med Food ; 22(6): 614-622, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31058564

RESUMO

This study focused on the evaluation of the chemopreventive potential of tissue in vitro culture of the "Mela Rosa Marchigiana" apple (MRM callus) that allows the amplification of secondary metabolites. The MRM pulp and MRM callus chemopreventive potential was evaluated in terms of antiproliferative activity, inhibition of tumorigenesis in soft agar cultures, cell cycle and western blotting analyses in CaCo2 and LoVo colon cancer cell lines and in JB6 promotion-sensitive (JB6 P+) cells. MRM callus induced a strong concentration-dependent inhibition of colon cancer cell proliferation and suppressed 12-o-tetra-decanoyl-phorbol-13-acetate-induced tumorigenesis of JB6 P+ cells in soft agar cultures. MRM callus inhibited the phosphorylation of JNK, p38, and eIF2alpha. Our data indicate that the MRM callus exerts a good antiproliferative and antitumorigenic potential through the MAP kinase inhibition and could provide natural compounds with chemopreventive properties.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/fisiopatologia , Malus/química , Extratos Vegetais/farmacologia , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Humanos , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Eur J Med Chem ; 175: 234-246, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082766

RESUMO

Selenocyanates and diselenides are potential antitumor agents. Here we report two series of selenium derivatives related to selenocyanates and diselenides containing carboxylic, amide and imide moieties. These compounds were screened for their potency and selectivity against seven tumor cell lines and two non-malignant cell lines. Results showed that MCF-7 cells were especially sensitive to the treatment, with seven compounds presenting GI50 values below 10 µM. Notably, the carboxylic selenocyanate 8b and the cyclic imide 10a also displayed high selectivity for tumor cells. Treatment of MCF-7 cells with these compounds resulted in cell cycle arrest at S phase, increased levels of pJNK and pAMPK and caspase independent cell death. Autophagy inhibitors wortmannin and chloroquine partially prevented 8b and 10a induced cell death. Consistent with autophagy, increased Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels were detected. Our results point to 8b and 10a as autophagic cell death inducers.


Assuntos
Adenilato Quinase/metabolismo , Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Citostáticos/farmacologia , MAP Quinase Quinase 4/metabolismo , Compostos Organosselênicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citostáticos/administração & dosagem , Citostáticos/química , Relação Dose-Resposta a Droga , Ativação Enzimática , Humanos , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/química , Fase S/efeitos dos fármacos
18.
J Ethnopharmacol ; 239: 111917, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31028857

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum indicum (C. indicum), a perennial plant, has long been used to treat inflammation-related disorders, such as pneumonia, hypertension, gastritis, and gastroenteritis. AIM OF THE STUDY: The inhibitory effect of C. indicum extract (C.I) on inflammasome activation was investigated to validate its potential in treating inflammation related disorders. MATERIALS AND METHODS: LPS-primed bone marrow-derived macrophages (BMDMs) were used to confirm the inhibitory effect of C.I on selective inflammasome activation in vitro. A monosodium urate (MSU)-induced murine peritonitis model was employed to study the effect of C.I in vivo. RESULTS: C.I inhibited activation of NLRP3 and AIM2 inflammasomes, leading to suppression of interleukin-1ß secretion in vitro. Further, C.I regulates the phosphorylation of apoptosis-associated speck-like protein containing a CARD (ASC), which could be the main contribution to attenuate these inflammasomes activation. C.I also suppressed secretion of pro-inflammatory cytokines and neutrophils recruitment in MSU-induced murine peritonitis model. CONCLUSIONS: This study provides scientific evidence substantiating the traditional use of C. indicum in the treatment of inflammatory diseases, including gout, which is induced by physiologically analogous cause to MSU-induced peritonitis.


Assuntos
Anti-Inflamatórios/farmacologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Chrysanthemum , Proteínas de Ligação a DNA/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peritonite/metabolismo , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Feminino , Gota/tratamento farmacológico , Gota/metabolismo , Supressores da Gota/farmacologia , Supressores da Gota/uso terapêutico , MAP Quinase Quinase 4/metabolismo , Camundongos Endogâmicos C57BL , Peritonite/induzido quimicamente , Peritonite/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Componentes Aéreos da Planta , Extratos Vegetais/uso terapêutico , Ácido Úrico
19.
Int Immunopharmacol ; 72: 367-373, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31030092

RESUMO

Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor (α2-AR) agonist, is widely used as sedative in clinical. Its potential anti-inflammatory properties have been found in recent studies. The current study has investigated the profound effects of DEX on acute liver injury in mice. The mice were intraperitoneally injected lipopolysaccharide (LPS) and D-galactosamine (D-Gal) to induce acute liver injury, and vehicle or DEX were treated 30 min before or 2 h after LPS/D-Gal exposure. The results showed that pre-treatment with DEX inhibited the raising of plasma aminotransferases, reduced the damage of liver tissue, and improved the survival rate in mice exposed to LPS/D-Gal. Pre-treatment with DEX also inhibited the release of TNF-α and suppressed the phosphorylation of c-jun-N-terminal kinase (JNK) in mice exposed to LPS/D-Gal. In addition, pre-treatment with DEX down-regulated the expression of cleavage of caspase-3, decreased the activities of caspase-3, caspase-8, caspase-9, and consequently, reduced hepatocyte apoptosis. Interestingly, post-treatment with DEX also resulted in beneficial outcomes. The current study indicates that administration of DEX might provide protective benefits in inflammatory liver disease.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Dexmedetomidina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dexmedetomidina/farmacologia , Galactosamina , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Substâncias Protetoras/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
20.
Nat Commun ; 10(1): 1897, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015486

RESUMO

The cellular decision regarding whether to undergo proliferation or death is made at the restriction (R)-point, which is disrupted in nearly all tumors. The identity of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in cell biology. We found that early after mitogenic stimulation, RUNX3 binds to its target loci, where it opens chromatin structure by sequential recruitment of Trithorax group proteins and cell-cycle regulators to drive cells to the R-point. Soon after, RUNX3 closes these loci by recruiting Polycomb repressor complexes, causing the cell to pass through the R-point toward S phase. If the RAS signal is constitutively activated, RUNX3 inhibits cell cycle progression by maintaining R-point-associated genes in an open structure. Our results identify RUNX3 as a pioneer factor for the R-point and reveal the molecular mechanisms by which appropriate chromatin modifiers are selectively recruited to target loci for appropriate R-point decisions.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Cromatina/química , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Animais , Butadienos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Subunidade alfa 3 de Fator de Ligação ao Core/antagonistas & inibidores , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células HEK293 , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Imidazóis/farmacologia , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Nitrilos/farmacologia , Piperazinas/farmacologia , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
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