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1.
JCI Insight ; 7(18)2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36048544

RESUMEN

Pseudomonas aeruginosa is one of the most common nosocomial infections worldwide, and it frequently causes ventilator-associated acute pneumonia in immunocompromised patients. Abundant neutrophil extracellular traps (NETs) contribute to acute lung injury, thereby aggravating ventilator-induced lung damage. While pattern recognition receptors (PRRs) TLR4 and TLR5 are required for host defense against P. aeruginosa invasion, the PRR responsible for P. aeruginosa-induced NET formation, proinflammatory cytokine release, and acute lung injury remains unclear. We found that myeloid C-type lectin domain family 5 member A (CLEC5A) interacts with LPS of P. aeruginosa and is responsible for P. aeruginosa-induced NET formation and lung inflammation. P. aeruginosa activates CLEC5A to induce caspase-1-dependent NET formation, but it neither causes gasdermin D (GSDMD) cleavage nor contributes to P. aeruginosa-induced neutrophil death. Blockade of CLEC5A attenuates P. aeruginosa-induced NETosis and lung injury, and simultaneous administration of anti-CLEC5A mAb with ciprofloxacin increases survival rate and decreases collagen deposition in the lungs of mice challenged with a lethal dose of P. aeruginosa. Thus, CLEC5A is a promising therapeutic target to reduce ventilator-associated lung injury and fibrosis in P. aeruginosa-induced pneumonia.


Asunto(s)
Lesión Pulmonar Aguda , Lectinas Tipo C/metabolismo , Neumonía , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Caspasas , Ciprofloxacina , Citocinas , Lipopolisacáridos/toxicidad , Ratones , Neumonía/metabolismo , Neumonía/patología , Pseudomonas aeruginosa , Receptores de Superficie Celular , Receptor Toll-Like 4 , Receptor Toll-Like 5
2.
Huan Jing Ke Xue ; 43(8): 4253-4261, 2022 Aug 08.
Artículo en Chino | MEDLINE | ID: mdl-35971721

RESUMEN

Taraxacum kok-saghyz Rodin (TSK) is an energy plant that can be used as a raw material for natural rubber. The aim of this study was to examine the remediation potential of TSK to lead (Pb)- and cadmium (Cd)-contaminated farmland soil. In this study, a pot experiment was conducted, and the "Soil Environmental Quality and Agricultural Land Soil Pollution Risk Control Standard (GB 15618-2018)" was used as reference. We set up four different concentrations of Pb and Cd pollution treatment to study the characteristics of the accumulation and tolerance of TSK to Pb and Cd. The results showed that as the content of Pb and Cd in the soil increased, the chlorophyll content and biomass of TSK gradually decreased, and the SOD, POD, and CAT enzyme activities gradually increased. The BCF and TF of Cd were between 1.20 and 1.50, indicating that TSK presented some characteristics of a Cd hyperaccumulator. The BCF and TF of Pb were between 0.71 and 1.11. Thus, TSK was a good Pb enrichment plant and possessed the potential to repair soil with ω(Pb) below 400 mg·kg-1. The accumulation of Pb and Cd gradually increased, and the maximum accumulation of Cd and Pb in the shoots was 9.832 µg·plant-1 and 1091.185 µg·plant-1, respectively. However, in lower concentrations of Pb- and Cd-contaminated soil, the removal rate was greater, and the remediation efficiency was better. Overall, using TSK to repair Pb- and Cd-contaminated farmland soil has good application prospects and economic value.


Asunto(s)
Contaminantes del Suelo , Taraxacum , Biodegradación Ambiental , Cadmio/análisis , Granjas , Plomo , Plantas , Suelo , Contaminantes del Suelo/análisis
3.
J Biomed Sci ; 29(1): 52, 2022 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-35820906

RESUMEN

BACKGROUND: Coronavirus-induced disease 19 (COVID-19) infects more than three hundred and sixty million patients worldwide, and people with severe symptoms frequently die of acute respiratory distress syndrome (ARDS). Recent studies indicated that excessive neutrophil extracellular traps (NETs) contributed to immunothrombosis, thereby leading to extensive intravascular coagulopathy and multiple organ dysfunction. Thus, understanding the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation would be helpful to reduce thrombosis and prevent ARDS in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We incubated SARS-CoV-2 with neutrophils in the presence or absence of platelets to observe NET formation. We further isolated extracellular vesicles from COVID-19 patients' sera (COVID-19-EVs) to examine their ability to induce NET formation. RESULTS: We demonstrated that antagonistic mAbs against anti-CLEC5A mAb and anti-TLR2 mAb can inhibit COVID-19-EVs-induced NET formation, and generated clec5a-/-/tlr2-/- mice to confirm the critical roles of CLEC5A and TLR2 in SARS-CoV-2-induced lung inflammation in vivo. We found that virus-free extracellular COVID-19 EVs induced robust NET formation via Syk-coupled C-type lectin member 5A (CLEC5A) and TLR2. Blockade of CLEC5A inhibited COVID-19 EVs-induced NETosis, and simultaneous blockade of CLEC5A and TLR2 further suppressed SARS-CoV-2-induced NETosis in vitro. Moreover, thromboinflammation was attenuated dramatically in clec5a-/-/tlr2-/- mice. CONCLUSIONS: This study demonstrates that SARS-CoV-2-activated platelets produce EVs to enhance thromboinflammation via CLEC5A and TLR2, and highlight the importance of CLEC5A and TLR2 as therapeutic targets to reduce the risk of ARDS in COVID-19 patients.


Asunto(s)
COVID-19 , Lectinas Tipo C , Neutrófilos , Neumonía , Síndrome de Dificultad Respiratoria , SARS-CoV-2 , Trombosis , Animales , Plaquetas/inmunología , Plaquetas/patología , Plaquetas/virología , COVID-19/sangre , COVID-19/inmunología , Humanos , Lectinas Tipo C/inmunología , Ratones , Neutrófilos/inmunología , Neutrófilos/patología , Neutrófilos/virología , Neumonía/inmunología , Neumonía/patología , Neumonía/virología , Receptores de Superficie Celular , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2/inmunología , Trombosis/sangre , Trombosis/inmunología , Trombosis/virología , Receptor Toll-Like 2/inmunología
4.
Curr Med Sci ; 42(1): 210-216, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34985609

RESUMEN

OBJECTIVE: Childhood obesity is a major health concern worldwide. Previous studies have explored the relationship between obesity and gut microbiota. However, the results from such studies remain contradictory. METHODS: In the present nested case-control study, based on a twin birth cohort study, the relationship between gut microbiota diversity and overweight/obesity in 1- and 6-month-old infants was explored. Twins were enrolled when one child had normal weight and the other child was overweight/obese at six months old. For both infants, stool samples were collected at 1 and 6 months of age. Finally, 12 twins were enrolled in the study. The gut microbiota was identified by 16S rRNA gene sequencing in the V3-V4 area. Six of the twins were monozygotic. RESULTS: The results revealed that the microbiota communities of monozygotic twins were similar to those of dizygotic twins. The relative abundance (RA) of microbiota of 1-month-old twins was significantly higher than that of 6-month-old twins. However, the microbiota diversity of 1-month-old twins was significantly lower than that of 6-month-old twins. In addition, 6-month-old twins had significantly higher RA levels of Bifidobacterium and Lachnospiracea incertae sedis than 1-month-old twins. The 6-month-old group had significantly lower RA levels of Veillonella, Klebsiella, Akkermansia, Streptococcus, or Staphylococcus than the 1-month-old group. At six months, the RA level of Clostridium sensu stricto was higher in the overweight/obesity group than the normal-weight group. CONCLUSION: These findings imply that changes in gut microbiota diversity during infancy may contribute to the development of obesity in early infancy.


Asunto(s)
Microbioma Gastrointestinal , Sobrepeso/microbiología , Obesidad Infantil/microbiología , Cohorte de Nacimiento , Estudios de Casos y Controles , Femenino , Humanos , Lactante , Masculino , ARN Ribosómico 16S
5.
Int J Mol Sci ; 22(21)2021 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-34769137

RESUMEN

Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway.


Asunto(s)
Aminopiridinas/uso terapéutico , Carcinoma/tratamiento farmacológico , Enzimas Desubicuitinizantes/antagonistas & inhibidores , Resistencia a Antineoplásicos/efectos de los fármacos , Tiocianatos/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Aminopiridinas/farmacología , Animales , Antineoplásicos/uso terapéutico , Carcinoma/metabolismo , Línea Celular Tumoral , Cisplatino/uso terapéutico , Humanos , Ratones Desnudos , Tiocianatos/farmacología , Ubiquitina Tiolesterasa/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Environ Res ; 200: 111459, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34126051

RESUMEN

BACKGROUND: Bisphenol A (BPA) and its alternatives, including BPF and BPS, exhibit endocrine disruption activities. However, the effects of bisphenols on fetal growth in twins remain unclear. OBJECTIVE: To explore the associations of prenatal BPA, BPF, and BPS exposure with birth outcome differences in twins. METHODS: We recruited 289 twin pregnant women who visited the hospital for prenatal examination during the first trimester from 2013 to 2016. Urinary bisphenol levels were determined during the first, second, and third trimesters. The associations of maternal exposure to bisphenols with birth outcome differences in twins were analyzed after stratification by different trimesters. We applied the multiple informant model to estimate trimester-specific associations between urinary bisphenol concentrations and birth outcome differences in twins. RESULTS: We found low reproducibility (ICC<0.40) for maternal urinary BPA and moderate reproducibility (0.40 < ICC<0.75) for BPF and BPS. Urinary BPA concentrations were positively associated with within-pair twin birth weight difference when comparing the third vs. the first tertile in each of the three trimesters (i.e., 133.06 g, 95% CI: 68.19, 197.94; 144.5 g, 95%CI: 81.82-207.18 g; and 135.04 g, 95%CI: 71.37-198.71 g for the 1st, 2nd, and 3rd trimester, respectively). The effect of urinary BPA concentration on increased birth length difference within-pair twins were also observed across different trimesters (All P for trends < 0.05). Urinary BPA levels were positively associated with the within-pair birth weight and birth length differences across pregnancy trimesters (All of Type 3 P for values < 0.05). CONCLUSION: Maternal BPA exposure appeared to influence birth wight and birth length differences in twins. Our results warrant further confirmation.


Asunto(s)
Efectos Tardíos de la Exposición Prenatal , Compuestos de Bencidrilo/toxicidad , Estudios de Cohortes , Femenino , Humanos , Exposición Materna/efectos adversos , Fenoles , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/epidemiología , Reproducibilidad de los Resultados
7.
Am J Cancer Res ; 11(1): 171-180, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33520367

RESUMEN

Chemotherapy with gemcitabine plus cisplatin remains the mainstay of treatment for metastatic urothelial carcinoma (UC); however, drug resistance occurs in most patients and eventually leads to treatment failure. In this study, we investigated the role of cyclin-dependent kinase 7 (CDK7) regulation in the treatment of human UCs. Moreover, we studied the effect of THZ1, a CDK7 inhibitor, alone and in combination with gemcitabine, on UCs and explored the underlying mechanism. Immunohistochemical staining showed that CDK7 expression was significantly higher in UC tumors than in counterpart urothelium. THZ1 elicited dose-dependent cytotoxicity and apoptosis in two high-grade UC cells (BFTC905 and T24). THZ1 co-treatment potentiated gemcitabine-induced cytotoxicity with suppression of B-cell lymphoma 2 (Bcl-2). Studies with a xenograft nude mouse model also confirmed that THZ1 enhanced the antitumor effect of gemcitabine on UC. These findings provide important pilot data to target CDK7 or Bcl-2 for the treatment of UCs and for overcoming chemoresistance in UCs.

8.
Cells ; 8(10)2019 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-31627336

RESUMEN

After chemotherapy for the treatment of metastatic bladder urothelial carcinoma (UC), most patients inevitably encounter drug resistance and resultant treatment failure. Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins and play a critical role in maintaining protein homeostasis. This study investigated the antitumor effect of PR-619, a DUBs inhibitor, in combination with cisplatin, for bladder UC treatment. Our results showed that PR-619 effectively induced dose- and time-dependent cytotoxicity, apoptosis, and ER-stress related apoptosis in human UC (T24 and BFTC-905) cells. Additionally, co-treatment of PR-619 with cisplatin potentiated cisplatin-induced cytotoxicity in UC cells and was accompanied by the concurrent suppression of Bcl-2. We also proved that Bcl-2 overexpression is related to the chemo-resistant status in patients with metastatic UC by immunohistochemistry (IHC) staining. In a xenograft mice model, we confirmed that PR-619 enhanced the antitumor effect of cisplatin on cisplatin-naïve and cisplatin-resistant UCs. Our results demonstrated that PR-619 effectively enhanced the cisplatin-induced antitumor effect via concurrent suppression of the Bcl-2 level. These findings provide promising insight for developing a therapeutic strategy for UC treatment.


Asunto(s)
Aminopiridinas/uso terapéutico , Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Enzimas Desubicuitinizantes/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tiocianatos/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Enzimas Desubicuitinizantes/metabolismo , Humanos , Inmunohistoquímica , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Theranostics ; 9(16): 4811-4826, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31367259

RESUMEN

The viral E proteins of dengue virus (DENV) and Zika virus (ZIKV) are the major viral proteins involved in receptor binding and fusion, and for the induction of protective antibodies against viral infections. DIII of the E proteins is an independent domain and stretches out on the virion surface that can elicit type-specific neutralizing antibodies. For recombinant DIII vaccine development, prime-boost immunizations can provide an advantage of eliciting more type-specific neutralizing antibodies by recalling DIII antigens after DIII booster to improve protection. Methods: The DIII of the E genes of DENV and ZIKV were fused with bacterial fliC gene for the expression of flagellin-DIII (FliC-DIII) fusion proteins. Prime-boost immunization strategies by the second-dose booster of four DENV serotype or ZIKV FliC-DIII fusion proteins were used to investigate the induction of neutralizing antibodies and protection against viral infections. Cross-reactive non-neutralizing antibodies in each group of antisera were also examined using in vitro antibody-dependent enhancement (ADE) assay. A series of glycan-masking E antigens were finally constructed for prime-boost immunizations to abolish the elicitation of cross-reactive non-neutralizing antibodies for ADE activity. Results: We showed that inclusion of a bivalent live-attenuated vaccine with a FliC-DIII booster is superior in eliciting neutralization titers and protection in vivo against all four-serotype DENVs. We also demonstrated that recombinant adenovirus vectors encoding four-serotype DENV prMEs with a FliC-DIII prime-boost scheme is capable of eliciting good antibody responses. In contract, recombinant adenovirus vector of ZIKV prME gene priming, followed by ZIKV FliC-DIII booster did not improve vaccine efficacy. The glycan-masking mutation on the ZIKV E protein ij loop (E-248NHT), but not on DENV2 E protein ij loop (E-242NHT), resulted in abolishing the elicitation of cross-reactive antibodies for DENV and ZIKV infection enhancements. Conclusions: Our findings can provide useful information for designing novel immunogens and vaccination strategies in an attempt to develop a safe and efficacious DENV or ZIKV vaccine.


Asunto(s)
Virus del Dengue/inmunología , Dengue/inmunología , Flagelina/inmunología , Proteínas del Envoltorio Viral/inmunología , Infección por el Virus Zika/inmunología , Virus Zika/inmunología , Animales , Anticuerpos Antivirales/inmunología , Reacciones Cruzadas , Dengue/prevención & control , Dengue/virología , Virus del Dengue/química , Virus del Dengue/genética , Flagelina/administración & dosificación , Flagelina/genética , Humanos , Inmunización , Inmunización Secundaria , Ratones , Ratones Endogámicos BALB C , Polisacáridos/administración & dosificación , Polisacáridos/inmunología , Dominios Proteicos , Salmonella typhimurium/genética , Salmonella typhimurium/inmunología , Proteínas del Envoltorio Viral/administración & dosificación , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/genética , Vacunas Virales/administración & dosificación , Vacunas Virales/genética , Vacunas Virales/inmunología , Virus Zika/química , Virus Zika/genética , Infección por el Virus Zika/prevención & control , Infección por el Virus Zika/virología
10.
Int J Mol Sci ; 20(13)2019 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-31262032

RESUMEN

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/genética
11.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-30866433

RESUMEN

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 Xenoinjerto
12.
J Mol Med (Berl) ; 97(3): 435-436, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30741319

RESUMEN

In Fig. 1b, upper part, the cell viability counts after treatment with cisplatin and TSA in T24 cells was by mistake a duplication of the image for NTUB1 on the left. In the corrected version of Fig. 1, the image was replaced appropriately.

13.
J Mol Med (Berl) ; 96(12): 1307-1318, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30288546

RESUMEN

In this study, we aimed to investigate the antitumor effects of trichostatin A (TSA), an antifungal antibiotic that inhibits histone deacetylase (HDAC) family of enzymes, alone or in combination with anyone of the three chemotherapeutic agents (cisplatin, gemcitabine, and doxorubicin) for the treatment of human urothelial carcinoma (UC). Two high-grade human UC cell lines (T24 and NTUB1) were used. Cytotoxicity and apoptosis were assessed by MTT assay and flow cytometry, respectively. The expression of phospho-c-Raf, phospho-MEK1/2, and phospho-ERK1/2 was measured by western blotting. ERK siRNA knockdown and the specific MEK inhibitor U0126 were used to examine the role of Raf/MEK/ERK signaling pathway in combined cytotoxicity of TSA and chemotherapy. TSA co-treatment with any one of the three chemotherapeutic agents induced synergistic cytotoxicity (combination index < 1) and concomitantly suppressed chemotherapeutic drug-induced activation of Raf-MEK-ERK pathway. Combination of ERK siRNA knockdown and treatment with the specific MEK inhibitor (U0126) enhanced the cytotoxic effects of the chemotherapy on UC cells. These observations were confirmed in a xenograft nude mouse model. Moreover, activated Raf/MEK/ERK pathway was observed in human bladder UC specimens from patients with chemoresistant status. In conclusion, TSA elicits a synergistic cytotoxic response in combination with chemotherapy via targeting the Raf/MEK/ERK pathway. TSA elicits synergistic cytotoxic response in combination with three DNA-damaging drugs (cisplatin, gemcitabine, and doxorubicin). Activated Raf/MEK/ERK pathway is involved in chemoresistant mechanism of UC. Combining chemotherapeutic agents with HDAC inhibitor (TSA) or with targeting Raf/MEK/ERK pathway is promising to circumvent chemoresistance in UCs.


Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Neoplasias Urológicas/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Sinergismo Farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Ácidos Hidroxámicos/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , ARN Interferente Pequeño/administración & dosificación , Neoplasias Urológicas/genética , Gemcitabina
14.
J Huazhong Univ Sci Technolog Med Sci ; 37(4): 605-611, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28786063

RESUMEN

It is recognized that prenatal care plays an important role in reducing adverse birth. Chinese pregnant women with medical condition were required to seek additional health care based on the recommended at least 5 times health care visits. This study was to estimate the association between prenatal care utilization (PCU) and preterm birth (PTB), and to investigate if medical conditions during pregnancy modified the association. This population-based case control study sampled women with PTB as cases; one control for each case was randomly selected from women with term births. The Electronic Perinatal Health Care Information System (EPHCIS) and a questionnaire were used for data collection. The PCU was measured by a renewed Prenatal Care Utilization (APNCU) index. Logistic regression models were used to estimate odds ratios (OR) and the 95% confidence interval (95% CI). Totally, 2393 women with PTBs and 4263 women with term births were collected. In this study, 695 (10.5%) women experienced inadequate prenatal care, and 5131 (77.1%) received adequate plus prenatal care. Inadequate PCU was associated with PTB (adjusted OR: 1.41, 95% CI: 1.32-1.84); the similar positive association was found between adequate plus PCU and PTB. Among women with medical conditions, these associations still existed; but among women without medical conditions, the association between inadequate PCU and PTB disappeared. Our data suggests that women receiving inappropriate PCU are at an increased risk of having PTB, but it does depend on whether the woman has a medical condition during pregnancy.


Asunto(s)
Pueblo Asiatico , Nacimiento Prematuro/epidemiología , Atención Prenatal/estadística & datos numéricos , Adulto , Estudios de Casos y Controles , Factores de Confusión Epidemiológicos , Femenino , Humanos , Factores de Riesgo
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