Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 189
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Mater Chem B ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31776521

RESUMO

In this report, a novel nanocomposite of highly dispersed Au nanoparticles deposited on NH2-MIL-125(Ti) was designed and proposed as a peroxidase-like mimic. Compared with individual Au nanoparticles and NH2-MIL-125(Ti), the peroxidase-like nanozyme exhibits enhanced peroxidase-like activity. Moreover, kinetic analysis reveals that the as-prepared nanozyme has lower Km values and stronger affinity towards both substrates than the natural horseradish peroxidase (HRP). The detection limits of the multifunctional platform for H2O2, cysteine and Hg2+ are down to 0.24 µM, 0.14 µM and 100 nM, respectively. This work provides rapid and sensitive colorimetric detection strategies for small biomolecules and Hg2+, which have great potential for application in biosensors and biotechnology.

2.
Oxid Med Cell Longev ; 2019: 4818106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781337

RESUMO

Breast cancer is the most common malignant disease of females. Overall, one woman in every nine will get breast cancer at some time in her life. Epidemiological studies have indicated that alcohol consumption has most consistently been associated with breast cancer risk. However, the mechanism of alcohol-associated breast cancer remains to be addressed. Little is known about the effects of alcohol consumption on Brf1 (TFIIIB-related factor 1) expression and RNA Pol III gene (RNA polymerase III-dependent gene) transcription, which are responsible for protein synthesis and tightly linked to cell proliferation, cell transformation, and tumor development. Emerging evidences have indicated that alcohol induces deregulation of Brf1 and Pol III genes to cause the alterations of cell phenotypes and tumor formation. In this paper, we summarize the progresses regarding alcohol-caused increase in the expression of Brf1 and Pol III genes and analysis of its molecular mechanism of breast cancer. As the earlier and accurate diagnosis approach of breast cancer is not available yet, exploring the molecular mechanism and identifying the biomarker of alcohol-associated breast cancer are especially important. Recent studies have demonstrated that Brf1 is overexpressed in most ER+ (estrogen receptor positive) cases of breast cancer and the change in cellular levels of Brf1 reflects the therapeutic efficacy and prognosis of this disease. It suggests that Brf1 may be a potential diagnosis biomarker and a therapeutic target of alcohol-associated breast cancer.

3.
Travel Med Infect Dis ; : 101499, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31604130

RESUMO

BACKGROUND: Chloroquine (CQ) and primaquine (PQ) remain the frontline drugs for radical cure of uncomplicated P. vivax malaria in the Greater Mekong Sub-region (GMS). Recent reports of decreased susceptibility of P. vivax to CQ in many parts of the GMS raise concerns. METHODS: From April 2014 to September 2016, 281 patients with uncomplicated P. vivax infection attending clinics in border settlements for internally displaced people in northeast Myanmar were recruited into this study. Patients were treated with standard regimen of 3-day CQ and concurrent 14-day PQ (3.5 mg/kg total dose) as directly observed therapy, and followed for recurrent parasitemia within 28 days post-patency. RESULTS: Within the 28-day follow-up period, seven patients developed recurrent parasitemia, resulting in a cumulative rate of parasite recurrence of 2.6%. Five of the seven parasitemias recurred within two weeks, and two of those failed to clear within seven days, indicating high-grade resistance. CONCLUSION: Although failure of CQ/PQ treatment of P. vivax was relatively infrequent in northeast Myanmar, this study nonetheless confirms that CQ/PQ-resistant strains do circulate in this area, some of them of a highly resistant phenotype. It is thus recommended that patients who acquire vivax malaria in Myanmar be treated an artemisinin-combination therapy along with hypnozoitocidal primaquine therapy to achieve radical cure.

4.
Cell Death Dis ; 10(7): 508, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263103

RESUMO

The accumulation of tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is associated with malignant progression in cancer. However, the mechanisms by which the hypoxic TME facilitates TAM infiltration are not fully understood. This study showed that high ZEB1 expression in hypoxic cervical cancer cell islets was positively correlated with CD163+ TAM accumulation. ZEB1 in hypoxic cancer cells promoted the migration of TAMs in vitro and altered the expression of multiple chemokines, especially CCL8. Mechanistically, hypoxia-induced ZEB1 activated the transcription of CCL8, which attracted macrophages via the CCR2-NF-κB pathway. Furthermore, ZEB1 and CCL8 were independent prognostic factors in cervical cancer patients based on The Cancer Genome Atlas (TCGA) data analysis. In conclusion, hypoxia-induced ZEB1 exerts unexpected functions in cancer progression by fostering a prometastatic environment through increased CCL8 secretion and TAM recruitment; thus, ZEB1 may serve as a candidate biomarker of tumour progression and provide a potential target for disrupting hypoxia-mediated TME remodelling.

5.
Cell Biol Int ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31329338

RESUMO

To investigate the roles of tripartite motif containing 52 (TRIM52) in human hepatic fibrosis in vitro, human hepatic stellate cell line LX-2 cells were transfected with hepatitis B virus (HBV) replicon to establish HBV-induced fibrosis in LX-2 cells, and then treated with small interfering RNA-mediated knockdown of TRIM52 (siTRIM52). LX-2 cells without HBV replicon transfection were treated with lentiviruses-mediated overexpression of TRIM52 and phosphatase magnesium dependent 1A (PPM1A). Fibrosis response of LX-2 cells were assessed by the production of hydroxyproline (Hyp) and collagen I/III, as well as protein levels of α-smooth muscle actin (α-SMA). PPM1A and phosphorylated (p)-Smad2/3 were measured to assess the mechanism. The correlation between TRIM52 and PPM1A was determined using co-immunoprecipitation, and whether and how TRIM52 regulated the degradation of PPM1A were determined by ubiquitination assay. Our data confirmed HBV-induced fibrogenesis of LX-2 cells, as evidenced by significant increase in Hyp and collagen I/III and α-SMA, which was associated with reduction of PPM1A and elevation of transforming growth factor-ß (TGF-ß), p-Smad2/3, and p-Smad3L. However, those changes induced by HBV were significantly attenuated with additional siTRIM52 treatment. Similar to HBV, overexpression of TRIM52 exerted promoted effect in the fibrosis of LX-2 cells. Interestingly, TRIM52 induced the fibrogenesis of LX-2 cells and the activation of TGF-ß/Smad pathway were significantly reversed by PPM1A overexpression. Furthermore, our data confirmed TRIM52 as a deubiquitinase that influenced the accumulation of PPM1A protein, and subsequently regulated the fibrogenesis of LX-2 cells. TRIM52 was a fibrosis promoter in hepatic fibrosis in vitro, likely through PPM1A-mediated TGF-ß/Smad pathway.

6.
Oxid Med Cell Longev ; 2019: 7417561, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205589

RESUMO

Both c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS) play important roles in myocardial ischemia/reperfusion (I/R) injury. Our previous studies suggest that N-n-butyl haloperidol iodide (F2) exerts cardioprotection by reducing ROS production and JNK activation caused by I/R. In this study, we hypothesized that there is a JNK/Sab/Src/ROS pathway in the mitochondria in H9c2 cells following hypoxia/reoxygenation (H/R) that induces oxidative stress in the mitochondria and that F2 exerts mitochondrial protective effects during H/R injury by modulating this pathway. The results showed that H/R induced higher-level ROS in the cytoplasm on the one hand and JNK activation and translocation to the mitochondria by colocalization with Sab on the other. Moreover, H/R resulted in mitochondrial Src dephosphorylation, and subsequently, oxidative stress evidenced by the increase in ROS generation and oxidized cardiolipin in the mitochondrial membranes and by the decrease in mitochondrial superoxide dismutase activity and membrane potential. Furthermore, treatment with a JNK inhibitor or Sab small interfering RNA inhibited the mitochondrial translocation of p-JNK, decreased colocalization of p-JNK and Sab on the mitochondria, and reduced Src dephosphorylation and mitochondrial oxidative stress during H/R. In addition, Src dephosphorylation by inhibitor PP2 increased mitochondrial ROS production. F2, like inhibitors of the JNK/Sab/Src/ROS pathway, downregulated the H/R-induced mitochondrial translocation of p-JNK and the colocalization of p-JNK and Sab on the mitochondria, increased Src phosphorylation, and alleviated the above-mentioned mitochondrial oxidative stress. In conclusion, F2 could ameliorate H/R-associated oxidative stress in mitochondria in H9c2 cells through the mitochondrial JNK/Sab/Src/ROS pathway.

7.
Appl Microbiol Biotechnol ; 103(17): 7129-7140, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31230101

RESUMO

Fumonisin B1 (FB1) contamination in cereals and cereal products remains an important aspect of food safety because of its wide distribution and the potential health hazard. However, only a few microorganisms have been reported to effectively degrade FB1. In this present study, a bacterial consortium SAAS79 with highly FB1-degrading activity was isolated from the spent mushroom compost. The combination of antibiotic-driven selection and 16S rDNA sequencing identified the Pseudomonas genus as the key FB1-degrading member. The microbial consortium could degrade more than 90% of 10 µg/mL FB1 after incubation for 24 h at pH of 5-7 and temperature of 28-35 °C. The enzymes from the intracellular space were proved to be responsible for FB1 degradation, which eliminated about 90% of 10 µg/mL FB1 in 3 h. Besides, liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS) analysis identified two degradation products of FB1, and their toxicity on the monkey kidney cells (MARC-145) was significantly lower (p < 0.05) compared with the parent FB1. Overall, the consortium SAAS79 and its crude enzymes may be a potential choice for the decontamination of FB1 in the feed and food industry. Also, the bacterial consortium provides a new source of genes for the development of enzymatic detoxification agent.

8.
Oncogene ; 38(29): 5792-5804, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31243299

RESUMO

Tumor-associated macrophages (TAMs) are the most abundant cancer stromal cells and play an essential role in tumor immunosuppression, providing a suitable microenvironment for cancer development and progression. However, mechanisms of regulating TAMs infiltration in tumor sites are not fully understood. Here, we show that inactivation of neddylation pathway significantly inhibits infiltration of TAMs, leading to the suppression of lung cancer metastasis. RNA-sequencing analysis revealed that neddylation inactivation suppresses the transactivation of chemotactic cytokine ligand 2 (CCL2). Mechanistically, neddylation inactivation inhibits the activity of Cullin-RING ligases (CRLs) and induces the accumulation of its substrate IκBα to block NF-κB transcriptional activity and CCL2 transactivation. As a result, neddylation inactivation exhibits lower chemotaxis of monocytes, thereby decreasing TAMs infiltration, which can be alleviated by CCL2 addition. Moreover, the expression level of NEDD8 is positively correlated with high CCL2 expression in lung adenocarcinoma, conferring a worse overall patient survival. Together, neddylation pathway promotes CCL2 transactivation and TAMs infiltration in lung cancer to provide a tumor-promoting microenvironment, which validates neddylation pathway as a promising target for anti-TAMs therapeutic strategies.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31009824

RESUMO

Mutations in the Kelch domain of the K13 gene (PF3D7_1343700) were previously associated with artemisinin resistance in Plasmodium falciparum. This study followed the dynamics of the K13 polymorphisms in P. falciparum parasites from the China-Myanmar border area obtained in 2007-2016, and their in vitro sensitivities to artesunate (AS) and dihydroartemisinin (DHA). The 50% effective concentration (EC5072h) values of 133 culture-adapted field isolates to AS and DHA, measured by the conventional 72 h SYBR Green I-based assay, varied significantly among the parasites from different years; all were significantly higher than that of the reference strain 3D7. Compared with parasites from 2007 to 2008, ring survival rates almost doubled in parasites obtained in later years. Sequencing the full-length K13 genes identified 11 point mutations present in 85 (63.9%) parasite isolates. F446I was the predominant (55/133) variant, and its frequency was increased from 17.6% (3/17) in 2007 to 55.9% (19/34) in 2014-2016. No wild-type (WT) Kelch domain sequences were found in the 34 samples obtained from 2014 to 2016. In the 2014-2016 samples, a new mutation (G533S) appeared and reached 44.1% (15/34). Collectively, parasites with the Kelch domain mutations (after amino acid 440) had significantly higher ring survival rates than the WT parasites. Individually, F446I, G533S and A676D showed significantly higher ring survival rates than the WT. Although the drug sensitivity phenotypes measured by the RSA6h and EC5072h assays may be intrinsically linked to the in vivo clinical efficacy data, the values determined by these two assays were not significantly correlated. This study identified the trend of K13 mutations in parasite populations from the China-Myanmar border area, confirmed an overall correlation of Kelch domain mutations with elevated ring-stage survival rates, and emphasized the importance of monitoring the evolution and spread of parasites with reduced artemisinin sensitivity along the malaria elimination course.

10.
Angiogenesis ; 22(3): 397-410, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30993566

RESUMO

AIMS: Recently, cancer-derived exosomes were shown to have pro-metastasis function in cancer, but the mechanism remains unclear. Angiogenesis is essential for tumor progression and is a great promising therapeutic target for advanced cervical cancer. Here, we investigated the role of cervical cancer cell-secreted exosomal miR-221-3p in tumor angiogenesis. METHODS AND RESULTS: miR-221-3p was found to be closely correlated with microvascular density in cervical squamous cell carcinoma (CSCC) by evaluating the microvascular density with immunohistochemistry and miR-221-3p expression with in situ hybridization in clinical specimens. Using the groups of CSCC cell lines (SiHa and C33A) with miR-221-3p overexpression and silencing, the CSCC exosomes were characterized by electron microscopy, western blotting, and fluorescence microscopy. The enrichment of miR-221-3p in CSCC exosomes and its transfer into human umbilical vein endothelial cells (HUVECs) were confirmed by qRT-PCR. CSCC exosomal miR-221-3p promoted angiogenesis in vitro in Matrigel tube formation assay, spheroid sprouting assay, migration assay, and wound healing assay. Then, exosome intratumoral injection indicated that CSCC exosomal miR-221-3p promoted tumor growth in vivo. Thrombospondin-2 (THBS2) was bioinformatically predicted to be a direct target of miR-221-3p, and this was verified by using the in vitro and in vivo experiments described above. Additionally, overexpression of THBS2 in HUVECs rescued the angiogenic function of miR-221-3p. CONCLUSIONS: Our results suggest that CSCC exosomes transport miR-221-3p from cancer cells to vessel endothelial cells and promote angiogenesis by downregulating THBS2. Therefore, CSCC-derived exosomal miR-221-3p could be a possible novel diagnostic biomarker and therapeutic target for CSCC progression.

11.
Clin Cancer Res ; 25(12): 3658-3672, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30833270

RESUMO

PURPOSE: How the neddylation pathway functions in breast tumor and regulation of estrogen receptor (ER) expression is rarely reported. The purpose of this study was to identify the role of neddylation in breast cancer and ER expression, and further explore the underlying mechanisms. EXPERIMENTAL DESIGN: Expression patterns of nedd8-activating enzyme (NAE) and nedd8, two key proteins in the neddylation pathway, were examined in human breast specimens. ER-α expression was investigated using animal 18F-FES-PET/CT and immunoblotting upon NAE inhibitor MLN4924 treatment. Chromatin immunoprecipitation assay, luciferase reporter promoter assay, and the CRISPR-Cas9 system were used to elucidate the mechanism of ER-α regulation by MLN4924. The ER-positive breast cancer mouse model was used to determine the synergetic effect of MLN4924 and fulvestrant on tumor growth. All statistical tests were two-sided. RESULTS: Both NAE1 and nedd8 expressions were higher in the ER-positive subgroup. Higher expressions of NAE1 and nedd8 indicated poorer prognosis. Importantly, ER-α expression was significantly downregulated upon MLN4924 treatment in vitro and in vivo. Mechanistically, MLN4924 treatment delayed serum and glucocorticoid-induced protein kinase (SGK) degradation and induced Forkhead box O3a (FOXO3a) nuclear export as well as decreased binding to the ESR1 promoter. Importantly, MLN4924 single or synergized with fulvestrant significantly suppressed the growth of ER-positive breast cancer in vitro and in vivo. CONCLUSIONS: Our proof-of-principle study determines the activation of neddylation in breast tumor tissues for the first time and reveals a new ER-α regulatory mechanism, as well as further explores an effective approach to improve fulvestrant sensitivity through a neddylation inactivation combination.

12.
Fish Shellfish Immunol ; 88: 53-64, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30790659

RESUMO

A 58-day feeding trial was conducted to evaluate the effects of dietary myo-inositol (MI) supplementation on growth performance, haematological parameters, hepatopancreas histopathology and antioxidant status of Litopenaeus vannamei fed with oxidized fish oil (OFO). Control diet contained fresh fish oil (FFO) without MI supplementation. The other four diets contained two oxidation levels of OFO (peroxide value: 133.2 and 268.7 meq kg-1) with or without 200 mg MI kg-1 diets (MI0+L, MI0+H, MI200 + L and MI200 + H). Results showed that OFO-supplemented groups (without MI supplementation) showed better growth performance and lower whole-body inositol content when opposed to control group. MI supplementation significantly improved whole-body inositol content in high-oxidized fish oil (HOFO) groups, and also reduced whole-body lipid in low-oxidized fish oil (LOFO) groups. Moreover, Supplementation of OFO and MI markedly hit the fatty acid profile of muscle. HOFO caused severe histopathological changes in hepatopancreas of shrimp, which slightly alleviated by MI supplementation. MI supplementation also grew the total protein (TP) content and alkaline phosphatase (AKP) activity and decreased the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of serum in OFO-supplemented groups. Ingestion of OFO increased levels of lipid peroxidation and protein oxidation in serum or hepatopancreas, which partly ameliorated by MI supplementation. Activities of antioxidant enzymes exhibited different expression patterns because of OFO and MI. In addition, HOFO markedly increased mRNA expression levels of antioxidant genes including ferritin (FT), thioredoxin (Trx), GPX, glutathione S-transferase (GST) and catalase (CAT) and decreased peroxiredoxin (Prx) expression, in which expression of GPX and Prx were increased owing to MI supplementation. Therefore, it suggested that dietary OFO stimulated growth performance, but also induced oxidative stress and caused impairment to hepatopancreas in L. vannamei. The negative impact brought about by OFO was partially mitigated by dietary MI supplementation.


Assuntos
Ração Animal/análise , Óleos de Peixe , Inositol/farmacologia , Penaeidae/efeitos dos fármacos , Animais , Antioxidantes/análise , Aquicultura/métodos , Dieta/veterinária , Hepatopâncreas/efeitos dos fármacos , Hepatopâncreas/patologia , Peroxidação de Lipídeos , Oxirredução , Penaeidae/crescimento & desenvolvimento , Penaeidae/metabolismo
13.
Orphanet J Rare Dis ; 13(1): 229, 2018 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-30577881

RESUMO

OBJECTIVE: To analyze the clinical audiological characteristics of X-Linked Alport syndrome (XLAS) in males and their relationships with genotypes. METHODS: The clinical data of 87 male patients with AS were reviewed. Hearing levels were evaluated using pure tone audiometry (PTA) testing, acoustic immittance, and otoacoustic emissions (OAE) testing. The genotypes of COL4A5 and the pathogenic variants were analyzed. The relationships between auditory phenotypes and genotypes were analyzed. RESULTS: Among the 87 patients, the number of patients with normal hearing and hearing loss were 32 and 55, respectively. In all cases, the hearing loss was characterized as bilateral symmetrical sensorineural deafness. Majority of the patients had mild-to-moderate hearing loss. Hearing loss usually started in the middle frequency range and gradually affected high frequencies, at school age and gradually increased with increasing age. However, it maintained a relatively steady level of 50-60 dB HL during the teenage years. The audiometric curves included groove-type in 51 cases (92.73%). Patients were identified to have 60 different COL4A5 pathogenic variants. Of the 49 patients who were followed-up for more than 2 years, 28 cases presented a decreasing trend in the hearing level of about 5 dB per year. The degree of hearing loss was positively correlated with gene mutation type and renal function. CONCLUSIONS: Hearing loss in males with XLAS is symmetrical sensorineural, and progressive with increasing age. There is a significant correlation between the degree of hearing loss and genotype, renal function, and age.


Assuntos
Nefrite Hereditária/genética , Adolescente , Adulto , Criança , Colágeno Tipo IV/genética , Genótipo , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Humanos , Masculino , Mutação/genética , Mutação de Sentido Incorreto/genética , Nefrite Hereditária/fisiopatologia , Fenótipo , Adulto Jovem
14.
Wei Sheng Yan Jiu ; 47(5): 756-762, 2018 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-30593300

RESUMO

OBJECTIVE: To explore the effect of childhood physical abuse on aggressive behaviors of 4-6 grade pupils in rural areas. METHODS: A questionnaire survey was conducted on physical abuse and aggression of 8406 students in rural primary schools from five provinces( Anhui, Yunnan, Guangdong, Heilongjiang, Hubei) by stratified cluster sampling method between November 2014 and May 2015. RESULTS: The aggression average score was( 68. 58 ± 16. 86), its level was intermediate. 4061 pupils( 48. 3%) experienced moderate or severe physical abuse, 954 of whom were severely abused. Statistical significance in different gender( t = 10. 413, P < 0. 001), different family economic level( F = 3. 868, P = 0. 021) had been found. The level of aggression onprimary school students who suffered physical abuse was higher than that of who did not, and the differences in scores of various aggressive types were statistically significant( F =285. 138, P < 0. 001). Regression analysis( F = 66. 16, P < 0. 001, R = 0. 335, R2=0. 112) showed that physical abuse had the greatest influence on children's aggressive( b' = 0. 288), followed by gender( b' =-0. 067). Family economic level can positively predict the level of child aggression, children lived in recombination family( t = 2. 823, P = 0. 005) and the grandparent family( t = 5. 004, P < 0. 001) were more aggressive than those living in the corer family. Children who lived in extended family performed well with less aggressive behaviors. Besides, children who were reared in democratic atmosphere got lower scores of the aggression than those who were educated by indulgent, laissez-faire, rough or capricious ways and the differences were statistically significant( P < 0. 05). CONCLUSION: Children's aggression is closely related with gender, family type, family income, parenting style, physical abuse in childhood. Among them, physical abuse in childhood is the most important risk factor for aggression of 4-6 grade students in rural primary schools.


Assuntos
Agressão , Comportamento Infantil , Abuso Físico , Criança , Maus-Tratos Infantis , China , Humanos , Instituições Acadêmicas , Estudantes
15.
IUBMB Life ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30452117

RESUMO

Myofibroblast apoptosis is essential for normal resolution of wound repair, including cardiac infarction repair. Impaired cardiac myofibroblast (CMF) apoptosis is associated with excessive extracellular matrix (ECM) deposition, which could be responsible for pathological cardiac fibrosis. Conventionally, angiotensin II (Ang II), a soluble peptide, is implicated in fibrogenesis because it induces cardiac fibroblast (CFb) proliferation, differentiation, and collagen synthesis. However, the role of Ang II in regulation of CMF survival and apoptosis has not been fully clarified. In this report, we cultured neonatal rat CFbs, which transform into CMFs after passage 3 (6-8 days), and investigated the effects of Ang II on CMFs challenged by TNF-α combined with cycloheximide and the underlying mechanisms. Here, we show that Ang II rapidly activates MAPKs but not AKT in CMFs and confers apoptosis resistance, as evidenced by the inhibition of caspase-3 cleavage, early apoptotic cells and late apoptotic cells. This inhibitory effect of Ang II was reversed by blockade of AT1 or inactivation of ERK1/2 or RSK1 but not AT2, indicating that activation of the prosurvival AT1/ERK1/2/RSK1 signaling pathway mediates apoptosis resistance. TGF-ß, a latent fibrotic factor, was found to have no relation to Ang II-induced apoptosis resistance in our study. Furthermore, Ang II-mediated apoptosis resistance, which was conferred by activation of the AT1/ERK1/2/RSK1 signaling pathway, was also confirmed in human adult ventricular cardiac myofibroblasts. Collectively, our findings suggest a novel profibrotic mechanism of Ang II in which it promotes myofibroblast resistance to apoptosis in addition to classical mechanisms, providing a potential novel therapeutic approach by targeting prosurvival signaling pathways. © 2018 IUBMB Life, 2018.

16.
Mol Carcinog ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30362630

RESUMO

To explore the mechanisms through which hypoxic tumor microenvironment (TME) modulates the transition of tumor-associated macrophages (TAMs). The migration ability of RAW264.7 macrophages was determined by transwell assay. Flow cytometric, western blot and immunofluorescence analyses of CD206 further validated the M2 polarization of macrophages. Immunofluorescence, western blot and qRT-PCR were performed to detect the expression of neuropilin-1 (Nrp-1) and carbonic anhydrase IX (CAIX). An intermittent hypobaric hypoxia (IH) animal model was established to evaluate the role of hypoxia in activating M2-like TAMs in vivo. We also used immunohistochemistry to analyze the association between CAIX, CD163+ macrophages and Nrp-1 in a series of 72 human cervical cancer specimens. We found that the hypoxic cervical TME educated the recruited macrophages to transform into the M2 phenotype. Nrp-1 expression was significantly increased in hypoxia-primed cervical cancer cells. Blocking Nrp-1 expression prevented hypoxic cells from recruiting and polarizing macrophages towards the M2 phenotype. Hypoxia exposure significantly increased the expression of Nrp-1 as well as the infiltration of macrophages in vivo. Consistently, immunochemical staining in serial tissue sections of cervical cancer revealed upregulated levels of Nrp-1 in CAIX-positive hypoxic regions along with a concurrent significant elevation of M2 macrophages. Nrp-1 and M2-like TAMs were related to the malignant properties of cervical cancer, such as the FIGO stage and lymph node metastasis. Nrp-1 plays critical roles in hypoxic TME-induced activation and pro-tumoral effects of TAMs in cervical cancer. Interfering with Nrp-1 may be a potential therapeutic strategy in treating cervical cancer.

17.
Gene ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30366081

RESUMO

Alcohol intake increases the risk of cancer development. Approximately 3.6% human cancers worldwide derive from chronic alcohol drinking, including oral, liver, breast and other organs. Our studies in vivo and in vitro have demonstrated that diluted ethanol increase RNA Pol III gene transcription and promotes cell proliferation and transformation, as well as tumor formation. However, it is unclear about the effect of red wines on the human cancer cells. In present study, we investigated the roles of red wine in human cancer cell growth, colony formation and RNA Pol III gene transcription. Low concentration (12.5 mM to 25 mM) of ethanol enhances cell proliferation of breast and esophageal cancer lines, whereas its higher concentration (100 mM to 200 mM) slightly decreases the rates. In contrast, red wines significantly repress cell proliferation of different human cancer lines from low dose to high dose. The results reveal that the red wine also inhibits colony formation of human breast cancer and esophageal carcinoma cells. The effects of repression on different human cancer lines are in a dose-dependent manner. Further analysis indicates that ethanol increases RNA Pol III gene transcription, whereas the red wines significantly reduce transcription of the genes. Interestingly, the effects of mature wine (brick red) on cancer cell phenotypes are much stronger than young wine (intense violet). Together, these new findings suggest that red wines may contain some bioactive components, which are able to inhibit human cancer cell growth and colony formation.

18.
Cell Prolif ; : e12536, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341788

RESUMO

OBJECTIVES: The present study aimed to reveal expression status of the neddylation enzymes in HNSCC and to elucidate the anticancer efficacy and the underlying mechanisms of inhibiting neddylation pathway. MATERIALS AND METHODS: The expression levels of neddylation enzymes were estimated by Western blotting in human HNSCC specimens and bioinformatics analysis of the cancer genome atlas (TCGA) database. Cell apoptosis was evaluated by Annexin V fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) stain and fluorescence-activated cell sorting (FACS). Small interfering RNA (siRNA) and the CRISPR-Cas9 system were used to elucidate the underlying molecular mechanism of MLN4924-induced HNSCC apoptosis. RESULTS: Expression levels of NAE1 and UBC12 were prominently higher in HNSCC tissues than that in normal tissues. Inactivation of the neddylation pathway significantly inhibited malignant phenotypes of HNSCC cells. Mechanistic studies revealed that MLN4924 induced the accumulation of CRL ligase substrate c-Myc that transcriptionally activated pro-apoptotic protein Noxa, which triggered apoptosis in HNSCC. CONCLUSIONS: These findings determined the over-expression levels of neddylation enzymes in HNSCC and revealed novel mechanisms underlying neddylation inhibition induced growth suppression in HNSCC cells, which provided preclinical evidence for further clinical evaluation of neddylation inhibitors (eg, MLN4924) for the treatment of HNSCC.

19.
Chemphyschem ; 19(22): 2989-2994, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30171653

RESUMO

Mixed-valence compounds are of great interest due to their interesting properties and wide applications. Recently, gold (Au) chemistry has experienced an unprecedented development. However, Au with mixed-valence states in Au-O compounds has not been reported thus far. Here, two hitherto unknown AuO2 and AuS compounds with mixed-valence character were identified with the aid of first-principles swarm structure searching calculations. AuO2 consists of quasi-square AuO4 moiety and AuO6 octahedron in which Au shows the mixed-valence states of III and V, the first example in Au-O binary compounds. AuS contains the linear AuS2 and quasi-square AuS4 units exhibiting AuI/III mixed-valence states. The analysis of electronic property demonstrates that AuO2 and AuS are narrow band gap semiconductors with strong hybridization between Au 5d and O 2p or S 3p. With the increase of pressure, Au-O and Au-S compounds show completely different thermodynamic stabilities, resulting from distinct shifting of pressure-induced atomic orbital energy levels of O and S atoms. Our work provides an opportunity for understanding mixed-valence character in Au-O and Au-S compounds.

20.
Gut Pathog ; 10: 37, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30214488

RESUMO

Background: Culture-based diagnostic methods cannot achieve rapid and precise diagnoses for the identification of multiple diarrhoeal pathogens (DPs). A high-throughput multiplex genetic detection system (HMGS) was adapted and evaluated for the simultaneous identification and differentiation of infectious DPs and a broad analysis of DP infection aetiology. Results: DP-HMGS was highly sensitive and specific for DP detection compared with culture-based techniques and was similar to singleplex real-time PCR. The uniform level of sensitivity of DP-HMGS for all DPs allowed us to remap the aetiology of acute diarrhoeal infections in Shanghai, correcting incidences of massively underdiagnosed DP species with accuracy approaching that of sequencing-based methods. The most frequent DPs were enteropathogenic Escherichia coli, rotavirus and Campylobacter jejuni. DP-HMGS detected two additional causes of infectious diarrhoea that were previously missed by routine culture-based methods: enterohemorrhagic E. coli and Yersinia enterocolitica. We demonstrated the age dependence of specific DP distributions, especially the distributions of rotavirus, intestinal adenovirus and Clostridium difficile in paediatric patients as well as those of dominant bacterial infections in adults, with a distinct "top 3" pattern for each age group. Finally, the multiplexing capability and high sensitivity of DP-HMGS allowed the detection of infections co-induced by multiple pathogens (approximately 1/3 of the cases), with some DPs preferentially co-occurring as infectious agents. Conclusions: DP-HMGS has been shown to be a rapid, specific, sensitive and appropriate method for the simultaneous screening/detection of polymicrobial DP infections in faecal specimens. Widespread use of DP-HMGS is likely to advance routine diagnostic and clinical studies on the aetiology of acute diarrhoea.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA