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Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.
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Neoplasias Colorretais , Simulação de Dinâmica Molecular , Humanos , Simulação de Acoplamento Molecular , Farmacóforo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Detecção Precoce de Câncer , Neoplasias Colorretais/tratamento farmacológicoRESUMO
BACKGROUND: Drug resistance is a major obstacle causing chemotherapy failure, and enabling cancer progression. Exosome excreted by cancer cells is participated in cancer progression and chemoresistance, and can be used as an prognostic biomarker. Previous studies have revealed that serum exosomal hsa-circ-0004771 is over-expressed in colorectal cancer (CRC) sufferers and suggested it as a predictive biomarker for early diagnosis and prognosis of CRC. This work will to investigate the role and mechanism of serum exosomal hsa-circ-0004771 in mediating resistance to 5-fluorouracil (5-FU) in CRC. METHODS: Serum and tissue samples were collected from 60 patients with CRC/ benign intestinal disease, and 60 healthy control. Exosomes were isolated and identified from serum samples and cell cultured media with TEM, WB, NTA, and flow cytometry. qRT-PCR and WB were performed to evaluate mRNA expressions of exosomal has-circ-0004771 and miR-653, and ZEB2 protein expression, respectively. Cell proliferation, migration, invasion, and apoptosis abilities were assessed with BrdU and colony formation assay, wound-healing assay, and flow cytometry, respectively. RESULTS: Exosomal hsa-circ-0004771 was over-expressed in CRC serum and cell cultured media, while miR-653 was lower-expressed in CRC tissues and cells. Negative correlations existed between exosomal hsa-circ-0004771 in the patients' serum/cell culture media and miR-653 in CRC tissues/cells, and between miR-653 and ZEB2 in CRC cells. Exosomal hsa-circ-0004771 in CRC cell cultured media was positively related to ZEB2 in CRC cells. MiR-653 was associated with poor prognosis of CRC patients, and its upregulation restrained CRC cell proliferation, migration and invasion, and stimulated apoptosis. Exosomal hsa-circ-0004771 was higher-expressed in 5-FU-resistant CRC serum and cell cultured media, miR-653 was downregulated and ZEB2 was overexpressed in 5-FU-resistant CRC cells. In vitro, exosomal hsa-circ-0004771 in cell cultured media may be involved in 5-FU-resistance by modulating miR-653/ZEB2 pathway. CONCLUSIONS: miR-653 plays as a tumour suppressor in CRC progression, and serum exosomal hsa-circ-0004771 may be a predictive biomarker for 5-FU-resistance in CRC patients, potentially through miR-653/ZEB2 axis.
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Pancreatic cancer is characterized by poor prognosis and high mortality, while its treatment remains unsatisfactory. Cinchonine, a natural compound present in cinchona bark, is a potential anticancer drug. Whether cinchonine is of relevance to pancreatic cancer therapeutics is unclear. This research showed that the ribosomal RNA-processing 15 homolog (RRP15) expression is decreased in the pancreatic cancer, and RRP15 knockdown inhibited autophagy, and caused apoptosis in pancreatic cancer cells. Cinchonine treatment inhibits the expression of RRP15 and autophagy, and caused apoptosis by leading to the activation of Nrf2 axis in pancreatic cancer cells. Taken together, the above results indicate that cinchonine treatment inhibited autophagy and induced apoptosis through activating Nrf2 axis by downregulating RRP15 in pancreatic cancer cells.
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Neoplasias Pancreáticas , RNA Ribossômico , Humanos , Fator 2 Relacionado a NF-E2 , Neoplasias Pancreáticas/metabolismo , Apoptose , Neoplasias PancreáticasRESUMO
OBJECTIVE: To investigate the effect of parental presence during induction of anesthesia (PPIA) in relieving preoperative anxiety of children undergoing tonsillectomy and adenoidectomy. METHODS: One hundred and sixty children undergoing tonsillectomy and adenoidectomy were divided into the control group and the trial group. The control group received routine nursing in the operation room, while anesthesia was induced in the trial group children in the presence of their parents as part of the routine nursing. The differences in heart rate and mean dynamic pressure during pre-operative visit and anesthesia induction between the two groups were observed and recorded. The Modified Yale Preoperative Anxiety Scale (m-YPAS) and the Induction Compliance Checklist (ICC) were scored. The anxiety status of the children and their family members in the two groups was scored at different times, and the psychological stress of anesthesiologists during anesthesia induction was scored by a visual analogue scale. The differences in each index between the two groups were compared. Operation time and costs in-hospital were also compared. RESULTS: Compared with the control group, the heart rate and blood pressure scores as well as the ICC in the trial group were lower than those in the control group (P < 0.01). On comparing the scores of m-YPAS between the two groups, we observed that the scores of the children in the trial group were lower than those in the control group before entering the induction room and anesthesia induction (P < 0.01). There was no statistical difference between the scores of the children in the trial group and the control group on the day of operation and on the way to the operating room (P > 0.05). The nursing satisfaction scores of the family members in the trial group were significantly superior to those in the control group (P < 0.01). The scores of the visual analogue scale for psychological pressure of anesthesiologists during anesthesia induction were higher in the trial group than in the control group (P < 0.05). The operation time and costs in study group were both significantly higher than those of control group (P < 0.05). CONCLUSION: PPIA can significantly reduce preoperative anxiety and surgical physiological stress response in children undergoing tonsillectomy and adenoidectomy, and it is worth being encouraged.
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Adenoidectomia , Tonsilectomia , Criança , Humanos , Anestesia Geral , Ansiedade/etiologia , Ansiedade/prevenção & controle , PaisRESUMO
BACKGROUND: Alcohol consumption and smoking are the leading risk factors for laryngeal cancer (LC). Understanding the variations in disease burden of LC attributable to alcohol use and smoking is critical for LC prevention. METHODS: Disease burden data of LC were retrieved from the Global Burden of Disease Study 2019. We used estimated average percentage change (EAPC) to measure the temporal trends of the age-standardized mortality rate (ASMR) of LC. RESULTS: Globally, while the ASMR of LC decreased by 1.49% (95% CI, 1.41-1.57%) per year between 1990 and 2019, the number of deaths from LC has increased 41.0% to 123.4 thousand in 2019. In 2019, 19.4 and 63.5% of total LC-related deaths were attributable to alcohol use and smoking worldwide, respectively. The ASMR of alcohol- and smoking-related LC decreased by 1.78 and 1.93% per year, whereas the corresponding death number has increased 29.2 and 25.1% during this period, respectively. The decreasing trend was more pronounced in developed countries. In some developing countries, such as Guinea and Mongolia, the LC mortality has shown an unfavorable trend. CONCLUSION: The ubiquitous decrease in LC mortality was largely attributed to the smoking control and highlighted the importance of smoking control policies. However, the disease burden of LC remained in increase and more effective strategies are needed to combat the global increase of alcohol consumption.
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Consumo de Bebidas Alcoólicas/mortalidade , Efeitos Psicossociais da Doença , Saúde Global/estatística & dados numéricos , Neoplasias Laríngeas/mortalidade , Fumar/mortalidade , Consumo de Bebidas Alcoólicas/efeitos adversos , Causas de Morte , Intervalos de Confiança , Países Desenvolvidos/estatística & dados numéricos , Países em Desenvolvimento/estatística & dados numéricos , Feminino , Humanos , Neoplasias Laríngeas/etiologia , Masculino , Mortalidade/tendências , Fatores de Risco , Fumar/efeitos adversos , Fatores de Tempo , Fumar Tabaco/efeitos adversosRESUMO
Lung cancer is one of the most common malignant neoplasms worldwide. CD24 is a marker of tumor stem cells that plays an important role in tumorigenesis. Hsp70 is an important molecular chaperone. However, the co-expression and interaction of CD24 and Hsp70, as well as the significance for the prognosis of lung cancer are still unclear. The expression levels of CD24 and Hsp70 were detected by immunohistochemistry and their correlation was analyzed. The expression levels of CD24 mRNA and protein were examined using qRT-PCR and western blotting in SPCA1, A549, H1975, and H1650 cell lines. A CD24-overexpressing cell model was established. The interaction between CD24 and Hsp70 was verified by co-immunoprecipitation and western blotting. CD24 and Hsp70 expression were significantly higher in lung cancer tissues than in adjacent tissues (CD24: p=0.008; Hsp70: p<0.001). CD24 protein expression showed a positive correlation with lymph node metastasis, TNM stage, and vascular cancer thrombus. Hsp70 protein expression showed a positive correlation with differentiation, lymph node metastasis, and TNM stage. CD24 and Hsp70 high expression were also correlated with poor survival. The positive co-expression rate of CD24 and Hsp70 in lung cancer tissues was 52.7% (49/93). CD24 and Hsp70 expression in lung cancer were positively correlated (r=0.368, p<0.001), and co-immunoprecipitation was verified that both endogenous and exogenous CD24 co-precipitated with Hsp70 directly or indirectly. When Hsp70 inhibitor VER15508 was added to A549 cells, Hsp70 and CD24 protein expression were significantly decreased. The present study demonstrated that CD24 and Hsp70 were highly expressed in lung cancer tissues, and associated with invasion, metastasis, and poor survival. Hsp70 may regulate CD24 expression. Co-expression of CD24 and Hsp70 may be a prognostic biomarker for lung cancer.
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Antígeno CD24 , Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Pulmonares , Biomarcadores Tumorais/genética , Proteínas de Choque Térmico HSP70/genética , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , PrognósticoRESUMO
Two new phenolic glycosides (1-2), along with six existing compounds (3-8), were isolated from the ethanolic extract of Ilex pubescens roots, a traditional folk medicine. These structures were determined using HR-ESI-MS, IR, UV, and NMR (including 1 D, 2 D-NMR). The anti-inflammatory activities of three phenolic glycosides (1-3) were evaluated in the human HepG2 cell lines. The results showed that compound 3 could induce P-gp and BCRP expression through the Nrf2-mediated pathway.[Formula: see text].
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Ilex , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Glicosídeos/farmacologia , Estrutura Molecular , Proteínas de Neoplasias , Raízes de PlantasRESUMO
Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode ß-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.
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Hipertensão Arterial Pulmonar/genética , Fatores de Transcrição SOXF/genética , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Mutação com Perda de Função , MasculinoRESUMO
OBJECTIVE: This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models. METHODS: A series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimised therapeutic molecule. The immunogenicity, therapeutic efficacy and mechanism of the candidate were investigated systematically. RESULTS: Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immunoenhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunised animals neutralised HBV infection in vitro and mediated efficient HBV/hepatitis B virus surface antigen (HBsAg) clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance. CONCLUSIONS: The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoural immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.
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Epitopos de Linfócito B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/imunologia , Hepatite B Crônica/imunologia , Adjuvantes Imunológicos , Animais , Antivirais/uso terapêutico , Terapia Combinada , DNA Viral/sangue , Relação Dose-Resposta Imunológica , Feminino , Anticorpos Anti-Hepatite B/biossíntese , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/terapia , Hepatite B Crônica/virologia , Imunidade Humoral/imunologia , Imunoterapia/métodos , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , CoelhosRESUMO
This study aims to investigate the vestibular function status of cochlear implant patients using cervical vestibular evoked myogenic potential (cVEMP) testing and estimate the effects of cochlear implants on vestibular function. The cVEMPs of 50 cochlear implant patients were measured preoperatively, and at one and six months postoperatively. Then, implanted ears and non-implanted ears were compared in terms of p13/n23 wave response rates, latency, amplitude and threshold. Preoperatively, the binaural cVEMP response rate was 92%, while the cVEMP response rates of implanted ears vs. non-implanted ears at postoperative one and six months were 24% vs. 80% and 52% vs. 82%, respectively. No significant difference between implanted and non-implanted ears was found preoperatively, in terms of latent period, amplitude, or threshold. However, significant changes were found in amplitude and threshold for implanted ears after the operation, but not in latency. No significant postoperative change was found in amplitude, latent period, or threshold for non-implanted ears. Significant differences between implanted and non-implanted ears were found in both amplitude and threshold. Cochlear implants affect vestibular function, especially saccular function, and reduce the cVEMP amplitude and threshold of implanted ears.
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Implantes Cocleares , Potenciais Evocados Miogênicos Vestibulares , Testes de Impedância Acústica , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Sáculo e Utrículo/fisiologia , Adulto JovemRESUMO
Alcohol abuse causes tissue and organ damage, and may participate neuropsychiatric diseases. Studies have shown that DNA methylation plays an important role in gene expression and behavioral changes induced by alcohol, however the causative neurobiological mechanisms have not been clarified. In this study, 32 healthy adult male SD rats were randomly divided into a drinking water control group (n=16) and a chronic alcohol exposure group (n=16). The alcohol preference and locomotor activity of rats were evaluated by two-bottle choice test (TBCT) and open-field test (OFT). DNA methylation in the medial prefrontal cortex (mPFC) tissue was detected by the reduced representative bisulfite sequencing (RRBS) technology. The methylation differential genes closely related to alcohol abuse were screened. qRT-PCR was used to verify the mRNA expression patterns of differential genes. qRT-PCR and Western blot were used to detect the expression of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MeCP2). Furthermore, the effect of short-term alcohol exposure (7 days) on DNMTs and MeCP2 in the mPFC of rats was tested (n=8/group). The results indicated that the methylation level of promoter region in the mPFC of rats exposed to chronic alcohol was significantly increased. In addition, the increased methylation levels in the promoter of Ntf3 and Ppm1G were accompanied by down-regulated mRNA levels in the chronic alcohol exposure group. The decreased methylation levels in the promoter of Hap1 and DUSP1 were accompanied by up-regulated mRNA levels. Furthermore, chronic alcohol exposure increased the mRNA and protein levels of DNMT3B and MeCP2. However, short term alcohol exposure did not affect their expression. This present study provides evidence that DNA methylation is associated with the development of alcohol abuse, which may be regulated by DNMT3B and MeCP2. The target genes Ntf3, Ppm1G, Hap1, and DUSP1 related to alcohol abuse were discovered as well, providing new insights into the neurobiological mechanism of alcohol abuse and the potential pharmacological targets for the treatment of alcohol abuse.
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Alcoolismo/fisiopatologia , Comportamento Animal , Metilação de DNA , Córtex Pré-Frontal/fisiopatologia , Animais , DNA (Citosina-5-)-Metiltransferases/genética , Locomoção , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , DNA Metiltransferase 3BRESUMO
The expression changes of CD2-associated protein (CD2AP) can lead to kidney diseases with proteinuria, including nephrotic syndrome (NS). A recent study reported that miRNAs may be important transcriptional regulators. In this study, we found increased expression of miR-939-5p and decreased expression of CD2AP in the peripheral blood of patients with NS. However, miR-939-5p did not show a regulatory effect on the 3'-untranslated region of CD2AP. The expression levels of specific protein 1 and adenovirus E2 promoter-binding factor 1, important transcription regulators in the promoter region of CD2AP, were also not affected by microRNA (miR)-939-5p. We confirmed that miR-939-5p is in the nucleus by fluorescent in situ hybridization and cytoplasmic separation polymerase chain reaction. The promoter plasmid and miR-939-5p were cotransfected into HEK-293 cells, and the luciferase reporter gene assay was used to analyze the promoter activity. We found that miR-939-5p binds to a specific sequence in the CD2AP promoter. miR-939-5p was confirmed to reduce the recruitment of RNA polymerase II to the CD2AP promoter region by chromatin immunoprecipitation. These findings improve our understanding of the mechanism of miR-939-5p in NS and provide potential molecular therapeutic targets for NS.
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BACKGROUND This study aimed to investigate the effectiveness of perioperative parecoxib sodium combined with transversus abdominis plane (TAP) block on postoperative pain management following hepatectomy in patients with hepatocellular carcinoma (HCC). MATERIAL AND METHODS One hundred patients with HCC who underwent hepatectomy were randomized into a study group (n=51) and a control group (n=49). The study group received 40 mg of parecoxib sodium 30 minutes before anesthetic induction, and 150 mg of 0.375% ropivacaine with 5 mg dexamethasone as TAP inhibitors, before closing the abdominal incision. The control group received 40 mg of placebo 30 minutes before anesthetic induction, without TAP block. Postoperatively, all patients received patient-controlled intravenous analgesia (PCIA) and evaluation with subjective visual analog scale (VAS) pain scores. Data on adverse events, postoperative ambulation (>6 hours/day), time of flatus and defecation, and hospitalization duration were recorded. RESULTS Pain scores of the study group were significantly lower compared with the control group on the first three postoperative days. No significant differences were found between the two groups in terms of adverse events. In the study group, the number of cases of postoperative ambulation was significantly more than the control group. The onset of flatus and defecation and duration of hospital stay in the study group were significantly shorter in the study group compared with the control group. CONCLUSIONS Parecoxib sodium combined with TAP block effectively reduced postoperative pain, improved ambulation, improved gastrointestinal function, and shortened hospitalization time following hepatectomy in patients with HCC without adverse effects.
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Isoxazóis/farmacologia , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Músculos Abdominais/efeitos dos fármacos , Adulto , Idoso , Analgesia Controlada pelo Paciente/métodos , Analgésicos Opioides/administração & dosagem , Anestésicos Locais/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , China , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Bloqueio Nervoso/métodos , Medição da Dor/métodos , Complicações Pós-Operatórias/tratamento farmacológico , Estudos Prospectivos , Ropivacaina/farmacologiaRESUMO
OBJECTIVE: Sudden sensorineural hearing loss (SSNHL) is a common acute disease with an incidence of 0.5-2/10,000. This study aimed to determine whether the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) could be indicators for SSNHL. METHODS: A total of 60 confirmed cases of SSNHL and 60 healthy volunteers were included in this study. Peripheral blood NLRs and PLRs were compared between these groups. The SSNHL patients were divided into two groups, according to therapeutic effect: an effective group and an ineffective group. Peripheral blood NLRs and PLRs before and after treatment were compared between these two groups. RESULTS: The average NLRs and PLRs of these patients were both significantly higher than in controls. The average NLRs and PLRs of the ineffective group were both significantly higher than those of the effective group. CONCLUSION: Peripheral blood NLR and PLR could be used as a convenient, reliable, and cost-effective indicator to predict the prognosis of SSNHL.
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Biomarcadores/sangue , Plaquetas , Perda Auditiva Neurossensorial/sangue , Perda Auditiva Súbita/sangue , Linfócitos , Neutrófilos , Adulto , Idoso , China , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Adulto JovemRESUMO
Liver cancer is a leading cause of cancer death worldwide, and novel chemotherapeutic drugs to suppress liver cancer are urgently required. Isovitexin (IV), a glycosylflavonoid, is extracted from rice hulls of Oryza sativa, and has various biological activities. However, the anti-tumor effect of IV against liver cancer has not yet been demonstrated in vitro or in vivo. In the present study, we showed that IV significantly suppressed the growth of liver cancer cells. Mechanistic studies indicated that IV induced apoptosis by the mitochondrial apoptotic pathway, as evidenced by the increase of Bax, cleaved Caspase-3, poly (ADP-ribose) polymerase (PARP), and cytoplasm Cyto-c released from mitochondria. In addition, IV resulted in autophagy in liver cancer cells, supported by the enhancement of LC3II, autophagy-related protein (Atg) 3, Atg5 and Beclin1. Suppressing autophagy using bafilomycin A1 (BFA) or siRNA Atg-5 reduced apoptotic cells in IV-treated cells, demonstrating that autophagy induction regulated apoptosis. Moreover, IV was found to cause endoplasmic reticulum (ER) stress in liver cancer cells, along with the promotion of ER stress-related molecules, including inositol-requiring enzyme 1α (IRE1α), X-box-binding protein-1s (XBP-1s), C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP)-78. Of note, inhibition of ER stress by use of its inhibitor, tauroursodeoxycholate (TUDCA), significantly reversed IV-induced apoptosis and autophagy. In vivo, IV treatment showed significant tumor growth inhibition compared to the non-treated group. IV could therefore be a strong candidate for liver cancer prevention.
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Apigenina/administração & dosagem , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/fisiopatologia , Proteínas Mitocondriais/metabolismo , Antineoplásicos/administração & dosagem , Proteínas Reguladoras de Apoptose/metabolismo , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismoRESUMO
OBJECTIVE: This study aims to investigate the correlation between thresholds of preoperative multiple auditory steady-state response (ASSR) and electrically evoked auditory brainstem response (EABR) and the behavioral threshold. METHODS: A total of 72 patients were elected to receive a multichannel cochlear implant. According to the residual hearing determined in a preoperative test using high-, moderate-, and low-frequency ASSR, these patients were divided into the following 2 groups: residual hearing and hearing loss. The EABR and behavioral thresholds 1 year after implantation were assayed, and differences between these 2 parameters were compared. RESULTS: Among the high-, moderate-, and low-frequency residual hearing groups, the EABR and behavioral thresholds of patients 1 year after implantation were significantly lower than those in the hearing loss group, and the differences were statistically significant (p < 0.01). CONCLUSION: Before the operation, ASSR results can be used to predict the efficacy of cochlear implantation in patients, and they serve as one of the reference conditions for choosing the ear for implantation. However, the threshold of ASSR is not equivalent to the actual auditory threshold of patients after implantation, and the deviation between these 2 thresholds is more significant at low frequencies.
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Limiar Auditivo/fisiologia , Implante Coclear/métodos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Perda Auditiva Neurossensorial/cirurgia , Doenças do Labirinto/fisiopatologia , Criança , Pré-Escolar , Implantes Cocleares , Feminino , Audição/fisiologia , Perda Auditiva Neurossensorial/fisiopatologia , Testes Auditivos , Humanos , Doenças do Labirinto/cirurgia , Masculino , Período Pós-Operatório , Resultado do TratamentoRESUMO
Congenital heart disease (CHD) is the most common type of developmental abnormality in humans, and is a leading cause for substantially increased morbidity and mortality in affected individuals. Increasing studies demonstrates a pivotal role of genetic defects in the pathogenesis of CHD, and presently mutations in more than 60 genes have been associated with CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic basis underpinning CHD in a large proportion of patients remains unclear. In the present study, the whole coding exons and splicing donors/acceptors of the MEF2C gene, which codes for a transcription factor essential for normal cardiovascular development, were sequenced in 200 unrelated patients affected with CHD, and a novel heterozygous missense mutation, p.L38P, was identified in an index patient with patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Genetic scan of the mutation carrier's family members available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with PDA, which was transmitted as an autosomal dominant trait with complete penetrance. The mutation changed the amino acid that was completely conserved evolutionarily, and did not exist in 300 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant MEF2C protein had a significantly reduced transcriptional activity. Furthermore, the mutation significantly diminished the synergistic activation between MEF2C and GATA4, another cardiac core transcription factor that has been causally linked to CHD. In conclusion, this is the first report on the association of a MEF2C loss-of-function mutation with an increased vulnerability to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD, implying potential implications for early diagnosis and timely prophylaxis of CHD.