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1.
Cochrane Database Syst Rev ; 1: CD013011, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33460048

RESUMO

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial. OBJECTIVES: To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults. SEARCH METHODS: In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI. MAIN RESULTS: We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest. AUTHORS' CONCLUSIONS: We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metilfenidato/administração & dosagem , Adulto , Antidepressivos de Segunda Geração/administração & dosagem , Ansiedade/tratamento farmacológico , Viés , Bupropiona/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Depressão/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Feminino , Flavonoides/administração & dosagem , Humanos , Compostos de Lítio/administração & dosagem , Masculino , Metilfenidato/efeitos adversos , Pessoa de Meia-Idade , Placebos/administração & dosagem , Extratos Vegetais/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Adulto Jovem
2.
Int J Nanomedicine ; 15: 10435-10451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33380794

RESUMO

Purpose: Nose-to-brain drug delivery is an effective approach for poorly soluble drugs to bypass the blood-brain barrier. A new drug intranasal delivery system, a nanosuspension-based in situ gel, was developed and evaluated to improve the solubility and bioavailability of the drug and to prolong its retention time in the nasal cavity. Materials and Methods: Breviscapine (BRE) was chosen as the model drug. BRE nanosuspensions (BRE-NS) were converted into BRE nanosuspension powders (BRE-NP). A BRE nanosuspension in situ gelling system (BRE-NG) was prepared by mixing BRE-NP and 0.5% gellan gum (m/v). First, the BRE-NP were evaluated in terms of particle size and by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Subsequently, the critical ionic concentration of the gellan gum phase transition, influence of the deacetylated gellan gum (DGG) concentration on the expansion coefficient (S%), water-holding capacity, rheological properties and in vitro release behaviour of the BRE-NG were investigated. The pharmacokinetics and brain distribution of the BRE-NG after intranasal administration were compared with those of the intravenously injected BRE-NP nanosuspensions in rats. Results: The rheology results demonstrated that BRE-NG was a non-Newtonian fluid with good spreadability and bioadhesion performance. Moreover, the absolute bioavailability estimated for BRE-NG after intranasal administration was 57.12%. The drug targeting efficiency (DTE%) of BRE in the cerebrum, cerebellum and olfactory bulb was 4006, 999 and 3290, respectively. The nose-to-brain direct transport percentage (DTP%) of the cerebrum, cerebellum and olfactory bulb was 0.975, 0.950 and 0.970, respectively. Conclusion: It was concluded that the in situ gel significantly increased the drug retention time at the administration site. Therefore, the nanosuspension-based in situ gel could be a convenient and effective intranasal formulation for the administration of BRE.


Assuntos
Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Flavonoides/administração & dosagem , Flavonoides/farmacocinética , Nanoestruturas/administração & dosagem , Administração Intranasal , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Liberação Controlada de Fármacos , Géis/administração & dosagem , Masculino , Nanoestruturas/química , Tamanho da Partícula , Polissacarídeos Bacterianos/química , Polissorbatos/química , Ratos Sprague-Dawley , Reologia , Solubilidade , Difração de Raios X
3.
Int J Nanomedicine ; 15: 5977-5989, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32904394

RESUMO

Purpose: Baicalin (BA) has a good neuroprotective effect, but it is eliminated quickly in the body and does not easily reach the brain. In this experiment, borneol (BO) was used as an auxiliary drug to prepare borneol-baicalin-liposomes (BO-BA-LP) to prolong the efficacy time of BA, synergistically synergize, introduce drugs into the brain, and better exert the therapeutic effect on cerebral ischemia-reperfusion (I/R) injury. Methods: Through single-factor inspection and response surface optimization analysis, obtained the best preparation process of BO-BA-LP and characterized by various analytical techniques. Validated the long-term effectiveness of BA-BO-LP through pharmacokinetic studies and conducted pharmacodynamic studies on the middle cerebral artery occlusion (MCAO) rat model to verify the therapeutic effect of BO-BA-LP on cerebral I/R injury. Results: The optimum preparation conditions of BO-BA-LP were as follows: the dosage of BO was 9.55 mg, the ratio of phospholipid to drug was 4.02:1, the ratio of phospholipid to cholesterol was 7.25:1, the entrapment efficiency (EE) was 41.49%, and the drug loading (DL) was 4.29%. The particle size range of the liposomes was 167.1 nm, and the polydispersity index (PDI) range was 0.113. The results of pharmacokinetic experiments showed that the combination of BA and BO liposomes effectively improved the pharmacokinetic parameters of BA and prolonged the half-life of BA. Pharmacodynamic studies have found that, compared with BA-LP, BO-BA-LP can significantly improve neurological deficits, cerebral infarction volume, and brain pathological states on MCAO rats. Conclusion: These results demonstrated that BO-BA-LP can improve the circulation of drugs in the blood, and the addition of BO can enhance the therapeutic effect of BA and effectively improve cerebral I/R.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Canfanos/farmacologia , Flavonoides/farmacologia , Lipossomos/química , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Canfanos/administração & dosagem , Canfanos/farmacocinética , Sinergismo Farmacológico , Flavonoides/administração & dosagem , Flavonoides/química , Flavonoides/farmacocinética , Meia-Vida , Infarto da Artéria Cerebral Média , Lipossomos/farmacocinética , Lipossomos/farmacologia , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Fosfolipídeos/química , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
4.
Life Sci ; 261: 118340, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860805

RESUMO

Severe acute pancreatitis (SAP) is a non-bacterial inflammatory disease that clinically causes a very high rate of mortality. Dihydrokaempferol (DHK) is a natural flavonoid extracted from Bauhinia championii. Our research aimed to establish the treatment function of DHK on SAP-induced pancreas injury and delve into its potential mechanism. In this study, SAP was induced by caerulein (CER) and Lipopolysaccharide (LPS). DHK was administered orally at different doses of 20, 40, or 80 mg/kg. Results from serum amylase/lipase, pancreas hematoxylin-eosin staining technique, pancreas malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) showed the therapeutic effect of DHK in a mice SAP model. MTT revealed DHK alleviated CER + LPS induced cytotoxicity in a dose-dependent manner in the pancreatic acinar cells of mice. Next, we verified DHK suppressed the level of Keap1 and promoted transcriptional activation of nuclear Nrf2 in the presence of CER + LPS. The molecular docking study suggested that there is a potential interaction between DHK and Keap1. To further look at the role of Keap1 using in vitro and in vivo models, Keap1 overexpression adenovirus (ad-Keap1) was performed. The results revealed that ad-Keap1suppressed the nuclear translocation of Nrf2 which is enhanced by DHK, and suppressed the antioxidative functionality of DHK both in mice and cell models. Collectively, this research demonstrated that DHK bettered the SAP induced pancreas injury by regulating the Keap1/Nrf2 pathway and regulating oxidative stress injury.


Assuntos
Flavonoides/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pancreatite/tratamento farmacológico , Animais , Ceruletídeo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Flavonoides/administração & dosagem , Glutationa/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença
5.
Life Sci ; 261: 118301, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32827546

RESUMO

AIM: Acrylamide (AC) is a carcinogenic substance which is formed during the heating of starchy foods at high temperatures and constitutes an important risk for human health. Therefore, reducing the detrimental effects of AC has become an important research topic. This study was performed to evaluate the protective effect of morin against the testicular toxicity induced by AC in male rats. MATERIALS AND METHODS: Testicular damage was evaluated after the rats were treated orally with AC (38.27 mg/kg body weight) alone or with morin (50 and 100 mg/kg body weight) for 10 consecutive days. KEY FINDINGS: Our results showed that treatment with morin could significantly decrease MDA level and considerably increase the activity of antioxidant enzymes (SOD, CAT, GPx) and GSH level in the testicular tissue of the AC-treated rats. Morin supplementation also suppressed the activation of inflammatory, apoptotic and autophagic pathways by increasing Bcl-2 and decreasing p38α MAPK, TNF-α, NF-κB, IL-1ß, IL-6, COX-2, cytochrome c, Bax, caspase-3, LC3A, LC3B and beclin-1 protein levels. Morin also alleviated the side effects caused by AC by regulating the PI3K/Akt/mTOR signaling pathway. SIGNIFICANCE: Collectively, our results have shown the possible protective mechanism of morin, a potential therapeutic agent for AC-induced testicular toxicity.


Assuntos
Acrilamida/toxicidade , Flavonoides/farmacologia , NF-kappa B/metabolismo , Testículo/patologia , Animais , Antioxidantes/metabolismo , Relação Dose-Resposta a Droga , Flavonoides/administração & dosagem , Masculino , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Testículo/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
6.
Life Sci ; 258: 118211, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768576

RESUMO

AIMS: Cisplatin is the mainstay of first-line treatment for advanced non-small cell lung cancer (NSCLC). Accumulating evidence suggests that flavonoids inhibit histone deacetylase (HDAC) to mediate their anticancer effect in various cancer types. The study was conducted to investigate the inhibition of HDAC and the modulation of apoptotic and cell cycle regulatory genes by selected flavonoids to potentiate the anticancer effect of cisplatin. MAIN METHODS: Combinations of cisplatin and selected flavonoids were investigated in three NSCLC cell lines (A549, H460, and H1299). Sulforhodamine B assay was used to evaluate cytotoxicity of drug combinations. Western blot analysis was conducted to evaluate histone acetylation. Flow cytometric assays were used to investigate the apoptotic and cell cycle effect. Chromatin immunoprecipitation assay was performed to elucidate the binding of transcription factors to promoters of selected apoptotic and cell cycle regulatory genes. KEY FINDINGS: Apigenin was found to exhibit the strongest HDAC inhibitory effect among all flavonoids tested. Cisplatin-apigenin combination was shown to produce significantly more S phase prolongation and G2/M cell cycle arrest, and apoptosis compared with cisplatin or apigenin alone, by inducing p21 and PUMA, respectively. More pronounced effect was observed in p53-proficient than p53-null NSCLC cells. Mechanistically, apigenin was found to reduce the binding of HDAC1 but increase the association of RNA polymerase II and Sp1 to p21 and PUMA promoters. SIGNIFICANCE: Our findings provide a better insight about the mechanism contributing to the HDAC inhibitory effect of apigenin to potentiate anticancer effect of cisplatin by inducing apoptosis and cell cycle arrest.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Cisplatino/administração & dosagem , Flavonoides/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Neoplasias Pulmonares/enzimologia , Células A549 , Antineoplásicos/química , Apigenina/administração & dosagem , Apigenina/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cisplatino/química , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Flavonoides/química , Inibidores de Histona Desacetilases/química , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia
7.
Int. j. morphol ; 38(3): 761-765, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098317

RESUMO

Oligozoospermia is a common infertility disease, and the incidence rate is increasing year by year. Cuscuta chinensis is a commonly used medicine for the treatment of oligozoospermia in Chinese medicine. Flavonoids are its main component. GM-CSF is a multifunctional cytokine that plays an important role in the inflammatory response. In this paper, we performed HE staining and immunohistochemical staining on the testis of rats with oligozoospermia. We intend to study the expression changes of GM-CSF in rats with oligospermia and the effect of flavonoids on the expression of GM-CSF in testis of rats with oligozoospermia.


La oligozoospermia es una enfermedad común de infertilidad, con una tasa de incidencia que aumenta año tras año. Cuscuta chinensis es un medicamento de uso común para el tratamiento de la oligozoospermia en la medicina china. Los flavonoides son su componente principal. GM-CSF es una citocina multifuncional que tiene un rol importante en la respuesta inflamatoria. En este trabajo, realizamos tinción con hematoxilina y eosina y tinción inmunohistoquímica en testículos de ratas con oligozoospermia. TNuestro objetivo fue estudiar los cambios de expresión de GM-CSF en ratas con oligozoospermia y el efecto de los flavonoides en la expresión de GM-CSF en testículos de ratas con oligozoospermia.


Assuntos
Animais , Masculino , Ratos , Oligospermia/metabolismo , Oligospermia/tratamento farmacológico , Flavonoides/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Cuscuta , Testículo/efeitos dos fármacos , Testículo/metabolismo , Imuno-Histoquímica , Ratos Sprague-Dawley
8.
Braz J Med Biol Res ; 53(6): e9489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401927

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease of knee joints involving pain and inflammation. Rhoifolin is a plant flavonoid known to have antioxidant and anti-inflammatory properties. This study was taken to identify the effect of rhoifolin on complete Freund's adjuvant (CFA)-induced arthritis in the rat model. Treatment with rhoifolin (10 and 20 mg/kg) showed a significant improvement in the overall health parameters such as paw edema and weight loss. This improvement in morphological parameters corroborated the findings with gross morphological changes observed in the histopathological analysis. Rhoifolin treatment also caused a significant decrease in oxidative stress, evident from changes in intracellular levels of glutathione, glutathione peroxidase, malondialdehyde, and superoxide dismutase in the articular cartilage tissue. Moreover, proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin(IL)-1ß, and IL-6 showed a significant downregulation of gene expression and intracellular protein concentration levels. The NF-κB pathway showed a significant attenuation as evident in the significant reduction in the levels of NF-κB p65 and p-IκB-α. These results indicated that rhoifolin can be a natural therapeutic alternative to the extant regimens, which include non-steroidal anti-inflammatory drugs and immunosuppressants. Additionally, the antioxidant and anti-inflammatory action of rhoifolin was probably mediated by the NF-κB pathway. However, the exact target molecules of this pathway need to be determined in further studies.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Citocinas/sangue , Dissacarídeos/administração & dosagem , Flavonoides/administração & dosagem , Adjuvante de Freund/administração & dosagem , Glicosídeos/administração & dosagem , NF-kappa B/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Biomarcadores/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , NF-kappa B/metabolismo , Ratos , Fator de Necrose Tumoral alfa/sangue
9.
Int J Mol Sci ; 21(9)2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32354030

RESUMO

BACKGROUND: On the 31 December 2019, the World Health Organization (WHO) was informed of a cluster of cases of pneumonia of unknown origin detected in Wuhan City, Hubei Province, China. The infection spread first in China and then in the rest of the world, and on the 11th of March, the WHO declared that COVID-19 was a pandemic. Taking into consideration the mortality rate of COVID-19, about 5-7%, and the percentage of positive patients admitted to intensive care units being 9-11%, it should be mandatory to consider and take all necessary measures to contain the COVID-19 infection. Moreover, given the recent evidence in different hospitals suggesting IL-6 and TNF-α inhibitor drugs as a possible therapy for COVID-19, we aimed to highlight that a dietary intervention could be useful to prevent the infection and/or to ameliorate the outcomes during therapy. Considering that the COVID-19 infection can generate a mild or highly acute respiratory syndrome with a consequent release of pro-inflammatory cytokines, including IL-6 and TNF-α, a dietary regimen modification in order to improve the levels of adiponectin could be very useful both to prevent the infection and to take care of patients, improving their outcomes.


Assuntos
Antioxidantes/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Dieta , Suplementos Nutricionais , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Adiponectina/metabolismo , Ácido Ascórbico/administração & dosagem , Infecções por Coronavirus/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/metabolismo , Flavonoides/administração & dosagem , Humanos , Interleucina-6/imunologia , Interleucina-6/metabolismo , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pneumopatias/terapia , Pandemias , Pneumonia Viral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
J Nutr ; 150(8): 2147-2155, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470977

RESUMO

BACKGROUND: Many of the health benefits of tea have been attributed to its flavonoid content. Tea consumption in US adults varies by socioeconomic status (SES). OBJECTIVES: The present objective was to explore intakes of total flavonoids and flavonoid subclasses by participant sociodemographics and by patterns of tea consumption. METHODS: The present analyses were based on 2 d of dietary recalls for 17,506 persons aged >9 y in the 2011-2016 NHANES. The What We Eat in America nutrient composition database was merged with the USDA Expanded Flavonoid database, which included total flavonoids and flavan-3-ols (including catechins), flavanones, flavonols, anthocyanidins, flavones, and isoflavones. Flavonoid intakes were compared by sex, age, race/ethnicity, education, and income-to-poverty ratio (IPR) in univariate analyses. Flavonoid intakes of children and adults were also compared by tea consumption status. Time trends in flavonoid intakes were also examined. RESULTS: Mean total flavonoid intake was 219 mg/d, of which flavan-3-ols provided 174 mg/d, or 79%. The highest total flavonoid intakes were found in adults aged 51-70 y (293 mg/d), non-Hispanic whites (251 mg/d) and in groups with college education (251 mg/d) and higher income (IPR >3.5: 249 mg/d) (P < 0.001 for all). The socioeconomic gradient was significant for anthocyanidins, flavonols, and flavones (P < 0.001 for all) but not for flavan-3-ols, and persisted across 3 cycles of NHANES. Adult tea consumers had higher intakes of total flavonoids (610 mg/d compared with 141 mg/d) and flavan-3-ols (542 mg/d compared with 97.8 mg/d) than did nonconsumers (P < 0.001). Time trend analyses showed that both tea consumption and flavonoid intakes were unchanged from 2011 to 2016. CONCLUSIONS: Flavonoid intakes in children and adults in the NHANES 2011-16 sample were associated with higher SES and were largely determined by tea consumption. Studies of diet and disease risk need to take sociodemographic gradients and eating and drinking habits into account.


Assuntos
Dieta/economia , Flavonoides/administração & dosagem , Inquéritos Nutricionais , Chá , Adolescente , Adulto , Idoso , Criança , Humanos , Pessoa de Meia-Idade , Fatores Socioeconômicos , Estados Unidos , Adulto Jovem
11.
Poult Sci ; 99(5): 2757-2765, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32359613

RESUMO

In the present study, for the purpose of investigating the effects of the total flavonoids of Epimedium (TFE) in regard to preventing the development of atrophied oviducts and follicles induced by forced molting, 300-day-old Hy-Line Brown layer hens were divided into 3 study groups as follows: the control (CON) group was the normal group, without forced molting and TFE treatments; the TFE1 group was treated by adding a 1‰ TFE treatment after forced molting; and the TFE0 group was not treated by TFE after forced molting. During this study's experimental process, the egg production rates were recorded each day. In addition, the hens were randomly chosen to be weighed every 4 D and also randomly selected to be sacrificed every 7 D. Then, sample tissues of albumen-secreting part and uterus from the fallopian tube of the layer hens were collected for PCR and hematoxylin-eosin staining tests. The results showed that the body weights, number of follicles, and weights and sizes of the fallopian tube for the TFE1 and TFE0 groups were significantly reduced when compared with those of the control group on the 15th D of the experiment. Furthermore, at the end of study, it was found that the egg production rates, weights of the fallopian tube, and ovarian follicles of TFE1 had recovered to normal levels. At the same time, the serum estrogen and the expressions of the progesterone receptor and estrogen receptor mRNA in fallopian tube were higher than those observed for the TFE0 group. The results of this study provided valuable evidence that TFE could improve the development of atrophied oviducts and increase the egg laying rates, thereby making it a potential multicomponent natural drug for egg production in the future.


Assuntos
Proteínas Aviárias/metabolismo , Galinhas/metabolismo , Epimedium/química , Tubas Uterinas/efeitos dos fármacos , Flavonoides/metabolismo , Folículo Ovariano/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Animais , Estrogênios/metabolismo , Tubas Uterinas/crescimento & desenvolvimento , Feminino , Flavonoides/administração & dosagem , Muda , Folículo Ovariano/crescimento & desenvolvimento , RNA Mensageiro/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
12.
Int J Nanomedicine ; 15: 3039-3056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431500

RESUMO

Background: Electrospinning is a widely used technology that can produce scaffolds with high porosity and surface area for bone regeneration. However, the small pore sizes in electrospun scaffolds constrain cell growth and tissue-ingrowth. In this study, novel drug-loading core-shell scaffolds were fabricated via electrospinning and freeze drying to facilitate the repair of tibia bone defects in rabbit models. Materials and Methods: The collagen core scaffolds were freeze-dried containing icariin (ICA)-loaded chitosan microspheres. The shell scaffolds were electrospun using collagen, polycaprolactone and hydroxyapatite materials to form CPH composite scaffolds with the ones containing ICA microspheres named CPHI. The core-shell scaffolds were then cross-linked by genipin. The morphology, microstructure, physical and mechanical properties of the scaffolds were assessed. Rat marrow mesenchymal stem cells from the wistar rat were cultured with the scaffolds. The cell adhesion and proliferation were analysed. Adult rabbit models with tibial plateau defects were used to evaluate the performance of these scaffolds in repairing the bone defects over 4 to 12 weeks. Results: The results reveal that the novel drug-loading core-shell scaffolds were successfully fabricated, which showed good physical and chemical properties and appropriate mechanical properties. Furthermore, excellent cells attachment was observed on the CPHI scaffolds. The results from radiography, micro-computed tomography, histological and immunohistochemical analysis demonstrated that abundant new bones were formed on the CPHI scaffolds. Conclusion: These new core-shell composite scaffolds have great potential for bone tissue engineering applications and may lead to effective bone regeneration and repair.


Assuntos
Regeneração Óssea , Flavonoides/farmacologia , Tíbia/efeitos dos fármacos , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Regeneração Óssea/efeitos dos fármacos , Quitosana/química , Colágeno/química , Durapatita/química , Flavonoides/administração & dosagem , Flavonoides/química , Masculino , Teste de Materiais , Células-Tronco Mesenquimais/citologia , Microesferas , Poliésteres/química , Porosidade , Coelhos , Ratos Wistar , Tíbia/diagnóstico por imagem , Microtomografia por Raio-X
13.
PLoS One ; 15(4): e0231543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32282828

RESUMO

Dipeptidyl peptidase-4 (DPP-4) is a proteolytic enzyme responsible for the rapid degradation of Glucagon-like peptide 1 (GLP-1) that is required for the secretion of insulin. DPP-4 also influences activation of node like receptor family, pyrin domain containing 3 (NLRP3) inflammasome under diabetic conditions. Although several polyphenols are reported for various bioactivities, they are consumed as part of the food matrix and not in isolation. Horsegram (Macrotyloma uniflorum) is a rich source of myricetin (Myr) (35 µg/g flour), reported for its anti-hyperglycemic effect. In this investigation, we aimed to study the effect of Myr, singly, and in the presence of co-nutrient horsegram protein (HP) on DPP-4 activity and its consequential impact on GLP-1, insulin, and NLRP3 inflammasome in high-fat diet and single low dose streptozotocin (STZ)-induced diabetic male Wistar rats. In diabetic control (DC), the activity of DPP-4 and its expression were higher compared to treated groups. The consequential decrease in the circulating GLP-1 levels in the DC group, but not treated groups, further indicated the effectiveness of our test molecules under diabetic conditions. Specifically, Myr decreased DPP-4 activity and its expression levels with enhanced circulating GLP-1 and insulin levels. Myr administration also resulted in a lessening of diabetes-induced NLRP3 inflammasome activation and enhanced antioxidant enzyme activities. HP also proved to be efficient in reducing elevated blood glucose levels and enhancing antioxidant enzyme activities. However, Myr, in the presence of HP as a co-nutrient, had diminished capacity to inhibit DPP-4 and, consequently, reduced potential in ameliorating diabetic conditions. Myr proved to be a potent inhibitor of DPP-4 in vitro and in vivo, resulting in enhanced circulating GLP-1 and insulin levels, thereby improving diabetic conditions. Though Myr and HP, individually ameliorate diabetic conditions, their dietary combination had reduced efficiency.


Assuntos
Diabetes Mellitus Experimental/terapia , Dipeptidil Peptidase 4/metabolismo , Flavonoides/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/administração & dosagem , Proteínas de Plantas/administração & dosagem , Animais , Antioxidantes/metabolismo , Glicemia , Diabetes Mellitus Experimental/metabolismo , Fabaceae , Feminino , Flavonoides/metabolismo , Inflamassomos/metabolismo , Insulina/sangue , Fígado/enzimologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Proteínas de Plantas/metabolismo , Gravidez , Ratos Wistar
14.
Environ Toxicol ; 35(9): 911-921, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32270916

RESUMO

Leukemia is one of the major diseases causing cancer-related deaths in the young population, and its cure rate is unsatisfying with side effects on patients. Fluorouracil (5-FU) is currently used as an anticancer drug for leukemia patients. Casticin, a natural polymethoxyflavone, exerts anticancer activity against many human cancer cell lines in vitro, but no other reports show 5-FU combined with casticin increased the mouse leukemia cell apoptosis in vitro. Herein, the antileukemia activity of 5-FU combined with casticin in WEHI-3 mouse leukemia cells was investigated in vitro. Treatment of two-drug combination had a higher decrease in cell viability and a higher increase in apoptotic cell death, the level of DNA condensation, and the length of comet tail than that of 5-FU or casticin treatment alone in WEHI-3 cells. In addition, the two-drug combination has a greater production rate of reactive oxygen species but a lower level of Ca2+ release and mitochondrial membrane potential (ΔΨm ) than that of 5-FU alone. Combined drugs also induced higher caspase-3 and caspase-8 activities than that of casticin alone and higher caspase-9 activity than that of 5-FU or casticin alone at 48 hours treatment. Furthermore, 5-FU combined with casticin has a higher expression of Cu/Zn superoxide dismutase (SOD [Cu/Zn]) and lower catalase than that of 5-FU or casticin treatment alone. The combined treatment has higher levels of Bax, Endo G, and cytochrome C of proapoptotic proteins than that of casticin alone and induced lower levels of B-cell lymphoma 2 (BCL-2) and BCL-X of antiapoptotic proteins than that of 5-FU or casticin only. Furthermore, the combined treatment had a higher expression of cleaved poly (ADP-ribose) polymerase (PARP) than that of casticin only. Based on these findings, we may suggest that 5-FU combined with casticin treatment increased apoptotic cell death in WEHI-3 mouse leukemia cells that may undergo mitochondria and caspases signaling pathways in vitro.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , Fluoruracila/farmacologia , Animais , Antineoplásicos/administração & dosagem , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Sinergismo Farmacológico , Flavonoides/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Leucemia/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Food Funct ; 11(4): 3516-3526, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32253400

RESUMO

Chronic obstructive pulmonary disease (COPD) is a chronic, progressive lung disease with few successful treatments, and is strongly associated with cigarette smoking (CS). Since the novel coronavirus has spread worldwide seriously, there is growing concern that patients who have chronic respiratory conditions like COPD can easily be infected and are more prone to having severe illness and even mortality because of lung dysfunction. Loquat leaves have long been used as an important material for both pharmaceutical and functional applications in the treatment of lung disease in Asia, especially in China and Japan. Total flavonoids (TF), the main active components derived from loquat leaves, showed remarkable anti-inflammatory and antioxidant activities. However, their protective activity against CS-induced COPD airway inflammation and oxidative stress and its underlying mechanism still remain not well-understood. The present study uses a CS-induced mouse model to estimate the morphological changes in lung tissue. The results demonstrated that TF suppressed the histological changes in the lungs of CS-challenged mice, as evidenced by reduced generation of pro-inflammatory cytokines including interleukin 6 (IL-6), IL-1ß, tumor necrosis factor α (TNF-α), nitric oxide (NO), and inducible nitric oxide synthase (iNOS) and diminished the protein expression of transient receptor potential vanilloid 1 (TRPV1). Moreover, TF also inhibited phosphorylation of IKK, IκB and NFκB and increased p-Akt. Interestingly, TF could inhibit CS-induced oxidative stress in the lungs of COPD mice. TF treatment significantly inhibited the level of malondialdehyde (MDA) and increased the activity of superoxide dismutase (SOD). In addition, TF markedly downregulated TRPV1 and cytochrome P450 2E1 (CYP2E1) and upregulated the expression of SOD-2, while the p-JNK level was observed to be inhibited in COPD mice. Taken together, our findings showed that the protective effect and putative mechanism of the action of TF resulted in the inhibition of inflammation and oxidative stress through the regulation of TRPV1 and the related signal pathway in lung tissues. It suggested that TF derived from loquat leaves could be considered to be an alternative or a new functional material and used for the treatment of CS-induced COPD.


Assuntos
Fumar Cigarros/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Eriobotrya/química , Flavonoides/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Canais de Cátion TRPV/imunologia , Animais , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Transdução de Sinais/efeitos dos fármacos , Fumaça/efeitos adversos , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia , Canais de Cátion TRPV/genética
16.
J Integr Neurosci ; 19(1): 101-109, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32259890

RESUMO

Medicinal plant breviscapine is shown to exhibit a protective role in tissue damage after cerebral hemorrhage. The effects of breviscapine on neurological deficit score, brain tissue water content, brain pathological tissue changes, blood-brain barrier bidirectional regulation, and inflammatory factors after cerebral hemorrhage in rats were observed. Western blot and real-time quantitative polymerase chain reaction were performed to explore how Periostin and nuclear factor kappa-B pathway-related factors protein expression contribute to the protective effects of breviscapine on brain injury. Breviscapine inhalation could reduce neurological deficit scores and brain tissue water content. Hematoxylin-eosin staining showed that breviscapine could improve the pathological changes of brain tissue and alleviate brain damage. Breviscapine reduced the abnormal increase of Evans blue content caused by a cerebral hemorrhage, and could significantly inhibit the levels of inflammatory factors interleukin-6 and tumor necrosis factor-α. Also, breviscapine significantly inhibited the expressions of Periostin and nuclear factor kappa-B pathway-related factors after cerebral hemorrhage, and alleviate brain damage by down-regulating Periostin expression and inhibiting nuclear factor kappa-ß signaling pathway.


Assuntos
Encéfalo/efeitos dos fármacos , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Flavonoides/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Moléculas de Adesão Celular/metabolismo , Hemorragia Cerebral/prevenção & controle , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Plantas Medicinais , Ratos Sprague-Dawley , Transdução de Sinais
17.
Medicine (Baltimore) ; 99(12): e19111, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195931

RESUMO

BACKGROUND: Thin endometrium, defined as <7 mm of the endometrial thickness around ovulation period, had been identified as a negative factor on pregnancy rate of infertile women. It was considered to be the toughest part in treatment of infertility, because there was a lack of significant effect, although many drugs had been already used. Icariin was one of the major bioactive pharmaceutical constituent extracted from the Chinese herb "Ying Yang Huo," in the genus of Epimedium, and some randomized controlled trials reported its application for thin endometrium. There is no systematic review focusing on the effective of icariin in treating infertile women with thin endometrium, so our review aims to explore it. METHODS: The bibliographic database and electronic library will be systematically searched online, such as MEDLINE, EMBASE, Web of Science, Clinicaltrails.org., China National Knowledge Infrastructure Database (CNKI), Wan fang Database, China Biology Medicine Database (CBM), VIP Science Technology Periodical Database, and Cochrane Library. And the reference listed for potential literatures of included studies will be scanned additionally. Related randomized controlled trials (RCTs) will be collected and selected before January 4, 2020. Trials will be screened by independent reviewers, and the literature will be search in English or Chinese, with the search terms as "Icariin," "Epimedium," "infertile women," "female infertility," "endometrium," "pregnancy rate." The software for Systematic review and Meta-analysis is RevMan 5.3. The protocol and the systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. RESULT AND CONCLUSION: The efficacy of icariin to treat thin endometrium will be evaluated, and the conclusion will be published to help clinicians determine treatment strategy for infertile women with thin endometirum by providing medical evidence. REGISTRATION INFORMATION: PROSPERO CRD42019148977.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Endométrio/fisiopatologia , Flavonoides/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , China , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Flavonoides/administração & dosagem , Flavonoides/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
J Photochem Photobiol B ; 205: 111846, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32151785

RESUMO

Propolis has been reported to possess rich content of antioxidant compounds and may provide health benefits through oxidative stress reduction. Presently, the formulation activities used to enhance the drug delivery have been hampered due to inherently low aqueous solubility and poor transdermal permeation of the bioactive phenols and flavonoids. Here, we show, the formulation of propolis extract (PE) into phytosome delivery systems. The optimum antioxidant activity was attained through extraction process using 75% v/v ethanol. The phytosome was prepared using thin-layer hydration technique with l-α-Phosphatidylcholine as a phospholipid. Fourier transform infrared (FTIR) was used to investigate the occurrence of molecular interactions between formulation components. This innovative approach could encapsulate >40% of bioactive compounds in PE, namely caffeic acid, quercetin, and kaempferol. FTIR spectroscopy indicated new hydrogen bond formation, supporting successful phytosome formulation. The phytosomes enhanced the dissolution up to 4-folds of bioactive compounds in bio-mimicked release media, as well as improved penetrability and skin retention up to 6-folds of the three main compounds of propolis, when compared to non-encapsulated PE formulation. Importantly, the hydrogel containing phytosome showed a potential for UVA and UVB radiation absorption, indicated by the SPF values of higher than 15. To conclude, this work shows promising novel delivery approaches for PE in the treatment of organ injured stress oxidative and skin aging.


Assuntos
Antioxidantes , Portadores de Fármacos , Hidrogéis , Nanopartículas , Própole/química , Protetores contra Radiação , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Compostos de Bifenilo/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Flavonoides/administração & dosagem , Flavonoides/análise , Hidrogéis/administração & dosagem , Hidrogéis/química , Técnicas In Vitro , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Fenóis/administração & dosagem , Fenóis/análise , Picratos/química , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/química , Ratos Sprague-Dawley , Pele/metabolismo , Absorção Cutânea , Fator de Proteção Solar , Raios Ultravioleta
19.
J Nutr ; 150(6): 1545-1553, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32211795

RESUMO

BACKGROUND: Although greater flavonoid intake is associated with a reduced risk of Alzheimer's disease (AD) and related dementias (ADRD), evidence relating dietary flavonoid intake to brain health based on MRI is lacking. OBJECTIVE: The objective of this study was to explore the association between dietary flavonoid intake and MRI measures of brain health, including total brain tissue volume (TBV), white matter hyperintensities volume (WMHV), and hippocampal volume (HV). METHODS: Eligible subjects included members of the Framingham Heart Study Offspring Cohort who were free of stroke at exam 7 and had at least 1 valid food frequency questionnaire from exams 5, 6, or 7 (n = 2086; mean age at exam 7, 60.6 y). Flavonoid intakes represented the cumulative mean of intakes across the 3 exams and were categorized based on quartiles categories of intake. TBV, WMHV, and HV were assessed at exam 7. Multiple linear regression models were used to examine the cross-sectional association between total and the 6 classes of flavonoids and the 3 aforementioned MRI measures. RESULTS: The mean (95% CI) of the WMHV of subjects in the highest quartile category of flavan-3-ols [0.56 (0.52, 0.61)] and flavonoid polymers [0.57 (0.52, 0.61)] intake was significantly smaller relative to that of subjects in the lowest quartile category of flavan-3-ols [0.65 (0.60, 0.71)] and flavonoid polymers [0.66 (0.60, 0.71)] after accounting for important demographic, lifestyle, and clinical factors. Inverse trend associations with WMHV were also seen for flavan-3-ols (P = 0.01) and flavonoid polymers (P = 0.01) as well as for total flavonoids (P = 0.01). TBV and HV were not associated with dietary flavonoid intake following the adjustment for potential confounders. CONCLUSIONS: Our results contribute to the literature on flavonoids and ADRD as they suggest that higher flavonoid intakes may affect ADRD risk in middle-aged and older adults by reducing WMHV, a marker strongly associated with ADRD.


Assuntos
Encéfalo/metabolismo , Flavonoides/administração & dosagem , Imagem por Ressonância Magnética/métodos , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
20.
Int J Oncol ; 56(3): 821-834, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32124960

RESUMO

Tumor necrosis factor­associated apoptosis­inducing ligand (TRAIL) is considered to be a potential therapeutic target for various types of cancer. However, colon cancer is difficult to treat due to its resistance to TRAIL. Therefore, various trials have been conducted to overcome TRAIL resistance in colon cancer. The present study aimed to determine whether icariin (ICA) may sensitize human colon cancer cells to TRAIL­induced apoptosis in vitro and in vivo. In the investigation of the effect of ICA on TRAIL­induced apoptosis, the LIVE/DEAD assay results demonstrated that TRAIL plus ICA synergistically induced apoptosis in 49% of HCT116 colon cancer cells. These results were confirmed using long­term colony formation assay. ICA potentiated TRAIL­induced apoptosis by modulating the expression of apoptotic proteins and the induction of cell surface death receptors (DRs) 4 and 5. Upregulation of DRs by ICA was also observed at the transcriptional level by RT­PCR. The expression of DR by ICA was increased through the production of reactive oxygen species (ROS). The results also suggested that increased expression of DR by ICA may be due to the activation of ERK and induction of the transcription factor CCAAT enhancer­binding protein homologous protein (CHOP). NAC, a ROS scavenger, reduced the effect of ICA on ERK activation, DR induction and sensitization of TRAIL­induced apoptosis. In addition, ICA enhanced the effects of TRAIL to reduce tumor growth in an in vivo xenograft mouse model. Overall, the present study provided evidence that ICA sensitized tumor cells to TRAIL­induced apoptosis via ROS­, ERK­ and CHOP­mediated upregulation of DR5 and DR4. Based on these results, it is suggested that the antitumor activity of ICA and TRAIL co­treatment in vitro and in vivo may be used as an effective therapeutic agent in chemotherapy.


Assuntos
Neoplasias do Colo/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/administração & dosagem , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Sinergismo Farmacológico , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Masculino , Camundongos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
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