Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
1.
J Cell Mol Med ; 28(8): e18356, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38668995

RESUMO

Trichospira verticillata is an annual herb that belongs to the family Asteraceae. Trichospira verticillata extract (TVE) elicits anti-plasmodial activity; however, there has been no detailed report about its anti-inflammatory effects and molecular mechanisms. In addition, herbal plants exhibit anti-inflammatory effects by suppressing the NLRP3 inflammasome. Therefore, the primary goal of this study was to examine the effects of TVE on NLRP3 inflammasome activation by measuring interleukin-1ß (IL-1ß) secretion. We treated lipopolysaccharides (LPS)-primed J774A.1 and THP-1 cells with TVE, which attenuated NLRP3 inflammasome activation. Notably, TVE did not affect nuclear factor-kappa B (NF-κB) signalling or intracellular reactive oxygen species (ROS) production and potassium efflux, suggesting that it inactivates the NLRP3 inflammasome via other mechanisms. Moreover, TVE suppressed the formation of apoptosis-associated speck-like protein (ASC) speck and oligomerization. Immunoprecipitation data revealed that TVE reduced the binding of NLRP3 to NIMA-related kinase 7 (NEK7), resulting in reduced ASC oligomerization and speck formation. Moreover, TVE alleviated neutrophilic asthma (NA) symptoms in mice. This study demonstrates that TVE modulates the binding of NLPR3 to NEK7, thereby reporting novel insights into the mechanism by which TVE inhibits NLRP3 inflammasome. These findings suggest TVE as a potential therapeutic of NLRP3 inflammasome-mediated diseases, particularly NA.


Assuntos
Anti-Inflamatórios , Asma , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neutrófilos , Espécies Reativas de Oxigênio , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Inflamassomos/metabolismo , Asma/metabolismo , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Camundongos , Anti-Inflamatórios/farmacologia , Humanos , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Espécies Reativas de Oxigênio/metabolismo , Lipopolissacarídeos , Quinases Relacionadas a NIMA/metabolismo , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Extratos Vegetais/farmacologia , Células THP-1
2.
Sci Rep ; 14(1): 5237, 2024 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-38433281

RESUMO

Inflammation is implicated as a cause in many diseases. Most of the anti-inflammatory agents in use are synthetic and there is an unmet need for natural substance-derived anti-inflammatory agents with minimal side effects. Aiouea padiformis belongs to the Lauraceae family and is primarily found in tropical regions. While some members of the Aiouea genus are known to possess anti-inflammatory properties, the anti-inflammatory properties of Aiouea padiformis extract (AP) have not been investigated. In this study, we aimed to examine the anti-inflammatory function of AP through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and elucidate the underlying mechanisms. Treatment with AP inhibited the secretion of interleukin-1 beta (IL-1ß) mediated by NLRP3 inflammasome in J774A.1 and THP-1 cells without affecting the viability. In addition, AP treatment did not influence NF-κB signaling, potassium efflux, or intracellular reactive oxygen species (ROS) production-all of which are associated with NLRP3 inflammasome activation. However, intriguingly, AP treatment significantly reduced the ATPase activity of NLRP3, leading to the inhibition of ASC oligomerization and speck formation. Consistent with cellular experiments, the anti-inflammatory property of AP in vivo was also evaluated using an LPS-induced inflammation model in zebrafish, demonstrating that AP hinders NLRP3 inflammasome activation.


Assuntos
Lauraceae , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Inflamassomos , Peixe-Zebra , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Adenosina Trifosfatases , Extratos Vegetais/farmacologia
3.
J Ethnopharmacol ; 323: 117711, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38176663

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Guarea genus comprises tropical and subtropical terrestrial herbs inhabiting Central and South America. These plants, including Guarea guidonia (L.) Sleumer, have anti-inflammatory, analgesic, antibacterial, antiviral, and immune-enhancing properties. AIM OF THE STUDY: Although various species of the Guarea genus are known for their medicinal properties, comprehensive data on their anti-inflammatory effects remain limited. Therefore, we investigated the NLRP3 inflammasome-inhibiting effects of the Guarea genus in this study. MATERIALS AND METHODS: To evaluate the anti-inflammatory activities of 18 members of the Guarea genus, we treated NLRP3 inflammasome activators with their extracts in LPS-primed J774A.1 and THP-1 cells. Cell viability was determined by water soluble tetrazolium salt (WST) and cytokine production, protein expression, and nuclear fractionation were determined by western blotting. Reactive oxygen species (ROS) production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization were measured using confocal microscopic analysis. Inflammation-induced zebrafish was used in the in vivo experiments. RESULTS: Among the 18 Guarea members tested, Guarea microcarpa C. DC. extract (GM) exhibited no cytotoxicity and specifically suppressed the activation of the NLRP3 inflammasome, but not of the AIM2 or NLRC4 inflammasomes, by inhibiting the ATPase activity of NLRP3. This was achieved without affecting NF-κB signaling, potassium efflux, or intracellular ROS production, all of which are involved in NLRP3 activation. The reduced ATPase activity of NLRP3 led to decreased ASC oligomerization. Furthermore, GM exhibited anti-inflammatory effects in vivo. Additionally, GM treatment alleviated inflammation at the organismal level in an LPS-induced inflammation model using zebrafish embryos. CONCLUSION: Our results demonstrate the anti-inflammatory effects of GM via suppressing the NLRP3 inflammasome. Therefore, GM can be a potential therapeutic candidate for various inflammatory diseases caused by aberrant NLRP3 inflammasome activation.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peixe-Zebra , Espécies Reativas de Oxigênio/metabolismo , Lipopolissacarídeos/farmacologia , Caspase 1/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Adenosina Trifosfatases , Interleucina-1beta/metabolismo
4.
PLoS One ; 14(10): e0222857, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31603952

RESUMO

Previous studies have revealed the anti-inflammatory properties of rice bran oil (RBO), but the detailed mechanisms are poorly understood. Recent studies on the molecular/cellular anti-inflammatory mechanisms of dietary components have demonstrated that mitochondrial respiration plays a key role in macrophage functioning. Since dietary lipids are major substrates for mitochondrial respiration through ß-oxidation, the current study examined whether RBO regulates inflammatory responses by modulating mitochondrial energy metabolism. Palm oil (PO), enriched with palmitic acid which are known to be effectively taken up by cells and used for oxidative phosphorylation, served as a positive control. In the in vitro model of LPS-stimulated RAW 264.7 murine cells, the levels of pro-inflammatory cytokines (IL-6 and TNF-α) in the culture supernatant were significantly reduced by RBO treatment. In contrast, secretion of the anti-inflammatory cytokine IL-10 was upregulated by RBO. Transcription of genes encoding inflammatory mediator molecules (COX-2 and iNOS) and expression of activation markers (CD80, CD86, and MHC-II) in LPS-stimulated RAW 264.7 cells were suppressed by RBO. Mitochondrial respiration (as assessed by an extracellular flux analyzer) increased upon RBO treatment, as the basal respiration, maximal respiration, ATP production, and spare respiratory capacity were upregulated. In an in vivo study, C57BL/6 mice were fed a negative control diet containing corn oil (CO), PO, or RBO for 4 weeks, and bone marrow-derived macrophages (BMDM) were isolated from their tibias and femurs. In pro-inflammatory M1-polarized BMDM (M1-BMDM), the RBO-induced suppression of IL-6 and TNF-α was recapitulated in vivo. Mitochondrial respiration in M1-BMDM also increased following the RBO intervention and the PO control treatment as compared to CO fed negative control. Overall, the current study for the first time demonstrates that RBO regulates inflammatory responses in murine macrophages by upregulating mitochondrial respiration. Further clinical studies are required to validate the animal study.


Assuntos
Trifosfato de Adenosina/biossíntese , Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Óleo de Farelo de Arroz/farmacologia , Animais , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígeno B7-2/genética , Antígeno B7-2/imunologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Regulação da Expressão Gênica , Inflamação/prevenção & controle , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Fosforilação Oxidativa/efeitos dos fármacos , Óleo de Palmeira/farmacologia , Cultura Primária de Células , Células RAW 264.7 , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
5.
J Med Food ; 20(8): 734-743, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28650205

RESUMO

This study aimed to identify the changes in the metabolomics profile of liver damage caused by alcohol consumption and verify the beneficial effect of Prunus mume Sieb. et Zucc extract (PME) in protection of alcohol-induced injury by attenuating the level of identified metabolites. Mice were treated with PME and saline or untreated once daily for 5 days, followed by alcohol injection. The plasma samples were analyzed using liquid chromatography-mass spectrometry-based high-resolution metabolomics followed by a multivariate statistical analysis using MetaboAnalyst 3.0 to obtain significantly expressed metabolites, using a false discovery rate threshold of q = 0.05. Metabolites were annotated using Metlin database and mapped through Kyoto Encyclopedia of Genes and Genomes (KEGG). Among 4999 total features, 101 features were significant among alcohol- and PME-treated mice groups. All the samples cluster showed a clear separation in the heat map, and the scores plot of orthogonal partial least squares-discriminant analysis (OPLS-DA) model discriminated the three groups. Phosphatidylcholine, Saikosaponin BK1, Ganoderiol I, and N-2-[4-(3,3-dimethylallyloxy) phenyl] ethylcinnamide were among the significant compounds with a low intensity in alcohol group compared to PME group, suggesting that these compounds have a relation in the development of PME's protective effect. The study confirms the hepatoprotective, antioxidant, and anti-inflammatory effects of PME against alcohol-induced liver steatosis, inflammation, and apoptosis.


Assuntos
Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/prevenção & controle , Fígado/efeitos dos fármacos , Prunus/química , Animais , Antioxidantes , Cromatografia Líquida , Modelos Animais de Doenças , Etanol/efeitos adversos , Fígado Gorduroso Alcoólico/genética , Humanos , Masculino , Espectrometria de Massas , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/metabolismo , Fosfatidilcolinas/metabolismo , Saponinas/metabolismo
6.
Blood Res ; 51(2): 113-21, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27382556

RESUMO

BACKGROUND: The association between baseline renal impairment (RI) and the prognosis of diffuse large B-cell lymphoma (DLBCL) was previously not defined. The aim of this study was to evaluate the prognostic value of RI in patients with DLBCL treated with three-weekly rituximab plus cyclophosphamide, Adriamycin, vincristine, and prednisolone immunochemotherapy (R-CHOP21). METHODS: Patients with newly diagnosed de novo DLBCLs treated with ≥1 cycle of R-CHOP21 were analyzed retrospectively. Pretreatment blood samples were collected and the glomerular filtration rate (GFR) was calculated. RI was defined by a GFR of <60 mL/min/1.73 m(2) according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. RESULTS: Of the 185 patients enrolled in the present study, 19 patients (10.3%) had RI. The reasons for baseline RI were pre-existing CKD (N=5), acute kidney injury due to either obstruction (N=2) or electrolyte imbalance (N=2) related to DLBCL, and undefined causes (N=10). Patients with baseline RI showed inferior overall survival (OS) compared to those without RI (P<0.001). In multivariate analysis, RI was identified as an International Prognostic Index (IPI)-independent prognostic indicator. A baseline hemoglobin level of <10 g/dL and the presence of RI effectively discriminated a portion of the patients with far inferior event-free survival and OS among the patients having high or high-intermediate risk cancers according to either the standard- or the National Comprehensive Cancer Network-IPI. CONCLUSION: Pretreatment RI was an independent prognostic marker for inferior OS in patients with DLBCL treated with R-CHOP21 immunochemotherapy.

7.
Mol Pharmacol ; 90(2): 140-50, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27251362

RESUMO

The large-conductance calcium-activated potassium channel (BKCa channel) plays critical roles in smooth muscle relaxation. In urinary bladder smooth muscle, BKCa channel activity underlies the maintenance of the resting membrane potential and repolarization of the spontaneous action potential triggering the phasic contraction. To identify novel BKCa channel activators, we screened a library of natural compounds using a cell-based fluorescence assay and a hyperactive mutant BKCa channel (Lee et al., 2013). From 794 natural compounds, kurarinone, a flavanone from Sophora flavescens, strongly potentiated BKCa channels. When treated from the extracellular side, this compound progressively shifted the conductance-voltage relationship of BKCa channels to more negative voltages and increased the maximum conductance in a dose-dependent manner. Whereas kurarinone strongly potentiated the homomeric BKCa channel composed of only the α subunit, its effects were much smaller on heteromeric channels coassembled with auxiliary ß subunits. Although the activation kinetics was not altered significantly, the deactivation of BKCa channels was dramatically slowed by kurarinone treatment. At the single-channel level, kurarinone increased the open probability of the BKCa channel without affecting its single-channel conductance. Kurarinone potently relaxed acetylcholine-induced contraction of rat bladder smooth muscle and thus decreased the micturition frequency of rats with overactive bladder symptoms. These results indicate that kurarinone can directly potentiate BKCa channels and demonstrate the therapeutic potentials of kurarinone and its derivatives for developing antioveractive bladder medications and supplements.


Assuntos
Flavonoides/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Relaxamento Muscular/efeitos dos fármacos , Bexiga Urinária/fisiologia , Acetilcolina/farmacologia , Animais , Cálcio/metabolismo , Linhagem Celular , Flavonoides/química , Fluorescência , Humanos , Técnicas In Vitro , Espaço Intracelular/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Cinética , Masculino , Subunidades Proteicas/metabolismo , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Xenopus laevis
8.
Diabetes ; 62(8): 2917-22, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23557704

RESUMO

Prepubertal African American (AA) youth compared with their Caucasian (C) peers have higher insulin secretion, which correlates positively with free fatty acid (FFA) concentration. In our continued efforts to explain the racial disparity in insulinemia, and because FFAs modulate insulin secretion, we hypothesized that AA youth would have a greater response to FFA-induced ß-cell insulin secretion than C youth. We compared the short-term effects of FFA elevation on fasting and glucose-stimulated C-peptide-modeled insulin secretion in prepubertal normal-weight AA versus C peers during a 2-h hyperglycemic clamp (12.5 mmol/L) on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid (IL). During IL infusion, insulin sensitivity (IS) declined comparably in AA and C youth. Glucose sensitivity of first- and second-phase insulin secretion showed a significant condition × race interaction being higher in AA youth. Disposition index, ß-cell function relative to IS, declined with IL infusion in AA and C youth, with a significantly greater decrease in Cs compared with AAs. In conclusion, AA and C prepubertal youth both demonstrated a decline in ß-cell function relative to IS during IL infusion, indicative of acute lipotoxicity. The greater decline in C youth compared with AAs may suggest that C youth are more susceptible to ß-cell lipotoxicity than AA youth, or alternatively, that AA youth are hypersensitive to FFA stimulation of ß-cell insulin secretion, consistent with our theory.


Assuntos
Emulsões Gordurosas Intravenosas/farmacologia , Ácidos Graxos não Esterificados/sangue , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Fosfolipídeos/farmacologia , Óleo de Soja/farmacologia , Negro ou Afro-Americano , Criança , Emulsões/farmacologia , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Resistência à Insulina/fisiologia , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , População Branca
9.
J Clin Endocrinol Metab ; 98(5): 2062-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23526462

RESUMO

OBJECTIVE: Overweight/obese (OW/OB) African American (AA) adolescents have a more diabetogenic insulin secretion/sensitivity pattern compared with their American white (AW) peers. The present study investigated ß-cell lipotoxicity to test whether increased free fatty acid (FFA) levels result in greater ß-cell dysfunction in AA vs AW OW/OB adolescents. RESEARCH DESIGN AND METHODS: Glucose-stimulated insulin secretion was modeled, from glucose and C-peptide concentrations during a 2-hour hyperglycemic (225 mg/dL) clamp in 22 AA and 24 AW OW/OB adolescents, on 2 occasions after a 12-hour overnight infusion of either normal saline or intralipid (IL) in a random sequence. ß-Cell function relative to insulin sensitivity, the disposition index (DI), was examined during normal saline and IL conditions. Substrate oxidation was evaluated with indirect calorimetry and body composition and abdominal adiposity with dual-energy X-ray absorptiometry and magnetic resonance imaging at L4-L5, respectively. RESULTS: Age, sex, body mass index, total and sc adiposity were similar between racial groups, but visceral adiposity was significantly lower in AAs. During IL infusion, FFAs and fat oxidation increased and insulin sensitivity decreased similarly in AAs and AWs. ß-Cell glucose sensitivity of first- and second-phase insulin secretion did not change significantly during IL infusion in either group, but DI in each phase decreased significantly and similarly in AAs and AWs. CONCLUSIONS: Overweight/obese AA and AW adolescents respond to an overnight fat infusion with significant declines in insulin sensitivity, DI, and ß-cell function relative to insulin sensitivity, suggestive of ß-cell lipotoxicity. However, contrary to our hypothesis, there does not seem to be a race differential in ß-cell lipotoxicity. Longer durations of FFA elevation may unravel such race-related contrasts.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos não Esterificados/sangue , Células Secretoras de Insulina/metabolismo , Metabolismo dos Lipídeos , Obesidade/metabolismo , Sobrepeso/metabolismo , Adiposidade/etnologia , Adolescente , Desenvolvimento do Adolescente , Negro ou Afro-Americano , Índice de Massa Corporal , Estudos de Coortes , Estudos Cross-Over , Emulsões , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina/etnologia , Secreção de Insulina , Células Secretoras de Insulina/patologia , Gordura Intra-Abdominal/patologia , Masculino , Obesidade/sangue , Obesidade/etnologia , Obesidade/patologia , Sobrepeso/sangue , Sobrepeso/etnologia , Sobrepeso/patologia , Pennsylvania , Fosfolipídeos , Óleo de Soja , População Branca
10.
Metabolism ; 62(3): 417-23, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23122836

RESUMO

OBJECTIVE: To explain the predisposition for insulin resistance among African American (AA) adolescents, this study aimed to: 1) examine changes in intramyocellular lipid content (IMCL), and insulin sensitivity with intralipid (IL) infusion; and 2) determine whether the increase in IMCL is comparable between AA and Caucasian adolescents. MATERIALS AND METHODS: Thirteen AA and 15 Caucasian normal-weight adolescents (BMI <85th) underwent a 3-h hyperinsulinemic-euglycemic clamp, on two occasions in random order, after an overnight 12-h infusion of: 1) 20% IL and 2) normal saline (NS). IMCL was quantified by (1)H magnetic resonance spectroscopy in tibialis anterior muscle before and after IL infusion. RESULTS: During IL infusion, plasma TG, glycerol, FFA and fat oxidation increased significantly, with no race differences. Hepatic insulin sensitivity decreased with IL infusion with no difference between the groups. IL infusion was associated with a significant increase in IMCL, which was comparable between AA (Δ 105%; NS: 1.9±0.8 vs. IL: 3.9±1.6 mmol/kg wet weight) and Caucasian (Δ 86%; NS: 2.8±2.1 vs. IL: 5.2±2.4 mmol/kg wet weight), with similar reductions (P<0.01) in insulin sensitivity between the groups (Δ -44%: NS: 9.1±3.3 vs. IL: 5.1±1.8 mg/kg/min per µU/ml in AA) and (Δ -39%: NS: 12.9±6.0 vs. IL: 7.9±3.8 mg/kg/min per µU/ml in Caucasian) adolescents. CONCLUSIONS: In healthy adolescents, an acute elevation in plasma FFA with IL infusion is accompanied by significant increases in IMCL and reductions in insulin sensitivity with no race differential. Our findings suggest that AA normal-weight adolescents are not more susceptible than Caucasians to FFA-induced IMCL accumulation and insulin resistance.


Assuntos
Negro ou Afro-Americano , Emulsões Gordurosas Intravenosas/administração & dosagem , Resistência à Insulina/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Fosfolipídeos/administração & dosagem , Óleo de Soja/administração & dosagem , População Branca , Adolescente , Criança , Emulsões/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Feminino , Técnica Clamp de Glucose , Glicerol/sangue , Humanos , Modelos Lineares , Espectroscopia de Ressonância Magnética , Masculino , Músculo Esquelético/ultraestrutura , Triglicerídeos/sangue
11.
J Med Food ; 14(7-8): 808-16, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21663495

RESUMO

Amentoflavone, a biflavonoid from Selaginella tamariscina, is known to possess several bioactivities such as antitumor, anti-inflammatory, and antifungal effects. However, the mechanism of the anticancer effects of amentoflavone on human cervical cancer cells has not been studied in detail. In this study, we demonstrated that amentoflavone induces apoptosis in SiHa and CaSki cervical cancer cells by suppressing human papillomavirus protein E7 expression. The cyclins and tumor suppressors were modulated by amentoflavone in SiHa and CaSki human cervical cancer cells: cyclin and hyperphosphorylated retinoblastoma (p-pRb) were down-regulated, whereas cyclin-dependent kinase inhibitors and p53 were enhanced. Amentoflavone up-regulated peroxisome proliferator-activated receptor γ (PPARγ) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression levels while inhibiting E7-mediated cyclooxygenase-2 (COX-2)/interleukin-32 (IL-32) expressions were downregulated, and Akt phosphorlylation was decreased in an amentoflavone-induced apoptotic process, suggesting that amentoflavone may be a PPARγ activator. Additionally, the expression of the anti-apoptotic factor Bcl-2 was decreased, whereas that of the well-known apoptotic factor Bax was increased, thereby releasing cytochrome c into cytosol in amentoflavone-treated cervical cancer cells. Furthermore, amentoflavone treatment led to the activation of caspase-3 and -9 and proteolytic cleavage of poly(ADP-ribose) polymerase. The expression level of the extrinsic death receptor Fas (CD95) was not altered by amentoflavone treatment. When these findings are taken together, the biflavonoid amentoflavone activates PPARγ/PTEN expressions and induces apoptosis via suppressing E7 expression, cell cycle arrest at sub-G1 phase, and mitochondria-emanated intrinsic pathways in SiHa and CaSki human cervical cancer cells. These findings suggest that amentoflavone has potential for development as a therapeutic agent for human cervical cancer.


Assuntos
Apoptose/efeitos dos fármacos , Biflavonoides/farmacologia , Ciclo Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas E7 de Papillomavirus/genética , Extratos Vegetais/farmacologia , Neoplasias do Colo do Útero/fisiopatologia , Feminino , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Mitocôndrias/genética , Proteínas E7 de Papillomavirus/metabolismo , Selaginellaceae/química , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA