RESUMEN
Bladder cancer is becoming one of the most common malignancies across the world. Although treatment strategy has been continuously improved, which has led to cisplatin-based chemotherapy becoming the standard medication, cancer recurrence and metastasis still occur in a high proportion of patients because of drug resistance. The high efficacy of regorafenib, a broad-spectrum kinase inhibitor, has been evidenced in treating a variety of advanced cancers. Hence, this study investigated whether regorafenib could also effectively antagonize the survival of cisplatin-resistant bladder cancer and elucidate the underlying mechanism. Two types of cisplatin-resistant bladder cancer cells, T24R1 and T24R2, were isolated from T24 cisplatin-sensitive bladder cancer cells. These cells were characterized, and T24R1- and T24R2-xenografted tumor mice were created to examine the therapeutic efficacy of regorafenib. T24R1 and T24R2 cells exhibited higher expression levels of epithelial-mesenchymal transition (EMT) and stemness markers compared to the T24 cells, and regorafenib could simultaneously inhibit the viability and the expression of EMT/stemness markers of both T24R1 and T24R2 cells. Moreover, regorafenib could efficiently arrest the cell cycle, promote apoptosis, and block the transmigration/migration capabilities of both types of cells. Finally, regorafenib could significantly antagonize the growth of T24R1- and T24R2-xenografted tumors in mice. These results demonstrated the therapeutic efficacy of regorafenib in cisplatin-resistant bladder cancers. This study, thus, provides more insights into the mechanism of action of regorafenib and demonstrates its great potential in the future treatment of cisplatin-resistant advanced bladder cancer patients.
Asunto(s)
Antineoplásicos , Neoplasias de la Vejiga Urinaria , Humanos , Animales , Ratones , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transición Epitelial-Mesenquimal , Línea Celular TumoralRESUMEN
BACKGROUND: Exposure to particulate matter (PM) may contribute to lung inflammation and injury. The therapeutic effect of N-acetylcysteine (NAC), a well-known antioxidant, with regards to the prevention and treatment of fine PM (PM2.5)-induced lung injury is poorly understood. This study aimed to determine the effect of PM2.5 on the recruitment of neutrophils and Ly6Chigh monocytes into lung alveoli and the production of proinflammatory proteins by stimulating the generation of reactive oxygen species (ROS), and to investigate the therapeutic effect of NAC on PM2.5-induced lung injury. METHODS: C57BL/6 mice were exposed to a single administration of PM2.5 (200 µg/100 µl/mouse) or phosphate-buffered saline (control) via intratracheal instillation. The mice were injected intratracheally via a microsprayer aerosolizer with NAC (20 or 40 mg/kg) 1 h before PM2.5 instillation and 24 h after PM2.5 instillation. Total protein, VEGF, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF) were measured. Oxidative stress was evaluated by determining levels of malondialdehyde (MDA) and nitrite in BALF. Flow cytometric analysis was used to identify and quantify neutrophils and Ly6Chigh and Ly6Clow monocyte subsets. RESULTS: Neutrophil count, total protein, and VEGF content in BALF significantly increased after PM2.5 exposure and reached the highest level on day 2. Increased levels of TNF-alpha, IL-6, nitrite, and MDA in BALF were also noted. Flow cytometric analysis showed increased recruitment of neutrophils and Ly6Chigh, but not Ly6Clow monocytes, into lung alveoli. Treatment with NAC via the intratracheal spray significantly attenuated the recruitment of neutrophils and Ly6Chigh monocytes into lung alveoli in PM2.5-treated mice in a dose-dependent manner. Furthermore, NAC significantly attenuated the production of total protein, VEGF, nitrite, and MDA in the mice with PM2.5-induced lung injury in a dose-dependent manner. CONCLUSION: PM2.5-induced lung injury caused by the generation of oxidative stress led to the recruitment of neutrophils and Ly6Chigh monocytes, and production of inflammatory proteins. NAC treatment alleviated PM2.5-induced lung injury by attenuating the ROS-mediated recruitment of neutrophils and Ly6Chigh monocytes and lung inflammation.
Asunto(s)
Lesión Pulmonar , Neumonía , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Animales , Interleucina-6/metabolismo , Pulmón , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/metabolismo , Ratones , Ratones Endogámicos C57BL , Monocitos , Neutrófilos/metabolismo , Nitritos/metabolismo , Material Particulado/efectos adversos , Neumonía/inducido químicamente , Neumonía/tratamiento farmacológico , Neumonía/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Hepatitis C virus-associated immune thrombocytopenia (HCV-ITP) has been assumed to be one of secondary ITP and associated with antiplatelet antibodies. This study was to clarify the antibody profile in HCV-ITP compared with primary ITP. We enrolled 55 HCV-ITP, 30 primary ITP, 11 Helicobacter pylori-ITP, 21 HCV control, and 16 healthy volunteers. We reviewed their blood cell counts, autoimmune markers, and spleen size. We used enzyme-linked immunosorbent assay kit to detect the specific antibody to glycoproteins IIb/IIIa, Ia/IIa, Ib/IX, IV, and human leukocyte antigen (HLA) class I. Compared with primary ITP patients, HCV-ITP patients had an older age, lower white blood cell (WBC) count and fewer presented with severe thrombocytopenia. The rate of positive antibody detection was 63.6% for the HCV-ITP group higher than the rate of 40% for the primary ITP. In the HCV control, antiplatelet antibodies were detected in 38.1% patients and no one had more than two types of antibodies. The antiplatelet antibodies correlated to severer thrombocytopenia. An HLA class I antibody was associated with lower WBCs and larger spleen. In conclusion, HCV-ITP patients had a high rate of positive antiplatelet antibody. The antibodies were associated with not only lower platelets but also leukopenia and splenomegaly.
Asunto(s)
Plaquetas/metabolismo , Hepacivirus/inmunología , Púrpura Trombocitopénica Idiopática/sangre , Trombocitopenia/sangre , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Diet is associated with self-reported indices of sexual health. The mechanisms responsible for these changes remain poorly understood. AIM: To investigate the hemodynamic and histological impact of dietary change in a rat model of hyperlipidemia-associated erectile dysfunction. METHODS: 40 2-month old male Sprague-Dawley rats were divided into 4 groups. 10 rats were fed a diet of standard chow and served as negative controls (N group). The remaining 30 age-matched rats were divided at random into 3 groups: (i) high-fat diet for 5 months starting at age 5 months (H group); (ii) high-fat diet for 5 months starting at age 4 months followed by 1 month of standard chow (H+N1M group); and (iii) high-fat diet for 5 months starting at age 2 months followed by 3 months of standard chow (H+N3M group). All rats underwent erectile function testing and sacrifice at age 10 months. OUTCOMES: Intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured to evaluate erectile function. Blood samples were collected to measure serum testosterone and lipid levels, and penile tissue specimens were obtained for histological examination. RESULTS: Total body weight, low-density lipoprotein, and serum glucose were significantly higher in the H group compared with the N and H+N3M groups. Serum high-density lipoprotein level was significantly lower in the H group compared with the N and H+N3M groups. The mean ICP/MAP ratio was significantly lower in the H group compared with the N and H+N3M groups (0.33 ± 0.05 vs 0.79 ± 0.07 vs 0.73 ± 0.13; P < .05 for both). Markers for intracorporal neuronal nitric oxide synthase and endothelial cells were more weakly expressed in the H group compared with the N and H+N3M groups. There was no significant difference in smooth muscle content among the groups. Mean cavernosal oxidative stress and the apoptotic index were significantly higher in the H group compared with the N and H+N3M groups. No significant between-group differences were noted with respect to serum testosterone; the H group had significantly higher serum glucose and low-density lipoprotein levels, effects that were partially mitigated in the H +N1M and H+N3M groups. CLINICAL TRANSLATION: Administration of a healthy diet is associated with normalization of functional and histological penile defects associated with a high-fat diet. STRENGTHS & LIMITATIONS: Metabolic changes were clearly linked to functional improvements in penile blood flow. Differences between rat and human lipoprotein metabolism are a limitation of this study. CONCLUSION: Dietary changes may have positive effects on penile hemodynamics in a rat model of hyperlipidemia-associated erectile dysfunction. Huang Y-C, Ho D-R, Lin J-H, et al. Dietary Modification Is Associated with Normalization of Penile Hemodynamics in Rats Fed a High-Fat Diet. J Sex Med 2019;16:791-802.
Asunto(s)
Dieta Alta en Grasa , Hemodinámica/fisiología , Pene/irrigación sanguínea , Animales , Peso Corporal , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Disfunción Eréctil/fisiopatología , Hiperlipidemias/fisiopatología , Lipoproteínas LDL/metabolismo , Masculino , Músculo Liso/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Estrés Oxidativo/fisiología , Erección Peniana/fisiología , Distribución Aleatoria , Ratas Sprague-DawleyRESUMEN
Mechanical ventilation is usually required for saving lives in critically ill patients; however, it can cause ventilator-induced lung injury (VILI). As VEGF-secreting Ly6Chigh monocytes are involved in VILI pathogenesis, we investigated whether cyclooxygenase-2 (COX-2) activity regulates the recruitment of VEGF-secreting Ly6Chigh monocytes during VILI. The clinically relevant two-hit mouse model of VILI, which involves the intravenous injection of lipopolysaccharide prior to high tidal volume (HTV)-mechanical ventilation, was used in this study. To investigate the role of COX-2 in the recruitment of VEGF-secreting Ly6Chigh monocytes during VILI, celecoxib, which is a clinical COX-2 inhibitor, was administered 1 h prior to HTV-mechanical ventilation. Pulmonary vascular permeability and leakage, inflammatory leukocyte infiltration, and lung oxygenation levels were measured to assess the severity of VILI. HTV-mechanical ventilation significantly increased the recruitment of COX-2-expressing Ly6Chigh, but not Ly6Clow, monocytes. Celecoxib significantly diminished the recruitment of Ly6Chigh monocytes, attenuated the levels of VEGF and total protein in bronchoalveolar lavage fluid, and restored pulmonary oxygenation during VILI. Our findings demonstrate that COX-2 activity is important in the recruitment of VEGF-secreting Ly6Chigh monocytes, which are involved in VILI pathogenesis, and indicate that the suppression of COX-2 activity might be a useful strategy in mitigating VILI.
Asunto(s)
Antígenos Ly/metabolismo , Ciclooxigenasa 2/metabolismo , Monocitos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/metabolismo , Animales , Permeabilidad Capilar/efectos de los fármacos , Modelos Animales de Enfermedad , Lipopolisacáridos/toxicidad , Pulmón/metabolismo , Pulmón/patología , Masculino , Monocitos/patología , Lesión Pulmonar Inducida por Ventilación Mecánica/inducido químicamente , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
Trichostatin A (TSA), an antifungal antibiotic derived from Streptomyces, inhibits mammalian histone deacetylases, and especially, selectively inhibits class I and II histone deacetylase (HDAC) families of enzymes. TSA reportedly elicits an antiproliferative response in multifarious tumors. This study investigated the antitumor effects of TSA alone and in combination with paclitaxel when applied to two high-grade urothelial carcinoma (UC) cell lines (BFTC-905 and BFTC-909). Fluorescence-activated cell sorting, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay were used to assess TSA's cytotoxicity and effects on apoptosis induction. TSA induced synergistic cytotoxicity, when combined with paclitaxel (combination index < 1), resulted in concomitant suppression of paclitaxel-induced activation of phospho-extracellular signal-regulated kinase (ERK) 1/2. A xenograft nude mouse model confirmed that TSA enhances the antitumor effects of paclitaxel. These findings demonstrate that the administration of TSA in combination with paclitaxel elicits a synergistic cytotoxic response. The results of this study indicate that the chemoresistance of UC could be circumvented by combining HDAC inhibitors to target the ERK pathway.
Asunto(s)
Carcinoma de Células Transicionales/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/administración & dosificación , Ácidos Hidroxámicos/administración & dosificación , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Paclitaxel/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ácidos Hidroxámicos/farmacología , Ratones , Paclitaxel/farmacología , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse. Reduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic agent, has demonstrated antitumor effects on various cancers. This study investigated the efficacy of TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism. Our results revealed that cisplatin-resistant UC cells (T24/R) upregulated the antiapoptotic factor, B-cell lymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells to the cisplatin cytotoxic effect. TFP (10-45 µM) alone elicited dose-dependent cytotoxicity, apoptosis, and G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in T24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with concurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed the T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the T24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and circumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a promising insight to develop a therapeutic strategy for chemoresistant UCs.
Asunto(s)
Antipsicóticos/farmacología , Carcinoma/tratamiento farmacológico , Resistencia a Antineoplásicos , Trifluoperazina/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Proteína bcl-X/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antipsicóticos/uso terapéutico , Apoptosis , Carcinoma/metabolismo , Línea Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Regulación hacia Abajo , Humanos , Ratones , Trifluoperazina/uso terapéutico , Neoplasias de la Vejiga Urinaria/metabolismo , Urotelio/efectos de los fármacos , Urotelio/metabolismo , Urotelio/patología , Proteína bcl-X/genéticaRESUMEN
Chondrosarcoma, a heterogeneous malignant bone tumor, commonly produces cartilage matrix, which generally has no response to conventional therapies. Studies have reported that MLN4924, a NEDD8-activating enzyme inhibitor, achieves antitumor effects against numerous malignancies. In this study, the suppressive effects of MLN4924 on human chondrosarcoma cell lines were investigated using in vitro and in vivo assays, which involved measuring cell viability, cytotoxicity, apoptosis, proliferation, cell cycles, molecule-associated cell cycles, apoptosis, endoplasmic reticulum (ER) stress, and tumor growth in a xenograft mouse model. Our results demonstrated that MLN4924 significantly suppressed cell viability, exhibited cytotoxicity, and stimulated apoptosis through the activation of caspase-3 and caspase-7 in chondrosarcoma cell lines. Furthermore, MLN4924 significantly inhibited cell proliferation by diminishing the phosphorylation of histone H3 to cause G2/M cell cycle arrest. In addition, MLN4924 activated ER stressâ»related apoptosis by upregulating the phosphorylation of c-Jun N-terminal kinase (JNK), enhancing the expression of GRP78 and CCAAT-enhancer-binding protein homologous protein (CHOP, an inducer of endoplasmic ER stressâ»related apoptosis) and activating the cleavage of caspase-4. Moreover, MLN4924 considerably inhibited the growth of chondrosarcoma tumors in a xenograft mouse model. Finally, MLN4924-mediated antichondrosarcoma properties can be accompanied by the stimulation of ER stressâ»related apoptosis, implying that targeting neddylation by MLN4924 is a novel therapeutic strategy for treating chondrosarcoma.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclopentanos/farmacología , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , Animales , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Caspasa 3/metabolismo , Línea Celular Tumoral , Condrosarcoma/tratamiento farmacológico , Condrosarcoma/metabolismo , Condrosarcoma/patología , Ciclopentanos/uso terapéutico , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Proteínas de Choque Térmico/metabolismo , Histonas/metabolismo , Humanos , Ratones , Ratones Desnudos , Proteína NEDD8/antagonistas & inhibidores , Proteína NEDD8/metabolismo , Fosforilación/efectos de los fármacos , Pirimidinas/uso terapéutico , Factor de Transcripción CHOP/metabolismo , Trasplante HeterólogoRESUMEN
The stress-upregulated catecholamines-activated ß1- and ß2-adrenergic receptors (ß1/2-ARs) have been shown to accelerate the progression of cancers such as colorectal cancer (CRC). We investigated the underlying mechanism of the inhibition of ß1/2-ARs signaling for the treatment of CRC and elucidated the significance of ß2-AR expression in CRC in vitro and in clinical samples. The impacts of ß1/2-AR antagonists in CRC in vitro and CRC-xenograft in vivo were examined. We found that repression of ß2-AR but not ß1-AR signaling selectively suppressed cell viability, induced G1-phase cell cycle arrest, caused both intrinsic and extrinsic pathways-mediated apoptosis of specific CRC cells and inhibited CRC-xenograft growth in vivo. Moreover, the expression of ß2-AR was not consistent with the progression of CRC in vitro or in clinical samples. Our data evidence that the expression profiles, signaling, and blockage of ß2-AR have a unique pattern in CRC comparing to other cancers. ß2-AR antagonism selectively suppresses the growth of CRC accompanying active ß2-AR signaling, which potentially carries wild-type KRAS, in vitro and in vivo via the inhibition of ß2-AR transactivated EFGR-Akt/ERK1/2 signaling pathway. Thus, ß2-AR blockage might be a potential therapeutic strategy for combating the progressions of ß2-AR-dependent CRC.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 2/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Apoptosis/efectos de los fármacos , Atenolol/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Citocromos c/metabolismo , Receptores ErbB/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Expresión Génica , Células HCT116 , Células HT29 , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Desnudos , Propanolaminas/farmacología , Propranolol/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores Adrenérgicos beta/clasificación , Receptores Adrenérgicos beta/genética , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Diabetes is usually asymptomatic in its early stage. Early diagnosis may improve outcomes by enabling initiation of treatment before end organ damage has progressed. The aim of this study was to determine whether the clinical sign of phimosis with preputial fissures is predictive of type 2 diabetes in patients not previously diagnosed with diabetes. Twenty-eight patients with acquired phimosis and preputial fissures were collected prospectively. Twenty-eight controls with acquired phimosis without preputial fissures were selected. Statistically significant differences were found in body mass index, random plasma glucose, glucosuria and glycosylated haemoglobin levels, but not in age, family history of diabetes, hypertension and classical hyperglycaemic symptoms. Diabetes was confirmed in all 28 patients in the preputial fissures group, but only 2 (7.1%) patients in the non-preputial fissures group (p < 0.0001). In conclusion, phimosis with preputial fissures may be a specific sign of undiagnosed diabetes mellitus.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Prepucio/patología , Fimosis/etiología , Adulto , Anciano , Biomarcadores/sangre , Glucemia/análisis , Estudios de Casos y Controles , Circuncisión Masculina , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Prepucio/cirugía , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Fimosis/diagnóstico , Fimosis/cirugía , Valor Predictivo de las Pruebas , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Oral squamous cell carcinoma (OSCC), an aggressive cancer originating in the oral cavity, is one of the leading causes of cancer deaths in males worldwide. This study investigated the antitumor activity and mechanisms of piperlongumine (PL), a natural compound isolated from Piper longum L., in human OSCC cells. The effects of PL on cell proliferation, the cell cycle, apoptosis, senescence and reactive oxygen species (ROS) levels in human OSCC cells were investigated. PL effectively inhibited cell growth, caused cell cycle arrest and induced apoptosis and senescence in OSCC cells. Moreover, PL-mediated anti-human OSCC behavior was inhibited by an ROS scavenger N-acetyl-l-cysteine (NAC) treatment, suggesting that regulation of ROS was involved in the mechanism of the anticancer activity of PL. These findings suggest that PL suppresses tumor growth by regulating the cell cycle and inducing apoptosis and senescence and is a potential chemotherapy agent for human OSCC cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Dioxolanos/farmacología , Acetilcisteína/farmacología , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fragmentación del ADN/efectos de los fármacos , Humanos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The CC chemokine receptor 6 (CCR6) and its ligand CCL20 are involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. In addition, interleukin-17 (IL-17), produced by a T cell subset named "Th17," has been identified as an important player in inflammatory responses, and has emerged as a mediator in inflammation-associated cancer. However, the relevance of IL-17 in the development and progression of CRC still remains to be explored. This study aimed to investigate the effect of IL-17 on the cell migration of CRC cells. Human CRC HCT-116 cells were used to study the effect of IL-17 on CCR6 expression and cell migration in CRC cells. IL-17 treatment induced migration of HCT-116 cells across the Boyden chamber membrane and increased the expression level of the CCR6. Inhibition of CCR6 by small interfering RNA (siRNA) and neutralizing antibody inhibited IL-17-induced cell migration. By using specific inhibitors and short hairpin RNA (shRNA), we demonstrated that the activation of ERK and p38 pathways are critical for IL-17-induced CCR6 expression and cell migration. Promoter activity and transcription factor ELISA assays showed that IL-17 increased NF-κB-DNA binding activity in HCT-116 cells. Inhibition of NF-κB activation by specific inhibitors and siRNA blocked the IL-17-induced CCR6 expression. Our findings support the hypothesis that CCR6 up-regulation stimulated by IL-17 may play an active role in CRC cell migration.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales , Interleucina-17/farmacología , Receptores CCR6/metabolismo , Quimiotaxis/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HCT116 , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Receptores CCR6/genética , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Accumulating data shows that exon 19 deletions and L858R, both activating epidermal growth factor receptor mutations in non-small-cell lung cancers (NSCLCs), are just two different entities in terms of prognosis and treatment response to tyrosine kinase inhibitors (TKIs). METHODS: A systematic review and meta-analysis of randomized controlled trials comparing TKIs with conventional chemotherapy was performed. Eight trials of 1498 patients and five trials of 1279 patients with either exon 19 deletions or L858R were included in the meta-analysis. RESULTS: TKI treatment demonstrated progression-free survival benefit in patients with exon 19 deletions (hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.21-0.35) and L858R (HR: 0.45, 95% CI: 0.35-0.58). Patients with exon 19 deletions had significant overall survival (OS) benefit under TKI treatment (HR: 0.72, 95% CI: 0.60-0.88). Subgroup analyses showed that irreversible TKIs, but not reversible TKIs, had statistically significant OS benefit in these patients (irreversible TKIs, HR: 0.59, 95% CI: 0.47-0.73; reversible TKIs, HR: 0.84, 95% CI: 0.69-1.02). Patients with L858R demonstrated no OS benefit under first-line TKI use (HR: 1.15, 95% CI: 0.95-1.39). CONCLUSIONS: In patients with advanced NSCLC harbouring exon 19 deletions, TKIs are associated with better OS compared with conventional chemotherapy. Future clinical trials should take exon 19 deletions and L858R as distinct disease entities and evaluate the treatment efficacy separately.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Eliminación de Secuencia , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Nephroureterectomy with bladder cuff excision may not be sufficient as monotherapy for patients with pT3N0M0 upper tract urothelial carcinoma. The efficacy of postoperative adjuvant chemotherapy in this setting remains controversial. We evaluated the efficacy of adjuvant chemotherapy for patients with pT3N0M0 upper tract urothelial carcinoma in overall, cancer specific and recurrence-free survival. MATERIALS AND METHODS: We retrospectively reviewed records on 171 consecutive patients with pT3N0M0 upper tract urothelial carcinoma treated with radical nephroureterectomy between 2004 and 2014 at 2 branches of the same institution. Postoperative adjuvant chemotherapy was gemcitabine/cisplatin or cisplatin/fluorouracil/leucovorin. Overall, cancer specific and recurrence-free survival rates were estimated using the Kaplan-Meier method. The values of prognostic factors were evaluated by Cox regression analysis. RESULTS: Postoperative adjuvant chemotherapy was administered in 60 patients vs nonadjuvant therapy in 111 patients. Median followup was 35.8 months. Between the adjuvant and nonadjuvant treatment groups there were statistically significant differences in 5-year cancer specific (80.5% vs 57.6%, p = 0.010) and recurrence-free (74.4% vs 52.9%, p = 0.026) survival rates. Although there was no statistically significant difference in overall survival (71.9% vs 49.0%, p = 0.072), there was a trend of better overall survival in the patients who received postoperative chemotherapy. On multivariable analysis age (p = 0.018), tumor location (p = 0.003) and adjuvant chemotherapy (p = 0.001) were predictors of cancer specific survival. CONCLUSIONS: Adjuvant chemotherapy improves cancer specific and recurrence-free survival in patients with pT3N0M0 upper tract urothelial carcinoma after radical nephroureterectomy.
Asunto(s)
Carcinoma de Células Transicionales/terapia , Cisplatino/uso terapéutico , Estadificación de Neoplasias , Nefrectomía , Cuidados Posoperatorios/métodos , Neoplasias Urológicas/terapia , Anciano , Antineoplásicos/uso terapéutico , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/mortalidad , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Taiwán/epidemiología , Resultado del Tratamiento , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/mortalidadRESUMEN
Lewis Y Ag (LeY) is a cell-surface tetrasaccharide that participates in angiogenesis. Recently, we demonstrated that LeY is a specific ligand of the recombinant lectin-like domain of thrombomodulin (TM). However, the biologic function of interaction between LeY and TM in endothelial cells has never been investigated. Therefore, the role of LeY in tube formation and the role of the recombinant lectin-like domain of TM-TM domain 1 (rTMD1)-in antiangiogenesis were investigated. The recombinant TM ectodomain exhibited lower angiogenic activity than did the recombinant TM domains 2 and 3. rTMD1 interacted with soluble LeY and membrane-bound LeY and inhibited soluble LeY-mediated chemotaxis of endothelial cells. LeY was highly expressed on membrane ruffles and protrusions during tube formation on Matrigel. Blockade of LeY with rTMD1 or Ab against LeY inhibited endothelial tube formation in vitro. Epidermal growth factor (EGF) receptor in HUVECs was LeY modified. rTMD1 inhibited EGF receptor signaling, chemotaxis, and tube formation in vitro, and EGF-mediated angiogenesis and tumor angiogenesis in vivo. We concluded that LeY is involved in vascular endothelial tube formation and rTMD1 inhibits angiogenesis via interaction with LeY. Administration of rTMD1 or recombinant adeno-associated virus vector carrying TMD1 could be a promising antiangiogenesis strategy.
Asunto(s)
Antígenos del Grupo Sanguíneo de Lewis/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Proteínas Recombinantes/farmacología , Trombomodulina/química , Animales , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma Pulmonar de Lewis/patología , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Femenino , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/fisiología , Células Endoteliales de la Vena Umbilical Humana/trasplante , Humanos , Lectinas/química , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/fisiología , Unión Proteica , Estructura Terciaria de Proteína/fisiología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico , Trombomodulina/metabolismo , Trombomodulina/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: The N-terminal lectin-like domain (domain 1 [D1]) of thrombomodulin (TM) is known to have an anti-inflammatory function. We previously showed that recombinant TM domain 1 (rTMD1) interacts with a carbohydrate molecule, Lewis Y (Le(y)), which is found to be expressed on adhesion molecules and involved in cell adhesion. Here, we tested the effect of rTMD1/Le(y) interaction on leukocyte recruitment in inflammation. APPROACH AND RESULTS: The expression of Le(y) on the surface of human umbilical vein endothelial cells was increased by tumor necrosis factor-α stimulation. Direct binding of rTMD1 to Le(y) on the cell surface was observed. rTMD1 inhibited Le(y)-mediated leukocyte adhesion on the Le(y)-immobilized flow chamber and activated endothelium under a shear flow. The following leukocyte transmigration to endothelium was also reduced by rTMD1 through binding Le(y). In vivo, treatment of rTMD1 reduced leukocyte recruitment to the inflammatory sites in carotid ligation injury and thioglycollate-induced peritonitis. rTMD1 administration in apolipoprotein E-deficient mice effectively suppressed atherosclerotic plaque formation and macrophage infiltration in atherosclerotic lesions. Increased Le(y) expression, as well as administered rTMD1, was observed in inflamed vessels. CONCLUSIONS: rTMD1 suppresses vascular inflammation by inhibiting leukocyte recruitment to endothelium through attenuating Le(y)-mediated adhesion and further protects against atherosclerosis progression. The present study provides a mechanism showing that rTMD1 can inhibit inflammation by binding to its carbohydrate ligand Le(y).
Asunto(s)
Antiinflamatorios/administración & dosificación , Aterosclerosis/prevención & control , Quimiotaxis de Leucocito/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Antígenos del Grupo Sanguíneo de Lewis/metabolismo , Neutrófilos/efectos de los fármacos , Trombomodulina/administración & dosificación , Vasculitis/prevención & control , Animales , Antiinflamatorios/metabolismo , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Traumatismos de las Arterias Carótidas/inmunología , Traumatismos de las Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/patología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana/inmunología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Antígenos del Grupo Sanguíneo de Lewis/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Neutrófilos/metabolismo , Placa Aterosclerótica , Estructura Terciaria de Proteína , Proteínas Recombinantes/administración & dosificación , Trombomodulina/metabolismo , Migración Transendotelial y Transepitelial/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Vasculitis/inmunología , Vasculitis/metabolismo , Vasculitis/patologíaRESUMEN
Sepsis results from the host hyperinflammatory response to bacterial infection, causing multiple organ failure and high mortality. We previously demonstrated that LPS binds to monocytic membrane-bound thrombomodulin (TM), but the role of monocytic TM in LPS-induced inflammation remains unknown. In this study, we demonstrated that TM knockdown in human monocytic cells attenuated LPS-induced signaling pathways and cytokine production. Coimmunoprecipitation and immunofluorescence assays showed that monocytic TM interacted with the LPS receptors, CD14 and TLR4/myeloid differentiation factor-2 (MD-2) complex, indicating that it binds to LPS and triggers an LPS-induced inflammatory response by interacting with the CD14/TLR4/MD-2 complex. We also found that monocytic TM knockdown reduced cytokine production induced by gram-negative bacteria Klebsiella pneumoniae, suggesting that monocytic TM plays an important role in gram-negative bacteria-induced inflammation. To further investigate the function of monocytic TM in vivo, myeloid-specific TM-deficient mice were established and were found to display improved survival that resulted from the attenuation of septic syndrome, including reduced systemic inflammatory response and resistance to bacterial dissemination, after K. pneumoniae infection or cecal ligation and puncture surgery. The inhibition of bacterial dissemination in mice with a deficiency of myeloid TM may be caused by the early increase in neutrophil infiltration. Therefore, we conclude that monocytic TM is a novel component in the CD14/TLR4/MD-2 complex and participates in the LPS- and gram-negative bacteria-induced inflammatory response.
Asunto(s)
Inflamación/inmunología , Monocitos/inmunología , Sepsis/inmunología , Trombomodulina/inmunología , Animales , Línea Celular , Citocinas/biosíntesis , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Técnicas de Silenciamiento del Gen , Infecciones por Bacterias Gramnegativas/inmunología , Humanos , Inmunoprecipitación , Inflamación/metabolismo , Lipopolisacáridos/inmunología , Ratones , Monocitos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sepsis/metabolismo , Trombomodulina/metabolismoRESUMEN
Introduction: Atherosclerotic cardiovascular disease is associated with a high mortality rate due to vascular calcification. The role of fetuin-A in aortic arch calcification (AAC) is less well understood. Methods: An analysis of secondary biomarkers was performed on 800 individuals from the biobank using the community database. AAC was defined by radiologists based on imaging. Multiple variables logical analysis was used for risk analysis. Results: A total of 736 individual samples were collected based on age and gender. The average age is 65 ± 10â years, and half the population comprises men. In spite of similar body weight, renal function, and hepatic function, the AAC group had higher blood pressure and fetuin-A levels independently: systolic blood pressure (SBP) index ≥130â mmHg [adjusted odds ratio (aOR) 1.85, 95% confidence interval (CI) 1.34-2.57, p = 0.002] and fetuin-A (aOR 0.62, 95% CI 0.50-0.76, p < 0.001). Moreover, it is evident that AAC can be predicted more accurately when combined with SBP ≥130â mmHg and a low fetuin-A level (<358â µg/ml: aOR 5.39, 95% CI 3.21-9.08) compared with the reference. Conclusion: Low fetuin-A levels are significantly correlated with AAC while there is an increased association between vascular calcification and coexisting hypertension.
RESUMEN
Colorectal cancer (CRC) is one of the leading causes of malignancy-related deaths worldwide. Radiotherapy is often combined with surgery to treat patients with more advanced CRC. Despite impressive initial clinical responses, radiotherapy resistance is the main reason for most treatment failures in colorectal cancer. The G protein-coupled adrenergic receptor (AR) has shown to involve in the development and radiotherapy resistance of CRC. The ß2-AR blockage (ICI-118,551) can use to inhibit the progression of CRC through downregulating EGFR-Akt-ERK1/2 signaling. Since catecholamines-activated the G protein-coupled AR activation has been shown to result in radioresistant, co-treatment with both ß2-AR blockage and radiation may be improved the clinical outcome of CRC. We demonstrated that selective ß2-AR blockage, but not selective ß1-AR blockage, significantly enhanced radiation-induced apoptosis in CRC cells with wild-type p53 in vitro. The molecular mechanism of the apoptotic pathway was possibly triggered by a change in the mitochondrial membrane permeability and release of cytosolic cytochrome C through phospho-P53 mitochondrial translocation. We also found that a P53 knockout in the HCT116 cells was correlated with reversing ß2-AR blockage-mediated apoptosis induction after radiation treatment. Furthermore, the ß2-AR blockage significantly inhibited CRC cell-xenograft growth in vivo. Our study suggests that ß2-AR blockage may be used as adjunct agent for improving the clinical outcomes of CRC following radiotherapy by inducing apoptosis in CRC cells.
RESUMEN
Sarcopenia has been associated with conventional chemotherapy-related toxicity, postoperative complications and poor overall survival in patients with genotype-unselected metastatic colorectal cancer (mCRC). This study aimed to evaluate the prognostic implications of sarcopenia and its change after perioperative cetuximab plus doublet chemotherapy and hepatectomy in patients with RAS wild-type colorectal liver metastasis (CRLM). Patients with CRLM from 2007 to 2018 in Chang Gung Research Database were retrospectively analyzed. Baseline characteristics as well as skeletal muscle index (SMI) at baseline and dynamic changes after interventions were collected. A multivariate Cox proportional hazard model was used to evaluate the effect of each parameter on overall survival (OS), and the Kaplan-Meier method was used to establish survival curves. A two-sided p value < 0.05 was considered statistically significance. Of 214 RAS wild-type mCRC patients who received both cetuximab and doublet chemotherapy, 77 who received upfront or subsequent hepatectomy were included in this study. The median follow-up time was 2.3 years. The rate of sarcopenia was higher in the patients who received neoadjuvant cetuximab-containing regimens than in those who received upfront hepatectomy (95% versus 63%, p = 0.001). Increased SMI after perioperative systemic therapy remained independently associated with better OS in multivariate analysis [hazard ratio (HR) = 0.27/10% increase, p = 0.013). The patients with sarcopenia had a trend of worse OS than those without sarcopenia (median OS: 4.5 versus 3.6 years, log-rank p = 0.282). Improvement in sarcopenia ([SMI after intervention - initial SMI]/initial SMI × 100%) is an important prognostic factor for OS. Future research is warranted to investigate direct interventions for sarcopenia and the impact on OS.