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Objective: The initial operation for type A aortic dissection has limitations, and there may be a need for reoperation in cases such as giant pseudoaneurysm formation and reduced blood supply to the distal vessels. In this study, we collected case data of patients who underwent cardiac major vascular surgery at our hospital to analyze the effectiveness of reoperation treatment options for type A aortic dissection and to summarize our treatment experience. Method: Between June 2018 and December 2022, 62 patients with type A aortic dissection (TAAD) underwent reoperation after previous surgical treatment. Of these, 49 patients (45 males) underwent endovascular aortic repair (EVAR) with a mean age of (49.69 ± 10.21) years (30-75 years), and 13 patients (11 males) underwent thoracoabdominal aortic replacement (TAAR) with a mean age of (41.00 ± 11.18) years (23-66 years). In this study, we retrospectively analyzed the recorded data of 62 patients. In addition, we summarized and analyzed their Computed Tomographic Angiography (CTA) results and perioperative complications. Outcome: In the EVAR group, 47 patients (95.92%) were successfully implanted with overlapping stents, and 2 patients died in the perioperative period. Postoperative complications included cerebral infarction (4.08%), acute renal insufficiency (30.61%), pulmonary insufficiency and need for ventilator (6.12%), poor wound healing (2.04%), postoperative reoperation (16.33%), and lower limb ischemia (2.04%). In the TAAR group, 12 patients (92.31%) were successfully revascularized and 1 patient died in the perioperative period. Postoperative complications included cerebral infarction (7.69%), acute kidney injury (46.15%), pulmonary insufficiency and need for ventilator (15.38%), poor wound healing (30.77%) and postoperative reoperation (15.38%). Conclusion: According to the results of the study, compared with TAAR, EVAR was less invasive, faster recovery, and offered a better choice for some high-risk and high-age patients with comorbid underlying diseases. However, the rate of revascularization was higher after EVAR than TAAR due to vascular lesions. Compared with the use of ascending aortic replacement + hemi-aortic arch replacement for acute type A aortic dissection in many countries and regions, the use of ascending aortic replacement + aortic arch replacement + elephant trunk stent is more traumatic in China, but facilitates reoperation. For young patients, the choice of treatment should be individualized combining vascular lesions and long-term quality of life.
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BACKGROUND: Kommerell's diverticulum (KD) with aberrant left subclavian artery is a rare congenital deformity and also has very little research literature about it (35% of case study). There are three types of aortic arch diverticulum. Even literature concerning the treatment options are limited. CASE SUMMARY: We present a case report of a 50-year-old male with KD in the right aortic arch with aberrant left subclavian artery. We conducted a total endovascular repair procedure, which is innovative and will spread more light in the medical world. Our patient has no past medical history and is a non-smoker and non-alcoholic. Patient presented with shortness of breath, chest pain and dizziness for six months. Blood tests were done and computerized tomography (CT) angiogram of the chest confirmed the diagnosis, illustrating showed a 3.9 cm KD. On Day 1, the CT angiogram showed mild dilatation of the thoracic aorta, adjacent esophagus, trachea was compressed and displaced. Surgery was planned as the treatment modality. Carotid-Subclavian artery bypass and endovascular aortic repair was conducted. We used prolene 5-0 C1 sutures to precisely anastomose a 6-mm Dacron graft to the left subclavian artery. Haemostasis was secured and wounds were closed. Protamine was administered and patient was shifted to intensive care unit. Post-operative, patient responded favorably and was discharged. Regular follow-up is done. CONCLUSION: The procedure we performed is novel. This will help the cardio-thoracic surgeons a better insight about the full procedures we conducted, thereby bringing more light and better treatment options in managing KD with aberrant subclavian artery.
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In this study, 2-benzyl-10a-(1H-pyrrol-2-yl)-2,3-dihydropyrazino[1,2-a]indole-1,4,10(10aH)-trione (DHPITO), a previously identified inhibitor against hepatocellular carcinoma cells, is shown to exert its cytotoxic effects by suppressing the proliferation and growth of CRC cells. An investigation of its molecular mechanism confirmed that the cytotoxic activity of DHPITO is mediated through the targeting of microtubules with the promotion of subsequent microtubule polymerisation. With its microtubule-stabilising ability, DHPITO also consistently arrested the cell cycle of the CRC cells at the G2/M phase by promoting the phosphorylation of histone 3 and the accumulation of EB1 at the cell equator, reduced the levels of CRC cell migration and invasion, and induced cellular apoptosis. Furthermore, the compound could suppress both tumour size and tumour weight in a CRC xenograft model without any obvious side effects. Taken together, the findings of the present study reveal the antiproliferative and antitumour mechanisms through which DHPITO exerts its activity, indicating its potential as a putative chemotherapeutic agent and lead compound with a novel structure.
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Antineoplásicos , Neoplasias Colorretais , Humanos , Linhagem Celular Tumoral , Tubulina (Proteína)/metabolismo , Pontos de Checagem do Ciclo Celular , Apoptose , Moduladores de Tubulina/farmacologia , Microtúbulos , Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Proliferação de CélulasRESUMO
PURPOSE: As a non-invasive treatment, stereotactic body radiation therapy (SBRT) has been an emerging and effective option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). The Cyber Knife has an SBRT system, which can realize real-time tracking of tumors during treatment. It can protect the surrounding normal liver tissue while the tumor gets the therapeutic dose. The purpose of this study was to evaluate the factors affecting the local control rate for patients after SBRT treatment, and to predict the factors affecting survival rates, then to report the 3-year actual survival rates after treatment and identify the influencing factors of 3-year survival rate. MATERIALS AND METHODS: We conducted a long-term follow-up of 43 patients with unresectable intrahepatic cholangiocarcinoma who underwent Cyber Knife in our hospital from January 2016 to December 2018. Regular medical check-ups were performed every 2-3 months after SBRT to evaluated the effect of treatment. RESULTS: The median follow-up time was 15 months (4-78 months), and the median progression-free survival (PFS) was 6 months (95% CI, 2.788-9.212) and the median overall survival (OS) was 12 months (95% CI, 3.434-20.566), respectively. Based on modified Response Evaluation and Criteria in Solid Tumor (mRECIST), response rate (RR) and disease control rate (DCR) of SBRT in unresectable ICC were 55.2% and 86%. The 1-, 2- and 3-years OS rate were 51.2%, 32.6% and 23.3%. Multivariate analysis based on competing risk survival analysis identified that patients with multiple nodules, large diameter, high level of CA199 and CEA, poor ECOG performance status had worse overall survival (p < 0.05). Patients who survived ≥3 years had significantly lower levels of CEA, CA199, smaller tumor diameters and lower number of lesions (p < 0.05). CONCLUSION: The SBRT might be a candidate option for patients who unable to perform surgery. The rate of 3-year survival after SBRT for unresectable ICC can be expected with 23.3%.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Radiocirurgia , Humanos , Radiocirurgia/efeitos adversos , Resultado do Tratamento , Colangiocarcinoma/radioterapia , Colangiocarcinoma/cirurgia , Ductos Biliares Intra-Hepáticos/patologia , Ductos Biliares Intra-Hepáticos/efeitos da radiação , Neoplasias dos Ductos Biliares/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) exhibits high invasiveness and mortality rates, and the molecular mechanisms of HCC have gained increasing research interest. The abnormal DNA damage response has long been recognized as one of the important factors for tumor occurrence and development. Recent studies have shown the potential of the protein RING finger and WD repeat domain 3 (RFWD3) that positively regulates p53 stability in response to DNA damage as a therapeutic target in cancers. AIM: To investigate the relationship between HCC and RFWD3 in vitro and in vivo and explored the underlying molecular signalling transduction pathways. METHODS: RFWD3 gene expression was analyzed in HCC tissues and adjacent normal tissues. Lentivirus was used to stably knockdown RFWD3 expression in HCC cell lines. After verifying the silencing efficiency, Celigo/cell cycle/apoptosis and MTT assays were used to evaluate cell proliferation and apoptosis. Subsequently, cell migration and invasion were assessed by wound healing and transwell assays. In addition, transduced cells were implanted subcutaneously and injected into the tail vein of nude mice to observe tumor growth and metastasis. Next, we used lentiviral-mediated rescue of RFWD3 shRNA to verify the phenotype. Finally, the microarray, ingenuity pathway analysis, and western blot analysis were used to analyze the regulatory network underlying HCC. RESULTS: Compared with adjacent tissues, RFWD3 expression levels were significantly higher in clinical HCC tissues and correlated with tumor size and TNM stage (P < 0.05), which indicated a poor prognosis state. RFWD3 silencing in BEL-7404 and HCC-LM3 cells increased apoptosis, decreased growth, and inhibited the migration in shRNAi cells compared with those in shCtrl cells (P < 0.05). Furthermore, the in vitro results were supported by the findings of the in vivo experiments with the reduction of tumor cell invasion and migration. Moreover, the rescue of RFWD3 shRNAi resulted in the resumption of invasion and metastasis in HCC cell lines. Finally, gene expression profiling and subsequent experimental verification revealed that RFWD3 might influence the proliferation and metastasis of HCC via the Wnt/ß-catenin signalling pathway. CONCLUSION: We provide evidence for the expression and function of RFWD3 in HCC. RFWD3 affects the prognosis, proliferation, invasion, and metastasis of HCC by regulating the Wnt/ß-catenin signalling pathway.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , RNA Interferente Pequeno , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases , Repetições WD40 , Via de Sinalização Wnt/genética , beta Catenina/metabolismoRESUMO
Ubiquitin-specific protease 3 (USP3), a kind of cysteine protease, is a crucial family member of deubiquitinating enzymes. USP3 is aberrantly expressed in several tumors, which may contribute to cancer progression. However, the role of USP3 in gallbladder cancer (GBC) is still unknown. In the current study, we detected the expression of USP3 in GBC tissues, measured its contribution to the cell proliferation in GBC progression, and further studied the underlying mechanism of USP3 in GBC through pyruvate kinase L/R (PKLR; a kind of glycolytic enzyme). We found that the expression of USP3 in GBC tissues were higher than that of adjacent tissues, and the protein levels of USP3 and PKLR were positively correlated. Additionally, overexpressed USP3 significantly promoted cell proliferation in vitro and tumor growth in vivo, while the silencing of USP3 inhibited proliferation and tumor growth. Glycolysis in GBC cells ws promoted by the USP3 overexpression and inhibited bye USP3 downregulation. Moreover, the loss of USP3 promoted the ubiquitination and weakened the stability of PKLR. Results of the rescue assay confirmed that PKLR knockdown suppressed USP3-induced oncogenic activity in USP3 overexpressed GBC cells. These findings imply that USP3 is an essential positive regulator in GBC progression, and USP3-PKLR plays a vital role in the progression and metabolism of GBC.
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Neoplasias da Vesícula Biliar , Humanos , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Piruvato Quinase/metabolismo , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo , Proliferação de Células , Ubiquitinação , Linhagem Celular TumoralRESUMO
BACKGROUND: Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region. METHODS: The genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed. RESULTS: A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, pmeta = 7.02×10-11, OR 1.19, 95%CI 1.13-1.26). The bioinformatics suggested that rs17268364 might affect the expression of CTLA4, not ICOS. The rs17268364 risk G allele containing sequence reduced the expression of the reporter gene by binding transcriptional repressor Ewing sarcoma breakpoint region 1 (EWSR1). Following genotype-mRNA expression, the analysis also showed the risk allele of rs17268364 was associated with low CTLA4 expression in lupus nephritis (LN) patients. Healthy individuals carrying rs17268364 risk G allele was significantly correlated with higher levels of IFN-α signature including increased lymphocyte antigen 6E (LY6E) (p=0.031), interferon-stimulated gene 15 (ISG15) (p=0.038), interferon regulatory factor 9 (IRF9) (p=0.028), and interferon regulatory factor 5 (IRF5) (p=0.040) mRNA expression. CONCLUSIONS: The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.
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Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico , Alelos , Antígeno CTLA-4/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Genótipo , Humanos , Fatores Reguladores de Interferon , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína EWS de Ligação a RNARESUMO
A recent genome-wide association study (GWAS) of Asian ancestry reported that single nucleotide polymorphism (SNP) in TERT (telomerase reverse transcriptase) was associated with systemic lupus erythematosus (SLE). TERT has a critical role in maintaining the chromosomal stability and the length of telomere. Given that only a small portion of the genetic heritability of SLE has been explained so far, we aimed to identify novel loci in telomere-related genes responsible for SLE susceptibility in Chinese populations. We performed a comprehensive genetic association analysis of SLE with telomere-related genes. To identify functional significance, we analyzed the publicly available HaploReg v4.1 and RegulomeDB databases. Differential gene expression analysis was also performed using ArrayExpress. A novel signal of PINX1 rs6984094 was identified (P discovery = 4.13 × 10-2, OR = 0.58, 95% CI 0.35-0.98) and successfully replicated (P replication = 5.73 × 10-3, OR = 0.45, 95% CI 0.26-0.81). Multiple layers of functional analysis suggested that the PINX1 rs6984094 risk T allele exhibited increased nuclear protein binding. We also observed an increased expression of PINX1 mRNA in peripheral blood mononuclear cells from SLE patients compared with healthy controls. Overall, we observed a novel genetic association between PINX1 (encodes the PinX1 protein, an inhibitory telomerase enzyme that lengthens telomeres) and SLE susceptibility in Chinese populations.
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Proteínas de Ciclo Celular/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Proteínas de Ciclo Celular/metabolismo , China/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero/genética , Proteínas Supressoras de Tumor/metabolismo , Adulto JovemRESUMO
BACKGROUND: This study was aimed to evaluate the association between interleukin-6 (IL-6) gene polymorphisms and the risk of hepatocellular carcinoma (HCC) in a meta-analysis. METHODS: A literature search was performed for case-control studies published during May, 1993 to May, 2020 focusing on IL-6 gene polymorphisms (-174Gâ>âC, -572Gâ>âC, and -597Gâ>âA) and HCC susceptibility by using PubMed, Cochrane Database, EMBASE, Web of science, and China National Knowledge Infrastructure. From 128 full-text articles, 11 were included in this meta-analysis. I index was used to assess heterogeneity and Newcastle-Ottawa Scale was utilized for quality assessment. RESULTS: For IL-6 -174Gâ>âC polymorphism, in codominant (GG vs CC: odds ratios [OR]â=â2.78, 95% confidence intervals [CI]â=â1.25-6.19, Pâ=â.01, Iâ=â16%) and recessive (GG+GC vs CC: ORâ=â2.76, 95% CIâ=â1.29-5.90, Pâ=â.009, Iâ=â3%) models, IL-6 -174G>C polymorphism was significantly associated with the risk of HCC. In dominant (GG vs CC+GC: ORâ=â1.80, 95% CIâ=â0.92-3.54, Pâ=â.09, Iâ=â86%) and allele (G vs C: ORâ=â1.49, 95% CIâ=â0.95-2.32, Pâ=â.08, Iâ=â68%) models, IL-6 -174G>C polymorphism had no impact on the risk of HCC. However, in non-Italian Caucasian population, IL-6 -174G>C polymorphism was significantly related to the occurrence of HCC in both dominant (GG vs CC+GC: ORâ=â3.26, 95% CIâ=â2.29-4.65, Pâ<â.00001, Iâ=â0%) and allele (G vs C: ORâ=â2.48, 95% CIâ=â1.48-4.15, Pâ=â.0006) models. Such correlations also could be observed when healthy individuals were selected as controls. For IL-6 -572G>C and -597G>A polymorphisms, no significant association was observed in all models, regardless of the source of control and population subgroups. No publication bias could be calculated when Begg and Egger tests were employed. CONCLUSION: This meta-analysis indicated that IL-6 -174G>C polymorphism was significantly related with the risk for HCC, especially in non-Italian Caucasian population. No significant association was observed for the correlation between IL-6 -572G>C and -597G>A polymorphisms and HCC susceptibility.
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Carcinoma Hepatocelular/genética , Interleucina-6/genética , Neoplasias Hepáticas/genética , Alelos , Carcinoma Hepatocelular/etnologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Neoplasias Hepáticas/etnologia , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População BrancaRESUMO
BACKGROUND: This study explored the relationships between the low-/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and other clinical indicators and ischaemic stroke (IS) in patients with non-valvular atrial fibrillation (NVAF) in Xinjiang. The findings could provide a theoretical and therapeutic basis for NVAF patients. METHODS: NVAF patients who were admitted to 10 medical centres across Xinjiang were divided into stroke (798 patients) and control (2671 patients) groups according to the occurrence of first acute IS. Univariate and multivariate logistic regression analysis were used to examine the independent risk factors for IS in NVAF patients. Factor analysis and principal component regression analysis were used to analyse the main factors influencing IS. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory ability of LDL-C/HDL-C for predicting the occurrence of IS. RESULTS: The stroke group had an average age of 71.64 ± 9.96 years and included 305 females (38.22%). The control group had a mean age of 67.30 ± 12.01 years and included 825 females (30.89%). Multivariate logistic regression showed that the risk of IS in the highest LDL-C/HDL-C quartile (≥2.73) was 16.23-fold that of the lowest quartile (< 1.22); IS risk was 2.27-fold higher in obese patients than in normal-weight subjects; IS risk was 3.15-fold higher in smoking patients than in non-smoking patients. The area under the ROC curve of LDL-C/HDL-C was 0.76, the optimal critical value was 2.33, the sensitivity was 63.53%, and the specificity was 76.34%. Principal component regression analysis showed that LDL-C/HDL-C, age, smoking, drinking, LDL-C and hypertension were risk factors for IS in NVAF patients. CONCLUSIONS: LDL-C/HDL-C > 1.22, smoking, BMI ≥24 kg/m2 and CHA2DS2-VASc score were independent risk factors for IS in NVAF patients; LDL-C/HDL-C was the main risk factor.
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Fibrilação Atrial/epidemiologia , AVC Isquêmico/epidemiologia , Obesidade/epidemiologia , Idoso , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Fibrilação Atrial/patologia , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/complicações , AVC Isquêmico/patologia , Masculino , Obesidade/sangue , Obesidade/complicações , Obesidade/patologia , Fatores de RiscoRESUMO
Inflammatory demyelination in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Besides MS disease-modifying therapy, targeting myelin sheath protection/regeneration is currently a hot spot in the treatment of MS. Here, we attempt to explore the therapeutic potential of Bilobalide (BB) for the myelin protection/regeneration in EAE model. The results showed that BB treatment effectively prevented worsening and demyelination of EAE, accompanied by the inhibition of neuroinflammation that should be closely related to T cell tolerance and M2 macrophages/microglia polarization. BB treatment substantially inhibited the infiltration of T cells and macrophages, thereby alleviating the enlargement of neuroinflammation and the apoptosis of oligodendrocytes in CNS. The accurate mechanism of BB action and the feasibility of clinical application in the prevention and treatment of demyelination remain to be further explored.
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Ciclopentanos/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Furanos/uso terapêutico , Ginkgolídeos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Feminino , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Regeneração Nervosa/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Oroxindin is a flavonoid isolated from the traditional Chinese medicine Huang-Qin, which has shown various pharmacological activities including anti-inflammatory, antitumor, antioxidant, etc. Thus far, the effect of oroxindin on colonic inflammation and the underlying mechanism remain unknown. In this study, we investigated the tissue distribution of oroxindin and its therapeutic effects on ulcerative colitis (UC) as well as the underlying mechanisms. UC model was established in mice by administrating dextran sulfate sodium (DSS) in drinking water for 7 d. We first showed that oroxindin was largely absorbed by the colon as an active ingredient after normal mice received Huang-Qin-Tang, a traditional Chinese medicine decoction. UC mice were then treated with oroxindin (12.5, 25, 50 mg ·kg-1 ·d-1, i.g.) for 10 d. We found that oroxindin treatment greatly suppressed massive macrophages infiltration and attenuated pathological changes in colonic tissue. Furthermore, oroxindin treatment significantly inhibited the generation of IL-1ß and IL-18 in the colon via inhibiting the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome formation and activation. In cultured macrophages, LPS induced NLRP3 inflammasome formation and caspase-1 activation, which were suppressed by oroxindin (12.5-50 µM). In LPS-treated macrophages, oroxindin dose-dependently restored the expression of TXNIP protein, leading to suppressing TXNIP-dependent NF-κB activation. In conclusion, these results demonstrate that oroxindin could be absorbed by the colon and attenuate inflammatory responses via inhibiting NLRP3 inflammasome formation and activation, which is related to the inhibitory effect on TXNIP-dependent NF-κB-signaling pathway. Hence, oroxindin has the potential of becoming an effective drug for treating UC.
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Proteínas de Transporte/antagonistas & inibidores , Cromonas/farmacologia , Colite Ulcerativa/tratamento farmacológico , Glucuronatos/farmacologia , Inflamassomos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Tiorredoxinas/antagonistas & inibidores , Administração Oral , Animais , Proteínas de Transporte/metabolismo , Cromonas/administração & dosagem , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Sulfato de Dextrana/administração & dosagem , Relação Dose-Resposta a Droga , Glucuronatos/administração & dosagem , Inflamassomos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Relação Estrutura-Atividade , Tiorredoxinas/metabolismoRESUMO
RATIONALE: Primary sclerosing cholangitis (PSC) is recognized as an autoimmune-mediated liver disease characterized by progressive biliary inflammation and fibrosis. Some PSC cases with elevated immunoglobulin G4 (IgG4) levels are likely to be misdiagnosed with immunoglobulin G4-related sclerosing cholangitis (IgG4-SC). Thus, distinguishing these 2 diseases is particularly important. PATIENT CONCERNS: A 34-year-old male presented with right hypochondrium abdominal intermittent pain and jaundice lasting for 1 month. Here, we present a case of PSC with increased IgG4 levels with improvement of quality of life upon liver transplantation (LT). DIAGNOSIS: The diagnosis of PSC was confirmed based on clinical symptoms, laboratory test results, imaging findings, pathologic results and a lack of response to steroid therapy. INTERVENTIONS: LT surgery was performed successfully when his vital parameters were stabilized. Immunosuppressive agents were routinely used after LT. OUTCOMES: Three years after LT, liver function values show that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were in the normal range. An abdominal ultrasonography showed no obvious abnormalities. LESSONS: There are similar biochemical characteristics and cholangiographic findings between PSC and IgG4-SC. Therefore, distinguishing these 2 diseases is particularly important. LT remains the only option for end-stage PSC. Early diagnosis and effective treatment can achieve a good prognosis.
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Colangite Esclerosante/diagnóstico , Imunoglobulina G/sangue , Dor Abdominal/etiologia , Adulto , Colangite Esclerosante/cirurgia , Humanos , Icterícia/etiologia , Transplante de Fígado , MasculinoRESUMO
Chemoresistance is a major unmet clinical obstacle in ovarian cancer treatment. Epigenetics plays a pivotal role in regulating the malignant phenotype, and has the potential in developing therapeutically valuable targets that improve the dismal outcome of this disease. Here we show that a series of transcription factors, including C/EBPß, GCM1, and GATA1, could act as potential modulators of histone methylation in tumor cells. Of note, C/EBPß, an independent prognostic factor for patients with ovarian cancer, mediates an important mechanism through which epigenetic enzyme modifies groups of functionally related genes in a context-dependent manner. By recruiting the methyltransferase DOT1L, C/EBPß can maintain an open chromatin state by H3K79 methylation of multiple drug-resistance genes, thereby augmenting the chemoresistance of tumor cells. Therefore, we propose a new path against cancer epigenetics in which identifying and targeting the key regulators of epigenetics such as C/EBPß may provide more precise therapeutic options in ovarian cancer.
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Biomarcadores Tumorais/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Cromatina/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Histonas/genética , Neoplasias Ovarianas/genética , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Cromatina/química , Cisplatino/farmacologia , Proteínas de Ligação a DNA , Bases de Dados Factuais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Histona-Lisina N-Metiltransferase , Histonas/metabolismo , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Cultura Primária de Células , Prognóstico , Análise de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
This study aims to construct and evaluate RGD-decorated chitosan (CS)-functionalized pH-responsive single-walled carbon nanotube (SWCNT) carriers using docetaxel (DTX) as a model anticancer drug. DTX was loaded onto SWCNT via π-π stacking interaction (SWCNT-DTX), followed by the non-covalent conjugation of RGD-decorated CS to SWCNT-DTX to prepare RGD-CS-SWCNT-DTX. The RGD-CS-SWCNT-DTX showed significantly higher drug release than the pure drug, giving higher release rate at pH 5.0 (68%) than pH 7.4 (49%). The RGD-CS-SWCNT-DTX could significantly inhibit the growth of A549 tumor cells in vitro, and the uptake amount of A549 cells was obviously higher than that of MCF-7 cells. Meanwhile, the cellular uptake of RGD-CS-SWCNT-DTX was higher than that of CS-SWCNT-DTX in A549 cells, mainly through clathrin and caveolae-mediated endocytosis. The RGD-CS-SWCNT-DTX significantly inhibited tumor growth of A549 cell-bearing nude mice through active tumor-targeting ability. Furthermore, no pathological changes were found in tissues and organs. The result demonstrated that RGD-CS-SWCNT-DTX displayed high drug loading, pH-responsive drug release, remarkable antitumor effect in vitro and in vivo, and also good safety to animal body.
Assuntos
Antineoplásicos/administração & dosagem , Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanotubos de Carbono , Oligopeptídeos/administração & dosagem , Taxoides/administração & dosagem , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Quitosana/uso terapêutico , Docetaxel , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanotubos de Carbono/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Oligopeptídeos/química , Oligopeptídeos/uso terapêutico , Taxoides/química , Taxoides/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Notch homolog 1 (Notch 1) signaling is regarded as a potential therapeutic target for modulating the inflammatory response and exhibiting neuroprotective effects in cerebral injury following stroke. N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine tbutylester (DAPT) efficiently inhibits activation of the Notch 1 signaling pathway in microglia and may protect brain tissue from ischemic damage. However, the temporal proliferation and morphological alterations of microglia/macrophages throughout progression of the disease, as well as the comprehensive alterations of the whole brain following DAPT treatment, remain to be elucidated. The present study evaluated the temporal proliferation and the morphological alterations of microglia/macrophages over the period of the subacute and chronic stages, in addition to dynamic alterations of brain tissue, using the magnetic resonance imaging (MRI) method, following DAPT treatment. SpragueDawley rats (n=40) were subjected to 90 min of middle cerebral artery occlusion and were treated with DAPT (n=20) or acted as controls with no treatment (n=20). The two groups of rats underwent MRI scans prior to the induction of stroke symptoms and at 24 h, 7, 14, 21 and 28 days following the stroke. A total of five rats from each group were sacrificed at 7, 14, 21 and 28 days following induction of stroke. Compared with control rats, the MRI data of the ipsilateral striatum in treated rats revealed ameliorated brain edema at the subacute stage and recovered brain tissue at the chronic stage. In addition to this, treatment attenuated the roundshape and promoted a ramifiedshape of microglia/macrophages. The present study confirmed the protective effect of DAPT treatment by dynamically monitoring the cerebral alterations and indicated the possibility of DAPT treatment to alter microglial characteristics to induce a protective effect, via inhibition of the Notch signaling pathway.
Assuntos
Isquemia Encefálica/diagnóstico , Isquemia Encefálica/metabolismo , Dipeptídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Imageamento por Ressonância Magnética , Microglia/efeitos dos fármacos , Microglia/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Processamento de Imagem Assistida por Computador , Substâncias Protetoras/farmacologia , Ratos , Receptores Notch/metabolismo , Transdução de SinaisRESUMO
A novel nanoscale molecular probe is formulated in order to reduce toxicity and side effects of antitumor drug doxorubicin (DOX) in normal tissues and to enhance the detection sensitivity during early imaging diagnosis. The mechanism involves a specific targeting of Arg-Gly-Asp peptide (RGD)-GX1 heterogeneous dimer peptide-conjugated dendrigraft poly-l-lysine (DGL)-magnetic nanoparticle (MNP) composite by αvß3-integrin/vasculature endothelium receptor-mediated synergetic effect. The physicochemical properties of the nanoprobe were characterized by using transmission electron microscope, Fourier transform infrared spectroscopy, X-ray diffraction, dynamic light scattering (DLS), and vibrating sample magnetometer. The average diameter of the resulting MNP-DGL-RGD-GX1-DOX nanoparticles (NPs) was ~150-160 nm by DLS under simulate physiological medium. In the present experimental system, the loading amount of DOX on NPs accounted for 414.4 mg/g for MNP-DGL-RGD-GX1-DOX. The results of cytotoxicity, flow cytometry, and cellular uptake consistently indicated that the MNP-DGL-RGD-GX1-DOX NPs were inclined to target HepG2 cells in selected three kinds of cells. In vitro exploration of molecular mechanism revealed that cell apoptosis was associated with the overexpression of Fas protein and the significant activation of caspase-3. In vivo magnetic resonance imaging and biodistribution study showed that the MNP-DGL-RGD-GX1-DOX formulation had high affinity to the tumor tissue, leading to more aggregation of NPs in the tumor. In vivo antitumor efficacy research verified that MNP-DGL-RGD-GX1-DOX NPs possessed significant antitumor activity and the tumor inhibitory rate reached 78.5%. These results suggested that NPs could be promising in application to early diagnosis and therapy in hepatocellular carcinoma as a specific nanoprobe.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Dendrímeros/química , Diagnóstico Precoce , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas de Magnetita/química , Sondas Moleculares/química , Peptídeos/química , Polilisina/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Citometria de Fluxo , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/ultraestrutura , Masculino , Camundongos Endogâmicos BALB C , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual/efeitos dos fármacos , Receptor fas/metabolismoRESUMO
Epithelial-mesenchymal transition (EMT) plays a critical role in promoting tumor invasion and metastasis. However, the key cofactors that modulate the signal transduction to induce EMT have note been fully explored to date. The present study reports that sine oculis homeobox homolog 1 (SIX1) is able to promote EMT of cervical cancer by coordinating with transforming growth factor (TGF)ß-SMAD signals. The expression of SIX1 was negatively correlated with the expression of the epithelial marker E-cadherin in two independent groups of cervical cancer specimens. SIX1 could promote the transition of mesenchymal phenotype in the presence of active TGFß signals in vitro and in vivo. TGFß-SMAD signals were required for the SIX1-mediated promotion of EMT and metastatic capacity of cervical cancer cells. Together, SIX1 and TGFß cooperated to induce more remarkable changes in the transition of phenotype than each of them alone, and coordinated to promote cell motility and tumor metastasis in cervical cancer. These results suggest that the coordination of SIX1 and TGFß signals may be crucial in the EMT program, and that SIX1/TGFß may be considered a valuable marker for evaluating the metastatic potential of cervical cancer cells, or a therapeutic target in the treatment of cervical cancer.
RESUMO
OBJECTIVE: To study the mechanism of Wnt/ß-catenin signaling pathway in the enhanced malignant phenotype of A549 cells of human non-small cell lung cancer induced by the anti-angiogenesis therapy. METHODS: The siRNA technique was employed to inhibit the expression of vascular endothelial growth factor (VEGF) in A549 cells and simulate the clinical course of anti-angiogenesis therapy. Real-time PCR and western blot were used to study the change in the expression of Wnt/ß-catenin signaling molecules at the mRNA and protein level respectively, as well as the effect on the epithelial mesenchymal transition in A549 cells. The proliferation and invasion abilities of tumor cells were detected to discuss the mechanism of Wnt/ß-catenin signaling pathway in the enhanced malignant phenotype of non-small cell lung cancer induced by the anti-angiogenesis therapy. RESULTS: The specific siRNA could significantly inhibit the expression of VEGF in cells to simulate the anti-angiogenesis therapy. Under the action of 50 nM VEGF siRNA, the proliferation ability of A549 significantly increased (P < 0.05). After being treated with VEGF siRNA, the invasion ability of cells increased. Twenty-four hours after the transcription of 50 nM siRNA into cells, the number of cells that come through the membrane was 278.3 ± 12.9. Compared with the Ctrl siRNA group, when VEGF was inhibited, the expression of ß-catenin and Cyclin D1 increased by 86% and 55% respectively. Meanwhile, the expression of E-cadherin decreased, while the one of vimentin increased. CONCLUSIONS: siRNA can significantly inhibit the expression of VEGF. For the anti-angiogenesis therapy, the inhibited expression of VEGF can activate the Wnt/ß-catenin signaling pathway to cause the epithelial mesenchymal transition and then the enhanced malignant phenotype of non-small cell lung cancer.