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1.
Cancers (Basel) ; 13(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34503074

RESUMO

Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper; it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL.

2.
J Affect Disord ; 295: 271-283, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34482059

RESUMO

BACKGROUND: Depression increases the risk of cardiovascular disease (CVD). The association between antidepressant medications (ADMs) and CVD remains controversial. Hyperlipidemia is a risk factor for CVD. We conducted a nationwide population-based retrospective cohort study to examine depression and ADM use on the risk of developing hyperlipidemia. The effects of ADMs on the expression of lipogenesis-related hepatic genes were also evaluated. METHODS: We obtained data from the Longitudinal Health Insurance Database of Taiwan on patients with new-onset depression and a comparison cohort without depression. A Cox proportional hazards regression model was used to analyze the differences in the risk of developing hyperlipidemia between these two cohorts. We also examined the influence of ADMs on the expression of lipogenesis-related hepatic genes. RESULTS: After adjustment for comorbidities and confounding factors, the case group (N = 38,322) had a higher risk for hyperlipidemia than that of the control cohort (N = 38,322) [adjusted hazards ratio (aHR) =1.16]. Patients with depression who did not receive ADM therapy exhibited a significantly higher risk of hyperlipidemia (aHR = 1.61). However, in patients with depression treated with ADMs, the risk of developing hyperlipidemia was significantly lowered compared to the patients without ADMs (all aHR < 0.81). Gene expression analysis indicated that ADMs downregulated the expression of lipogenesis-related hepatic genes. LIMITATIONS: Unmeasured confounding risk factors for hyperlipidemia might not have been included in the study. CONCLUSIONS: ADMs reduced hyperlipidemia risk in patients with depression, partly by downregulating the expression of lipogenesis-related genes and improving the patients' lipid profiles. Early diagnosis and management of hyperlipidemia would further facilitate the prevention of CVD.


Assuntos
Hiperlipidemias , Antidepressivos , Estudos de Coortes , Comorbidade , Depressão/epidemiologia , Depressão/genética , Expressão Gênica , Humanos , Hiperlipidemias/epidemiologia , Hiperlipidemias/genética , Incidência , Lipogênese/genética , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia
3.
Biomed Res Int ; 2021: 8857230, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33506043

RESUMO

The relationship between depression, antidepressant medications (ADMs), and the risk of subsequent type 2 diabetes mellitus (T2DM) development remains controversial. Thus, we investigated this aspect by a population-based retrospective cohort study using the Longitudinal Health Insurance Database 2000 available in Taiwan. This large, observational study included 46,201 patients with depression and a 1 : 1 age- and sex-matched nondepression cohort enrolled between January 1, 2000, and December 31, 2013, and the newly diagnosed T2DM incidence rates were determined. We estimated the effects of depression on T2DM and the cumulative incidence curves by Cox proportional regression hazard models and Kaplan-Meier methods, respectively. We found that 47.97% of the patients with depression did not receive ADM. Among patients with depression who received ADM, 29.71%, 6.29%, 0.05%, 9.65%, and 6.32% received selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), heterocyclic antidepressants, and other medications, respectively. Patients without ADM treatment had a 39% higher risk of developing T2DM. However, those who received ADM treatment had a significantly lower risk of T2DM development in every treatment category. Depressive disorder treated with ADMs, especially with long-term use, was associated with an 11-48% decrease in the risk of T2DM in all ADM groups; however, heterocyclic antidepressant treatment for shorter periods (<80 days) was not significantly associated with a decreased risk of T2DM. The incidence of T2DM in Taiwan was found to be associated with an a priori history of depression and was inversely correlated with ADM treatment.


Assuntos
Antidepressivos/uso terapêutico , Depressão , Diabetes Mellitus Tipo 2 , Adulto , Idoso , Comorbidade , Depressão/complicações , Depressão/tratamento farmacológico , Depressão/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taiwan
4.
Mediators Inflamm ; 2020: 8890300, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33273891

RESUMO

Patients with gout are at a higher risk of cardiovascular disease, which is associated with hyperlipidemia. Management of gout in Taiwan is poor, and the association between urate-lowering therapy (ULT) among gout patients and hyperlipidemia is unclear. We conducted a retrospective cohort study using data from the Longitudinal Health Insurance Database (LHID) of Taiwan on new-onset gout patients and a comparison cohort without gout. A Cox proportional hazards model was used to analyze differences in the risk of hyperlipidemia between patients with and without gout after considering related comorbidities. We also examined the ULT medications on the hepatic expression of lipogenesis-related genes. After adjusting for potential confounders, the case group (44,413 patients) was found to have a higher risk of hyperlipidemia than the control cohort (177,652 patients) [adjusted hazards ratio (aHR) = 2.55]. Gout patients without antigout treatment had significantly higher risk of hyperlipidemia than the control cohort (aHR = 3.10). Among gout patients receiving ULT, except those receiving probenecid (aHR = 0.80), all had significantly lower risk of hyperlipidemia than gout patients without ULT (all aHR < 0.90). Using real-time polymerase chain reaction, we found that most of the antigout drugs decreased the expression of hepatic genes related to lipogenesis in differentiated HepaRG cells. These data indicate that these antigout drugs reduce hyperlipidemia in gout patients, partly via the reduction in expression of lipogenesis-related genes, leading to improved blood lipid profiles. We provide evidence of the strong association between gout and hyperlipidemia and highlight the need for appropriate treatment guidelines.

5.
Sci Rep ; 10(1): 15702, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973190

RESUMO

To investigate the particle size distribution of particulate matter and the concentration of specific perfluorinated compounds in indoor dust samples from several locations. Then, we used cell-based assays to investigate the effect of perfluorinated compounds on human corneal epithelial (HCEpiC), endothelial cells (HCEC) and retinal pigment epithelial cells (RPE). Indoor dust samples were collected at five different locations and PM50-10, PM10-2.5, and PM2.5-1 were fractionized. The presence and levels of 8:2 fluorotelomer alcohol, 10:2 fluorotelomer alcohol, and perfluorooctanoic acid were detected by gas chromatography-mass spectrometry. The effect of perfluorooctanoic acid on the activation of reactive oxygen species, transepithelial resistance as well as the expression of interleukin (IL)-6 and IL-8 were determined. The basolateral media of human corneal epithelial or human corneal endothelial cells were used to treat human corneal endothelial or retinal pigment epithelial cells, respectively to indicate the potential of ocular surface inflammation may result in retinal inflammation. Among perfluorinated compounds, only perfluorooctanoic acid was detected in all indoor dust samples. Perfluorooctanoic acid had the highest concentration among all perfluorinated compounds in the samples. Exposure to perfluorooctanoic acid impaired tight junction sealing and increased the levels of reactive oxygen species in human corneal epithelial cells. In human corneal epithelial cells, secretion of IL-6 and IL-8 in both apical and basolateral media was promoted significantly by perfluorooctanoic acid treatment. Stimulation with the basolateral media from perfluorooctanoic acid-treated human corneal epithelial cells induced inflammation in human corneal endothelial cells. The treatment of retinal pigment epithelial cells with the basolateral media from stimulated human corneal endothelial cells also elicited the secretion of proinflammatory cytokines. The results indicate that perfluorooctanoic acid exposure impaired the tight junction of corneal cells and caused inflammatory reactions in the retina. Exposure of the cornea to perfluorooctanoic acid contained in particulate matter might induce oxidative stress and inflammation in the retina and represent a risk factor for age-related macular degeneration.


Assuntos
Caprilatos/farmacologia , Córnea/efeitos dos fármacos , Fluorcarbonetos/farmacologia , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/farmacologia , Retina/efeitos dos fármacos , Córnea/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Retina/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo
6.
Biomed Res Int ; 2020: 6358954, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32775432

RESUMO

Gout is the most prevalent inflammatory arthritis in adults. Although the link between gout and type 2 diabetes mellitus (T2DM) has been documented, our understanding of the association between urate-lowering therapy (ULT) among gout patients and T2DM development remains poor. We included 69,326 patients with new-onset gout in 2000-2011. Each case was matched randomly with 1 patient without gout during the study period, and 69,326 patients were recognized as the comparison cohort. A Cox proportional hazard regression model was used to analyze differences in the risk of T2DM development between patients with and without gout after considering related comorbidities. After adjusting for potential confounders, the case group had a higher risk of T2DM than the control cohort (adjusted hazard ratio (aHR) = 1.30, 95%confidence interval (CI) = 1.24-1.38; P < 0.001). Gout patients without appropriate ULT had significantly higher risk of T2DM development than the control cohort (aHR = 1.39; 95%CI = 1.30-1.48; P < 0.001). Among gout patients, those receiving ULT excluding probenecid (aHR = 0.80; 95%CI = 0.64-1.00), all had significantly lower risk of T2DM than gout patients without ULT (all aHR < 0.90; all P < 0.001). In this study, we found that gout increased the risk of T2DM; however, patients with any ULT exhibited a lower risk of T2DM than gout patients without any ULT (all aHR < 0.90, P < 0.001; excluding probenecid).


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Supressores da Gota/uso terapêutico , Gota/complicações , Gota/tratamento farmacológico , Ácido Úrico/metabolismo , Idoso , Comorbidade , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Gota/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos
7.
Environ Toxicol ; 35(12): 1352-1363, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32677756

RESUMO

Although pipoxolan (PIPO) is a smooth muscle relaxant, its anti-inflammatory capability has not been studied. Therefore, we investigated the anti-inflammatory molecular mechanisms of PIPO in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. In this study, we used the MTT assay to evaluate the cytotoxicity, applied the enzyme-linked immunosorbent assay to determine the inflammatory cytokines, and performed Western blotting to assess protein expression. The results showed that PIPO significantly inhibited cytokine production, including nitric oxide, prostaglandin E2 , tumor necrosis factor-α, and interleukin-6. PIPO also suppressed the pro-inflammatory mediator expression with inducible nitric oxide synthase and cyclooxygenase-2. Moreover, PIPO prohibited the multiple inflammatory transcription factor pathways, including inhibitor kappa B/nuclear factor of the κ light chain enhancer of B cells (NF-κB), mitogen-activated protein kinase/activator protein-1 (AP-1), Janus kinase/signal transducer and activator of transcription (STAT), and toll-like receptor 4 (TLR4)/serine/threonine kinase (AKT). Besides, PIPO effectively activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 antioxidative pathway. Collectively, PIPO may attenuate the inflammatory effects via influencing the LPS/TLR4 receptor binding; suppress the expression of anti-inflammatory transcription factors NF-κB, AP-1, and STAT; and activating the antioxidative transcription factor Nrf2 in LPS-stimulated mouse RAW 264.7 cells.


Assuntos
Anti-Inflamatórios/farmacologia , Dioxolanos/farmacologia , Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Antioxidantes/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
8.
Toxicol Appl Pharmacol ; 402: 115115, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32634518

RESUMO

Physalin A (PA), a withanolide, was isolated from Physalis angulata L. In this study, it is shown that PA can inhibit the production of inflammatory cytokines such as PGE2, NO, IL-1ß, IL-6, and TNF-α in LPS-induced RAW 264.7 cells. Furthermore, the results indicated that PA suppressed the IκB/NF-κB and JNK/ AP-1 inflammatory signaling pathways and inhibited the levels of pro-inflammatory factors iNOS and COX-2 in LPS-stimulated RAW 264.7 cells. In the carrageenan-induced mouse hind paw edema study, PA was shown to inhibit the production of inflammatory mediators such as NO, MDA, and TNF-α production. Conversely, the antioxidant factor levels of SOD, CAT, and GPx were all increased by the treated PA. According to the data, we are suggesting that the anti-inflammatory effects of PA may be through the suppressions of the JNK/AP-1 and IκB/NF-κB signaling pathways and up-regulation of the anti-oxidative activity.


Assuntos
Inflamação/tratamento farmacológico , Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fator de Transcrição AP-1/metabolismo , Vitanolídeos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Masculino , Malondialdeído , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Physalis/química , Células RAW 264.7 , Distribuição Aleatória , Fator de Transcrição AP-1/genética , Vitanolídeos/química
9.
Front Med (Lausanne) ; 7: 228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32549042

RESUMO

There have been no reports on the association of hyperthyroidism with hyperlipidemia in patients undergoing treatment especially in Asia. To determine the association between hyperthyroidism and the risk of hyperlipidemia in patients, we conducted a retrospective cohort study using Longitudinal Health Insurance Database (LHID) from Taiwan, R.O.C. We also evaluate the influence of 6-n-propyl-2-thiouracil (PTU) and methimazole (MMI) on hepatic genes to explain changes in blood lipid levels in a hepatic cell line model. The cohort study involved 13,667 patients with hyperthyroidism, and the corresponding comparison cohort had four times as many patients. Using Kaplan-Meier analysis method, the results showed that, compared to patients without hyperthyroidism, the overall incidence of hyperlipidemia was significantly higher in the hyperthyroidism patients (18.7 vs. 11.8 cases/1,000 persons-years; adjusted HR 1.5; 95% CI, 1.41-1.59). With only PTU or MMI/carbimazole (CBM) treatment, patients with hyperthyroidism showed a 1.78-fold (95% CI, 1.50-2.11) and 1.43-fold (95% CI, 1.27-1.60) higher risk of hyperlipidemia than those without hyperthyroidism, respectively. Additionally, hyperthyroidism patients that received surgery only or surgery with I131 therapy tended to have a higher risk of hyperlipidemia. Although PTU and MMI treatment decreased the expression levels of genes responsible for circulating remnant lipoproteins, they increased the levels of lipogenic gene expression in hepatic cells. Thus, treatment of hyperthyroid patients with anti-thyroid drugs (ATDs), I131, or surgery is likely to induce hyperlipidemia. ATDs downregulate the expression of genes involved in lipoproteins clearance; increases lipogenic genes expression, which may partly contribute to abnormal blood lipid profiles.

10.
Int J Mol Sci ; 20(21)2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31731481

RESUMO

Aloperine, an alkaloid isolated from Sophora alopecuroides, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, including multiple myeloma; colon, breast, and prostate cancers; and osteosarcoma. Cell cycle arrest, apoptosis induction, and tumorigenesis suppression have been demonstrated following aloperine treatment. In a previous study, we demonstrated antitumor effects of aloperine on human thyroid cancer cells through anti-tumorigenesis and caspase-dependent apoptosis induction via the Akt signaling pathway. In the present study, we demonstrated the modulation of the autophagy mechanism following the incubation of multidrug-resistant papillary and anaplastic human thyroid cancer cells with aloperine; we also illustrate the underlying mechanisms, including AMPK, Erk, JNK, p38, and Akt signaling pathways. Further investigation revealed the involvement of the Akt signaling pathway in aloperine-modulated autophagy in human thyroid cancer cells. These results indicate a previously unappreciated function of aloperine in autophagy modulation in human thyroid cancer cells.


Assuntos
Morte Celular Autofágica/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Piperidinas/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
11.
Environ Pollut ; 254(Pt B): 113031, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454569

RESUMO

Myopia is caused by complex genetic and environmental factors. However, information regarding the effect of long-term exposure to air pollutants on the risk of development of myopia is lacking. We collected data from two linked databases: the Taiwan National Health Insurance Research Database (NHIRD) and the Taiwan Air Quality-Monitoring Database (TAQMD). A total of 15,822 children (16.3%) were diagnosed with myopia within the cohort. The incidence rate of myopia increased with exposure to increasing concentrations of particulate matter (PM2.5) and nitrogen oxides (NOx), increasing from 15.8 to 24.5 and from 13.7 to 34.4, per 1000 person-years, respectively. The adjusted hazard ratio for myopia increased with elevated PM2.5 and NOx exposure concentrations in Q4 to 1.57 and 2.60, respectively, compared to those exposed to the corresponding concentrations in Q1. In the animal experiments, PM2.5 induced myopia in hamsters by enhancing inflammation and was inhibited by resveratrol treatment compared to the control group. The change in axial length in the PM2.5 group was 0.386 ± 0.069 mm versus 0.287 ± 0.086 mm in the control group and 0.257 ± 0.059 mm in the PM2.5 + resveratrol group. We provide both clinical and experimental correlations that exposure to ambient air pollutants is associated with the pathogenesis of myopia.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição Ambiental/efeitos adversos , Miopia/etiologia , Óxidos de Nitrogênio/efeitos adversos , Material Particulado/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Animais , Criança , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Masculino , Miopia/epidemiologia , Óxidos de Nitrogênio/análise , Material Particulado/análise , Modelos de Riscos Proporcionais , Taiwan/epidemiologia
12.
J Food Drug Anal ; 27(2): 542-550, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987726

RESUMO

High-density lipoprotein (HDL) carbamylation has been known in uremia patients. Paraoxonase-1 (PON-1) is an important HDL protein responsible for HDL anti-oxidant, arylesterase and lactonase activities. PON-1 carbamylation in uremic HDL has never been explored. We isolated HDL from uremia patients and control healthy subjects for study. Sandwich ELISA was used to estimate carbamylated PON-1 protein expression in HDL, and nanoflow liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) was applied to identify the amino acid in PON-1 carbamylated. PON-1 enzyme activities were estimated by substrates conversion method. HDL anti-oxidant activity was gauged by fluorescence changes of indicator dye in the presence of H2O2. Our study results proved that the degree of PON-1 carbamylation was higher in uremic HDL than in control HDL. Sandwich ELISA study showed that carbamylated PON-1 concentration in uremic HDL was 1.49 ± 0.08 fold higher than that in HDL from controls (p < 0.05). The nanoLC-MS/MS showed that the carbamylation of lysine 290 (K290) of PON-1, a residue adjacent to PON-1 activity determining site, was detected in uremic HDL but not detected in control HDL. K290 carbamylation leads to local conformation changes that reduce accessible solvent accessibility. The HDL paraoxonase, arylesterase, and lactonase activities were all significantly lower in uremia patients than in control subjects. Additionally, HDL anti-antioxidant ability was also lower in uremia patients. Carbamylation of PON-1 in uremia patients could be one of the factors in impairing PON-1 enzyme activities and HDL anti-oxidation function.


Assuntos
Arildialquilfosfatase/metabolismo , Lipoproteínas HDL/metabolismo , Uremia/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carbamilação de Proteínas
13.
Artigo em Inglês | MEDLINE | ID: mdl-31976003

RESUMO

Liver X receptor (LXR) is a nuclear receptor that regulates various biological processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver disease (NAFLD). Sesamin is a naturally occurring lignan in many dietary plants and has a wide range of beneficial effects on metabolism. The mechanism underlying sesamin action especially on the regulation of LXR remains elusive. Reporter assays, mRNA and protein expression, and in silico modeling were used to identify sesamin as an antagonist of LXRα. Sesamin was applied to the hepatic HepaRG and intestinal LS174T cells and showed that it markedly ameliorated lipid accumulation in the HepaRG cells, by reducing LXRα transactivation, inhibiting the expression of downstream target genes. This effect was associated with the stimulation of AMP-activated protein kinase (AMPK) signaling pathway, followed by decreased T0901317-LXRα-induced expression of SREBP-1c and its downstream target genes. Mechanistically, sesamin reduced the recruitment of SRC-1 but enhanced that of SMILE to the SREBP-1c promoter region under T0901317 treatment. It regulated the transcriptional control exerted by LXRα by influencing its interaction with coregulators and thus decreased mRNA and protein levels of genes downstream of LXRα and reduced lipid accumulation in hepatic cells. Additionally, sesamin reduced valproate- and rifampin-induced LXRα and pregnane X receptor (PXR) transactivation. This was associated with reduced expression of target genes and decreased lipid accumulation. Thus, sesamin is an antagonist of LXRα and PXR and suggests that it may alleviate drug-induced lipogenesis via the suppression of LXRα and PXR signaling.

14.
J Agric Food Chem ; 66(44): 11647-11662, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30359008

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a very common liver disease, and its incidence has significantly increased worldwide. The liver X receptor α (LXRα) is a multifunctional nuclear receptor that controls lipid homeostasis. Inhibition of LXRα transactivation may be beneficial for NAFLD and hyperlipidemia treatment. Ursolic acid (UA) is a plant triterpenoid with many beneficial effects; however, the mechanism of its action on LXRα remains elusive. We evaluated the effects of UA on T0901317 (T090)-induced LXRα activation and steatosis. UA significantly decreased the LXR response element and sterol regulatory element-binding protein-1c ( SREBP-1c) gene promoter activities, mRNA, protein expression of LXRα target genes, and hepatic cellular lipid content in a T090-induced mouse model. A molecular docking study indicated that UA bound competitively with T090 at the LXRα ligand binding domain. UA stimulated AMP-activated protein kinase (AMPK) phosphorylation in hepatic cells and increased corepressor, small heterodimer partner-interacting leucine zipper protein (SMILE) but decreased coactivator, steroid receptor coactivator-1 (SRC-1) recruitment to the SREBP-1c promoter region. In contrast, UA induced SRC-1 binding but decreased SMILE binding to reverse cholesterol transport-related gene promoters in intestinal cells, increasing lipid excretion from intestinal cells. Additionally, UA reduced valproate-induced LXRα mediated and rifampin-induced pregnane X receptor mediated lipogenesis, offering potential treatments for drug-induced hepatic steatosis. Thus, UA displays liver specificity and can be selectively repressed while RCT stimulation by LXRα is preserved and enhanced. This is a novel therapeutic option to treat NAFLD and may be helpful in developing LXR agonists to prevent atherosclerosis.


Assuntos
Lipogênese/efeitos dos fármacos , Receptores X do Fígado/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Triterpenos/administração & dosagem , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Humanos , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/química , Ligantes , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado/química , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/química , Triterpenos/química
15.
J Agric Food Chem ; 66(42): 10964-10976, 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30351048

RESUMO

Liver X receptor α (LXRα) controls important biological and pathophysiological processes such as lipid homeostasis. Inhibiting LXRα transactivation may beneficial in the treatment of nonalcoholic fatty liver disease (NAFLD), which is one of the main causes of liver diseases and hyperlipidemia. Oleanolic acid (OA) is a naturally occurring triterpenoid found in many plants. It has several beneficial effects on biological pathways; however, the mechanisms underlying its effects on LXRα are unclear. Therefore, we evaluated the effects of OA on T0901317-induced LXRα activation and explored whether OA can attenuate hepatic lipogenesis. The results showed that OA significantly decreased the promoter activities of LXR response element and sterol regulatory element binding protein-1c (SREBP-1c). It also decreased the mRNA and protein expression of LXRα target genes. These resulted in reduced hepatocellular lipid content. Our results also revealed that the overall binding pose of OA is similar to the X-ray pose of T0901317. Furthermore, OA stimulated AMP-activated protein kinase phosphorylation in hepatic cells. Additionally, it increased small heterodimer partner-interacting leucine zipper protein (SMILE) but decreased steroid receptor coactivator-1 (SRC-1) recruitment to the SREBP-1c promoter region. OA also enhanced LXRα-mediated induction of reverse cholesterol transport (RCT)-related gene, ATP-binding cassette transporter (ABC) A1, and ABCG1 expression in intestinal cells. It was found that OA increased the binding of SRC-1 but decreased SMILE recruitment to the ABCG1 gene promoter region. Furthermore, it reduced valproate- and rifampin-induced LXRα- and pregnane X receptor-mediated lipogenesis, respectively, which indicates its potential benefit in treating drug-induced hepatic steatosis. The results also show that OA is liver-specific and can be selectively repressed of lipogenesis. Moreover, it preserves and enhances LXRα-induced RCT stimulation. The results show that OA may be a promising treatment for NAFLD. Additionally, it can be used in the development of LXRα agonists to prevent atherosclerosis.


Assuntos
Hepatócitos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Ácido Oleanólico/farmacologia , Receptor de Pregnano X/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Hidrocarbonetos Fluorados/farmacologia , Ligantes , Receptores X do Fígado/genética , Coativador 1 de Receptor Nuclear/genética , Coativador 1 de Receptor Nuclear/metabolismo , Receptor de Pregnano X/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Sulfonamidas/farmacologia
16.
Anal Cell Pathol (Amst) ; 2018: 8623937, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30155403

RESUMO

Objective: Human colorectal cancer (CRC) is the third most common cancer; patients with metastatic colorectal cancer (mCRC) show poor prognosis than those with CRC cases. There are no reliable molecular biomarkers for the diagnosis of CRC prognosis except with pathological features. Therefore, it is urgent to develop a biomarker for diagnosis and/or prediction of human CRC. In addition, capping actin protein (CapG) belongs to the gelsolin family and has been reported to contribute on tumor invasion/metastasis in multiple human cancers. Here, we are the first to evaluate the expression of CapG in human CRCs. Study Design: To investigate the expression levels of CapG in human tissue array by immunohistochemistry (IHC) staining. Moreover, the mRNA and protein levels were also confirmed in four CRC cell lines and determined using real-time RT-PCR and Western blotting. Finally, a Matrigel transwell invasion assay was used to evaluate the invasion ability in CapG high or low expression cells. Results: We demonstrated that CapG could be determined in the normal colon tissue and human CRC specimens. However, CapG was significantly overexpressed in the mCRC specimens compared with that in CRC specimens and normal cases. It was also detectable in the four CRC cell lines including mRNA and protein levels. We also found that knockdown of the expression of CapG reduced tumor migration. Conclusions: In this study, we suggested that CapG could be used as a biomarker for metastatic CRC in the clinical specimens. Moreover, our in vitro study demonstrated that CapG might contribute on tumor metastasis in human CRCs.


Assuntos
Proteínas de Capeamento de Actina/metabolismo , Neoplasias Colorretais/metabolismo , Proteínas de Capeamento de Actina/genética , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Neoplasias Colorretais/genética , Células HCT116 , Células HT29 , Humanos , Imuno-Histoquímica
17.
Arch Toxicol ; 92(9): 2829-2844, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30003287

RESUMO

To characterize the association between epilepsy, use of antiepileptic drugs (AEDs), and the risk of hyperlipidemia, we conducted a nationwide population-based cohort study with data obtained from the National Health Insurance Research Database of Taiwan. The effects of AEDs on lipogenic gene expression were also examined in vitro. We identified 3617 cases involving patients, whose epilepsy was newly diagnosed between 2000 and 2011, and selected a comparison cohort comprising 14,468 patients without epilepsy. The Cox proportional hazards model was used to evaluate the association between epilepsy, AED use, and hyperlipidemia. The incidence rate of hyperlipidemia was higher in the epilepsy cohort than in the comparison cohort, with an adjusted hazard ratio (aHR) of 1.21 [95% confidence interval (CI): 1.06-1.38] after adjusting for comorbidities and medications. Epilepsy patients not taking AEDs had a higher risk of hyperlipidemia (aHR 1.65; 95% CI 1.35-2.03). Among AEDs, only valproate treatment showed a higher risk of hyperlipidemia (aHR 1.53; 95% CI 1.01-2.33), although the dose-dependent effect did not reach statistical significance. In vitro studies with two hepatic cell lines showed that valproate may exert its effects by activating the liver X receptor alpha (LXRα) signaling pathway, inducing the expression of lipogenesis-related genes and increasing cellular lipid contents. In silico calculations concluded that valproate can bind stably with the ligand-binding domain of LXRα. Thus, valproate-induced hepatic lipogenic gene expression may occur through LXRα activation. Predicting the 'off-target' effects of valproate may prove valuable in developing antiepileptic agents with fewer adverse reactions. Monitoring blood lipid levels throughout the course of treatment is recommended.


Assuntos
Anticonvulsivantes/efeitos adversos , Hiperlipidemias/epidemiologia , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Adulto , Idoso , Estudos de Coortes , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Incidência , Receptores X do Fígado/química , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Taiwan/epidemiologia
18.
Int J Mol Sci ; 19(1)2018 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-29361731

RESUMO

The global incidence of thyroid cancer, one of the most common endocrine malignancies, is especially high among women. Although most patients with thyroid cancers exhibit a good prognosis with standard treatment, there are no effective therapies for patients with anaplastic thyroid cancers or cancers that have reached an advanced or recurrent level. Therefore, it is important to develop highly effective compounds for treating such patients. Aloperine, a natural compound isolated from Sophora alopecuroides, has been reported to possess antioxidant, anti-inflammatory, anti-neuronal injury, anti-renal injury, antitumor, anti-allergic, and antiviral properties. In this study, we show that aloperine can inhibit cell growth in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Moreover, it could suppress in vitro tumorigenesis and promote cellular apoptosis. Further analysis demonstrated the involvement of caspase-dependent apoptosis, including intrinsic and/or extrinsic pathways, in aloperine-induced cellular apoptosis. However, cell cycle regulation was not detected with aloperine treatment. This study suggests the potential therapeutic use of aloperine in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Piperidinas/farmacologia , Neoplasias da Glândula Tireoide/metabolismo , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Citometria de Fluxo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
19.
In Vivo ; 32(1): 47-54, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29275298

RESUMO

The association between anti-tuberculosis (TB) treatments and the risk of developing hyperlipidemia remains unclear. Data were obtained from the Longitudinal Health Insurance Database 2000 (LHID2000). The case group included patients newly diagnosed with hyperlipidemia (n=16,054) between 2006 and 2011 selected from the LHID2000. A four-fold number of hyperlipidemia-free cases (n=64,216) were matched with case patients by age, sex, and index year to create the control group. Univariable and multivariable unconditional logistic regression analyses were conducted to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between hyperlipidemia and anti-TB medication use. Patients that used isoniazid (INH) were significantly associated with a decreased risk of hyperlipidemia (OR=0.71, 95%CI=0.57-0.88). After adjustment for age, sex, urbanization level, and income as well as ethambutol, pyrazinamide, streptomycin, and anti-human immunodeficiency virus drug medications, a dose-dependent risk of hyperlipidemia was observed in the INH, rifampin (RIF), and INH and RIF groups with the ORs progressively decreasing as the cumulative dose increased. In the Taiwanese patients who used anti-TB medications, INH and RIF use was associated with a decreased risk of hyperlipidemia.


Assuntos
Antituberculosos/uso terapêutico , Hiperlipidemias/epidemiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Hiperlipidemias/diagnóstico , Hiperlipidemias/etnologia , Isoniazida/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mycobacterium tuberculosis/fisiologia , Vigilância da População/métodos , Estudos Retrospectivos , Rifampina/uso terapêutico , Fatores de Risco , Taiwan/epidemiologia , Tuberculose/etnologia , Tuberculose/microbiologia , Adulto Jovem
20.
Phytomedicine ; 36: 37-49, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29157826

RESUMO

BACKGROUND: Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy. PURPOSE: In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3). METHODS: The hepatocellular carcinoma cell line, HepG2, was used to evaluate the promoter activity of PXR and CAR target genes, CYP3A4 and CYP2B6, respectively. Catalytic activities, mRNA, and protein expression of CYP3A4 and CYP2B6 were evaluated in a differentiated HepaRG cell line. Coregulation of PXR with coregulators on CYP3A4 promoter response elements was also been characterized. RESULTS: Transient transfection assays showed that UA effectively attenuated CYP3A4 and CYP2B6 promoter activities mediated by rifampin (RIF, human PXR agonist) and CITCO (human CAR agonist). These inhibitory effects were well correlated with the expression and catalytic activities of CYP3A4 and CYP2B6. Furthermore, the interaction of co-regulators with PXR and the transcriptional complexes in the CYP3A4 promoter activity and CYP3A4 promoter xenobiotic response element (everted repeat 6, ER6), respectively, were disrupted in the presence of UA. UA showed an antagonistic effect against PXR, and reversed the cytotoxic effects of isoniazid (INH) induced by RIF. Taken together, these results show that UA inhibits the transactivation effects of PXR and CAR, and reduces the expression and function of CYP3A4 and CYP2B6. CONCLUSION: The present study suggests that UA could be a powerful agent for reducing potentially dangerous interactions between transcriptional inducers of CYP enzymes and therapeutic drugs.


Assuntos
Isoniazida/toxicidade , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Triterpenos/farmacologia , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Receptor de Pregnano X , Regiões Promotoras Genéticas/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/genética , Rifampina/farmacologia , Transfecção
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