RESUMEN
TNKS is a new target for the treatment of lung adenocarcinoma, the synergistic effects of the TCM compound Xiaoyan decoction and the TNKS inhibitor E7449 in the intervention on TNKS were investigated, and the possible underlying mechanisms involved were clarified. Immunohistochemistry was used to analyse TNKS expression in tumour tissues. The impact of targeting TNKS on cell growth, invasion, apoptosis, key genes and signalling pathways was investigated in tumour cells by Western blotting, rescue experiments, colony formation assays, flow cytometry and label-free experiments. Tumour xenografts with A549 cells were then transplanted for in vivo study. We found that TNKS high expression was closely related to the advanced tumour stage and tumour size in lung adenocarcinom. After TNKS was knocked down in vitro, the growth, proliferation, migration and invasion were markedly reduced in A549 and H1975 cells. We subsequently applied the Xiaoyan decoction and TNKS inhibitors to intervene in lung adenocarcinoma. Xiaoyan decoction and E7449 suppressed TNKS expression and inhibited adenocarcinoma cell proliferation, migration, invasion and apoptosis in vitro. Proteomic analysis revealed that E7449 treatment may be most closely associated with the classic Wnt/ß-catenin pathway, whereas Xiaoyan decoction treatment may be related to the WNT/PLAN pathway. Xenograft studies confirmed that E7449 or Xiaoyan decoction inhibited lung tumour growth in vivo and attenuated the Wnt signalling pathway in adenocarcinoma. These findings suggest that TNKS is a novel therapeutic target. TCM preparations and small molecule inhibitors are expected to constitute an effective combination strategy.
Asunto(s)
Adenocarcinoma del Pulmón , Apoptosis , Movimiento Celular , Proliferación Celular , Medicamentos Herbarios Chinos , Neoplasias Pulmonares , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Medicamentos Herbarios Chinos/farmacología , Proliferación Celular/efectos de los fármacos , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/patología , Células A549 , Ratones Desnudos , Masculino , Femenino , Proteómica/métodos , Ratones Endogámicos BALB CRESUMEN
Recent studies on co-transformation of the growth regulator, TaGRF4-GIF1 chimera (Growth Regulating Factor 4-GRF Interacting Factor 1), in cultivated wheat varieties (Triticum aestivum), showed improved regeneration efficiency, marking a significant breakthrough. Here, a simple and reproducible protocol using the GRF4-GIF1 chimera was established and tested in the medicinal orchid Dendrobium catenatum, a monocot orchid species. TaGRF4-GIF1 from T. aestivum and DcGRF4-GIF1 from D. catenatum were reconstructed, with the chimeras significantly enhancing the regeneration efficiency of D. catenatum through in planta transformation. Further, mutating the microRNA396 (miR396) target sites in TaGRF4 and DcGRF4 improved regeneration efficiency. The target mimicry version of miR396 (MIM396) not only boosted shoot regeneration but also enhanced plant growth. Our methods revealed a powerful tool for the enhanced regeneration and genetic transformation of D. catenatum.
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Dendrobium , MicroARNs , Brotes de la Planta , Regeneración , Dendrobium/genética , Dendrobium/crecimiento & desarrollo , MicroARNs/genética , MicroARNs/metabolismo , Brotes de la Planta/genética , Brotes de la Planta/crecimiento & desarrollo , Regeneración/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genéticaRESUMEN
OBJECTIVE: This study aimed to evaluate the clinical efficacy and safety of anlotinib as maintenance therapy in patients with advanced cholangiocarcinoma following first-line chemotherapy. METHODS: This retrospective study enrolled 154 patients with advanced biliary tract cancer admitted to the hospital between January 2020 and December 2022. All patients received first-line intravenous chemotherapy with gemcitabine combined with cisplatin, oxaliplatin, or tegafur. Among the 106 patients who achieved disease control, 47 received oral anlotinib hydrochloride (12 mg daily, 2 weeks on/1 week off) as maintenance therapy. Clinical efficacy, including ORR, DCR, DOR, PFS, and OS, was compared between the anlotinib maintenance and non-maintenance groups. Subgroup analysis based on NLR levels was also performed. RESULTS: Among the 47 anlotinib maintenance patients, the ORR was 21.28% and the DCR was 51.06%. The median DOR was 36 weeks, and the median PFS was 43 weeks in the anlotinib group, versus 28 weeks and 38 weeks in the non-maintenance group, respectively. The median OS was not reached in the anlotinib group but was 48 weeks in the non-maintenance group. Patients receiving anlotinib maintenance had significantly longer DOR, PFS, and OS (all p < 0.05). Patients with low NLR levels had better survival benefits from anlotinib. CONCLUSION: Maintenance therapy with anlotinib demonstrates potential efficacy and a reliable safety profile in patients with advanced cholangiocarcinoma following first-line treatment. The efficacy of anlotinib therapy appears to be influenced by NLR levels. Further validation with larger sample sizes is warranted to strengthen the robustness and reliability of the results.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Indoles , Linfocitos , Neutrófilos , Quinolinas , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Quinolinas/administración & dosificación , Quinolinas/uso terapéutico , Indoles/administración & dosificación , Indoles/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/sangre , Neutrófilos/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfocitos/patología , Tasa de Supervivencia , Pronóstico , Estudios de Seguimiento , Adulto , Quimioterapia de Mantención/métodos , Cisplatino/administración & dosificación , Oxaliplatino/administración & dosificación , Gemcitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificaciónRESUMEN
Vacuolar H+ -ATPase (V-ATPase) has diverse functions related to plant development and growth. It creates the turgor pressure that drives cell growth by generating the energy needed for the active transport of solutes across the tonoplast. V-ATPase is a large protein complex made up of multiheteromeric subunits, some of which have unknown functions. In this study, a forward genetics-based strategy was employed to identify the vab3 mutant, which displayed resistance to isoxaben, a cellulose synthase inhibitor that could induce excessive transverse cell expansion. Map-based cloning and genetic complementary assays demonstrated that V-ATPase B subunit 3 (VAB3) is associated with the observed insensitivity of the mutant to isoxaben. Analysis of the vab3 mutant revealed defective ionic homeostasis and hypersensitivity to salt stress. Treatment with a V-ATPase inhibitor exacerbated ionic tolerance and cell elongation defects in the vab3 mutant. Notably, exogenous low-dose Ca2+ or Na+ could partially restore isoxaben resistance of the vab3 mutant, suggesting a relationship between VAB3-regulated cell growth and ion homeostasis. Taken together, the results of this study suggest that the V-ATPase subunit VAB3 is required for cell growth and ion homeostasis in Arabidopsis.
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Arabidopsis , ATPasas de Translocación de Protón Vacuolares , Arabidopsis/metabolismo , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismo , Benzamidas/farmacología , Benzamidas/metabolismo , HomeostasisRESUMEN
Recently, chimeric antigen receptor T cell (CAR-T) therapy has received increasing attention as an adoptive cellular immunotherapy that targets tumors. However, numerous challenges remain for the effective use of CAR-T to treat solid tumors, including ovarian cancer, which is an aggressive and metastatic cancer with a poor therapeutic response. We screened for an effective anti-MSLN single-chain Fv antibody with comparable binding activity and non-off-target properties using human phage display library. A second-generation of anti-MSLN CAR was designed and generated. We demonstrated the efficacy of our anti-MSLN CAR-T cells for ovarian cancer treatment in an in vitro experiment to kill ovarian tumor cell lines. The anti-MSLN CAR-T cells impeded MSLN-positive tumor growth concomitant with a significant increase in cytokine levels compared with the control. Then, we demonstrated the efficacy of anti-MSLN CAR-T cells in an in vivo experiment against ovarian cancer cell-derived xenografts. Furthermore, we herein report three cases with ovarian cancer who were treated with autologous anti-MSLN CAR-T cells and evaluate the safety and effectiveness of adoptive cell therapy. In this investigator-initiated clinical trials, no patients experienced cytokine release syndrome or neurological symptoms over 2 grads. Disease stabilized in two patients, with progression-free survival times of 5.8 and 4.6 months. Transient CAR expression was detected in patient blood after infusion each time. The tumor partially subsided, and the patient's condition was relieved. In conclusion, this work proves the efficacy of the anti-MSLN CAR-T treatment strategy in ovarian cancer and provides preliminary data for the development of further clinical trials.
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Inmunoterapia Adoptiva , Neoplasias Ováricas , Receptores Quiméricos de Antígenos , Femenino , Humanos , Línea Celular Tumoral , Proteínas Ligadas a GPI , Inmunoterapia , Neoplasias Ováricas/terapia , AnimalesRESUMEN
Peroxidase proliferator receptors (PPARs) are defined as key sensors and regulators of cell metabolism, transcription factors activated by ligands, involved in lipid, glucose and amino acid metabolism, participating in the processes of cell differentiation, apoptosis, inflammation regulation, and acute and chronic nerve damage. Among them, PPARγ is expressed in different brain regions and can regulate lipid metabolism, mitochondrial disorders, oxidative stress, and cell apoptosis. It has anti-inflammatory activity and shows neuroprotection. The regulation of Aß levels in Alzheimer's disease involves cholesterol metabolism and inflammation, so this article first analyzes the biological functions of PPARγ, then mainly focuses on the relationship between cholesterol and inflammation and Aß, and elaborates on the regulation of PPARγ on key proteins and the corresponding molecules, which provides new ideas for the treatment of AD.
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Enfermedad de Alzheimer , PPAR gamma , Humanos , Factores de Transcripción , Inflamación/metabolismo , ColesterolRESUMEN
Phospholipase C Beta 1 (PLCB1) regulates the abundance of PI(4,5)P2 in the plasma membrane and is implicated in various kinds of cancers. This study aimed to investigate the role and underlying mechanisms of PLCB1 in gastric cancer. Herein, it was found that PLCB1 mRNA and protein were highly expressed in gastric cancer, and high levels of PLCB1 were correlated with poor outcomes of patients with gastric cancer via the GEPIA database. Moreover, our results revealed that PLCB1 depletion inhibited gastric cancer cell proliferation, migration, and invasion. Meanwhile, PLCB1 overexpression resulted in an inverse result. Furthermore, PLCB1 mediated actin cytoskeleton rearrangement and activated the RhoA/LIMK/Cofilin pathway. Besides, PLCB1 promoted the Epithelial-Mesenchymal transition process via activating ATK signaling. In conclusion, PLCB1 promoted gastric cancer cell migratory and invasive abilities via regulating actin cytoskeleton rearrangement and Epithelial-Mesenchymal transition process. These findings imply that targeting PLCB1 may be a potential strategy to improve the prognosis of gastric cancer patients.
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Citoesqueleto de Actina , Transición Epitelial-Mesenquimal , Fosfolipasa C beta , Neoplasias Gástricas , Humanos , Movimiento Celular , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Fosfolipasa C beta/genética , Invasividad Neoplásica , Masculino , Femenino , Persona de Mediana Edad , Línea Celular Tumoral , PronósticoRESUMEN
BACKGROUND AND OBJECTIVES: The Asian Working Group for Sarcopenia (AWGS) recommended various measures for identifying patients with possible sarcopenia in its 2019 consensus. The present survey aimed to assess older adults in a senior home to determine the prevalence and associated factors for possible sarcope-nia and to compare the differences between various assessment pathways based on AWGS 2019 criteria. METHODS AND STUDY DESIGN: This cross-sectional study examined 583 participants of a senior home. Patients with possible sarcopenia were determined through the following four pathways: [I] calf circumference (CC) + handgrip strength (HGS); [II] SARC-F+HGS; (III) SARC-CalF+HGS; and (IV) CC, SARC-F, and/or SARC-CalF+HGS. RESULTS: The four assessment pathways revealed a high prevalence of possible sarcopenia in the older adults in the senior home ([I]=50.6%; [II]=46.8%; [III]=48.2%; [IV]=65.9%). There is significant difference in prevalence between pathway IV and the other pathways (p<0.001). A multivariate analysis revealed that advanced age, risk of malnutrition, malnutrition, high level of care, an exercise frequency of <3 times per week, and osteoporosis were correlated with a higher risk of possible sarcopenia. By contrast, oral nutritional supplements (ONS) reduced the risk of possible sarcopenia. CONCLUSIONS: This survey reported a high prevalence of possible sarcopenia in the older adults of the senior home and determined the associated influencing factors. Furthermore, our findings suggested that pathway IV is the most suitable pathway for the examined older adults which enabled the detection and early intervention of more possible sarcopenia.
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Desnutrición , Sarcopenia , Humanos , Anciano , Recién Nacido , Sarcopenia/epidemiología , Fuerza de la Mano , Estudios Transversales , China/epidemiología , Factores de Riesgo , Evaluación Geriátrica/métodos , Encuestas y CuestionariosRESUMEN
BACKGROUND AND OBJECTIVES: Older adults residing in senior homes are at a high risk of malnutrition. In this study, we investigated the nutritional status of these individuals and factors associated with malnutrition in this population. METHODS AND STUDY DESIGN: This cross-sectional study (September 2020-January 2021) included a total of 583 older adults residing in a senior home in Shanghai (mean age, 85.0±6.6 years). The Mini Nutritional Assessment Short Form (MNA-SF) questionnaire was administered to assess the nutritional status of the participants. Patients with possible sarcopenia were identified according to the guidelines recommended by the Asian Working Group for Sarcopenia in its 2019 consensus (AWGS 2019). Moreover, the factors influencing malnutrition were determined through multivariate analyses. RESULTS: The likelihoods of having malnutrition and being at a risk of malnutrition were noted in 10.5% and 37.4% of the participants, respectively. In both male and female participants, handgrip strength (HGS) and calf circumference (CC) increased significantly with increasing scores on the aforementioned questionnaire (p<0.001). Among the participants, 44.6% had ≥3 chronic diseases and 48.2% used multiple medicines. Multivariate analyses revealed that dys-phagia (OR, 3.8; 95% CI, 1.7-8.5), possible sarcopenia (OR, 3.6; 95% CI, 2.2-5.6), and dementia (OR, 4.5; 95% CI, 2.8-7.0) were correlated with a relatively high prevalence of malnutrition/malnutrition risk. Exercise (at least thrice a week) reduced malnutrition risk. CONCLUSIONS: Malnutrition is common among older adults residing in senior homes; therefore, the associated factors must be identified, and appropriate interventions should be administered.
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Desnutrición , Sarcopenia , Humanos , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Sarcopenia/epidemiología , Fuerza de la Mano , Estudios Transversales , Evaluación Geriátrica/métodos , China/epidemiología , Desnutrición/epidemiología , Estado Nutricional , Evaluación Nutricional , Factores de RiesgoRESUMEN
TLR7 (Toll-like receptor 7), the sensor for single-stranded RNA, contributes to systemic inflammation and mortality in murine polymicrobial sepsis. Recent studies show that extracellular miR-146a-5p serves as a TLR7 ligand and plays an important role in regulating host innate immunity. However, the role of miR-146a-5p and TLR7 signaling in pulmonary inflammation, endothelial activation, and sepsis-associated acute respiratory distress syndrome remains unclear. Here, we show that intratracheal administration of exogenous miR-146a-5p in mice evokes lung inflammation, activates endothelium, and increases endothelial permeability via TLR7-dependent mechanisms. TLR7 deficiency attenuates pulmonary barrier dysfunction and reduces lung inflammatory response in a murine sepsis model. Moreover, the impact of miR-146a-5p-TLR7 signaling on endothelial activation appears to be a secondary effect because TLR7 is undetectable in the human pulmonary artery and microvascular endothelial cells (ECs), which show no response to direct miR-146a-5p treatment in vitro. Both conditioned media of miR-146a-5p-treated macrophages (MÏ) and septic sera of wild-type mice induce a marked EC barrier disruption in vitro, whereas MÏ conditioned media or septic sera of TLR7-/- mice do not exhibit such effect. Cytokine array and pathway enrichment analysis of the MÏ conditioned media and septic sera identify TNFα (tumor necrosis factor α) as the main downstream effector of miR-146a-5p-TLR7 signaling responsible for the EC barrier dysfunction, which is further supported by neutralizing anti-TNFα antibody intervention. Together, these data demonstrate that TLR7 activation elicits pulmonary inflammation and endothelial barrier disruption by sensing extracellular miR-146a-5p and contributes to sepsis-associated acute respiratory distress syndrome.
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Glicoproteínas de Membrana , MicroARNs , Síndrome de Dificultad Respiratoria , Sepsis , Receptor Toll-Like 7 , Animales , Medios de Cultivo Condicionados , Células Endoteliales/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Síndrome de Dificultad Respiratoria/inmunología , Sepsis/complicaciones , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismoRESUMEN
Camptothecin has been used in tumor therapy for a long time but its antitumor effect is rather limited due to the side effect and the drug resistance. FEN1, a major component of DNA repair systems, plays important roles in maintaining genomic stability via DNA replication and repair. Here we found that FEN1 inhibitor greatly sensitizes cancer cells to low-dose camptothecin. The combinative treatment of FEN1 inhibitor and 1 nM camptothecin induced a synthetic lethal effect, which synergistically suppressed cancer cell proliferation and significantly mediated apoptosis both in vitro and in vivo. Our study suggested that targeting FEN1 could be a potent strategy for tumor-targeting cancer therapy.
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Camptotecina , Endonucleasas de ADN Solapado , Neoplasias , Apoptosis , Camptotecina/farmacología , Daño del ADN , Endonucleasas de ADN Solapado/antagonistas & inhibidores , Humanos , Mitocondrias/metabolismoRESUMEN
DNA Polymerase ß (Polß) is a key enzyme in base excision repair (BER), which is very important in maintaining the stability and integrity of the genome. Mutant Polß is closely associated with carcinogenesis. However, Polß is highly expressed in most cancers, but the underlying mechanism is not well understood. Here, we found that breast cancer cells MCF-7 with Polß knockdown exhibited high levels of type I interferon and were easily eliminated by natural killer (NK) cells.Similarly, Polß-mutant (R137Q) mice exhibited chronic inflammation symptoms in multiple organs and upregulated type I interferon levels. Further results showed that Polß deficiency caused more DNA damage accumulation in cells and triggered the leakage of damaged DNA into the cytoplasm, which activated the STING/IRF3 pathway, promoted phosphorylated IRF3 translocating into the nucleus and enhanced the expression of type I interferon and proinflammatory cytokines. In addition, this effect could be eliminated by Polß overexpression, STING inhibitor or STING knockdown. Taken together, our findings provide mechanistic insight into the role of Polß in cancers by linking DNA repair and the inflammatory STING pathway.
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ADN Polimerasa beta/metabolismo , Interferón Tipo I , Animales , Daño del ADN , Reparación del ADN , Proteínas de la Membrana/metabolismo , RatonesRESUMEN
Sepsis-associated encephalopathy (SAE) occurs in sepsis survivors and is associated with breakdown of the blood-brain barrier (BBB), brain inflammation, and neurological dysfunction. We have previously identified a group of extracellular microRNAs (ex-miRNAs), such as miR-146a-5p, that were upregulated in the plasma of septic mice and human, and capable of inducing potent pro-inflammatory cytokines and complements. Here, we established a clinically relevant mouse model of SAE and investigated the role of extracellular miRNAs and their sensor Toll-like receptor 7 (TLR7) in brain inflammation and neurological dysfunction. We observed BBB disruption and a profound neuroinflammatory responses in the brain for up to 14 days post-sepsis; these included increased pro-inflammatory cytokines production, microglial expansion, and peripheral leukocyte accumulation in the CNS. In a battery of neurobehavioral tests, septic mice displayed impairment of motor coordination and neurological function. Sepsis significantly increased plasma RNA and miRNA levels for up to 7 days, such as miR-146a-5p. Exogenously added miR-146a-5p induces innate immune responses in both cultured microglia/astrocytes and the intact brain via a TLR7-dependent manner. Moreover, mice genetically deficient of miR-146a showed reduced accumulation of monocytes and neutrophils in the brain compared to WT after sepsis. Finally, ablation of TLR7 in the TLR7-/- mice preserved BBB integrity, reduced microglial expansion and leukocyte accumulation, and attenuated GSK3ß signaling in the brain, but did not improve neurobehavioral recovery following sepsis. Taken together, these data establish an important role of extracellular miRNA and TLR7 sensing in sepsis-induced brain inflammation.
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MicroARNs , Sepsis , Animales , Encéfalo/metabolismo , Citocinas/metabolismo , Inmunidad Innata , Glicoproteínas de Membrana , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismoRESUMEN
Glutathione S-transferase pi (GSTpi) is an important phase II detoxifying enzyme that participates in various physiological processes, such as antioxidant, detoxification, and signal transduction. The high expression level of GSTpi has been reported to be related to drug-resistant and anti-inflammatory and it functioned via its non-catalytic ligandin. However, the previous protection mechanism of GSTpi in DNA damage has not been addressed so far. Nijmegen breakage syndrome 1 (NBS1) is one of the most important sensor proteins to detect damaged DNA. Here, we investigated the interaction between GSTpi and NBS1 in HEK-293 T cells and human breast adenocarcinoma cells during DNA damage. Our results showed that overexpression of GSTpi in cells by transfecting DNA vector decreased the DNA damage level after methyl methanesulfonate (MMS) or adriamycin (ADR) treatment. We found that cytosolic GSTpi could increase NBS1 ubiquitin-mediated degradation in unstimulated cells, which suggested that GSTpi could maintain the basal level of NBS1 during normal conditions. In response to DNA damage, GSTpi can be phosphorylated in Ser184 and inhibit the ubiquitination degradation of NBS1 mediated by Skp2 to recover NBS1 protein level. Phosphorylated GSTpi can further enhance NBS1 nuclear translocation to activate the ATM-Chk2-p53 signaling pathway. Finally, GSTpi blocked the cell cycle in the G2/M phase to allow more time for DNA damage repair. Thus, our finding revealed the novel mechanism of GSTpi via its Ser184 phosphorylation to protect cells from cell death during DNA damage and it enriches the function of GSTpi in drug resistance.
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Proteínas de Ciclo Celular/metabolismo , Daño del ADN , Gutatión-S-Transferasa pi/fisiología , Síndrome de Nijmegen/metabolismo , Proteínas Nucleares/metabolismo , Células HEK293 , Humanos , Células MCF-7 , Fosforilación , UbiquitinaciónRESUMEN
BACKGROUND This retrospective cohort study from a single center aimed to compare patient outcomes following the use of the water-soluble contrast medium Gastrografin in the treatment of adhesive small bowel obstruction (ASBO) in patients with and without a history of chronic radiation enteropathy (CRE). MATERIAL AND METHODS Fifty-nine patients with CRE-induced small bowel obstruction (SBO) and 53 patients with ASBO at Jinling Hospital between April 2014 and February 2018 were enrolled. The patients were given 100 ml Gastrografin through a naso-jejunal tube, and erect abdominal X-rays were taken. Risk factors were found to be correlated with successful non-operative management (SNM) through statistical analyses. RESULTS The success rate of conservative treatment was higher in the Gastrografin group than in the control group (P<0.05). The Gastrografin challenge test is predictive of need for surgery in CRE-induced SBO and ASBO (AUC=0.860 and 0.749, respectively). The predictors associated with SNM in the CRE-induced SBO group were the total dose of radiotherapy, the Gastrografin challenge test, and previous operations for SBO. In the ASBO group, the predictors were the Gastrografin challenge test and previous operations for SBO. The operation rate of SBO patients with Gastrografin treatment was significantly lower than that in the control group (P<0.05). CONCLUSIONS The findings from this study showed that the use of Gastrografin effectively resolved ASBO in patients with and without a history of CRE, but a long-term requirement for surgery could not be avoided. The Gastrografin challenge may be a useful test to predict surgical outcomes.
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Medios de Contraste/uso terapéutico , Diatrizoato de Meglumina/uso terapéutico , Obstrucción Intestinal/tratamiento farmacológico , Intestino Delgado/patología , Traumatismos por Radiación/tratamiento farmacológico , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Obstrucción Intestinal/cirugía , Intestino Delgado/efectos de los fármacos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Solubilidad , Adherencias Tisulares , Resultado del Tratamiento , AguaRESUMEN
CONTEXT: Andrographolide (Andro) has a neuroprotective effect and a potential for treating Alzheimer's disease (AD), but the mechanism has not been elucidated. OBJECTIVE: The efficacy of Andro on p62-mediated Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathways in the aluminium maltolate (Al(mal)3)-induced neurotoxicity in PC12 cell was explored. MATERIALS AND METHODS: PC12 cells were induced by Al(mal)3 (700 µM) to establish a neurotoxicity model. Following Andro (1.25, 2.5, 5, 10, 20, 40 µM) co-treatment with Al(Mal)3, cell viability was detected with MTT, protein expression levels of ß-amyloid precursor protein (APP), ß-site APP cleaving enzyme 1 (BACE1), Tau, Nrf2, Keap1, p62 and LC3 were measured via western blotting or immunofluorescence analyses. Nrf2, Keap1, p62 and LC3 mRNA, were detected by reverse transcription-quantitative PCR. RESULTS: Compared with the 700 µM Al(mal)3 group, Andro (5, 10 µM) significantly increased Al(mal)3-induced cell viability from 67.4% to 91.9% and 91.2%, respectively, and decreased the expression of APP, BACE1 and Keap1 proteins and the ratio of P-Tau to Tau (from 2.75- fold to 1.94- and 1.70-fold, 2.12-fold to 1.77- and 1.56-fold, 0.68-fold to 0.51- and 0.55-fold, 1.45-fold to 0.82- and 0.91-fold, respectively), increased the protein expression of Nrf2, p62 and the ratio of LC3-II/LC3-I (from 0.67-fold to 0.93- and 0.94-fold, 0.64-fold to 0.88- and 0.87-fold, 0.51-fold to 0.63- and 0.79-fold, respectively), as well as the mRNA expression of Nrf2, p62 and LC3 (from 0.48-fold to 0.92-fold, 0.49-fold to 0.92-fold, 0.25-fold to 0.38-fold). Furthermore, Nrf2 and p62 nuclear translocation were increased and keap1 in the cytoplasm was decreased in the presence of Andro. Silencing p62 or Nrf2 can significantly reduce the protein and mRNA expression of Nrf2 and p62 under co-treatment with Andro and Al(mal)3. DISCUSSION AND CONCLUSIONS: Our results suggested that Andro could be a promising therapeutic lead against Al-induced neurotoxicity by regulating p62-mediated keap1-Nrf2 pathways.
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Diterpenos/farmacología , Fármacos Neuroprotectores/farmacología , Compuestos Organometálicos/toxicidad , Pironas/toxicidad , Animales , Diterpenos/administración & dosificación , Relación Dosis-Respuesta a Droga , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Células PC12 , ARN Mensajero/metabolismo , Ratas , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismoRESUMEN
Alzheimer's disease(AD) is a chronic progressive neurodegenerative disease with recent memory impairment as the main clinical manifestation and senile plaques and neurofibrillary tangles as the main pathological changes. In recent years, the effect of microRNAs on AD has attracted widespread attention. Patients with AD have abnormal expression of miRNA, which is closed related to regulation of AD pathophysiology-related genes. Therefore, this paper first elaborated neuroprotective and toxic effects of microRNA in AD, and then explored relevant traditional Chinese medicines that can regulate miRNA in the treatment of AD, so as to provide basis for revealing the pathogenesis relationship between miRNA and AD and provide ideas for further development of anti-AD traditional Chinese medicine.
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Enfermedad de Alzheimer , MicroARNs , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Humanos , Medicina Tradicional China , MicroARNs/genéticaRESUMEN
Oxidative stress-induced vascular endothelial cell (VEC) injury is a major mechanism in the initiation and development of atherosclerosis. Lunasin, a soybean-derived 43-aa peptide, has been previously shown to possess potent antioxidant and anti-inflammatory activities other than its established anticancer activities. This study investigated the effects of lunasin on protecting VECs from oxidative damage and inhibiting atherosclerotic plaque progression in apolipoprotein E-deficient (ApoE-/-) mice and explored its underlying mechanism. Biochemical and histologic analyses were performed by using EA.hy926 human VECs and a high-fat diet (HFD) ApoE-/- mouse atherosclerosis model. Our data indicated that lunasin attenuated H2O2-induced, mitochondria-dependent endothelial apoptosis via down-regulating Bax and up-regulating Bcl-2, inhibiting the mitochondrial depolarization, and reducing the release of cytochrome c, as well as decreasing the activation of caspase-9 and caspase-3 in vitro and in vivo. Mechanic studies showed that lunasin significantly up-regulated heme oxygenase-1 via the PI3K/Akt/nuclear factor erythroid 2-related factor 2/antioxidant response element pathway, and reduced H2O2-induced ROS production in VECs, thereby attenuating oxidant-induced endothelial injury and inhibiting atherosclerotic plaque progression in ApoE-/- mice. In conclusion, our in vitro and in vivo data suggest that lunasin protects VECs from oxidative damage by enhancing heme oxygenase-1 expression via activation of the PI3K/Akt/nuclear factor erythroid 2-related factor 2/antioxidant response element pathway and inhibiting mitochondria-dependent apoptosis, thereby effectively attenuating atherosclerosis in HFD-fed ApoE-/- mice. Lunasin may act as a potential therapeutic agent for the prevention and treatment of atherosclerosis.-Gu, L., Ye, P., Li, H., Wang, Y., Xu, Y., Tian, Q., Lei, G., Zhao, C., Gao, Z., Zhao, W., Tan, S. Lunasin attenuates oxidant-induced endothelial injury and inhibits atherosclerotic plaque progression in ApoE-/- mice by up-regulating heme oxygenase-1 via PI3K/Akt/Nrf2/ARE pathway.
Asunto(s)
Apolipoproteínas E/metabolismo , Hemo-Oxigenasa 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas de Plantas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Apolipoproteínas E/genética , Apoptosis/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo/efectos de los fármacosRESUMEN
This work provides a simple and rapid method for synthesis uniform simetryn imprinted nanoparticles, which can be used to pretreat the tested samples before detecting. A series of computational approach were employed for design simetryn-imprinted polymer. Based on the conclusion of theoretical calculation, the simetryn imprinted nanoparticles were synthesized using simetryn as template, methacrylic acid as monomer with different solvent volume and synthesis conditions. The obtained nanoparticles have small size, uniform distribution and high imprinted factor. Scatchard analysis and quantum chemical calculations were applied for evaluating the interaction of simetryn with methacrylic acid in the imprinting process. The selectivity and recognition ability of the simetryn imprinted nanoparticles for six triazine herbicides and two other type herbicides were investigated. The results show that the simetryn imprinted nanoparticles had high selectivity and binding capacity and could be used for the separation and enrichment of four triazine pesticide residues from actual samples. A method of molecularly imprinted matrix solid phase extraction ultra-performance liquid chromatography tandem mass spectrometry was established for detecting four kinds of triazine herbicide residues in tobacco. The recovery rate of terbuthylazine, simetryn, atrazine, and prometryn in tobacco was 84.03-119.05%, and the relative standard deviation was 0.35-10.12%.
Asunto(s)
Impresión Molecular , Nanopartículas/química , Residuos de Plaguicidas/análisis , Triazinas/análisis , Cromatografía Líquida de Alta Presión , Teoría Funcional de la Densidad , Espectrometría de Masas en Tándem , Triazinas/síntesis química , Triazinas/químicaRESUMEN
The purpose of this study was to investigate the effects of moderate-intensity static magnetic field (SMF) on diabetic mice. We studied the effects of SMF on blood glucose of normal mice by starch tolerance and glucose tolerance tests. Then, we evaluated the effects of SMF on blood glucose of diabetic mice by establishing alloxan-induced type 1 diabetic mice and high-fat diet + streptozotocin (STZ)-induced type 2 diabetic mice. The results showed that different magnetic field intensities and blank control did not affect the blood glucose of normal mice. After starch and glucose administration, different magnetic fields could improve the glucose tolerance of normal mice, and this was obvious in the 600 mT group. In the experiment of type 1 diabetic mice induced by alloxan, the results showed that different magnetic field intensities could improve the starch tolerance of mice, and that in the 400 mT group was obvious. In the experiment of type 2 diabetic mice induced by a high-fat diet + STZ, the 400 mT group could reduce food intake and water consumption in the later period. The 600 mT group could improve the starch tolerance of mice. The 400 and 600 mT groups could reduce fasting blood glucose. At the same time, total cholesterol and triglyceride decreased in different magnetic field intensities, and the 600 mT group could significantly increase the serum insulin content of mice. In summary, the results of this study suggest that SMF has a protective role in diabetic mice. Bioelectromagnetics. © 2020 Bioelectromagnetics Society.