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1.
J Agric Food Chem ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32186876

RESUMO

Harvesting uncapped immature honey (IMH) followed by dehydration is a typical counterfeit honey production process, but the differences between IMH and capped mature honey (MH) have not been well described previously. In this study, MH and IMH from Apis mellifera colonies during the same rapeseed flower season were compared. MH was found to have lower water content, lower acidity, and higher fructose content. High-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry-based untargeted metabolomic analysis indicated that MH had a distinct metabolite composition to IMH. Targeted metabolomic analysis on 20 major polyphenolic constituents showed higher accumulation in MH. MH had greater bacteriostatic effect and stronger free radical scavenging effect. While both the honeys mitigated cell damage caused by H2O2, the effective dosage of IMH was higher and its inducing effect on the antioxidant gene expression was weaker. Overall, MH was shown to be of better quality than IMH not only because of its richer polyphenolic composition but also because of its stronger biological activity.

2.
Biomed Pharmacother ; 125: 109864, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32007915

RESUMO

BACKGROUND: To evaluate whether the level of myeloid-derived suppressor cells is related to the complication of sepsis after esophageal cancer surgery and whether changing the myeloid-derived suppressor cells levels can improve the prognosis of patients cancer-related sepsis. METHODS: A total of 178 esophageal cancer patients from Harbin Medical University Cancer Hospital were included in this study. Blood samples were taken from the patients for the analysis of the levels of G-MDSCs and M-MDSCs by flow cytometry. The conditions of the patients was recorded. Male C57BL/6 mice were implanted with Lewis lung cancer cells (2 × 106/mice) by subcutaneous injection into the iliac fossa. Three weeks later, we performed CLP in the mice. All-trans-retinoic acid (ATRA) was intraperitoneally injected at 20 mg/kg, and the control group was injected with 0.9 % NS. We observed the mortality of the mice with cancer-related sepsis. RESULTS: In all, 95 % of the esophageal cancer patients had a high level of G-MDSCs (>50 %). A high level of G-MDSCs (>82.5 %) can lead to high morbidity from sepsis after surgery. The increase in M-MDSCs was suggestive of a poor prognosis in patients with cancer-related sepsis. ATRA can improve the survival of patients with cancer-related sepsis. CONCLUSIONS: A high level of G-MDSCs can be used to determine the incidence of sepsis in preoperative esophageal cancer patients, M-MDSCs might be effective prognostic indicators for cancer-sepsis patients, and changing the MDSC levels can improve the mortality of patients with cancer-related sepsis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31709584

RESUMO

The aim of this study was to determine the efficacy of immunonutrition vs standard nutrition in cancer patients treated with surgery. Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, EBSCOhost, and Web of Science were searched. Sixty-one randomized controlled trials were included. Immunonutrition was associated with a significantly reduced risk of postoperative infectious complications (risk ratio [RR] 0.71 [95% CI, 0.64-0.79]), including a reduced risk of wound infection (RR 0.72 [95% CI, 0.60-0.87]), respiratory tract infection (RR 0.70 [95% CI, 0.59-0.84]), and urinary tract infection (RR 0.69 [95% CI, 0.51-0.94]) as well as a decreased risk of anastomotic leakage (RR 0.70 [95% CI, 0.53-0.91]) and a reduced hospital stay (MD -2.12 days [95% CI -2.72 to -1.52]). No differences were found between the 2 groups with regard to sepsis or all-cause mortality. Subgroup analyses revealed that receiving arginine + nucleotides + ω-3 fatty acids and receiving enteral immunonutrition reduced the rates of wound infection and respiratory tract infection. The application of immunonutrition at 25-30 kcal/kg/d for 5-7 days reduced the rate of respiratory tract infection. Perioperative immunonutrition reduced the rate of wound infection. For malnourished patients, immunonutrition shortened the hospitalization time. Therefore, immunonutrition reduces postoperative infection complications and shortens hospital stays but does not reduce all-cause mortality. Patients who are malnourished before surgery who receive arginine + nucleotides + ω-3 fatty acids (25-30 kcal/kg/d) via the gastrointestinal tract during the perioperative period (5-7 days) may show better clinical efficacy.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31709589

RESUMO

OBJECTIVE: We conducted a systematic review to assess the effects of immunonutrition on chemoradiotherapy patients. METHODS: We searched the Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, CINAHL, and the Web of Science. We assessed the risk of bias using the Cochrane Risk of Bias tool. Our primary outcomes were the incidence of oral mucositis and diarrhea. The secondary outcomes were the incidence of esophagitis, grade ≥3 oral mucositis, grade ≥3 diarrhea, grade ≥3 esophagitis, and body weight loss. RESULTS: A total of 1478 patients and 27 studies were included. There were no significant differences in the incidence of oral mucositis (relative risk [RR] = 0.91; 95% confidence interval [CI], 0.79-1.05), diarrhea (RR = 0.89; 95% CI, 0.76-1.05), or esophagitis (RR = 0.55; 95% CI, 0.11-2.86) between the immunonutrition group and standard nutrition/placebo group. Nevertheless, immunonutrition significantly reduced the incidence of grade ≥3 oral mucositis (RR = 0.45; 95% CI, 0.22-0.92), grade ≥3 diarrhea (RR = 0.56; 95% CI, 0.35-0.88), grade ≥3 esophagitis (RR = 0.15; 95% CI, 0.04-0.54), and losing >5% body weight (RR = 0.34; 95% CI, 0.18-0.64). CONCLUSIONS: In this study, immunonutrition failed to reduce the incidence rates of oral mucositis, diarrhea, or esophagitis but was conducive to significantly improving the severity of oral mucositis and diarrhea esophagitis and reducing the rate of body weight loss.

5.
Biomed Pharmacother ; 117: 109200, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387194

RESUMO

Bee pollen (BP) is a natural medicine from the hive with various potential health-promoting benefits, but until now there is no study to determine its protective roles in inflammatory bowel disease (IBD). The aim of this study was to reveal the in vitro gastrointestinal protective effects of BP against IBD using molecular and metabolic methods. Dextran sulfate sodium (DSS) challenged Caco-2 cell monolayers were applied to mimic intestinal epithelial cell dysfunctions and metabolic disorders. The pretreatment with BP extract rich in polyphenols ameliorated DSS-induced cell viability losses. It also exerted protective effects against intestinal barrier impairment by strengthening epithelial integrity and tight junction losses induced by DSS. BP up-regulated anti-oxidant (NQO1, Txnrd1, Nrf2) and down-regulated inflammatory (TNF-α and IL-6) mRNA expressions, in accompany with MAPK signaling inhibition. Furthermore, metabolomics analysis based on UPLC-Q-TOF/MS revealed that BP, and DSS treated Caco-2 cells have different metabolomic profiles, with significant changes on key metabolites involved in glycerophospholipid metabolism. Our results showed that BP has great therapeutic potential throughout the early stages of DSS-induced colitis.


Assuntos
Abelhas/química , Produtos Biológicos/farmacologia , Gastroenteropatias/tratamento farmacológico , Intestinos/efeitos dos fármacos , Pólen/química , Substâncias Protetoras/farmacologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Sulfato de Dextrana/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Polifenóis/farmacologia , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
6.
J Orthop Surg Res ; 14(1): 269, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443671

RESUMO

PURPOSE: The clinical outcomes of using a cortical screw (CS) for lumbar interbody fusion were evaluated by comparison with conventional pedicle screw (PS) fixation. METHODS: All of the comparative studies published in the PubMed, Cochrane Library, MEDLINE, Web of Science, and EMBASE databases recently as 18 March 2019, were included. All outcomes were analyzed by using Review Manager 5.3. RESULTS: Twelve studies were included with a total of 835 patients, and two of the studies were randomized controlled trials. The outcomes of the meta-analysis indicated that the use of CS fixation for lumbar interbody fusion was better than conventional PS fixation in regard to operating time (p = 0.02), intraoperative blood loss (p < 0.00001), length of stay (p = 0.02), incidence of complications (p = 0.02), adjacent segmental disease (ASD) incidence (p = 0.03), and Oswestry Disability Index (ODI) (p = 0.03). However, there were no statistically significant differences in the back and leg pain visual analog scale (VAS), Japanese Orthopaedic Association (JOA) scale, and intervertebral fusion rate (all p > 0.05) between the CS fixation group and the PS fixation group. CONCLUSIONS: Based on this systematic review and meta-analysis, our outcomes indicated that both CS and conventional PS can result in good postoperative outcomes in lumbar interbody fusion. No significant differences were found in the back and leg pain VAS, JOA scale, and intervertebral fusion rate. However, CS fixation is superior to PS fixation in the following measures: operating time, intraoperative blood loss, length of stay, incidence of complications, ASD incidence, and ODI. TRIAL REGISTRATION: PROSPERO registration number is CRD 42019132226 .


Assuntos
Osso Cortical/cirurgia , Vértebras Lombares/cirurgia , Parafusos Pediculares/tendências , Fusão Vertebral/instrumentação , Fusão Vertebral/tendências , Humanos , Tempo de Internação/tendências , Duração da Cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do Tratamento
7.
Anal Biochem ; 581: 113340, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226253

RESUMO

Colorectal cancer (CRC) is the third most common cancer worldwide. To date, no non-invasive and specific biomarkers have been identified for the diagnosis of CRC. The analysis of volatile organic compounds (VOCs) is attracting increasing attention and provides the possibility of a non-invasive diagnosis. Solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) have been used to analyze the VOCs released from the headspace gas of LS174T (Dukes' type B colorectal adenocarcinoma) cells, arsenic trioxide (ATO)-treated LS174T cells and the blood from tumor-bearing mice. The data were processed using principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA), which showed that the levels of decanal, 2,4-dimethyl- heptane, and twelve other metabolites were significantly greater in the headspace gas of the LS174T cells and blood of tumor-bearing mice. Additionally, in vivo experiments indicated that formic acid, ethenyl ester and p-trimethylsilyloxyphenyl-(trimethylsilyloxy)trimethylsilylacrylate were consumed during tumor growth. In conclusion, VOCs such as 1-methoxy-hexane and 2,4-dimethyl-heptane could be useful diagnostic markers for CRC. Further research should focus on the potential metabolic pathways associated with these profiles.

8.
J Biomed Nanotechnol ; 15(3): 531-543, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165698

RESUMO

MDR (multi-drug resistance) is a major obstacle to the successful treatment of cancers. The combination therapeutic based on RNAi has been investigated as a potential strategy for reversing the MDR. However, the effective delivery of siRNA in vivo remains the challenge for the reality of these candidate RNAi drugs. Cationic peptides for gene delivery have attracted considerable attention due to their biocompatibility and high safety. Herein, self-assembled polypeptide nanoparticles LAH4-L1-siRNA (PNLS) were prepared and loaded with a siRNA (siMDR1) for overcoming MDR in human breast cancer MCF-7/ADR cells in vitro and in vivo. Owing to its cationic charges and α-helical conformation, the histidinerich peptide enhanced cellular uptake of siRNA and represented high gene silencing efficiency. The cellular uptake pathways and internalization process of PNLS into cells were further investigated. In vivo biodistribution indicated that the PNLS exhibited higher tumor-targeted delivery. More importantly, PNLS combined with PTX (Paclitaxel) showed antitumor effects and high MDR1 gene silencing efficiency in the tumor-bearing nude mice. Overall, the PNLS achieved the genetargeted knockdown in vivo and hold immense promise for a new therapeutic drug for breast cancer treatment.


Assuntos
Neoplasias da Mama , Nanopartículas , Animais , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inativação Gênica , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Paclitaxel , Peptídeos , RNA Interferente Pequeno , Distribuição Tecidual
10.
J Pharm Biomed Anal ; 167: 30-37, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738241

RESUMO

Early diagnosis and early treatment are important factors in reducing colorectal cancer (CRC) metastasis and mortality. Volatile organic compounds (VOCs) released by the human body have great potential for use in clinical diagnosis and therapeutic monitoring for CRC. The aim of our study was to identify VOCs with high specificity and high sensitivity for CRC and to provide a method for early diagnosis of CRC. Gas chromatography-mass spectrometry (GC-MS) was utilized to analyze metabolites in both the in vivo and in vitro experimental groups. In vivo, VOCs were analyzed in the blood of mice after cell inoculation and tumor resection. In vitro experiments were performed by comparing changes in VOCs in an HCoEpiC cell group, control group, SW620 cell group and Arsenic trioxide + SW620 group. We observed changes in VOCs in a series of CRC SW620 cells in vivo and in vitro. Among these changes, we found that the concentrations of 8 substances, including acetone, increased with tumor growth. Nine substances were found to be significantly elevated in the SW620 cancer cell group compared with the other groups. Only one substance was consumed by the tumor in both the in vivo and in vitro experiments. Our study showed that alkanes, lipids, alcohols, ketones, aldehyde, butylated hydroxytoluene (BHT) and hexamethylcyclotrisiloxane all existed at different levels in SW620 CRC cells compared to those in normal cells. We need more research to further confirm this hypothesis.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/metabolismo , Compostos Orgânicos Voláteis/análise , Animais , Arseniatos , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Microextração em Fase Sólida , Compostos Orgânicos Voláteis/sangue
11.
Brain Topogr ; 32(1): 111-117, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203260

RESUMO

Effortful control (EC), considered as one component of temperament, describes an individual's capacity for self-regulation. Previous neuroimaging studies have provided convergent evidence that individual differences in EC are determined by the functioning of neural systems subserving executive attention, primarily comprising the anterior cingulate cortex (ACC) and the lateral prefrontal cortex (PFC). Notwithstanding, as previous neuroimaging findings highlighted the structural neural bases of EC in adolescence, during which the PFC is prominently remodeled, the underlying neuroanatomical substrates of EC remain uncertain in young adults. In this study, we included 246 healthy young adults and used voxel-based morphometry analysis to investigate the relationship between EC and grey matter (GM) volumes. Additionally, permutation testing and cross-validation were applied to determine whether GM volumes in the detected regions could predict individual differences in EC. Our results revealed that EC was associated with GM volumes in the dorsal anterior cingulate cortex (dACC) and the pre-supplementary motor area (pre-SMA), demonstrating that these two regions may play a crucial role in EC. Furthermore, the identified regional GM volumes reliably contribute to the prediction of EC confirmed by cross-validation. Overall, these findings provide further evidence for the involvement of the executive attention system in EC, and shed more light on the neuroanatomical substrates of EC in young adulthood.


Assuntos
Atenção/fisiologia , Substância Cinzenta/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Individualidade , Córtex Pré-Frontal/diagnóstico por imagem , Adolescente , Mapeamento Encefálico , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Tamanho do Órgão/fisiologia , Inquéritos e Questionários , Temperamento , Adulto Jovem
12.
Medicine (Baltimore) ; 97(51): e13144, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30572426

RESUMO

There are no specific treatment drugs and vaccine for Hand Foot and Mouth Disease (HFMD). Taking effective preventive measures is particularly important for control of HFMD infection. The objective of this study is to evaluate the effect of intervention of intensive education on hand hygiene on HFMD.We randomized 64 villages into intervention and control groups in Handan, Hebei province, China. Parents and caregivers of children 6 to 40 months age group in intervention villages received intensive education on hand hygiene. Control group received general education. The intervention period was from April 1 to July 31, 2011 and April 1 to July 31, 2012. We measured and compare the knowledge and incidences of HFMD between 2 groups.We collected 6484 questionnaires, including 3583 in the intervention group [response rate: 96% (3583/3726)] and 2901 in the control group [response rate: 90% (2901/3224)]. We observed that hand washing habit of children and parent, knowledge of HFMD of parents, children's daily cleaning habits scores improved in the intervention group and higher than that in the control group at both the end of year 1 (April 1-July 31, 2011)and year 2 (April 1-July 31, 2012). The incidence of HFMD (2.1%) in intervention group was significantly lower than that in control group (4.2%) at year 2 (χ = 22.138, P <.001). The positive percent of coli-form on the hand swabs in intervention group (2.00%) were significantly lower than that in control group (9.45%) at the end of year 2.The intervention of intensive education on hand hygiene effectively improved the personal hygiene both of children and parents, as well as reduced the incidence of HFMD. We suggested expanding the intervention measures in community to prevent HFMD.


Assuntos
Cuidadores/educação , Desinfecção das Mãos , Doença de Mão, Pé e Boca/prevenção & controle , Educação em Saúde , Pais/educação , Pré-Escolar , Utensílios de Alimentação e Culinária , Enterobacteriaceae , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Lactente , Masculino , Jogos e Brinquedos
13.
Curr Mol Med ; 18(7): 436-447, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30539697

RESUMO

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an inherited disease caused by mutations in alanine-glyoxylate aminotransferase (AGXT). It is characterized by abnormal metabolism of glyoxylic acid in the liver leading to endogenous oxalate overproduction and deposition of oxalate in multiple organs, mainly the kidney. Patients of PH1 often suffer from recurrent urinary tract stones, and finally renal failure. There is no effective treatment other than combined liver-kidney transplantation. METHODS: Microinjection was administered to PH1 rats. Urine samples were collected for urine analysis. Kidney tissues were for Western blotting, quantitative PCR, AGT assays and histological evaluation. RESULTS: In this study, we generated a novel PH1 disease model through CRISPR/Cas9 mediated disruption of mitochondrial localized Agxt gene isoform in rats. Agxt-deficient rats excreted more oxalate in the urine than WT animals. Meanwhile, mutant rats exhibited crystalluria and showed a slight dilatation of renal tubules with mild fibrosis in the kidney. When supplied with 0.4% ethylene glycol (EG) in drinking water, mutant rats excreted greater abundance of oxalate and developed severe nephrocalcinosis in contrast to WT animals. Significantly elevated expression of inflammation- and fibrosisrelated genes was also detected in mutants. CONCLUSION: These data suggest that Agxt-deficiency in mitochondria impairs glyoxylic acid metabolism and leads to PH1 in rats. This rat strain would not only be a useful model for the study of the pathogenesis and pathology of PH1 but also a valuable tool for the development and evaluation of innovative drugs and therapeutics.


Assuntos
Sistemas CRISPR-Cas , Modelos Animais de Doenças , Hiperoxalúria Primária , Nefrocalcinose , Transaminases/deficiência , Animais , Glioxilatos/metabolismo , Hiperoxalúria Primária/genética , Hiperoxalúria Primária/patologia , Hiperoxalúria Primária/urina , Mitocôndrias/genética , Mitocôndrias/metabolismo , Nefrocalcinose/genética , Nefrocalcinose/patologia , Nefrocalcinose/urina , Oxalatos/urina , Ratos , Ratos Transgênicos
14.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 34(4): 334-340, 2018 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-29973324

RESUMO

Objective To investigate the effect of knockdown of Polo-like kinase 1 (PLK1) on the growth of HeLa cells. Methods Flow cytometry was used to evaluate the delivery efficiency of siGFP by LAH4-L1 vector. Reverse transcription PCR was used to detect the mRNA level of PLK1. Western blot analysis was performed to detect the level of PLK1 protein. And CCK-8 assay was used to detect the viability and growth of HeLa cells. Results About 70% gene and protein silence was achieved in HeLa cells after LAH4-L1-siPLK1 nanocomplexes transfection, and the proliferation of HeLa cells was significantly inhibited. Besides, the high delivery efficiency of LAH4-L1 could maintain at a stable level. Conclusion Knockdown of PLK1 in HeLa cells can inhibit the growth of HeLa cells. LAH4-L1 is a good gene delivery vector.


Assuntos
Proteínas de Ciclo Celular/genética , Sobrevivência Celular , Vetores Genéticos , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proliferação de Células , Técnicas de Silenciamento de Genes , Células HeLa , Humanos
15.
Mol Pharm ; 15(5): 1853-1861, 2018 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-29621396

RESUMO

The mortality of ovarian cancer stably ranks first in gynecological malignancies due to the lack of specific symptoms and diagnostic methods at an early stage. For most patients, the cancer cells had metastasized before they were diagnosed. As a result, 90% of them died of multidrug resistance (MDR) to chemotherapeutics. In our study, RNAi technology was introduced and applied to overcome this big problem. LAH4-L1, an amphipathic cationic polypeptide, was reported to have high transfection efficiency and was first selected by us to deliver siMDR1 for overcoming ovarian cancer cells MDR. In this research, LAH4-L1-siRNA nanocomplexes (LSCs) delivery system was designed via electrostatic interactions. The nanocomplexes could realize 87.3% MDR1 gene silence and 85% P-gp down-regulation on SKOV-3 cells. What's more, with the combination of chemotherapeutics, SKOV-3 cells growth inhibition can reach to 82.9%. We have also found that there was about 50% reduction on cells migration when MDR1 gene was down-regulated. Besides what have been mentioned above, physicochemical characteristics, cytotoxicity, pH responsivity, cells cycle, cellular uptake, and endosomal escape abilities were also studied in this research. In conclusion, lower cytotoxicity, higher down-regulation of targeted gene, and great cell inhibition, when combined with chemotherapeutics, all show the great potential of LSCs for the reversal of multidrug resistance on SKOV-3 cells in the future.


Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Penetradores de Células/genética , Regulação para Baixo/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Nanopartículas/química , Neoplasias Ovarianas/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Quimioterapia Adjuvante/métodos , Regulação para Baixo/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Ovarianas/tratamento farmacológico , RNA Interferente Pequeno/genética
16.
J Biol Chem ; 293(18): 6883-6892, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29507093

RESUMO

Hereditary tyrosinemia type I (HTI) is a metabolic genetic disorder caused by mutation of fumarylacetoacetate hydrolase (FAH). Because of the accumulation of toxic metabolites, HTI causes severe liver cirrhosis, liver failure, and even hepatocellular carcinoma. HTI is an ideal model for gene therapy, and several strategies have been shown to ameliorate HTI symptoms in animal models. Although CRISPR/Cas9-mediated genome editing is able to correct the Fah mutation in mouse models, WT Cas9 induces numerous undesired mutations that have raised safety concerns for clinical applications. To develop a new method for gene correction with high fidelity, we generated a Fah mutant rat model to investigate whether Cas9 nickase (Cas9n)-mediated genome editing can efficiently correct the Fah First, we confirmed that Cas9n rarely induces indels in both on-target and off-target sites in cell lines. Using WT Cas9 as a positive control, we delivered Cas9n and the repair donor template/single guide (sg)RNA through adenoviral vectors into HTI rats. Analyses of the initial genome editing efficiency indicated that only WT Cas9 but not Cas9n causes indels at the on-target site in the liver tissue. After receiving either Cas9n or WT Cas9-mediated gene correction therapy, HTI rats gained weight steadily and survived. Fah-expressing hepatocytes occupied over 95% of the liver tissue 9 months after the treatment. Moreover, CRISPR/Cas9-mediated gene therapy prevented the progression of liver cirrhosis, a phenotype that could not be recapitulated in the HTI mouse model. These results strongly suggest that Cas9n-mediated genome editing is a valuable and safe gene therapy strategy for this genetic disease.


Assuntos
Proteína 9 Associada à CRISPR/metabolismo , Desoxirribonuclease I/metabolismo , Edição de Genes , Terapia Genética/métodos , Tirosinemias/genética , Adenoviridae/genética , Animais , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Células HEK293 , Hepatócitos/citologia , Humanos , Hidrolases/genética , Mutação INDEL , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Masculino , Ratos , Tirosinemias/complicações , Tirosinemias/imunologia , Tirosinemias/terapia
17.
Molecules ; 23(1)2017 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-29267186

RESUMO

Blaps rynchopetera Fairmaire has long been used as a folk medicine by the Yi and Bai ethnic groups in China to treat fever, cough, gastritis, boils, and tumors. In the present study, the cytotoxicity of the defensive secretion (TDS) of B. rynchopetera against AGS Caco-2, HepG2 U251 and Bel-7402 was tested, and the results revealed that TDS had potent cytotoxicity against testing cells with IC50 values of 45.8, 17.4, 53.6, 98.4 and 23.4 µg/mL, respectively. Gas chromatography-mass spectrometry (GC-MS) analysis was employed to clarify the cytotoxic constituents in TDS of B. rynchopetera and five volatile compounds, including 2-ethyl-2,5-cyclohexadiene-1,4-dione (3, 31.00%), 1-tridecene (5, 28.02%), 2-methyl-2,5-cyclohexadiene-1,4-dione (2, 22.86%), hydroquinone (4, 1.33%), and p-benzoquinone (1, 1.01%), were identified. Chemical constituent investigation on TDS further supported the presence of 5 above compounds. A cytotoxic assay indicated that compounds 1, 2, 3 and 4 exhibited significant cytotoxicity against the testing cell lines, implying that benzoquinones and hydroquinone played important roles in the cytotoxicity of TDS of B. rynchopetera. TDS is a cytotoxic natural material and further studies investigating mechanisms and inhibitory activities on other cell lines is warranted.


Assuntos
Antineoplásicos/química , Secreções Corporais/química , Compostos Orgânicos Voláteis/química , Alcenos/química , Alcenos/farmacologia , Animais , Antineoplásicos/farmacologia , Benzoquinonas/química , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Besouros , Cicloexenos/química , Cicloexenos/farmacologia , Humanos , Hidroquinonas/química , Hidroquinonas/farmacologia , Estrutura Molecular , Compostos Orgânicos Voláteis/farmacologia
18.
Int J Pharm ; 530(1-2): 291-299, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28619457

RESUMO

The application of RNAi therapeutics is promising in combating several major human diseases including malignant tumors. However, this approach is limited due to its delivery barriers. In this study, we designed a new carrier system loaded with a functional siRNA targeting MDR1 gene to reverse multi-drug resistance (MDR) in human breast cancer MCF-7/ADR cells. Phospholipid-modified PAMAM-siMDR1 complexes were designed on the external decoration of polyamidoamine (PAMAM) with phospholipid (PL) and the electrostatical interaction between PAMAM and siMDR1 to form hybrid nanocomplexes (PL-dendriplexes). Compared with siMDR1 and dendriplexes (PAMAM-siMDR1), this delivery system represented higher gene silencing efficiency, enhanced cellular uptake of siMDR1, decreased p-gp expression, raised cellular accumulation of doxorubicin (DOX) and inhibited the tumor cell migration. Moreover, the siMDR1 loaded PL-dendriplexes worked synergistically with paclitaxel (PTX) for treating MDR, leading to increased cell apoptosis and cell phase regulation. Overall, this study shows that the PL-dendriplexes hold great promise in reversing the drug-resistance in MCF-7/ADR cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Dendrímeros/química , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Interferência de RNA , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Humanos , Células MCF-7 , Fosfolipídeos/química
19.
Neuropsychologia ; 100: 1-9, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28391034

RESUMO

Human visual system is found to be much efficient in searching for a fearful face. Some individuals are more sensitive to this threat-related stimulus. However, we still know little about the neural correlates of such variability. In the current study, we exploited a visual search paradigm, and asked the subjects to search for a fearful face or a target gender. Every subject showed a shallower search function for fearful face search than face gender search, indicating a stable fearful face advantage. We then used voxel-based morphometry (VBM) analysis and correlated this advantage to the gray matter volume (GMV) of some presumably face related cortical areas. The result revealed that only the left fusiform gyrus showed a significant positive correlation. Next, we defined the left fusiform gyrus as the seed region and calculated its resting state functional connectivity to the whole brain. Correlations were also calculated between fearful face advantage and these connectivities. In this analysis, we found positive correlations in the inferior parietal lobe and the ventral medial prefrontal cortex. These results suggested that the anatomical structure of the left fusiform gyrus might determine the search efficiency of fearful face, and frontoparietal attention network involved in this process through top-down attentional modulation.


Assuntos
Atenção/fisiologia , Encéfalo/fisiologia , Face , Medo , Reconhecimento Visual de Modelos/fisiologia , Vias Visuais/fisiologia , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Estimulação Luminosa , Vias Visuais/diagnóstico por imagem , Adulto Jovem
20.
Int J Pharm ; 511(1): 436-445, 2016 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-27444552

RESUMO

Multidrug resistance (MDR) among breast cancer cells is the paramount obstacle for the successful chemotherapy. In this study, anti-EGFR antibody h-R3 was designed to self-assembled h-R3-siRNA-PAMAM-complexes (HSPCs) via electrostatic interactions for siRNA delivery. The physicochemical characterization, cell uptake, MDR1 silencing efficiency, cell migration, cell growth and cell apoptosis were investigated. The HSPCs presented lower cytotoxicity, higher cellular uptake and enhanced endosomal escape ability. Also, HSPCs encapsulating siMDR1 knockdowned 99.4% MDR1 gene with up to ∼6 times of enhancement compared to naked siMDR1, increased the doxorubicin accumulation, down-regulated P-glycoprotein (P-gp) expression and suppressed cellular migration in breast cancer MCF-7/ADR cells. Moreover, the combination of anticancer drug paclitaxel (PTX) and siMDR1 loaded HSPCs showed synergistic effect on overcoming MDR, which inhibited cell growth and induced cell apoptosis. This h-R3-mediated siMDR1 delivery system could be a promising vector for effective siRNA therapy of drug resistant breast cancer.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Dendrímeros/administração & dosagem , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Anticorpos Monoclonais Humanizados/química , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Dendrímeros/química , Resistência a Múltiplos Medicamentos/fisiologia , Feminino , Humanos , Células MCF-7
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