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1.
Blood ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31697837

RESUMO

Lineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a Salt-Inducible Kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF MEF2C. In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C. Here, we evaluated whether inhibition of SIK3 with the tool compound YKL-05-099 can suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells under in vitroand in vivoconditions. Similar phenotypes were obtained when exposing cells to YKL-05-099, which caused cell cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. Using a gatekeeper allele of SIK3, we found that the anti-proliferative effects of YKL-05-099 occurred through on-target inhibition of SIK3 kinase activity. Based on these findings, we treated two different mouse models of MLL-AF9 AML with YKL-05-099, which attenuated disease progression in vivoand extended animal survival at well-tolerated doses. These findings validate SIK3 as a therapeutic target in MEF2C-addicted AML and provide a rationale for developing drug-like inhibitors of SIK3 for definitive pre-clinical investigation and for studies in human patients.

2.
Environ Pollut ; 255(Pt 2): 113325, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31614327

RESUMO

Associations between single metal and fasting blood glucose (FBG) levels have been reported in previous studies. However, the association between multi-metals exposure and FBG level are little known. To assess the joints of arsenic (As), nickel (Ni), cadmium (Cd), selenium (Se), and zinc (Zn) co-exposure on FBG levels, Bayesian kernel machine regression (BKMR) statistical method was used to estimate the potential joint associations between As, Ni, Cd, Se, and Zn co-exposure and FBG levels among 1478 community-based Chinese adults from two counties, Shimen (n = 696) and Huayuan (n = 782), with different exposure profiles in Hunan province of China. The metals levels were measured in spot urine (As, Ni, and Cd) and plasma (Se and Zn) using inductively coupled plasma-mass spectrometry, respectively. The exposure levels of all the five metals were significantly higher in Shimen area (median: As = 57.76 µg/L, Cd = 2.75 µg/L, Ni = 2.73 µg/L, Se = 112.67 µg/L, Zn = 905.68 µg/L) than those in Huayuan area (As = 41.14 µg/L, Cd = 2.22 µg/L, Ni = 1.88 µg/L, Se = 65.59 µg/L, Zn = 819.18 µg/L). The BKMR analyses showed a significantly positive over-all effect of the five metals on FBG levels when metals concentrations were all above the 50th percentile while a statistically negative over-all effect when metals concentrations were all under the 50th percentile in Shimen area. However, a totally opposite over-all effect of the mixture of the five metals on FBG levels was found in Huayuan area. BKMR also revealed a non-linear exposure-effect of Zn on FBG levels in Huayuan area. In addition, interaction effects of As and Se on FBG level were observed. The relationship between single or combined metals exposure and FBG was different against different exposure profiles. Potential interaction effects of As and Se on FBG levels may exist.

3.
World Neurosurg ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31568902

RESUMO

PURPOSE: To investigate the ultrasonographic characteristics in hourglass-like constriction of peripheral nerve in the upper extremity, and to evaluate the value of ultrasonography in the diagnosis. METHODS: 19 patients with hourglass-like constriction of peripheral nerve in the upper extremity underwent ultrasonography and the results were compared with surgery. The ultrasonographic characteristics, the accurate rate, and the relation between the ultrasonography and surgery were analyzed. RESULTS: There were 22 affected nerves involved in 19 patients, including 17 radial neuropathies, 4 median neuropathies, and 1 musculocutaneous neuropathy. The accuracy rate of ultrasonography in diagnosing hourglass-like constriction of upper limb nerve was 87.93%. Ultrasonography showed that the constriction sites were completely consistent with the operation. The ultrasonography characteristics of hourglass-like constriction of upper limb nerves were hourglass-like nerve incompleteness or complete constriction, and the nerves at both ends were thickened, and no compression structure was seen around. All lesions with complete constriction diagnosed by ultrasonography were treated with resection of the lesion with or without graft. Besides, 71.43% with incomplete constriction were treated with neurolysis, 28.57% with resection of the lesion with direct repair. CONCLUSION: Ultrasonography could be used as a routine non-invasive examination for hourglass-like constriction of upper limb nerves. Ultrasonography suggests that resection of the lesion rather than neurolysis should be considered in the treatment of complete constriction. For patients with clinical symptoms, ultrasonography showed local nerve enlargement but no constriction, clinicians should be prompted to explore carefully during operation to avoid missing nerve hourglass-like constriction.

4.
Med Sci Monit ; 25: 6554-6562, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31473760

RESUMO

BACKGROUND In previous studies, higher expression of PREX1 (PtdIns (3,4,5)P3-dependent Rac exchanger 1) has been detected in some subsets of breast cancer, and activation of PREX1 has been associated with tumor progression in vivo. However, an association between PREX1 and breast cancer prognosis has not been examined. MATERIAL AND METHODS In this study, we investigated the expression and correlation of PREX1 with important clinical factors and prognosis of patients with breast cancer. Immunohistochemical staining was performed for 121 tumor tissue specimens obtained from primary breast cancer lesions. RESULTS We found that 55 tissues exhibited positive staining for PREX1. Moreover, tumors positive for PREX1 were found to have significant association with recurrence rate (P=0.000) and metastasis rate (P=0.001). Univariate and multivariate regression analyses also identified PREX1 expression as an independent variable of disease-free survival. Our analyses indicate that high levels of PREX1 expression were related to longer disease-free survival in patients with breast cancer (P=0.013). CONCLUSIONS PREX1 is a favorable variable of prognosis for breast cancer patients, these study results need to be confirmed in larger research studies.

5.
Nanoscale ; 11(35): 16515-16522, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31453606

RESUMO

An electrochemical functionalization method is developed to fabricate N- and O-rich graphene films (F-RGO-60) with an expanded interlayer distance. In particular, the functionalization process could be completed within 60 seconds at room temperature, which is conducive to large-scale commercial applications. Electrochemical synthesis of F-RGO-60 leads to two synergetic effects simultaneously: (1) the expansion of the interlayer distance caused by a bubble effect, which leads to more exposure of the active surface area and (2) the introduction of N-doped sites and oxygen-containing functional groups, which not only improves the hydrophilicity of F-RGO-60 but also provides extra pseudocapacitance. It is worth mentioning that after electrochemical functionalization, F-RGO-60 can still maintain a high density of 1.47 g cm-3. Due to their optimal surface area, good electrolyte wettability and massive redox-active sites, the specific capacitance of F-RGO-60 films can reach up to 319.4 F cm-3 (217.3 F g-1) at 1 A g-1 in a three-electrode system, which is about 3.6 times larger than that of RGO films (60 F g-1). The integration of the low-cost preparation method and outstanding performance suggests that F-RGO-60 has great development prospects as supercapacitor electrode materials.

6.
J Drug Target ; : 1-10, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31429596

RESUMO

Background and purpose: The present study aimed to explore the feasibility and efficacy of the targeted non-invasive implantation of mesenchymal stromal cells (MSCs) by low-intensity ultrasound-targeted microbubble destruction (LI-UTMD) assisted blood-brain barrier (BBB) opening and its improvement on neurobehavioural outcomes in brain ischaemic rats. Methods: A transcranial irradiation of low-intensity ultrasound by diagnostic devices was performed, and lipid microbubbles (MBs) and MSCs were simultaneously infused. Then, the MSC transmigration from brain vessels to parenchyma was demonstrated, and MSCs were statistically analysed on days 1, 4, 7 and 14. Behavioural function was statistically analysed. Results: The extra-vascular leakage of lanthanum and EB was observed at the brain ischaemic area receiving ultrasound. MSCs were observed at the ultrasound irradiated brain hemisphere, and the number of MSCs in LI-UTMD assisted MSCs group was significantly higher than that in the MSCs group (p < .01). The attachment, traversing and trans-migration of MSCs across the BBB were recorded. Neuro-behavioural function was improved with this approach. Conclusions: The transcranial irradiation of low intensity ultrasound targeted MBs destruction on brain ischaemic rats might be a safe and efficient BBB opening approach to prompt the successful delivery of MSCs into the targeted area of brain ischaemia, and ameliorate neurological function.

7.
Neurobiol Dis ; 132: 104567, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31394202

RESUMO

Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aß) accumulation. However, the mechanism by which Aß induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75NTR) is a receptor for Aß and mediates Aß neurotoxicity, implying that p75NTR may mediate Aß-induced tau phosphorylation in AD. Here, we showed that Aß-induced tau hyperphosphorylation and neurodegeneration, including tau phosphorylation, synaptic disorder and neuronal loss, in the brains of both male wild-type (Wt) mice and male P301L transgenic mice (a mouse model of human tauopathy) were alleviated by genetic knockout of p75NTR in the both mouse models. We further confirmed that the activation or inhibition of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3ß (GSK3ß) significantly changed Aß/p75NTR-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75NTR extracellular domain (p75ECD-Fc), which antagonizes the binding of Aß to p75NTR, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75NTR meditates Aß-induced tau pathology and is a potential druggable target for AD and other tauopathies.

8.
Environ Int ; 129: 497-506, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31158596

RESUMO

BACKGROUND: Metals exposure from natural environment and pollution have been linked to cardiovascular disease (CVD). However, whether associations existing between plasma multiple metals and incident cardiovascular disease in patients with type 2 diabetes (T2D) is unknown. OBJECTIVES: We conducted a prospective cohort study to investigate whether plasma levels of metals are associated with incident CVD risk in patients with T2D. METHODS: In a prospective study of 3897 type 2 diabetes embedded in the Dongfeng-Tongji cohort, fasting blood samples were collected in 2008 at baseline and in 2013 in the first follow-up period. Plasma concentrations of 23 metals were measured by inductively coupled plasma mass spectrometry (ICP-MS). The associations between plasma metal concentrations and CVD risk in patients with T2D were investigated with Cox proportional hazards models. RESULTS: During an average of 6.2 years follow-up, 1114 participants developed CVD. In the single-metal models adjusting for established cardiovascular risk factors, plasma zinc and selenium levels were negatively and strontium was positively associated with incident CVD risk in patients with T2D. Similar results were obtained in the multiple-metal model, the HRs (95% CIs) for zinc, selenium, and strontium comparing extreme quartiles were 0.78 (95% CI: 0.65-0.93; P trend = 0.011), 0.76 (95% CI: 0.64-0.91; P trend = 0.001), and 1.51 (95% CI: 1.26-1.81; P trend <0.001), respectively. In the joint association analyses of two metals, individuals with high plasma levels of zinc and selenium had significantly lower risk of incident CVD in patients with T2D than those with low levels (HR = 0.77, 95% CI: 0.65-0.91). CONCLUSIONS: The present study suggested that plasma levels of zinc and selenium had an inverse association with incident CVD risk in patients with T2D, while strontium had a positive correlation. Plasma zinc and selenium combinedly decreased incident CVD risk in patients with T2D. Further research is still needed to verify these findings in other populations.

9.
J Alzheimers Dis ; 70(2): 399-412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31177213

RESUMO

Emerging evidence suggests that gut microbiota dysbiosis plays a role in neurodegenerative disorders. However, whether the composition and diversity of the gut microbiota are altered in tauopathies remains largely unknown. This study was aimed to examine the diversity and composition of the gut microbiota in tauopathies, as well as the correlation with pathological changes in the brain. We collected fecal samples from 32 P301L tau transgenic mice and 32 age- and gender-matched littermate mice at different ages. The 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. Brain tau pathology levels were measured by immunohistochemistry. The diversity and composition of the gut microbiota significantly changed with aging. At the phylum level, the relative abundance of Bacteroidetes was increased, while Firmicutes were decreased in P301L mice compared with that in Wt mice after 3 months of age. In addition, Actinobacteria was decreased in P301L mice at 3 and 6 months of age, meanwhile Tenericutes was decreased in P301L mice at 10 months of age. Moreover, several specific macrobiota were highly associated with the levels of AT8-tau or pT231-tau protein in the brain. Our findings suggest that gut microbiota changed with aging, as well as in the tauopathy mice model. Modulation of the gut microbiota may be a potential strategy for treatment of tauopathy.

10.
Environ Pollut ; 252(Pt A): 171-179, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146232

RESUMO

Organic pollutants are widely detected in surface water, groundwater and irrigation sewage in farmland soil, some of which can form complexes with heavy metal ions as ligands in the environment. Acesulfame (ACE), one of the most popular artificial sweeteners, has been found in wastewater sometimes at tens of microgram per liter. However, the combined effects of heavy metals and ACE are still unclear. In the present study, the effects of ACE on cadmium (Cd) absorption and translocation in rice seedlings (Oryza sativa L.) under different exposure conditions were investigated using hydroponic experiments. Under the combined exposure treatments of ACE and Cd, absorption of Cd and ACE in rice significantly decreased when compared with the single exposure treatments, while the alleviation of oxidative damage in rice was also found. Under the sequential exposure treatments of Cd and ACE, the post-exposed ACE activated the pre-absorbed Cd in plant, and accelerated the release of Cd to the environment as well as its translocation from the roots to shoots. In addition, compared with the single Cd exposure, the accumulated ACE can alleviate the oxidative damage in rice shoots induced by Cd, although the Cd concentrations in shoots changed little. In summary, the combined pollution of artificial sweetener ACE was beneficial to relieve the toxicological damage and ecological risk caused by Cd.


Assuntos
Biodegradação Ambiental/efeitos dos fármacos , Cádmio/metabolismo , Oryza/metabolismo , Poluentes do Solo/análise , Edulcorantes/farmacologia , Tiazinas/farmacologia , Transporte Biológico/efeitos dos fármacos , Cádmio/análise , Poluição Ambiental/análise , Hidroponia , Oryza/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Plântula/efeitos dos fármacos , Solo
11.
Neurotox Res ; 36(1): 101-107, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30977102

RESUMO

The neurotrophin receptor p75 (p75NTR) plays important roles in regulating amyloid-beta (Aß) metabolism in the brain. The expression of p75NTR is altered in the brain of patients with Alzheimer's disease (AD). In this study, we aimed to evaluate whether p75NTR mRNA level in the peripheral blood cells is changed among AD patients and its potential to be a biomarker for AD. The study subjects included 26 patients with AD (PiB-PET positive) and 28 cognitively normal controls (PiB-PET negative). RNA was extracted from peripheral blood cells of fast blood. p75NTR mRNA was measured using quantitative real-time PCR assay. p75NTR mRNA levels in blood cells were comparable between AD patients and controls. p75NTR mRNA levels in blood cells were not correlated with MMSE scores, ApoE genotypes, gender, and age. p75NTR mRNA expression in blood cells is not changed in AD patients and is unlikely to be a biomarker for AD.

12.
Cancer Res ; 79(11): 2865-2877, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31015230

RESUMO

C/EBPα is an essential transcription factor involved in regulating the expression or function of certain cell-cycle regulators, including in breast cancer cells. Although protein arginine methyltransferases have been shown to play oncogenic roles in a variety of cancers, little is known about the role of arginine methylation in regulating the antiproliferation activity of C/EBPα. Here, we report that the protein arginine methyltransferase 1 (PRMT1) is overexpressed in human breast cancer and that elevated PRMT1 correlates with cancer malignancy. RNA-sequencing analysis revealed that knockdown of PRMT1 in breast cancer cells is accompanied by a decrease in the expression of pro-proliferative genes, including cyclin D1. Furthermore, tandem affinity purification followed by mass spectrometry identified PRMT1 as a component of the C/EBPα complex. C/EBPα associated with and was methylated by PRMT1 at three arginine residues (R35, R156, and R165). PRMT1-dependent methylation of C/EBPα promoted the expression of cyclin D1 by blocking the interaction between C/EBPα and its corepressor HDAC3, which resulted in rapid growth of tumor cells during the pathogenesis of breast cancer. Inhibition of PRMT1 significantly impeded the growth of cancer cells from patients with triple-negative breast cancer. This evidence that PRMT1 mediates C/EBPα methylation sheds light on a novel pathway and potential therapeutic target in breast cancer. SIGNIFICANCE: This study provides novel mechanistic insight of the role of the arginine methyltransferase PRMT1 in breast cancer pathogenesis.

13.
Angew Chem Int Ed Engl ; 58(18): 5915-5919, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30840345

RESUMO

Highly efficient detection in the aqueous phase for water-insoluble organic molecule probes is challenging. The bright aggregated-state electrochemiluminescence (ECL) of 1,1-disubstituted 2,3,4,5-tetraphenylsiloles by a co-reactant approach was discovered, and a heterogeneous aggregation-induced emission ECL (HAIE-ECL) was constructed at the electrode surface, showing very high ECL efficiency (37.8 %) and selective recognition for industrially important DNBP plasticizer with a low detection limit of 0.15 nm in the water phase. A mechanistic study indicates that ECL is mainly generated due to the high electron affinity of siloles and restriction of the intramolecular motions caused by their propeller-like noncoplanar structures. This system realizes the sensing of organic-based ECL in the water phase by solving the crucial problems of water insolubility and aggregation-caused quenching (ACQ), and demonstrates potential for further application because of its design and high efficiency.

14.
Talanta ; 194: 493-500, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609563

RESUMO

This paper developed a sensitive method for detecting hydroquinone by combining the unique optical properties of quantum dots and the specificity of enzymatic reactions. The interesting results shown that the fluorescence of graphite phase carbon nitride quantum dot (g-CNQDs) was quenched directly by benzoquinone or indirectly by hydroquinone (H2Q), and the possible quenching mechanism was proposed. Quinone might generate by catalyzing the oxidation of H2Q with horseradish peroxidase (HRP) in the presence of hydrogen peroxide. The intermediate quinone could effectively quench the fluorescence of g-CNQDs quantum dots. Therefore, a novel fluorescence probe based on g-CNQDs Quantum Dots was successfully used to detect H2Q by strongly quenching the fluorescence of g-CNQDs Quantum Dots which mediated by horseradish peroxidase enzymes. The detection limit was as low as 0.04 µM (S/N = 3), and the linear range was 0.5-11.6 µM. This kind of quantum dot-enzyme system has the advantages of simple operation, no modification of quantum dots, low cost, high sensitivity and short detection time.

15.
Nat Prod Res ; : 1-4, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30394110

RESUMO

Epicatechin (EC) is the most effective compound in Euonymus alatus (Thunb.)Sieb, and possesses a series of benefits, including anti-inflammatory, antioxidant, antiobesity and anticancer effects. In this study, we investigated the protective effects of EC in Acetaminophen(N-acetyl-p-aminophenol, APAP)-induced acute liver injury in C57BL/6J mice and explored the possible mechanisms involved in these effects.

16.
Cell Rep ; 25(7): 1741-1755.e7, 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30428345

RESUMO

The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔNp63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition.

17.
Cell Physiol Biochem ; 50(5): 2004-2016, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30404076

RESUMO

BACKGROUND/AIMS: Non-small-cell lung carcinoma (NSCLC) is the leading cause of cancer death, with tumor metastasis being mainly responsible for lung cancer-associated mortality. Our previous studies have found that tubulin polymerization promoting protein family member 3 (TPPP3) acted as a potential oncogene in NSCLC. Little is known about the function of TPPP3 in tumor metastasis. METHODS: RT-qPCR and IHC were used to investigate the expression of TPPP3 in NSCLC tissues. CCK8 assay and transwell assay were used to measure proliferation and migration of NSCLC cells in vitro and xenograft model was performed to assess the tumor growth and metastasis in vivo. RESULTS: In the present study, upregulation of TPPP3 was found to correlate with an increased metastasis capability of NSCLC. Ectopic expression of TPPP3 significantly enhanced cell proliferation in vitro and promoted tumor growth in vivo. Furthermore, overexpression of TPPP3 remarkably promoted NSCLC cell migration and invasion along with the upregulation of Twist1 both in vitro and in vivo. Further investigations showed that activation of STAT3 was required for TPPP3-mediated upregulation of Twist1, cell migration and invasion. A strong positive correlation between TPPP3 and Twist1 expression was identified in NSCLC tissues. Patients with low TPPP3 or low Twist1 in NSCLC tissues had a better prognosis with longer overall survival (OS) and disease-free survival (DFS). CONCLUSION: Overall, this study demonstrates that TPPP3 promotes the metastasis of NSCLC through the STAT3/Twist1 pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Fenantrenos/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Proteína 1 Relacionada a Twist/antagonistas & inibidores , Proteína 1 Relacionada a Twist/genética
18.
Sci Rep ; 8(1): 17415, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30479372

RESUMO

Tumor angiogenesis plays a critical role in hepatocellular carcinoma (HCC) development and progression, but its mechanism is unclear. Krüppel-like factor 8 (KLF8) is a transcription factor that plays an important role in HCC progression. Here, we investigated the role of KLF8 in angiogenesis in HCC and its possible mechanism. Immunohistochemistry, quantitative RT-PCR, western blotting, promoter reporter assays, chromatin immunoprecipitation (ChIP), and chicken chorioallantoic membrane (CAM) and nude mouse tumor models were used to show that the mRNA and protein expression levels of KLF8 and VEGFA are highly correlated in HCC tissue samples. The up-regulation of KLF8 increased VEGFA protein levels and induced VEGFA promoter activity by binding to the CACCC region of the VEGFA promoter. In addition, KLF8 regulated HIF-1α and Focal adhesion kinase (FAK) expression. The PI3K/AKT inhibitor LY294002 inhibited KLF8-induced VEGFA expression, whereas PI3K/AKT signaling pathway proteins, such as P-PDK1(Ser241) and P-AKT(Thr308), were decreased significantly. KLF8-overexpressing HCC cells had a higher potential for inducing angiogenesis. Thus, our results indicate that KLF8 may induce angiogenesis in HCC by binding to the CACCC region of the VEGFA promoter to induce VEGFA promoter activity and through FAK to activate PI3K/AKT signaling to regulate HIF-1α expression levels.

19.
Free Radic Biol Med ; 130: 458-470, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30448512

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain. It cannot be cured currently, and those suffering from AD place a great burden on their caregivers and society. AD is characterized by high levels of iron ions in the brain, which catalyze radicals that damage the neurons. Knowing that the Aß42 peptide precipitates iron by binding iron ions at amino acid residues D1, E3, H11, H13, and H14, we synthesized a 5-repeat (HAYED) sequence peptide. By treating iron-stressed SH-SY5Y cells with it and injecting it into the cerebrospinal fluid (CSF) of naturally senescence Kunming mouse, which displaying AD-similar symptoms such as learning and memory dysfunction, neuron degeneration and high level of iron in brain, we found that HAYED (5) decreased the iron and radical levels in the cell culture medium and in the CSF. Specially, the synthesized peptide prevented cell and brain damage. Furthermore, functional magnetic resonance imaging (fMRI), Morris water maze and passive avoidance tests demonstrated that the peptide ameliorated brain blood-oxygen metabolism and slowed cognitive loss in the experimental senescence mice, and clinical and blood tests showed that HAYED (5) was innoxious to the kidney, the liver and blood and offset the AD-associated inflammation and anemia.

20.
Neural Regen Res ; 13(5): 862-868, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29863017

RESUMO

Exogenous discharge can positively promote nerve repair. We, therefore, hypothesized that endogenous discharges may have similar effects. The phrenic nerve and intercostal nerve, controlled by the respiratory center, can emit regular nerve impulses; therefore these endogenous automatically discharging nerves might promote nerve regeneration. Action potential discharge patterns were examined in the diaphragm, external intercostal and latissimus dorsi muscles of rats. The phrenic and intercostal nerves showed rhythmic clusters of discharge, which were consistent with breathing frequency. From the first to the third intercostal nerves, spontaneous discharge amplitude was gradually increased. There was no obvious rhythmic discharge in the thoracodorsal nerve. Four animal groups were performed in rats as the musculocutaneous nerve cut and repaired was bland control. The other three groups were followed by a side-to-side anastomosis with the phrenic nerve, intercostal nerve and thoracodorsal nerve. Compound muscle action potentials in the biceps muscle innervated by the musculocutaneous nerve were recorded with electrodes. The tetanic forces of ipsilateral and contralateral biceps muscles were detected by a force displacement transducer. Wet muscle weight recovery rate was measured and pathological changes were observed using hematoxylin-eosin staining. The number of nerve fibers was observed using toluidine blue staining and changes in nerve ultrastructure were observed using transmission electron microscopy. The compound muscle action potential amplitude was significantly higher at 1 month after surgery in phrenic and intercostal nerve groups compared with the thoracodorsal nerve and blank control groups. The recovery rate of tetanic tension and wet weight of the right biceps were significantly lower at 2 months after surgery in the phrenic nerve, intercostal nerve, and thoracodorsal nerve groups compared with the negative control group. The number of myelinated axons distal to the coaptation site of the musculocutaneous nerve at 1 month after surgery was significantly higher in phrenic and intercostal nerve groups than in thoracodorsal nerve and negative control groups. These results indicate that endogenous autonomic discharge from phrenic and intercostal nerves can promote nerve regeneration in early stages after brachial plexus injury.

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