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1.
Environ Toxicol ; 39(2): 857-868, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37860891

RESUMO

Corosolic acid (CA), a plant-derived pentacyclic triterpenoid, has potent anti-inflammatory, anti-metabolic, and anti-neoplastic actions against a variety of human cancers. However, the specific mechanism by which CA inhibits the progression of renal cell carcinoma (RCC) is yet unclear. We found that CA (≤8 µM) had no influence on either the growth or viability of RCC cell lines (786-O, ACHN, and Caki-1) or normal HK2 cells. However, in a dose-dependent manner, CA prevented the invasion and migration of RCC cells. Human protease array analysis showed that CA reduced MMP2 expression. At increasing concentrations of CA, the expression of MMP2 was dose-dependently reduced, as shown by western blot and RT-PCR analyses as well as immunofluorescence staining. CA also stimulated ERK1/2 phosphorylation in 786-O and Caki-1 cells. Transfection of CA-treated RCC cells with siRNA-ERK restored MMP2 protein expression and the motility and invasion capabilities of RCC cells. Molecular docking study results showed that CA and MMP2 interact strongly. These findings elucidate the mechanism by which CA prevents RCC cells from migrating and invading, and these findings indicate that CA may be a potential anti-metastatic therapy for RCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica
2.
Environ Toxicol ; 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39171862

RESUMO

Oxyresveratrol (OxyR) exerts biological and pharmacological effects in a variety of tumor cells, including antioxidant action, antitumor activity, and proapoptotic effects. However, the regulation of targeted signaling pathways by OxyR and the mechanism underlying these effects in human renal cell carcinoma (RCC) have been less studied. We observed that OxyR at noncytotoxic doses did not affect the growth of human RCC cells or normal kidney HK2 cells. OxyR inhibited ACHN and Caki-1 cell migration and invasion through targeting matrix metalloproteinase 1 (MMP1) expression. Analysis of clinical databases showed that high MMP1 expression is associated with lower overall survival (OS) in these cancers (p < 0.01). OxyR significantly inhibited the mRNA and protein expression of Sp1. Furthermore, luciferase assay results showed that OxyR inhibited Sp1 transcriptional activity. Additionally, OxyR preferentially suppressed the activation of ERK and PKCα. Treatment with U0126 (MEK inhibitor) or G06976 (PKCα inhibitor) clearly decreased Sp1 and MMP1 expression and inhibited RCC cell migration and invasion. In conclusion, OxyR may be a potential antitumor therapy for the inhibition of migration and invasion by controlling p-ERK/Sp1 and p-PKCα/Sp1-mediated MMP1 expression in RCC.

3.
Int J Mol Sci ; 25(1)2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38203509

RESUMO

Vascular endothelial growth factor (VEGF) plays a significant role as a pro-angiogenic and pro-permeability factor within the kidney. Bevacizumab is a pharmaceutical monoclonal anti-VEGF antibody that inhibits the growth of new blood vessels, which blocks blood supply and thereby restricts tumor growth. Thus, we conducted a nationwide study to explore the risk of chronic kidney disease (CKD) development in Taiwan residents after bevacizumab therapy. We drew data from the extensive National Health Insurance Research Database (NHIRD), which encompasses data from >99% of Taiwan's population from 1995 onwards. Individuals who received bevacizumab between 2012-2018 were identified as the bevacizumab cohort, with the index date set at the first usage. We randomly selected dates within the study period for the control group to serve as index dates. We excluded patients with a history of CKD prior to the index date or those <20 years old. In both cohorts, patients' propensity scores matched in a 1:1 ratio based on sex, age, index year, income, urbanization level, comorbidities, and medications. We found patients treated with bevacizumab had a significantly higher risk of contracting CKD than patients without bevacizumab (adjusted hazard ratio = 1.35, 95% confidence interval = 1.35-1.73). The risk of CKD was 1.35-fold higher in participants with bevacizumab treatment than those in the control group. These findings suggest that close monitoring of CKD development after bevacizumab administration is needed.


Assuntos
Insuficiência Renal Crônica , Fator A de Crescimento do Endotélio Vascular , Humanos , Adulto Jovem , Adulto , Bevacizumab/efeitos adversos , Estudos Retrospectivos , Taiwan/epidemiologia , Insuficiência Renal Crônica/epidemiologia
4.
Int J Med Sci ; 19(7): 1138-1146, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35919818

RESUMO

Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), protein-bound uremic toxins, can induce oxidative stress and cause renal disease progression. However, the different cytotoxic effects on renal cells between IS and PCS are not stated. Due to uremic toxins are generally found in CKD patients, the mechanisms of uremic toxins-induced renal injury are required to study. Curcumin has anti-oxidant, anti-inflammatory and anti-apoptotic effects which may be potential used to protect against renal damage. In contrast, curcumin also exert cytotoxic effects on various cells. In addition, curcumin may reduce or enhance cytotoxicity combined with different chemicals treatments. However, whether curcumin may influence uremic toxins-induced renal injury is unclear. The goal of this study is to compare the different cytotoxic effects on renal cells between IS and PCS treatment, as well as the synergistic or antagonistic effects by combination treatments with curcumin and PCS. Our experimental result shows the PCS exerts a stronger antiproliferative effect on renal tubular cells than IS treatment. In addition, our study firstly demonstrates that curcumin enhances PCS-induced cell cytotoxicity through caspase-dependent apoptotic pathway and cell cycle alteration.


Assuntos
Curcumina , Insuficiência Renal Crônica , Cresóis/metabolismo , Curcumina/farmacologia , Curcumina/uso terapêutico , Humanos , Indicã/metabolismo , Indicã/toxicidade , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Sulfatos , Ésteres do Ácido Sulfúrico/metabolismo , Ésteres do Ácido Sulfúrico/toxicidade
5.
Int J Med Sci ; 19(6): 1023-1028, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35813302

RESUMO

Triple-negative breast cancer (TNBC) is the third most common female cancer in Taiwan. EZH2 plays an important role in cancer development through transcriptional repression by chromatin remodeling. However, the expression of EZH2 in breast cancer is highly correlated with tumorigenesis, and patient survival is not matched to TNBC. Furthermore, it has not been determined if specific EZH2 genetic variants are associated with breast cancer risk. In this paper, we evaluated the survival of different types of breast cancer. The results indicated that a lower expression of EZH2 led to poor survival of TNBC patients. Therefore, we aimed at studying the relationship between genetic polymorphisms of EZH2 and susceptibility to TNBC in Taiwan. Four single-nucleotide polymorphisms (SNPs) of EZH2 (rs6950683, rs2302427, rs3757441, and rs41277434) were analyzed by real-time PCR genotyping in 176 patients with TNBC and 1000 cancer-free controls. The results showed that TNBC patients under 60 years old who carried a TC or CC genotype at EZH2 rs6950683 and re3757441 had a tumor size of 20 mm or smaller (T1). Thus, this study is the first to examine the age and mutant genes associated with EZH2 SNPs in TNBC progression and development in Taiwan.


Assuntos
Neoplasias de Mama Triplo Negativas , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Taiwan/epidemiologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
Nephrology (Carlton) ; 27(11): 877-885, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36045565

RESUMO

INTRODUCTION: Patients with end-stage kidney disease (ESKD) exhibit an elevated cardiovascular risk. Chronic inflammation is one of the main mechanisms of cardiovascular disease (CVD). Lipopolysaccharide has been proposed as a link between systemic inflammation and CVD. Herein, we evaluated whether lipopolysaccharide-binding protein (LBP), a surrogate marker of lipopolysaccharide and consequent inflammation, is associated with cardiovascular events in ESKD. METHODS: We performed a prospective cohort study of maintenance haemodialysis patients. Baseline serum LBP levels were categorized into tertiles and also modelled continuously for analyses. Cox regression methods were used to evaluate the association of serum LBP levels with cardiovascular events. RESULTS: A total of 360 haemodialysis patients were included in this analysis. During a median follow-up of 3.1 years, 90 (25.0%) patients had cardiovascular events. Patients in the upper tertile of serum LBP levels had a significantly greater risk of cardiovascular events [hazard ratio (HR) 4.87; 95% confidence intervals (CI), 2.12-11.15] than those in the lower tertile, independent of age, sex, hypertension, diabetes, CVD, dialysis vintage, body mass index, non-high-density lipoprotein cholesterol, albumin, phosphorus, high-sensitivity C-reactive protein, and interleukin-6. The association was consistent regardless of whether competing risk of death was accounted for (subdistribution HR 4.87; 95% CI, 1.96-12.11 for upper versus lower tertiles) or serum LBP was analysed as a continuous variable (HR 1.30; 95% CI, 1.02-1.66 per 1 SD increment). CONCLUSIONS: Serum LBP levels were independently associated with cardiovascular events in heomodialysis patients. LBP might serve as a novel biomarker for CVD in ESKD.


Assuntos
Doenças Cardiovasculares , Falência Renal Crônica , Proteínas de Fase Aguda , Biomarcadores , Proteína C-Reativa , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Proteínas de Transporte , Humanos , Inflamação , Interleucina-6 , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Lipopolissacarídeos , Glicoproteínas de Membrana , Fósforo , Estudos Prospectivos , Diálise Renal/efeitos adversos
7.
J Ren Nutr ; 31(2): 189-198, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32900583

RESUMO

OBJECTIVES: This study was performed to determine the effects of probiotic supplementation on cholesterol-triglyceride ratio, an indirect marker of insulin resistance, protein-bound uremic toxins, biomarkers of inflammation, and microbial translocation in end-stage renal disease patients on hemodialysis. METHODS: Fifty-six patients aged 39-75 years were assigned into two groups to receive either probiotic sachets (n = 28) or a placebo (n = 28) in a randomized double-blinded placebo-controlled clinical trial. The patients in the probiotic group received twice daily sachets that contained a mixture of three viable and freeze-dried strains: Lactococcus lactis subsp. Lactis LL358, Lactobaccillus salivarius LS159, and Lactobaccillus pentosus LPE588 at high dose (100 billion; 1 × 1011 cfu/day) for 6 months. RESULTS: A total of 50 patients were available for final analysis. Probiotic supplementation did not have a significant influence on cholesterol-triglyceride ratio. Probiotic supplementation for 6 months caused a significant decrease in serum levels of indoxyl sulfate. Compared with the placebo, probiotic supplementation did not result in significant changes in hemoglobin levels, blood urea nitrogen, blood glucose, serum p-cresyl sulfate, inflammatory, and microbial translocation markers. No clinically significant changes in body composition were observed between the two groups during the study period. The probiotic supplementation was well tolerated by all subjects with minimal adverse effects during the 6-month-long study. CONCLUSION: Our results suggest that high-dose multistrain lactobaccillus probiotic supplementation over 6 months as a monotherapy did not significantly decrease markers of insulin resistance, cholesterol-triglyceride ratio, and most of the studied markers, with the exception of levels of indoxyl sulfate in patients on HD.


Assuntos
Lactobacillus , Probióticos , Método Duplo-Cego , Humanos , Lactobacillus acidophilus , Diálise Renal , Toxinas Urêmicas
8.
Blood Purif ; 47(1-3): 28-36, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30219816

RESUMO

BACKGROUND: In hemodialysis (HD) patients, impaired gut barrier and alteration in microbiota in the gut is thought to increase the risk of bacterial translocation and chronic inflammation. Lipopolysaccharide-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by microbial products. Our aim is to investigate the relationship between circulating levels of LBP, and various metabolic and inflammatory markers in HD patients. Besides, we also aim to determine its relationship among -patients with different body mass index. PATIENTS AND METHODS: A total of 123 HD patients were stratified into three -tertiles, according to serum LBP level. The LBP and inflammatory markers were determined using immunoassay methods. A bioimpedance spectroscopy device was used for body composition measurement. RESULTS: The serum levels of the two proinflammatory markers, high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-6, were significantly higher in patients in the upper tertile when compared with the rest of the tertiles. In HD patients, a significant positive correlation was found between serum LBP levels and CRP, IL-6, soluble CD14 (sCD14), and fasting blood glucose levels. Patients with metabolic syndrome and pre-existing cardiovascular disease had higher LBP levels than those without metabolic syndrome. Besides, obese patients were also associated with higher serum LBP levels. Multivariate regression analyses showed that IL-6 level was the strongest correlate of LBP level, followed by hsCRP level and sCD14. CONCLUSIONS: Our study suggested that elevated plasma LBP was associated with metabolic syndrome and obesity. In addition, increased LBP level was correlated positively to markers of inflammation, and sCD14 levels.


Assuntos
Doenças Cardiovasculares , Proteínas de Transporte/sangue , Glicoproteínas de Membrana/sangue , Síndrome Metabólica , Obesidade , Diálise Renal , Proteínas de Fase Aguda , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/terapia , Doença Crônica , Estudos Transversais , Feminino , Humanos , Inflamação/sangue , Inflamação/terapia , Interleucina-6/sangue , Receptores de Lipopolissacarídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Síndrome Metabólica/terapia , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Obesidade/terapia
9.
Mediators Inflamm ; 2017: 1070959, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29200664

RESUMO

Despite the continuous progression in dialysis medicine, mortality and the burden of cardiovascular disease (CVD) among hemodialysis patients are still substantial. Substantial evidence suggests that proinflammatory (CD16+) monocytes contribute to the development of atherosclerosis. A cohort of 136 stable hemodialysis patients (follow-up: 6.25 year) was assessed to investigate the association between the proportion of CD16+ monocytes for all-cause and CVD mortalities. The CD16+ monocytes were associated with both mortalities after adjusting for a preexisting CVD history. Compared to the reference group (CD16+ monocytes within [15.6-18.6], the first and second quartile), patients with CD16+ monocytes above the highest quartile level (>21.5) had an adjusted hazard ratio (HR) of 30.85 (95% confidence interval [CI]: 7.12-133.8) for CVD mortality and 5.28 (2.07-13.49) for all-cause mortality, and those with CD16+ monocytes below the lowest quartile ≤15.6), had significantly elevated death risks after 3.5-year follow-up (HR [95% CI]: 10.9 [2.42-48.96] and 4.38 [1.45-13.24] for CV and all-cause mortalities, respectively). The hemodialysis patients with CD16+ monocyte level in a low but mostly covering normal range also portended a poor prognosis. The findings shed some light for nephrologists on future prospects of early recognizing immune dysfunction and improving early intervention outcomes.


Assuntos
Doenças Cardiovasculares/metabolismo , Monócitos/metabolismo , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Receptores de IgG/metabolismo , Diálise Renal
10.
J Ren Nutr ; 27(4): 267-274, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28431808

RESUMO

OBJECTIVE: Rapid screening and monitoring of nutritional status is mandatory in hemodialysis population because of the increasingly encountered nutritional problems. Considering the limitations of previous composite nutrition scores applied in this population, we tried to develop a standardized composite nutrition score (SCNS) using low lean tissue index as a marker of protein wasting to facilitate clinical screening and monitoring and to predict outcome. DESIGN AND METHODS: This retrospective cohort used 2 databases of dialysis populations from Taiwan between 2011 and 2014. First database consisting of data from 629 maintenance hemodialysis patients was used to develop the SCNS and the second database containing data from 297 maintenance hemodialysis patients was used to validate this developed score. RESULTS: SCNS containing albumin, creatinine, potassium, and body mass index was developed from the first database using low lean tissue index as a marker of protein wasting. When applying this score in the original database, significantly higher risk of developing protein wasting was found for patients with lower SCNS (odds ratio 1.38 [middle tertile vs highest tertile, P < .0001] and 2.40 [lowest tertile vs middle tertile, P < .0001]). The risk of death was also shown to be higher for patients with lower SCNS (hazard ratio 4.45 [below median level vs above median level, P < .0001]). These results were validated in the second database. CONCLUSION: We developed an SCNS consisting of 4 easily available biochemical parameters. This kind of scoring system can be easily applied in different dialysis facilities for screening and monitoring of protein wasting. The wide application of body composition monitor in dialysis population will also facilitate the development of specific nutrition scoring model for individual facility.


Assuntos
Falência Renal Crônica/epidemiologia , Desnutrição Proteico-Calórica/epidemiologia , Diálise Renal/efeitos adversos , Idoso , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Creatinina/sangue , Feminino , Seguimentos , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Modelos Logísticos , Masculino , Avaliação Nutricional , Estado Nutricional , Potássio/sangue , Desnutrição Proteico-Calórica/sangue , Desnutrição Proteico-Calórica/diagnóstico , Desnutrição Proteico-Calórica/etiologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Albumina Sérica/metabolismo , Taiwan/epidemiologia , Triglicerídeos/sangue
11.
Blood Purif ; 40(3): 243-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26406805

RESUMO

BACKGROUND: Albumin, the most abundant protein in the extracellular fluid, displays an important antioxidant activity. Increased levels of oxidized albumin levels (high human non-mercaptoalbumin (HNA) level) have been reported in the serum of patients with end-stage renal disease. In this study, we attempted to identify the albumin redox status in the serum of patients on peritoneal dialysis (PD) and examined the relationship between these proteins and the transport type of the peritoneal membrane and other clinical and laboratory variables. METHODS: We performed a cross-sectional study of a cohort of 80 patients with end-stage renal disease receiving PD. Peritoneal transport characteristics were identified and after peritoneal equilibration test patients were grouped as high (high(H)/high-average (HA) group, n = 31) or low (low (L)/low-average (LA) group, n = 49) transporters. The redox state of human serum albumin was measured using high-performance liquid chromatography. RESULTS: The fraction of human mercaptoalbumin (HMA) showed significantly higher values in patients with high transport status than those with low transport status (f(HMA) 64.0 ± 5.4 and 52.7 ± 10.4%, respectively). Our data showed that the H/HA transport characteristic was associated with lower albumin (3.76 ± 0.48 vs. 4.00 ± 0.35, p < 0.05), and lower levels of advanced oxidized protein product (p = 0.008) when compared with the L/LA type. A correlation analysis showed that there was a positive correlation between dialysate/plasma (D/P) creatinine and f(HMA) levels (r = 0.511, p < 0.0001), as well as hemoglobin levels r = 0.231, p = 0.044 and a negative correlation between D/P creatinine and serum albumin, cholesterol and LDL levels (r = -0.236, p = 0.039; r = -0.237, p = 0.038; r = -0.272, p = 0.018, respectively). CONCLUSIONS: This study showed that higher serum levels of reduced albumin f(HMA) appear to be associated with high/high average peritoneal membrane transport characteristics in the incident PD patients.


Assuntos
Antioxidantes/metabolismo , Falência Renal Crônica/sangue , Diálise Peritoneal Ambulatorial Contínua/instrumentação , Albumina Sérica/metabolismo , Adulto , Idoso , Antioxidantes/química , Transporte Biológico , Colesterol/sangue , Estudos de Coortes , Creatinina/sangue , Estudos Transversais , Feminino , Produtos Finais de Glicação Avançada/sangue , Hemoglobinas/metabolismo , Hemorreologia , Humanos , Falência Renal Crônica/patologia , Falência Renal Crônica/terapia , Rins Artificiais , Lipoproteínas LDL/sangue , Masculino , Membranas Artificiais , Pessoa de Meia-Idade , Oxirredução , Análise de Regressão , Albumina Sérica/química
12.
Naunyn Schmiedebergs Arch Pharmacol ; 397(7): 4799-4808, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38153512

RESUMO

Systemic vascular endothelial growth factor (VEGF) blockade has been the top adjunctive chemotherapy since 1990. Anti-VEGF therapy has also been associated with worsened renal function in some patients. However, the association between patient outcomes and use of intravitreal VEGF inhibitors remains controversial. Thus, it is necessary to determine the action mechanism and long-term renal effects of ranibizumab. The National Health Insurance Research Database (NHIRD) is one of the largest global databases that are extensively used for epidemiological research. NHIRD contains the medical information of all insureds, such as inpatient, outpatient, emergency, and traditional Chinese medicine records. We selected subjects aged ≥ 20 years who recently administered ranibizumab for the ranibizumab cohort. Non-ranibizumab cohort consisted of subjects who did not receive ranibizumab, and the index date was a random date between 2008 and 2018. We excluded subjects with missing sex and age records and those in which the date of primary outcome was before the index date. The two cohorts were matched via 1:1 propensity score matching based on sex, age, index year, hypertension, diabetes mellitus, hyperlipidemia, stroke, coronary artery disease, alcoholism, chronic obstructive pulmonary disease, and age-related macular degeneration, retinal vein occlusion, and diabetic macular edema. Medical confounders were angiotensin I-converting enzyme inhibitors, statins, corticosteroids, VEGF inhibitors including bevacizumab and aflibercept, lithium, amphotericin B, adefovir, NSAIDS, cisplatin, and calcineurin inhibitors. Among 48,248 participants aged ≥ 20 years, 24,136 (50%) received ranibizumab (13,565 male [56.20%] and 10,571 female [43.80%]). Moreover, 24,136 participants who did not receive ranibizumab were matched by age, sex, comorbidities, and medications. Subjects who received ranibizumab exhibited a significantly higher risk of CKD than those who did not receive ranibizumab (adjusted hazard ratio = 1.88, 95% CI = 1.79-1.96). Our findings revealed that exposure to intravitreal ranibizumab is an independent risk factor for CKD. Therefore, physicians and ophthalmologists should make the patients aware of such a correlation to increase patient safety and decrease the CKD burden.


Assuntos
Inibidores da Angiogênese , Injeções Intravítreas , Ranibizumab , Insuficiência Renal Crônica , Humanos , Masculino , Feminino , Taiwan/epidemiologia , Pessoa de Meia-Idade , Ranibizumab/administração & dosagem , Ranibizumab/efeitos adversos , Insuficiência Renal Crônica/epidemiologia , Idoso , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/administração & dosagem , Adulto , Fatores de Risco , Bases de Dados Factuais , Estudos de Coortes , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos Retrospectivos
13.
J Dermatol Sci ; 107(3): 142-150, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36075780

RESUMO

BACKGROUND: Lysosomal cell death is induced by lysosomal membrane permeabilization (LMP) and the subsequent release of lysosomal proteolytic enzymes, including cathepsins (CTSs), which results in mitochondrial dysfunction and apoptosis. Imiquimod (IMQ), a synthetic TLR7 ligand, has both antiviral and antitumor activity against various skin malignancies in clinical treatment. Previously, we demonstrated IMQ not only caused lysosomal dysfunction but also triggered lysosome biogenesis to achieve lysosomal adaptation in cancer cells. OBJECTIVE: To determine whether lysosomes are involved in IMQ-induced apoptosis. METHODS: The human skin cancer cell lines BCC, A375 and mouse melanoma cell line B16F10 were used in all experiments. Cell death was determined by the Cell Counting Kit-8 (CCK-8) assay and DNA content assay. Protein expression was determined by immunoblotting. Caspase-8 activity was assessed using a fluorescence caspase-8 kit and determined by flow cytometry and confocal microscopy. RESULTS: IMQ not only induced lysosome damage but also abrogated lysosome function in skin cancer cells. IMQ-induced caspase-8 activation contributed to the processes of lysosomal cell death. Moreover, the use of ROS scavengers significantly abolished caspase-8 activation and inhibited IMQ-induced LMP. Additionally, pharmacological inhibition of CTSD not only abrogated caspase-8 activation but also rescued IMQ-induced cell death. Finally, lysosome-alkalizing agents enhanced the cytotoxicity of IMQ in vitro and in vivo. CONCLUSIONS: IMQ-induced ROS accumulation promotes LMP, releases CTSs into the cytosol, stimulates caspase-8 activation and finally causes lysosomal cell death. Lysosomal cell death and the CTSD/caspase-8 axis may play a crucial role in IMQ-induced cell death.


Assuntos
Neoplasias Cutâneas , Receptor 7 Toll-Like , Animais , Antivirais/uso terapêutico , Apoptose , Caspase 8/metabolismo , Caspase 8/farmacologia , Caspase 8/uso terapêutico , Catepsinas/metabolismo , Catepsinas/farmacologia , Catepsinas/uso terapêutico , DNA/metabolismo , Humanos , Imiquimode/farmacologia , Ligantes , Lisossomos/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Receptor 7 Toll-Like/metabolismo
14.
Anticancer Res ; 41(8): 3789-3799, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281838

RESUMO

BACKGROUND/AIM: Cetyltrimethylammonium bromide (CTAB), a quaternary ammonium surfactant, was shown to have antitumor effects in a cellular mode of head and neck squamous cell carcinoma (HNSCC), modulating apoptotic and cytotoxic processes. However, the mechanisms by which CTAB exerts its effects against the epithelial- mesenchymal transition in HNSCC remain poorly understood. In the present study, we investigated whether CTAB inhibits cellular mobility and invasiveness of hypopharyngeal squamous cell carcinoma (HPSCC) cells. MATERIALS AND METHODS: WST-1, cell-cycle phase distribution, and wound healing, as well as transwell assays were conducted. Changes in protein expression patterns and related signaling pathways involved in effects of CTAB on HPSCC cell lines were evaluated by western blotting. RESULTS: Treatment of human HPSCC cell lines with CTAB significantly altered their morphology from spindle-like to cobblestone-like by diminishing mesenchymal-like phenotypic characteristics. CTAB also hindered cell functional properties, including migration and invasion, independently of cell viability. In addition, western blot results demonstrated that treatment with CTAB reduced expression of mesenchymal markers. Further investigation showed that CTAB treatment suppressed the phosphorylation of extracellular-regulated kinase 1/2, mechanistic target of rapamycin kinase and AKT serine/threonine kinase 1. CTAB also repressed the expression and phosphorylation levels of epidermal growth factor receptor (EGFR) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and the partial restoration of mesenchymal phenotype by EGF addition confirmed that CTAB inhibited migration and invasion in HPSCC cells by blocking the EGFR signaling pathway. CONCLUSION: Our results suggest that CTAB is involved in the suppression of EGFR-mediated mesenchymal phenotype and the molecular mechanism by which CTAB obstructs HPSCC cell metastasis may represent a promising strategy for use in HPSCC treatment.


Assuntos
Cetrimônio/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Serina-Treonina Quinases TOR/metabolismo
15.
Food Sci Nutr ; 9(6): 3308-3316, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34136195

RESUMO

Vitamin C and vitamin E are well-known antioxidant vitamins, both of which are also applied as adjunct treatments for cancer therapy. Methotrexate (MTX) is a clinical drug that is used widely for rheumatoid arthritis and cancer treatment. Human glioblastoma multiforme (GBM) is an aggressive malignant brain tumor; the mean survival time for GBM patients is <2 years with traditional therapies. Developing and investigating novel treatments are important for clinical GBM therapy. Therefore, the aim of this study was to investigate whether combined treatment with vitamin C/E and MTX can display anticancer activities on GBM. Our studies showed that MTX displays anticancer effects on GBM in a dose-dependent manner, while vitamins C and E are not cytotoxic to glioblastoma. Importantly, this study showed that vitamins C and E can promote anticancer effects on low-concentration methotrexate-treated glioblastoma. Additionally, this study suggested that MTX alone or combined with vitamins C/E inhibits GBM cell growth via the caspase-3 death pathway.

16.
Anticancer Res ; 40(9): 5059-5069, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878794

RESUMO

BACKGROUND/AIM: Liver cancer is the fourth leading cause of cancer-related mortality globally, of which hepatocellular carcinoma (HCC) accounts for 85-90% of total primary liver cancer. A drug shortage for HCC therapy triggered us to screen the small-molecule database with a high-throughput cellular screening system. Herein, we examined whether cetyltrimethylammonium bromide (CTAB) inhibits cellular mobility and invasiveness of Mahlavu HCC cells. MATERIALS AND METHODS: The effects of CTAB on cell viability were assessed using WST-1 assay, cell-cycle distribution using flow cytometric analysis, migration/invasion using woundhealing and transwell assays, and associated protein levels using western blotting. RESULTS: Treatment of Mahlavu cells with CTAB transformed its mesenchymal spindle-like morphology. In addition, CTAB exerted inhibitory effects on the migration and invasion of Mahlavu cells dose-dependently. CTAB also reduced the protein levels of matrix metalloproteinase-2 (MMP2), MMP9, RAC family small GTPase 1, SNAIL family transcriptional repressor 1 (SNAI1), SNAI2, TWIST family basic helix-loop-helix transcription factor 1 (TWIST1), vimentin, N-cadherin, phospho-fibroblast growth factor (FGF) receptor, phospho-phosphoinositide 3-kinase, phospho-v-Akt murine thymoma viral oncogene and phospho-signal transducer and activator of transcription 3 but increased the protein levels of tissue inhibitor of metalloproteinases-1/2 and E-cadherin. Rescue experiments proved that CTAB induced mesenchymal-epithelial transition in Mahlavu cells and this was significantly dose-dependently mitigated by basic FGF. CONCLUSION: CTAB suppressed the migration and invasion of Mahlavu cells through inhibition of the FGF signaling pathway. CTAB seems to be a potential agent for preventing metastasis of hepatic cancer.


Assuntos
Antineoplásicos/farmacologia , Cetrimônio/farmacologia , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Sci Rep ; 9(1): 3207, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30824757

RESUMO

p-Cresyl sulfate (pCS), a uremic toxin, can cause renal damage and dysfunction. Studies suggest that renal dysfunction increases the prevalence of renal cancer. However, the effect of pCS on the proliferation and migration of renal cancer is unclear. Clear cell renal cell carcinoma (ccRCC) expresses mutant von Hippel-Lindau gene and is difficult to treat. Hypoxia-inducible factor-1α and 2-α (HIF-1α and HIF-2α) as well as microRNA-21 (miR-21) can regulate the proliferation and migration of ccRCC cells. However, the association between HIF-α and miR-21 in ccRCC remains unclear. Therefore, the effects of pCS on ccRCC cells were investigated for HIF-α and miR-21 signals. Our results showed that pCS induced overexpression of HIF-1α and promoted the proliferation and regulated epithelial-mesenchymal transition-related proteins, including E-cadherin, fibronectin, twist and vimentin in ccRCC cells. pCS treatment increased miR-21 expression. Specifically, inhibition of miR-21 blocked pCS-induced proliferation and migration. Taken together, the present results demonstrate that pCS directly induced the proliferation and migration of ccRCC cells through mechanisms involving miR-21/HIF-1α signaling pathways.


Assuntos
Carcinoma de Células Renais/patologia , Movimento Celular/efeitos dos fármacos , Cresóis/toxicidade , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/patologia , MicroRNAs/metabolismo , Transdução de Sinais , Ésteres do Ácido Sulfúrico/toxicidade , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/genética , MicroRNAs/genética , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
18.
Anticancer Res ; 39(7): 3621-3631, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262888

RESUMO

BACKGROUND/AIM: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells. MATERIALS AND METHODS: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis. RESULTS: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, snail, slug, twist, vimentin, fibronectin, N-cadherin, Smad2, Smad3, Smad4, phosphoinositide-3-kinase (PI3K), p-PI3K, Akt, p-Akt, ß-catenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3ß. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-ß (TGF-ß) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-ß signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K. CONCLUSION: CTAB is involved in the suppression of TGF-ß-mediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Cetrimônio/farmacologia , Neoplasias Hepáticas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adenocarcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Invasividade Neoplásica , Transdução de Sinais/efeitos dos fármacos
19.
Nephrology (Carlton) ; 13(8): 677-83, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19019166

RESUMO

AIM: The CD40-CD40L system has been implicated in the pathogenesis of atherothrombotic complications in cardiovascular disease. The aim of this study was to determine the relationship between plasma soluble CD40 ligand (sCD40L) and symptomatic coronary heart disease (CHD) in end-stage renal disease (ESRD) patients on maintenance haemodialysis (HD). METHODS: This cross-sectional study included 57 HD patients, 31 of whom had symptomatic CHD. Lipid profile, markers of endothelial activation such as sCD40L, and both inflammatory and oxidative stress markers were measured and analyzed. RESULTS: The sCD40L concentration was significantly higher in HD patients than in controls (1.34 +/- 0.53 vs 0.86 +/- 0.12 ng/mL, P < 0.01). Plasma concentration of sCD40L (P < 0.01), soluble vascular adhesion molecule-1 (sVCAM-1; P < 0.01) and high-sensitivity CRP (hsCRP; P < 0.01) were higher in HD patients with symptomatic CHD than in those without CHD. In addition, we also found that oxidative stress biomarkers such as nitrotyrosine (NT), malonaldehyde (MDA) and protein carbonyl (PC) were significantly elevated in patients with symptomatic CHD compared to those without. There was a strong overall positive relationship between sCD40L concentration and sVCAM-1 (r = 0.54, P < 0.001), MDA (r = 0.365, P < 0.01), NT (r = 0.293, r < 0.05) and log-transformed triglycerides (r = 0.275, P < 0.05). CONCLUSION: Circulating concentrations of sCD40L were elevated in HD patients with symptomatic CHD. This study suggests that CD40-CD40L may play a potentially important role in the atherosclerotic complications of HD patients.


Assuntos
Ligante de CD40/sangue , Doença das Coronárias/imunologia , Falência Renal Crônica/terapia , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Doença das Coronárias/sangue , Doença das Coronárias/complicações , Estudos Transversais , Feminino , Humanos , Mediadores da Inflamação/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/imunologia , Lipídeos/sangue , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo , Projetos Piloto , Carbonilação Proteica , Tirosina/análogos & derivados , Tirosina/sangue , Regulação para Cima , Molécula 1 de Adesão de Célula Vascular/sangue
20.
Mol Med Rep ; 17(1): 31-36, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29115579

RESUMO

Aristolochic acid (AA) is a component identified in traditional Chinese remedies for the treatment of arthritic pain, coughs and gastrointestinal symptoms. However, previous studies have indicated that AA can induce oxidative stress in renal cells leading to nephropathy. α­tocopherol exists in numerous types of food, such as nuts, and belongs to the vitamin E isoform family. It possesses antioxidant activities and has been used previously for clinical applications. Therefore, the aim of the present study was to determine whether α­tocopherol could reduce AA­induced oxidative stress and renal cell cytotoxicity, determined by cell survival rate, reactive oxygen species detection and apoptotic features. The results indicated that AA markedly induced H2O2 levels and caspase­3 activity in renal tubular epithelial cells. Notably, the presence of α­tocopherol inhibited AA­induced H2O2 and caspase­3 activity. The present study demonstrated that antioxidant mechanisms of α­tocopherol may be involved in the increased survival rates from AA­induced cell injury.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Aristolóquicos/efeitos adversos , Caspase 3/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Túbulos Renais/citologia , Estresse Oxidativo/efeitos dos fármacos , Vitamina E/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , alfa-Tocoferol/farmacologia
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