RESUMO
The aim of this cohort study was to compare the effectiveness of statin regimens for primary prevention among seniors aged ≥ 75 years. Seniors aged 75-100 years for whom statin therapies for primary prevention were newly initiated between 1 January 2009 and 31 December 2011, and who continued the same statin regimen during the first year after the index date were identified using the claims data from the South Korean National Health Insurance Database. A propensity score matching and multivariable Cox proportional hazards model were developed to evaluate adjusted ischaemic cardiovascular-cerebrovascular event (CCE) risk and all-cause mortality risk for all patients, as well as for subgroups. A total of 5629 older patients aged 75-100 years were included in the study population. Compared to moderate-intensity statin therapy, low-intensity statin therapy was significantly associated with increased risk of ischaemic CCEs, while high-intensity statin therapy was associated with reduced risk of ischaemic CCEs; however, compared to moderate-intensity statin therapy, both low-intensity and high-intensity statin therapies were associated with increased risk of all-cause mortality. For the 4689 older patients who regularly received moderate-intensity statin therapy including 10 mg atorvastatin, 20 mg atorvastatin, 10 mg rosuvastatin or 20 mg simvastatin for primary prevention, multivariable regression adjusting for potential covariates revealed no significant difference in ischaemic CCEs or all-cause mortality between the moderate-intensity statin users and 10 mg atorvastatin users both before and after propensity scoring matching. No significant heterogeneity was detected in the patient subgroups. The results of this study based on real-world data can supply evidence-based reasons for choice of statin regimen for the primary prevention of CCEs in older people aged ≥ 75 years.
Assuntos
Doenças Cardiovasculares/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Prevenção Primária/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/prevenção & controle , Bases de Dados Factuais/estatística & dados numéricos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Programas Nacionais de Saúde/estatística & dados numéricos , Prevenção Primária/estatística & dados numéricos , Pontuação de Propensão , República da Coreia/epidemiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIMS: Betaine plays an important role in cellular homeostasis. However, the physiological roles of betaine-γ-aminobutyric acid (GABA) transporter (BGT-1) are still being disputed in cancer. In this study, we tried to find the possibility of the antitumor effect on colorectal cancer (CRC) cell via lactate calcium salt (CaLa)-induced BGT-1 downregulation. MAIN METHODS: The CRC cell viability and clonogenic assay was performed using different doses of BGT-1 inhibitor. The expression level of BGT-1 was measured following the treatment of 2.5mM CaLa. Betaine was treated to confirm the resistance of the antitumor activity by CaLa. Tumor growth was also measured using a xenograft animal model. KEY FINDINGS: Long-term exposure of 2.5mM CaLa clearly decreased the expression of BGT-1 in the CRC cells. As a result of the downregulation of BGT-1 expression, the clonogenic ability of CRC cells was also decreased in the 2.5mM CaLa-treated group. Reversely, the number of colonies and cell viability was increased by combination treatment with betaine and 2.5mM CaLa, as compared with a single treatment of 2.5mM CaLa. Tumor growth was significantly inhibited in the xenograft model depending on BGT-1 downregulation by 2.5mM CaLa treatment. SIGNIFICANCE: These results support the idea that long-lasting calcium supplementation via CaLa contributes to disruption of betaine homeostasis in the CRC cells and is hypothesized to reduce the risk of CRC. In addition, it indicates the possibility of CaLa being a potential incorporating agent with existing therapeutics against CRC.
Assuntos
Betaína/metabolismo , Compostos de Cálcio/farmacologia , Proteínas de Transporte/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Lactatos/farmacologia , Animais , Compostos de Cálcio/administração & dosagem , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Proteínas da Membrana Plasmática de Transporte de GABA , Homeostase , Humanos , Lactatos/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To examine whether quercetin interacts with vitamin D receptor, we investigated the effects of quercetin on vitamin D receptor activity in human intestinal Caco-2 cells. The effects of quercetin on the expression of the vitamin D receptor target genes, vitamin D3 24-hydroxylase, cytochrome P450 3A4, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were measured using quantitative polymerase chain reaction. The vitamin D receptor siRNA was used to assess the involvement of the vitamin D receptor. Vitamin D receptor activation using a vitamin D responsive element-mediated cytochrome P450 3A4 reporter gene assay was investigated in Caco-2 cells transfected with human vitamin D receptor. We also studied the magnitude of the vitamin D receptor activation and/or synergism between 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and quercetin-like flavonoids. Slight but significant increases in the mRNA expression of cytochrome P450 3A4, vitamin D3 24-hydroxylase, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were observed after 3 days of continual quercetin treatment. The silencing effect of vitamin D receptor by vitamin D receptor siRNA in Caco-2 cells significantly attenuated the induction of the vitamin D receptor target genes. Moreover, quercetin significantly enhanced cytochrome P450 3A4 reporter activity in Caco-2 cells in a dose-dependent manner, and the expression of exogenous vitamin D receptor further stimulated the vitamin D receptor activity. Quercetin-like flavonoids such as kaempferol stimulated the vitamin D receptor activity in a manner similar to that seen with quercetin. Taken together, the data indicates that quercetin upregulates cytochrome P450 3A4 and multidrug resistance protein 1 expression in Caco-2 cells likely via a vitamin D receptor-dependent pathway.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Citocromo P-450 CYP3A/metabolismo , Quercetina/farmacologia , Receptores de Calcitriol/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Células CACO-2 , Citocromo P-450 CYP3A/genética , Humanos , Estrutura Molecular , Quercetina/química , Transfecção , Regulação para CimaRESUMO
AIMS: Calcium supplements appear to reduce the risk of developing colorectal cancer (CRC), and it is necessary to clarify the mechanisms by which they exert their effects. In the present study, we investigate the supplementation effect of calcium via lactate calcium salt (CaLa) on CRC cells, focusing on ß-catenin destabilization. MAIN METHODS: The clonogenic assay was performed using different doses of CaLa. The expression level of c-Myc and Cyclin D1 was measured in addition to the confirmation of ß-catenin expression in the CRC cells. Glycogen synthase kinase (GSK)-3ß expression was also confirmed in order to investigate the mechanism of ß-catenin degradation. Tumorigenic ability was confirmed using a xenograft animal model. KEY FINDINGS: The number of colonies was significantly decreased after 2.5mM CaLa treatment. CaLa-treated CRC cells showed a decrease in the ß-catenin expression. The quantitative level of the ß-catenin protein was significantly decreased in the CRC cell lysates, hence the expression level of c-Myc and cyclin D1 was significantly decreased following 2.5mM CaLa treatment. We also confirmed that an increased expression of GSK-3ß by CaLa is a key pathway in ß-catenin degradation. In the xenograft study, tumorigenicity was significantly inhibited to a maximum of 45% in the CaLa-treated group as compared with the control. SIGNIFICANCE: These results support the idea that calcium supplementation via CaLa contributes to ß-catenin degradation and is hypothesized to reduce the risk of CRC. In addition, it indicates the possibility of CaLa being a potential incorporating agent with existing therapeutics against CRC.
Assuntos
Antineoplásicos/uso terapêutico , Compostos de Cálcio/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Lactatos/uso terapêutico , beta Catenina/metabolismo , Animais , Antineoplásicos/farmacologia , Compostos de Cálcio/farmacologia , Linhagem Celular Tumoral , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactatos/farmacologia , Camundongos Endogâmicos BALB C , Proteólise/efeitos dos fármacos , Reto/efeitos dos fármacos , Reto/metabolismo , Reto/patologia , beta Catenina/análise , beta Catenina/genéticaRESUMO
Alzheimer's disease (AD), characterized by progressive dementia and deterioration of cognitive function, is an unsolved social and medical problem. Age, nutrition, and toxins are the most common causes of AD. However, currently no credible treatment is available for AD. Traditional herbs and phytochemicals may delay its onset and slow its progression and also allow recovery by targeting multiple pathological causes by antioxidative, anti-inflammatory, and antiamyloidogenic properties. They also regulate mitochondrial stress, apoptotic factors, free radical scavenging system, and neurotrophic factors. Neurotrophins such as BDNF, NGF, NT3, and NT4/5 play a vital role in neuronal and nonneuronal responses to AD. Neurotrophins depletion accelerates the progression of AD and therefore, replacing such neurotrophins may be a potential treatment for neurodegenerative disease. Here, we review the phytochemicals that mediate the signaling pathways involved in neuroprotection specifically neurotrophin-mediated activation of Trk receptors and members of p75(NTR) superfamily. We focus on representative phenolic derivatives, iridoid glycosides, terpenoids, alkaloids, and steroidal saponins as regulators of neurotrophin-mediated neuroprotection. Although these phytochemicals have attracted attention owing to their in vitro neurotrophin potentiating activity, their in vivo and clinical efficacy trials has yet to be established. Therefore, further research is necessary to prove the neuroprotective effects in preclinical models and in humans.