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1.
J Nanobiotechnology ; 22(1): 295, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38807131

RESUMEN

The signal sequence played a crucial role in the efficacy of mRNA vaccines against virus pandemic by influencing antigen translation. However, limited research had been conducted to compare and analyze the specific mechanisms involved. In this study, a novel approach was introduced by substituting the signal sequence of the mRNA antigen to enhance its immune response. Computational simulations demonstrated that various signal peptides differed in their binding capacities with the signal recognition particle (SRP) 54 M subunit, which positively correlated with antigen translation efficiency. Our data revealed that the signal sequences of tPA and IL-6-modified receptor binding domain (RBD) mRNA vaccines sequentially led to higher antigen expression and elicited more robust humoral and cellular immune protection against the SARS-CoV-2 compared to the original signal sequence. By highlighting the importance of the signal sequence, this research provided a foundational and safe approach for ongoing modifications in signal sequence-antigen design, aiming to optimize the efficacy of mRNA vaccines.


Asunto(s)
Señales de Clasificación de Proteína , SARS-CoV-2 , Vacunas de ARNm , Animales , Ratones , SARS-CoV-2/inmunología , COVID-19/prevención & control , COVID-19/inmunología , Ratones Endogámicos BALB C , ARN Mensajero/genética , Vacunas contra la COVID-19/inmunología , Femenino , Humanos , Antígenos Virales/inmunología , Antígenos Virales/genética , Antígenos Virales/química , Anticuerpos Antivirales/inmunología , Inmunidad Humoral , Vacunas Sintéticas/inmunología , Inmunidad Celular
2.
Gastroenterology ; 162(4): 1226-1241, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34954226

RESUMEN

BACKGROUND & AIMS: Sulfoconjugation of small molecules or protein peptides is a key mechanism to ensure biochemical and functional homeostasis in mammals. The PAPS synthase 2 (PAPSS2) is the primary enzyme to synthesize the universal sulfonate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS). Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF), in which oxidative stress is a key pathogenic event, whereas sulfation of APAP contributes to its detoxification. The goal of this study was to determine whether and how PAPSS2 plays a role in APAP-induced ALF. METHODS: Gene expression was analyzed in APAP-induced ALF in patients and mice. Liver-specific Papss2-knockout mice using Alb-Cre (Papss2ΔHC) or AAV8-TBG-Cre (Papss2iΔHC) were created and subjected to APAP-induced ALF. Primary human and mouse hepatocytes were used for in vitro mechanistic analysis. RESULTS: The hepatic expression of PAPSS2 was decreased in APAP-induced ALF in patients and mice. Surprisingly, Papss2ΔHC mice were protected from APAP-induced hepatotoxicity despite having a decreased APAP sulfation, which was accompanied by increased hepatic antioxidative capacity through the activation of the p53-p2-Nrf2 axis. Treatment with a sulfation inhibitor also ameliorated APAP-induced hepatotoxicity. Gene knockdown experiments showed that the hepatoprotective effect of Papss2ΔHC was Nrf2, p53, and p21 dependent. Mechanistically, we identified p53 as a novel substrate of sulfation. Papss2 ablation led to p53 protein accumulation by preventing p53 sulfation, which disrupts p53-MDM2 interaction and p53 ubiquitination and increases p53 protein stability. CONCLUSIONS: We have uncovered a previously unrecognized and p53-mediated role of PAPSS2 in controlling oxidative response. Inhibition of p53 sulfation may be explored for the clinical management of APAP overdose.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Fallo Hepático Agudo , Acetaminofén/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Humanos , Hígado/metabolismo , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/metabolismo , Fallo Hepático Agudo/prevención & control , Mamíferos/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Proteína p53 Supresora de Tumor/metabolismo
3.
J Environ Manage ; 326(Pt A): 116681, 2023 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-36384056

RESUMEN

Vertical supervision is an important institutional arrangement designed to overcome the challenges of environmental governance and promotion of green development in the region. Based on the panel data of 278 cities in China from 2010 to 2018, we use Central Environmental Protection Inspection (CEPI) as an exogenous policy and the multi-period Difference-in-Differences method to test the role of vertical supervision in promoting regional green transformation. Our findings indicate that CEPI, a typical vertical supervision policy, effectively promotes green transformation regionally by reducing local pollution emissions and improving total factor productivity. The analysis of mechanism shows that local governments mainly promote regional green transformation by increasing the investment in pollutant governance, research and development in green technologies, and updating fixed assets. Our study provides a valuable reference for the implementation of vertical supervision policies and effective governance of local governments by the central government.


Asunto(s)
Conservación de los Recursos Naturales , Política Ambiental , Políticas , Contaminación Ambiental , Inversiones en Salud
4.
Zhongguo Dang Dai Er Ke Za Zhi ; 25(7): 739-744, 2023 Jul 15.
Artículo en Zh | MEDLINE | ID: mdl-37529957

RESUMEN

OBJECTIVES: To explore the relationship between atherogenic index of plasma (AIP) and childhood asthma. METHODS: This retrospective study included 86 children with asthma admitted to the Changzhou Second People's Hospital Affiliated to Nanjing Medical University from July 2020 to August 2022 as the asthma group and 149 healthy children undergoing physical examination during the same period as the control group. Metabolic parameters including total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and blood glucose, as well as general information of the children such as height, weight, body mass index, presence of specific dermatitis, history of inhalant allergen hypersensitivity, family history of asthma, and feeding history, were collected. Multivariable logistic regression analysis was used to study the relationship between AIP, triglycerides, and high-density lipoprotein cholesterol and asthma. The value of AIP, triglycerides, and high-density lipoprotein cholesterol for predicting asthma was assessed using receiver operating characteristic (ROC) curve analysis. RESULTS: The AIP and triglyceride levels in the asthma group were significantly higher than those in the control group, while high-density lipoprotein cholesterol was significantly lower (P<0.05). However, there was no significant difference in total cholesterol and low-density lipoprotein cholesterol between the two groups (P>0.05). Before and after adjusting for height, weight, presence of specific dermatitis, history of inhalant allergen hypersensitivity, family history of asthma, feeding method, and blood glucose, multivariable logistic regression analysis showed that AIP, triglycerides, and high-density lipoprotein cholesterol were associated with asthma (P<0.05). ROC curve analysis showed that the optimal cutoff value for predicting asthma with AIP was -0.333, with a sensitivity of 80.2%, specificity of 55.0%, positive predictive value of 50.71%, and negative predictive value of 82.85%. The area under the curve (AUC) for AIP in predicting asthma was significantly higher than that for triglycerides (P=0.009), but there was no significant difference in AUC between AIP and high-density lipoprotein cholesterol (P=0.686). CONCLUSIONS: AIP, triglycerides, and high-density lipoprotein cholesterol are all associated with asthma. AIP has a higher value for predicting asthma than triglycerides and comparable value to high-density lipoprotein cholesterol.


Asunto(s)
Asma , Dermatitis , Humanos , Niño , Estudios Retrospectivos , Glucemia , Triglicéridos , HDL-Colesterol , LDL-Colesterol , Asma/etiología , Factores de Riesgo
5.
Gastroenterology ; 161(1): 271-286.e11, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33819483

RESUMEN

BACKGROUND & AIMS: Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study was to determine whether and how PAPSS2 plays a role in colitis and colonic carcinogenesis. METHODS: Tissue arrays of human colon cancer specimens, gene expression data, and clinical features of cancer patients were analyzed. Intestinal-specific Papss2 knockout mice (Papss2ΔIE) were created and subjected to dextran sodium sulfate-induced colitis and colonic carcinogenesis induced by a combined treatment of azoxymethane and dextran sodium sulfate or azoxymethane alone. RESULTS: The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. Papss2ΔIE mice showed heightened sensitivity to colitis and colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2ΔIE mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids, including the Farnesoid X receptor antagonist bile acid tauro-ß-muricholic acid, and deficiency in the formation of bile acid sulfates in the colon of Papss2ΔIE mice. CONCLUSIONS: We have uncovered an important role of PAPSS2-mediated sulfation in colitis and colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer.


Asunto(s)
Neoplasias Asociadas a Colitis/prevención & control , Colitis/prevención & control , Colon/enzimología , Mucosa Intestinal/enzimología , Mucinas/metabolismo , Complejos Multienzimáticos/metabolismo , Sulfato Adenililtransferasa/metabolismo , Animales , Ácidos y Sales Biliares/metabolismo , Colitis/enzimología , Colitis/genética , Colitis/patología , Neoplasias Asociadas a Colitis/enzimología , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/patología , Colon/patología , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Humanos , Mucosa Intestinal/patología , Metaboloma , Metabolómica , Ratones Endogámicos C57BL , Ratones Noqueados , Complejos Multienzimáticos/genética , Pronóstico , Receptores Citoplasmáticos y Nucleares/metabolismo , Sulfato Adenililtransferasa/genética
6.
Acta Pharmacol Sin ; 43(7): 1843-1856, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34845369

RESUMEN

Ras has long been viewed as a promising target for cancer therapy. Farnesylthiosalicylic acid (FTS), as the only Ras inhibitor has ever entered phase II clinical trials, has yielded disappointing results due to its strong hydrophobicity, poor tumor-targeting capacity, and low therapeutic efficiency. Thus, enhancing hydrophilicity and tumor-targeting capacity of FTS for improving its therapeutic efficacy is of great significance. In this study we conjugated FTS with a cancer-targeting small molecule dye IR783 and characterized the anticancer properties of the conjugate FTS-IR783. We showed that IR783 conjugation greatly improved the hydrophilicity, tumor-targeting and therapeutic potential of FTS. After a single oral administration in Balb/c mice, the relative bioavailability of FTS-IR783 was increased by 90.7% compared with FTS. We demonstrated that organic anion transporting polypeptide (OATP) and endocytosis synergistically drove the uptake of the FTS-IR783 conjugate in breast cancer MDA-MB-231 cells, resulting in superior tumor-targeting ability of the conjugate both in vitro and in vivo. We further revealed that FTS-IR783 conjugate could bind with and directly activate AMPK rather than affecting Ras, and subsequently regulate the TSC2/mTOR signaling pathway, thus achieving 2-10-fold increased anti-cancer therapeutic efficacy against 6 human breast cancer cell lines compared to FTS both in vivo and in vitro. Overall, our data highlights a promising approach for the modification of the anti-tumor drug FTS using IR783 and makes it possible to return FTS back to the clinic with a better efficacy.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Farnesol/análogos & derivados , Farnesol/farmacología , Farnesol/uso terapéutico , Femenino , Humanos , Ratones , Salicilatos , Proteínas ras/metabolismo , Proteínas ras/uso terapéutico
7.
J Cell Physiol ; 236(10): 7144-7158, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33694161

RESUMEN

Transition metals refer to the elements in the d and ds blocks of the periodic table. Since the success of cisplatin and auranofin, transition metal-based compounds have become a prospective source for drug development, particularly in cancer treatment. In recent years, extensive studies have shown that numerous transition metal-based compounds could modulate autophagy, promising a new therapeutic strategy for metal-related diseases and the design of metal-based agents. Copper, zinc, and manganese, which are common components in physiological pathways, play important roles in the progression of cancer, neurodegenerative diseases, and cardiovascular diseases. Furthermore, enrichment of copper, zinc, or manganese can regulate autophagy. Thus, we summarized the current advances in elucidating the mechanisms of some metals/metal-based compounds and their functions in autophagy regulation, which is conducive to explore the intricate roles of autophagy and exploit novel therapeutic drugs for human diseases.


Asunto(s)
Autofagia/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Complejos de Coordinación/uso terapéutico , Metales/uso terapéutico , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Elementos de Transición/uso terapéutico , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Complejos de Coordinación/metabolismo , Humanos , Metales/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Elementos de Transición/metabolismo
8.
Toxicol Appl Pharmacol ; 425: 115606, 2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34087332

RESUMEN

Triptolide (TP), a primary bioactive ingredient isolated from the traditional Chinese herbal medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted great interest for its therapeutic biological activities in inflammation and autoimmune disease. However, its clinical use is limited by severe testicular toxicity, and the underlying mechanism has not been elucidated. Our preliminary evidence demonstrated that TP disrupted glucose metabolism and caused testicular toxicity. During spermatogenesis, Sertoli cells (SCs) provide lactate as an energy source to germ cells by glycolysis. The transcription factors GATA-binding protein 4 (GATA4) and specificity protein 1 (Sp1) can regulate glycolysis. Based on this evidence, we speculate that TP causes abnormal glycolysis in SCs by influencing the expression of the transcription factors GATA4 and Sp1. The mechanism of TP-induced testicular toxicity was investigated in vitro and in vivo. The data indicated that TP decreased glucose consumption, lactate production, and the mRNA levels of glycolysis-related transporters and enzymes. TP also downregulated the protein expression of the transcription factors GATA4 and Sp1, as well as the glycolytic enzyme phosphofructokinase platelet (PFKP). Phosphorylated GATA4 and nuclear GATA4 protein levels were reduced in a dose- and time-dependent manner after TP incubation. Similar effects were observed in shGata4-treated TM4 cells and BALB/c mice administered 0.4 mg/kg TP for 28 days, and glycolysis was also inhibited. Gata4 knockdown downregulated Sp1 and PFKP expression. Furthermore, the Sp1 inhibitor plicamycin inhibited PFKP protein levels in TM4 cells. In conclusion, TP inhibited GATA4-mediated glycolysis by suppressing Sp1-dependent PFKP expression in SCs and caused testicular toxicity.


Asunto(s)
Diterpenos/farmacología , Factor de Transcripción GATA4/metabolismo , Glucólisis/efectos de los fármacos , Fenantrenos/farmacología , Fosfofructoquinasa-1 Tipo C/metabolismo , Células de Sertoli/efectos de los fármacos , Factor de Transcripción Sp1/metabolismo , Animales , Línea Celular , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo , Compuestos Epoxi/farmacología , Factor de Transcripción GATA4/efectos de los fármacos , Factor de Transcripción GATA4/genética , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Fosfofructoquinasa-1 Tipo C/efectos de los fármacos , Fosfofructoquinasa-1 Tipo C/genética , Células de Sertoli/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Transcripción Sp1/efectos de los fármacos , Factor de Transcripción Sp1/genética
9.
Pharmacol Res ; 170: 105723, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34116210

RESUMEN

FAT atypical cadherin 4 (FAT4) has been identified as a tumor suppressor in lung cancers. However, no agent for lung cancer treatment targeting FAT4 has been used in the clinic. Jujuboside A (JUA) is a major active compound in Semen Ziziphi Spinosae. Semen Ziziphi Spinosae is a traditional Chinese herbal medicine used clinically for tumor treatment to improve patients' quality of life. However, the anti-lung cancer activity and the underlying mechanisms of JUA are not yet fully understood. Here, we demonstrated the anti-lung cancer activity of JUA in two lung cancer mice models and three non-small cell lung cancer (NSCLC) cell lines, and further illustrated its underlying mechanisms. JUA suppressed the occurrence and development of lung cancer and extended mice survival in vivo, and suppressed NSCLC cell activities through cell cycle arrest, proliferation suppression, stemness inhibition and senescence promotion. Moreover, JUA directly bound with and activated FAT4, subsequently activating FAT4-HIPPO signaling and inhibiting YAP nuclear translocation. Knockdown of FAT4 diminished JUA's effects on HIPPO signaling, YAP nuclear translocation, cell proliferation and cellular senescence. In conclusion, JUA significantly suppressed NSCLC tumorigenesis by regulating FAT4-HIPPO-YAP signaling. Our findings suggest that JUA is a novel FAT4 activator that can be developed as a promising NSCLC therapeutic agent targeting the FAT4-HIPPO-YAP pathway.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Cadherinas/agonistas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Vía de Señalización Hippo/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Saponinas/farmacología , Proteínas Supresoras de Tumor/agonistas , Proteínas Señalizadoras YAP/metabolismo , Transporte Activo de Núcleo Celular , Animales , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Proteínas Supresoras de Tumor/metabolismo
10.
Molecules ; 26(2)2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33478072

RESUMEN

The use of arginine deiminase (ADI) for arginine depletion therapy is an attractive anticancer approach. Combination strategies are needed to overcome the resistance of severe types of cancer cells to this monotherapy. In the current study, we report, for the first time, that the antioxidant N-acetylcysteine (NAC), which has been used in therapeutic practices for several decades, is a potent enhancer for targeted therapy that utilizes arginine deiminase. We demonstrated that pegylated arginine deiminase (ADI-PEG 20) induces apoptosis and G0/G1 phase arrest in murine MC38 colorectal cancer cells; ADI-PEG 20 induces Ca2+ overload and decreases the mitochondrial membrane potential in MC38 cells. ADI-PEG 20 induced the most important immunogenic cell death (ICD)-associated feature: cell surface exposure of calreticulin (CRT). The antioxidant NAC enhanced the antitumor activity of ADI-PEG 20 and strengthened its ICD-associated features including the secretion of high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). In addition, these regimens resulted in phagocytosis of treated MC38 cancer cells by bone marrow-derived dendritic cells (BMDCs). In conclusion, we describe, for the first time, that NAC in combination with ADI-PEG 20 not only possesses unique cytotoxic anticancer properties but also triggers the hallmarks of immunogenic cell death. Hence, ADI-PEG 20 in combination with NAC may represent a promising approach to treat ADI-sensitive tumors while preventing relapse and metastasis.


Asunto(s)
Acetilcisteína/química , Neoplasias de la Mama/patología , Neoplasias Colorrectales/patología , Hidrolasas/química , Hidrolasas/farmacología , Muerte Celular Inmunogénica/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Ratones , Polietilenglicoles/química
11.
Lipids Health Dis ; 18(1): 5, 2019 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-30611277

RESUMEN

OBJECTIVE: Coronary artery disease (CAD) is a multi-factor disease. Complement component 3 (C3) plays an important role in the development of CAD. The present study investigated the association between DNA methylation status of C3 gene promoter and the risk of CAD. METHODS: One hundred CAD patients and 1 hundred age-and gender- matched controls were recruited in current study. Methylation levels in CpG island in C3 promoter were determined by the method of bisulfite amplicon sequencing. RESULTS: Methylation levels of four CpG sites in C3 promoter were measured. There were no significant difference in methylation level of each CpG site between CAD patients and controls. Average methylation rate was also calculated. No significant difference in average methylation rate was observed between CAD and control groups. Stratified analyses based on EH, DM and smoking status were carried out, no significant association between C3 promoter methylation levels and the susceptibility of CAD was observed. Furthermore, seven haplotypes were established and no significant difference in haplotypes was observed between CAD and control groups. However, our study showed that C3 DNA methylation levels were positively associated with LDL-C levels. CONCLUSION: The present study showed no association between methylation levels of C3 promoter and the risk of CAD. However, the methylation levels might be related to LDL-C levels.


Asunto(s)
Complemento C3/genética , Enfermedad de la Arteria Coronaria/genética , Metilación de ADN , Epigénesis Genética , Regiones Promotoras Genéticas , Anciano , Estudios de Casos y Controles , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Complemento C3/inmunología , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/inmunología , Enfermedad de la Arteria Coronaria/patología , Islas de CpG , Diabetes Mellitus/sangre , Diabetes Mellitus/inmunología , Diabetes Mellitus/fisiopatología , Femenino , Expresión Génica , Haplotipos , Humanos , Hipertensión/sangre , Hipertensión/inmunología , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fumar/sangre , Fumar/inmunología , Fumar/fisiopatología , Triglicéridos/sangre
12.
Toxicol Appl Pharmacol ; 355: 269-285, 2018 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-30009776

RESUMEN

Triptolide (TP), a major active component of Tripterygium wilfordii Hook f., is widely used in the treatment of inflammation and autoimmune disorders. Its clinical application is limited by severe adverse effects, especially cardiotoxicity. Accumulative evidences indicate that TP induces DNA damage by inhibiting RNA polymerase. Considering the relationship among DNA damage, p53, and the role of p53 in mitochondria-dependent apoptosis, we speculate that TP-induced cardiotoxicity results from p53 activation. In this study, the role of p53 in TP-induced cardiotoxicity was investigated in H9c2 cells, primary cardiomyocytes, and C57BL/6 genetic background p53-/- mice. p53 protein level was elevated by TP in vitro and in acute heart injury models. With TP administration (1.2 mg/kg), p53 deficiency prevented heart histology injury and decreased serum cardiac troponin I (cTn-I) and apoptotic proteins. Mechanistically, immunoblotting and immunofluorescence staining identified that TP-induced toxicity is dependent on p53 nuclear translocation and transactivation of Bcl2 family genes, leading to mitochondrial outer membrane permeabilization (MOMP) and mitochondria dysfunction. Consistently, p53 antagonist PFTα counteracted TP-induced p53 overexpression and regulation of Bcl2 family transcription, which improved mitochondrial membrane integrity and prevented apoptosis. Moreover, Bax antagonist Bax inhibitor peptide (BIP) V5 ameliorated TP-induced apoptosis through suppressing membrane depolarization and ROS accumulation. These results suggest that TP-induced cardiotoxicity is p53-dependent by promoting Bax-induced mitochondria-mediated apoptosis.


Asunto(s)
Antiinflamatorios no Esteroideos/toxicidad , Diterpenos/toxicidad , Cardiopatías/inducido químicamente , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias Cardíacas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Fenantrenos/toxicidad , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Diterpenos/antagonistas & inhibidores , Compuestos Epoxi/antagonistas & inhibidores , Compuestos Epoxi/toxicidad , Cardiopatías/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/patología , Fenantrenos/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Proteína X Asociada a bcl-2/antagonistas & inhibidores
13.
Toxicol Appl Pharmacol ; 342: 1-13, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29407771

RESUMEN

Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma with rapid growth and dissemination propensity. Triptolide (TP), an active component extracted from Chinese herb Tripterygium wilfordii Hook f., has broad-spectrum anti-tumor activities. This study aimed to explore the in vitro and in vivo anti-cancer effects of TP on BL and the potential molecular mechanisms. In this study, the in vitro anti-tumor activity of TP was determined by CCK-8 and flow cytometry assays in Raji, NAMALWA and Daudi cells. The expression of SIRT3, phosphorylation and acetylation of glycogen synthase kinase-3ß (GSK-3ß) were analyzed by Western blot assay. Moreover, we examined the mitochondrial membrane potential by JC-1 method and measured apoptosis related protein using Western blot assay. BL xenograft model in NOD/SCID mice were established to evaluate the in vivo anti-cancer effect of TP. We discovered that TP inhibited BL cell growth and induced apoptosis in a dose-dependent manner. Loss of SIRT3 provides growth advances for BL cells. However, TP could up-regulate SIRT3 expression, which resulted in suppression of BL cells proliferation. GSK-3ß was activated by SIRT3-mediated deacetylation, which subsequently induced mitochondrial translocation and accumulation of Bax and decrease of mitochondrial membrane potential. Anti-tumor studies in vivo showed that TP (0.36 mg/kg) inhibited the growth of BL xenografts in NOD/SCID mice with an inhibitory rate of 73.13%. Our data revealed that TP triggered mitochondrial apoptotic pathway in BL by increasing SIRT3 expression and activating SIRT3/GSK-3ß/Bax pathway. This study indicated that TP is a potential anti-cancer Chinese herbal medicine against BL.


Asunto(s)
Antineoplásicos/farmacología , Linfoma de Burkitt/metabolismo , Diterpenos/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Fenantrenos/farmacología , Sirtuina 3/metabolismo , Acetilación , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diterpenos/uso terapéutico , Compuestos Epoxi/farmacología , Compuestos Epoxi/uso terapéutico , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos NOD , Ratones SCID , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Fenantrenos/uso terapéutico , Carga Tumoral/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo
14.
Lipids Health Dis ; 17(1): 213, 2018 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-30205809

RESUMEN

BACKGROUND: Genetic and environment factors affect the occurrence and development of coronary artery disease (CAD). Proprotein convertase subtilisin/kexin type 9 (PCSK9), has been investigated extensively in the field of lipid metabolism and CAD. We performed this case-control study to investigate the relationship between serum PCSK9 levels and PCSK9 polymorphisms and lipid levels and CAD risk in a southern Chinese population. METHODS: A hospital-based case-control study with 1, 096 subjects, including 626 CAD patients and 470 controls, were conducted. Genotyping of PCSK9 polymorphisms was performed using polymerase chain reaction-ligase detection reaction (PCR-LDR) method. RESULTS: The frequencies of the AA, AG and GG genotypes of PCSK9 E670G polymorphism were 90.58, 9.27, and 0.16% in the CAD patients, compared with 88.72, 10.85 and 0.43% in the controls, respectively. No R46L variant was detected in this population. There were no significant differences in genotype and allele frequencies of PCSK9E670G polymorphism between the CAD group and the controls. Serum lipid levels were not significantly different in carriers with the G allele and those with the AA genotype. The median (QR) of PCSK9 concentration was 1205.00 ng/l (577.28-1694.13 ng/l) in cases and 565.87 ng/l (357.17-967.50 ng/l) in controls, respectively. Compared with controls, CAD patients had significantly higher PCSK9 levels (z = 4.559, P < 0.001). After adjusting for age, gender, essential hypertension, diabetic mellitus, smoking and lipid profiles, PCSK9 levels remain significantly associated with increased CAD susceptibility (OR = 1.002, 95% CI = 1.001-1.002, P < 0.001). The correlation analyses showed that serum PCSK9 levels were positively associated with triglyceride (TG), Apo B and atherogenic index of plasma (AIP) levels in controls. No significant association between the PCSK9 E670G polymorphism and serum PCSK9 levels was observed in the CAD group and the controls. CONCLUSIONS: The present study shows that serum PCSK9 levels, but not PCSK9 polymorphisms, are associated with CAD risk in Southern Chinese Han population, and that serum PCSK9 levels are positively associated with AIP.


Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Estudios de Asociación Genética , Lípidos/genética , Anciano , Alelos , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/patología , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
15.
Toxicol Appl Pharmacol ; 313: 195-203, 2016 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-27751939

RESUMEN

Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3ß (GSK-3ß) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes. Our study aimed to investigate the role of GSK-3ß in TP-induced cardiotoxicity. Inhibition of GSK-3ß activity by SB 216763, a potent and selective GSK-3 inhibitor, prominently ameliorated the detrimental effects in C57BL/6J mice with TP administration, which was associated with a correction of GSK-3ß overactivity. Consistently, in TP-treated H9c2 cells, SB 216763 treatment counteracted GSK-3ß overactivity, improved cell viability, and prevented apoptosis by modulating the expression of Bcl-2 family proteins. Mechanistically, GSK-3ß interacted with and phosphorylated cyclophilin F (Cyp-F), a key regulator of mitochondrial permeability transition pore (mPTP). GSK-3ß inhibition prevented the phosphorylation and activation of Cyp-F, and desensitized mPTP. Our findings suggest that pharmacological targeting of GSK-3ß could represent a promising therapeutic strategy for protecting against cardiotoxicity induced by TP.


Asunto(s)
Diterpenos/toxicidad , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Lesiones Cardíacas/prevención & control , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Fenantrenos/toxicidad , Animales , Línea Celular , Compuestos Epoxi/toxicidad , Lesiones Cardíacas/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Poro de Transición de la Permeabilidad Mitocondrial
16.
Pharmacol Res ; 114: 1-12, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27697644

RESUMEN

Epigenetic modifications include DNA methylation, histone modification, and other patterns. These processes are associated with carcinogenesis and cancer progression. Thus, epigenetic modification-related enzymes, such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone demethylases (HDMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs), as well as some related proteins, including methyl-CpG binding proteins (MBPs) and DNMT1-associated protein (DMAP 1), are considered as potential targets for cancer prevention and therapy. Numerous natural compounds, mainly derived from Chinese herbs and chemically ranging from polyphenols and flavonoids to mineral salts, inhibit the growth and development of various cancers by targeting multiple genetic and epigenetic alterations. This review summarizes the epigenetic mechanisms by which active compounds from Chinese herbs exert their anti-cancer effect. A subset of these compounds, such as curcumin and resveratrol, affect multiple epigenetic processes, including DNMT inhibition, HDAC inactivation, MBP suppression, HAT activation, and microRNA modulation. Other compounds also regulate epigenetic modification processes, but the underlying mechanisms and clear targets remain unknown. Accordingly, further studies are required.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Medicamentos Herbarios Chinos/farmacología , Epigénesis Genética/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Metilación de ADN/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Código de Histonas/efectos de los fármacos , Humanos , MicroARNs/genética , Neoplasias/prevención & control
17.
Pharmazie ; 71(9): 514-523, 2016 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-29441847

RESUMEN

Clinical application of triptolide (TP), a main active ingredient of the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), is limited by a series of severe toxicities, including cardiotoxicity. In previous studies, we found the activation of sirtuin 3 (SIRT3) attenuated TP-induced toxicity in cardiomyocytes. Resveratrol (RSV), a polyphenol from the skins of grapes and red wine, is an activator of SIRT3. The current study aimed to investigate the protective effect of RSV against TP-induced cardiotoxicity and the underlying mechanisms. Mice were treated with a single dose of TP (2.5 mg/kg) via the intragastric (i.g.) route. After 24 h, TP induced abnormal changes of serum biochemistry, activity decrease of antioxidant enzymes and damage of heart tissue such as myocardial fiber rupture, cell swelling and interstitial congestion. In contrast, administration with RSV (50 mg/kg i.g. 12 h before and 2 h after the administration of TP) attenuated the detrimental effects induced by TP in BALB/c mice. Moreover, the cardiomyocyte protective effects of RSV on TP-induced heart injury were associated with the activation of SIRT3 and its downstream targets. In vitro study also indicated that RSV counteracted TP-induced cardiotoxicity through SIRT3-FOXO3 signaling pathway in H9c2 cells. Collectively, these findings suggest the potential of RSV as a promising agent in protecting heart from TP-induced damage.


Asunto(s)
Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Cardiotoxicidad , Diterpenos/toxicidad , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Fenantrenos/toxicidad , Sirtuina 3/efectos de los fármacos , Estilbenos/farmacología , Estilbenos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Diterpenos/antagonistas & inhibidores , Compuestos Epoxi/antagonistas & inhibidores , Compuestos Epoxi/toxicidad , Femenino , Proteína Forkhead Box O3/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Miocardio/enzimología , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Fenantrenos/antagonistas & inhibidores , Resveratrol , Transducción de Señal/efectos de los fármacos
18.
Mol Biol Rep ; 42(5): 997-1012, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25413568

RESUMEN

Epidemiologic studies have been performed to explore the relationship between MCP-1 polymorphism and ischemic heart disease (IHD) and ischemic stroke (IS). But, the results are not consistent. Because of the poor effect of each individual study, we've performed a systematic review and a meta-analysis. A comprehensive search was carried out from PubMed, Embase, Foreign Medical Journal Service (FMJS), China National Knowledge Infrastructure and Wanfang Data. Odds ratios (OR) with 95% confidence interval (CI) were used to evaluate the strength of associations between the MCP-1 A-2518G polymorphism (rs1024611) and IHD and IS susceptibilities. The pooled OR was calculated by the allelic model (G vs A), the additive model (GG vs AA), the dominant model (GG+GA vs AA) and the recessive model (GG vs AA+GA), respectively. The homogeneity among studies was checked using Cochrane Q statistic. The stability of results was checked by one-way sensitivity analysis. The publication bias between studies was examined by Begg's funnel plots and Egger's test. 28 eligible case-control studies met all the criteria and were involved in the present meta-analysis, including a total of 8,901 cases and 12,623 controls. Overall, the MCP-1 A-2518G polymorphism was significantly associated with the IHD susceptibility. The pooled OR was 1.27 (95% CI 1.09-1.48, P = 0.002) in the dominant model, 1.20 (95% CI 1.07-1.35, P = 0.001) in the allelic model, 1.25 (95% CI 1.05-1.50, P = 0.015) in the recessive model and 1.39 (95% CI 1.10-1.75, P = 0.005) in the additive model. At the same time, the MCP-1 A-2518G polymorphism was significantly associated with the IS susceptibility. The pooled OR was 1.72 (95% CI 1.12-2.65, P = 0.013) in the dominant model, 1.39 (95% CI 1.12-1.74, P = 0.003) in the allelic model, 1.59 (95% CI 1.30-1.93, P = 0.000) in the recessive model, and 2.33 (95% CI 1.76-3.08, P = 0.000) in the additive model, respectively. No significant publication bias was found in the present meta-analysis. The results of the present meta-analysis suggest that MCP-1 gene A-2518G polymorphism may be associated with the IHD and IS susceptibilities. But the positive result exists in relatively small sample size subgroup.


Asunto(s)
Quimiocina CCL2/genética , Isquemia Miocárdica/genética , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/genética , Anciano , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Sesgo de Publicación
19.
J Cell Mol Med ; 18(1): 80-90, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24373582

RESUMEN

Activating transcription factor (ATF) 4 is involved in the regulation of oxidative stress in fibroblasts and neurons. The role of ATF4 in hepatocytes, however, is unknown. The aim of this study was to investigate the role of ATF4 in hepatocytes in oxidative stress under a high-fat diet (HFD). Here, we showed that palmitate-stimulated reactive oxygen species (ROS) production and triglyceride (TG) accumulation is blocked by ATF4 deficiency in primary hepatocytes. Consistently, HFD-induced oxidative stress, TG accumulation and expression of cytochrome P450, family 2, subfamily, polypeptide 1 (CYP2E1) are also blocked by knocking down ATF4 expression in the mouse liver. This suggests that ATF4 might regulate oxidative stress via CYP2E1 under an HFD. In addition, we observed that expression of CYP2E1 is indirectly regulated by ATF4 in a cAMP-responsive element binding protein (CREB)-dependent manner, which can directly activate the CYP2E1 promoter activity. Notably, ATF4-stimulated ROS production is inhibited in vivo by treatment with diallyl sulphide, a selective CYP2E1 inhibitor. Finally, we showed that ATF4 expression in the liver is responsible for the protective effects against HFD-induced CYP2E1 expression, oxidative stress, and TG accumulation. Taken together, these observations suggest that ATF4 is a novel regulator of oxidative stress as well as accumulation of TG in response to HFD.


Asunto(s)
Factor de Transcripción Activador 4/deficiencia , Citocromo P-450 CYP2E1/metabolismo , Hepatocitos/enzimología , Estrés Oxidativo , Factor de Transcripción Activador 4/genética , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Citocromo P-450 CYP2E1/genética , Dieta Alta en Grasa/efectos adversos , Represión Enzimática , Células HEK293 , Humanos , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Palmitatos/toxicidad , Fosforilación , Regiones Promotoras Genéticas , Procesamiento Proteico-Postraduccional , Especies Reactivas de Oxígeno/metabolismo , Triglicéridos/metabolismo
20.
Lipids Health Dis ; 13: 85, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24886585

RESUMEN

BACKGROUND: Studies had investigated the relationships between endothelial lipase (EL) 584C/T polymorphism and high density lipoprotein cholesterol (HDL-C) level and coronary heart disease (CHD), but the results were controversial. To investigate a more authentic associations between EL 584C/T polymorphism and HDL-C level, and the risk of CHD, we performed this meta-analysis. METHODS: We searched electric databases for all articles on the associations between EL 584C/T polymorphism and HDL-C level, and CHD risk. Odds ratios (ORs) with 95% confidence interval (CI) were used to evaluate the strength of the association between the EL 584C/T polymorphism and the CHD susceptibility. The pooled standardized mean difference (SMD) with 95% CI was used for the meta-analysis of EL 584C/T polymorphism and HDL-C level. Begg's funnel plots and Egger's test were used to examine the publication bias. RESULTS: For CHD association, the pooled OR was 0.829 (95% CI: 0.701-0.980, P = 0.028) for the dominant model and 0.882 (95% CI: 0.779-0.999, P = 0.049) for the allelic model. By meta-regression analysis, we found that only total sample size could influence the initial heterogeneity. When the subgroup analysis was carried out, we found that the protective effect only existed in the subgroups of relatively small sample size. Sensitivity analyses indicated that Tang's study influenced the overall results significantly. We calculated the pooled ORs again after excluding Tang's study and found the association between EL 584C/T polymorphism and the risk of CHD was not significant for any genetic model. For HDL-C level association, the carriers of 584 T allele had a higher HDL-C level than the non-carriers. The pooled SMD was 0.399 (95% CI: 0.094-0.704, P = 0.010). When the studies were stratified by ethnicity and total sample size, the positive effects existed in the Caucasians and in subgroups of larger sample size. No significant publication bias was found in the present meta-analysis. CONCLUSIONS: The results of the present meta-analysis suggest that the carriers of EL 584 T allele have a higher HDL-C level in Caucasian populations. Whereas, it might not be a protective factor for CHD.


Asunto(s)
Enfermedad Coronaria/genética , Lipasa/genética , Polimorfismo Genético/genética , Predisposición Genética a la Enfermedad/genética , Humanos
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