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1.
Int J Infect Dis ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31521852

RESUMO

OBJECTIVES: To determine blood Brucella DNA loads between brucellosis patients and those without brucellosis. METHODS: The patient group included 350 brucellosis patients. The control was composed of 200 subjects without brucellosis. The extracted DNA from blood, was tested by quantitative polymerase chain reaction (qPCR). The cutoff value was determined by receiver operating characteristic curve analysis. A portion of the brucellosis patients were monitored by qPCR during therapy. RESULTS: The detection limit of qPCR was between 1E + 01 cfu/µL and 1E + 08 cfu/µL. The standard curve R2 reached 0.998. The cutoff value was 4E + 01 cfu/µL, which was determined by comparison of the patient group and the control. The qPCR assay had a specificity of 100% and a sensitivity of 93.14%. The monitoring results showed that the Brucella DNA load decreased in most patients during the first 4 weeks of treatment. One patient with bad treatment compliance showed a rebound. CONCLUSIONS: The qPCR results were in accordance with the course of brucellosis in the clinic. The DNA load often reflects the situation of the Brucella-infected patient. The cutoff value provides an important reference of infection. This qPCR-based method can be used to assist in the diagnosis of brucellosis and to adjust the therapy.

2.
Cancer Res ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383647

RESUMO

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and has limited treatment options. Snail family transcriptional repressor 1 (SNAI1) is a master regulator of epithelial-mesenchymal transition (EMT) and has been implicated in HCC initiation and progression. However, the precise role of SNAI1 and the way it contributes to hepatocarcinogenesis have not been investigated in depth, especially in vivo. Here, we analyzed the functional relevance of SNAI1 in promoting hepatocarcinogenesis in the context of the AKT/c-Met driven mouse liver tumor model (AKT/c-Met/SNAI1). Overexpression of SNAI1 did not accelerate AKT/c-Met-induced HCC development or induce metastasis in mice. Elevated SNAI1 expression rather led to the formation of cholangiocellular (CCA) lesions in the mouse liver, a phenotype that was paralleled by increased activation of Yap and Notch. Ablation of Yap strongly inhibited AKT/c-Met/SNAI-induced HCC and CCA development, whereas inhibition of the Notch pathway specifically blocked the CCA-like phenotype in mice. Intriguingly, overexpression of SNAI1 failed to induce EMT, indicated by strong E-cadherin expression and lack of vimentin expression by AKT/c-Met/SNAI tumor cells. SNAI1 mRNA levels strongly correlated with the expression of CCA markers including SOX9, CK19 and EPCAM, but not with EMT markers such as E-cadherin and ZO-1, in human HCC samples. Overall, our findings suggest SNAI1 regulates the CCA-like phenotype in hepatocarcinogenesis via regulation of Yap and Notch.

3.
J Food Sci ; 84(8): 2121-2127, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31269247

RESUMO

The effects of thermal oxidation at 65 °C for 24 days on oxidation indices, fatty acid positional distribution, thermal properties, vitamin E composition and sterol composition of kenaf seed oil are investigated. The results showed that total oxidation value (TOTOX) of the oil increased from initial 8.83 to 130.74 at the end of 24 days storage. Linoleic acid at sn-1, 3 positon of kenaf seed oil was less stable than the one at sn-2 positon. Oxidative degradation changed the melting profile of kenaf seed oil, the value of endothermic enthalpy reduced from 58.17 to 20.25 J/g after 24 days of storage. Moreover, the content of vitamin E and total sterol decreased by 84.26% and 38.47%, respectively. Tocotrienols were more stable than tocopherols during the accelerated storage. Correlation analysis indicated vitamin E content was significantly related to p-anisidine value, while sterol content was significantly related to peroxide value. PRACTICAL APPLICATION: Kenaf seed oil is rich in polyunsaturated fatty acids and bioactive compounds. Heating process and long-term storage cause oil oxidation and bioactive compounds degradation. The oxidation process of kenaf seed oil is simulated with accelerated storage. The study evaluates fatty acid composition and distribution, vitamin E and sterol content, melting thermal characteristics of kenaf seed oil at different oxidation levels. The research shows the stability of fatty acid is related with its type and position in backbone of triacylglycerol molecule. There are good correlation among oxidation level, vitamin E and sterol content, and melting enthalpy value of kenaf seed oil.

4.
J Hepatol ; 71(4): 742-752, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31195063

RESUMO

BACKGROUND & AIMS: The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized as a tumor suppressor in many cancer types due to its ability to promote the degradation of numerous oncogenic target proteins. Herein, we aimed to elucidate its role in intrahepatic cholangiocarcinoma (iCCA). METHODS: Herein, we first confirmed that FBXW7 gene expression was reduced in human iCCA specimens. To identify the molecular mechanisms by which FBXW7 dysfunction promotes cholangiocarcinogenesis, we generated a mouse model by hydrodynamic tail vein injection of Fbxw7ΔF, a dominant negative form of Fbxw7, either alone or in association with an activated/myristylated form of AKT (myr-AKT). We then confirmed the role of c-MYC in human iCCA cell lines and its relationship to FBXW7 expression in human iCCA specimens. RESULTS: FBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. While forced overexpression of Fbxw7ΔF alone did not induce any appreciable abnormality in the mouse liver, co-expression with AKT triggered cholangiocarcinogenesis and mice had to be euthanized by 15 weeks post-injection. At the molecular level, a strong induction of Fbxw7 canonical targets, including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-MYC was consistently confirmed as a FBXW7 target in human CCA cell lines. Most importantly, selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 only delayed tumorigenesis in the same model. In human iCCA specimens, an inverse correlation between the expression levels of FBXW7 and c-MYC transcriptional activity was observed. CONCLUSIONS: Downregulation of FBXW7 is ubiquitous in human iCCA and cooperates with AKT to induce cholangiocarcinogenesis in mice via c-Myc-dependent mechanisms. Targeting c-MYC might represent an innovative therapy against iCCA exhibiting low FBXW7 expression. LAY SUMMARY: There is mounting evidence that FBXW7 functions as a tumor suppressor in many cancer types, including intrahepatic cholangiocarcinoma, through its ability to promote the degradation of numerous oncoproteins. Herein, we have shown that the low expression of FBXW7 is ubiquitous in human cholangiocarcinoma specimens. This low expression is correlated with increased c-MYC activity, leading to tumorigenesis. Our findings suggest that targeting c-MYC might be an effective treatment for intrahepatic cholangiocarcinoma.

5.
Hepatology ; 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31062368

RESUMO

Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with limited treatment options. The c-Myc transcription factor is a pivotal player in hepatocarcinogenesis, but the mechanisms underlying c-Myc oncogenic activity in the liver remain poorly delineated. Mammalian target of rapamycin complex 2 (mTORC2) has been implicated in cancer by regulating multiple AGC kinases, especially AKT proteins. In the liver, AKT1 and AKT2 are widely expressed. While AKT2 is the major isoform downstream of activated phosphoinositide 3-kinase and loss of phosphatase and tensin homolog-induced HCC, the precise function of AKT1 in hepatocarcinogenesis is largely unknown. In the present study, we demonstrate that mTORC2 is activated in c-Myc-driven mouse HCC, leading to phosphorylation/activation of Akt1 but not Akt2. Ablation of Rictor inhibited c-Myc-induced HCC formation in vivo. Mechanistically, we discovered that loss of Akt1, but not Akt2, completely prevented c-Myc HCC formation in mice. Silencing of Rictor or Akt1 in c-Myc HCC cell lines inhibited phosphorylated forkhead box o1 expression and strongly suppressed cell growth in vitro. In human HCC samples, c-MYC activation is strongly correlated with phosphorylated AKT1 expression. Higher expression of RICTOR and AKT1, but not AKT2, is associated with poor survival of patients with HCC. In c-Myc mice, while rapamycin, an mTORC1 inhibitor, had limited efficacy at preventing c-Myc-driven HCC progression, the dual mTORC1 and mTORC2 inhibitor MLN0128 effectively promoted tumor regression by inducing apoptosis and necrosis. Conclusion: Our study indicates the functional contribution of mTORC2/Akt1 along c-Myc-induced hepatocarcinogenesis, with AKT1 and AKT2 having distinct roles in HCC development and progression; targeting both mTORC1 and mTORC2 may be required for effective treatment of human HCC displaying c-Myc amplification or overexpression.

6.
EBioMedicine ; 44: 50-59, 2019 Jun.
Artigo em Francês | MEDLINE | ID: mdl-31097410

RESUMO

BACKGROUND: Clinical trials on multiple sclerosis with repeated injections of monoclonal antibodies depleting CD4+ T cells have not resulted in much success as a disease therapy. Here, we developed an immunotherapy for EAE in mice by combining a transient depletion of T cells together with the administration of neuron derived peptides. METHODS: EAE was induced in SJL and C57BL/6 mice, by proteolipid protein peptide PLP139-151 (pPLP) and myelin-oligodendrocyte glycoprotein MOG35-55 (pMOG) peptides, respectively. Anti-CD4 and anti-CD8 antibody were injected intraperitoneally before or after peptide immunization. EAE scores were evaluated and histology data from brain and spinal cord were analyzed. Splenocytes were isolated and CD4+, CD4+CD25- and CD4+CD25+ T cells were purified and cultured in the presence of either specific peptides or anti-CD3 antibody and proliferation of T cells as well as cytokines in supernatant were assessed. FINDINGS: This experimental treatment exhibited therapeutic effects on mice with established EAE in pPLP-susceptible SJL mice and pMOG-susceptible C57BL/6 mice. Mechanistically, we revealed that antibody-induced apoptotic T cells triggered macrophages to produce TGFß, and together with administered auto-antigenic peptides, generated antigen-specific Foxp3+ regulatory T cells (Treg cells) in vivo. INTERPRETATION: We successfully developed a specific immunotherapy to EAE by generating autoantigen-specific Treg cells. These findings have overcome the drawbacks of long and repeated depletion of CD4+ T cells, but also obtained long-term immune tolerance, which should have clinical implications for the development of a new effective therapy for multiple sclerosis. FUND: This research was supported by the Intramural Research Program of the NIH, NIDCR.

7.
Sensors (Basel) ; 19(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027374

RESUMO

As the size of the radar hardware platform becomes smaller and smaller, the cost becomes lower and lower. The application of indoor radar-based human motion recognition has become a reality, which can be realized in a low-cost device with simple architecture. Compared with narrow-band radar (such as continuous wave radar, etc.), the human motion echo signal of the carrier-free ultra-wideband (UWB) radar contains more abundant characteristic information of human motion, which is helpful for identifying different types of human motion. In this paper, a novel feature extraction method by two-dimensional variational mode decomposition (2D-VMD) algorithm is proposed. And it is used for extracting the primary features of human motion. The 2D-VMD algorithm is an adaptive non-recursive multiscale decomposition method for nonlinear and nonstationary signals. Firstly, the original 2D radar echo signals are decomposed by the 2D-VMD algorithm to capture several 2D intrinsic mode function (BIMFs) which represent different groups of central frequency components of a certain type of human motion. Secondly, original echo signals are reconstructed according to the several BIMFs, which not only have a certain inhibitory effect on the clutter in the echo signal, but can also further demonstrate that the BIMFs obtained by the 2D-VMD algorithm can represent the original 2D echo signal well. Finally, based on the measured ten different types of UWB radar human motion 2D echo analysis signals, the characteristics of these different types of human motion are extracted and the original echo signal are reconstructed. Then, the three indicators of the PCC, UQI, and PSNR between the original echo signals and extraction/reconstruction 2D signals are analyzed, which illustrate the effectiveness of 2D-VMD algorithm to extract feature of human motion 2D echo signals of the carrier-free UWB radar. Experimental results show that BIMFs by 2D-VMD algorithm can well represent the echo signal characteristics of this type of human motion, which is a very effective tool for human motion radar echo signal feature extraction.


Assuntos
Movimento (Física) , Radar , Algoritmos , Humanos , Processamento de Sinais Assistido por Computador
8.
BMC Cancer ; 19(1): 343, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975125

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. The PI3K cascade is one of the major signaling pathways underlying HCC development and progression. Activating mutations of PI3K catalytic subunit alpha (PIK3CA) and/or loss of Pten often occur in human HCCs. Serum and glucocorticoid kinase 3 (SGK3) belongs to the SGK family of AGK kinases and functions in parallel to AKT downstream of PI3K. Previous studies have shown that SGK3 may be the major kinase responsible for the oncogenic potential of PIK3CA helical domain mutants, such as PIK3CA(E545K), but not kinase domain mutants, such as PIK3CA(H1047R). METHODS: We investigated the functional contribution of SGK3 in mediating activated PIK3CA mutant or loss of Pten induced HCC development using Sgk3 knockout mice. RESULTS: We found that ablation of Sgk3 does not affect PIK3CA(H1047R) or PIK3CA(E545K) induced lipogenesis in the liver. Using PIK3CA(H1047R)/c-Met, PIK3CA(E545K)/c-Met, and sgPten/c-Met murine HCC models, we also demonstrated that deletion of Sgk3 moderately delays PIK3CA(E545K)/c-Met driven HCC, while not affecting PIK3CA(H1047R)/c-Met or sgPten/c-Met HCC formation in mice. Similarly, in human HCC cell lines, silencing of SGK3 reduced PIK3CA(E545K) -but not PIK3CA(H1047R)- induced accelerated tumor cell proliferation. CONCLUSION: Altogether, our data suggest that SGK3 plays a role in transducing helical domain mutant PIK3CA signaling during liver tumor development.


Assuntos
Carcinoma Hepatocelular/patologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Idoso , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/genética , Modelos Animais de Doenças , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Domínios Proteicos/genética , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
9.
Gut ; 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954949

RESUMO

OBJECTIVE: Increased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). DESIGN: We investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies. RESULTS: Ablation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. CONCLUSION: Our study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.

10.
Nat Commun ; 10(1): 1250, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890696

RESUMO

Hydroxyl radicals (OH) play a central role in the interstellar medium. Here, we observe highly rotationally excited OH radicals with energies above the bond dissociation energy, termed OH "super rotors", from the vacuum ultraviolet photodissociation of water. The most highly excited OH(X) super rotors identified at 115.2 nm photolysis have an internal energy of 4.86 eV. A striking enhancement in the yield of vibrationally-excited OH super rotors is detected when exciting the bending vibration of the water molecule. Theoretical analysis shows that bending excitation enhances the probability of non-adiabatic coupling between the [Formula: see text] and [Formula: see text] states of water at collinear O-H-H geometries following fast internal conversion from the initially excited [Formula: see text] state. The present study illustrates a route to produce extremely rotationally excited OH(X) radicals from vacuum ultraviolet water photolysis, which may be related to the production of the highly rotationally excited OH(X) radicals observed in the interstellar medium.

11.
Cell Death Dis ; 10(2): 120, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30741922

RESUMO

PD901, a MEK inhibitor, has been demonstrated of therapeutic efficacy against cholangiocarcinoma (CCA) harboring K-Ras oncogenic mutations. However, most CCA exhibit no K-Ras mutations. In the current study, we investigated the therapeutic potential of PD901, either alone or in combination with the pan-mTOR inhibitor MLN0128, for the treatment of K-Ras wild-type CCA in vitro using human CCA cell lines, and in vivo using AKT/YapS127A CCA mouse model. We discovered that in vitro, PD901 treatment strongly inhibited CCA cell proliferation, and combined PD901 and MLN0128 therapy further increased growth inhibition. In vivo, treatment of PD901 alone triggered tumor regression, which was not further increased when the two drugs were administered simultaneously. Mechanistically, PD901 efficiently hampered ERK activation in vitro and in vivo, leading to strong inhibition of CCA tumor cell cycle progression. Intriguingly, we discovered that PD901, but not MLN0128 treatment resulted in changes affecting the vasculature and cancer-associated fibroblasts in AKT/YapS127A mouse lesions. It led to the decreased hypoxia within tumor lesions, which may further enhance the anti-cell proliferation activities of PD901. Altogether, our study demonstrates that MEK inhibitors could be effective for the treatment of K-Ras wild-type CCA via inhibiting cell proliferation and modulating tumor microenvironment.

12.
BMJ Open ; 9(2): e023848, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30808669

RESUMO

OBJECTIVES: Autoimmune connective tissue diseases (ACTDs) commonly involve the shoulder joint; however, clinical epidemiological studies investigating their association with tendons are scant. Rotator cuff (RC) tears can cause shoulder disability, and surgical intervention is usually required. The study investigated RC repair surgery risk in ACTD patients. The effect of anti-inflammatory medication on RC repair surgery risk was also investigated. METHODS: We conducted a retrospective cohort study with a 7-year longitudinal follow-up period. Patients with systemic lupus erythematosus, systemic sclerosis, sicca syndrome, dermatomyositis and polymyositis diagnoses between 2004 and 2008 were enrolled. The control cohort comprised age- and sex-matched controls. The HR and adjusted HR (aHR) were estimated for the risk of RC surgery between ACTD and control cohorts after adjustment for confounders. Furthermore, the effects of steroid and non-steroidal anti-inflammatory drug (NSAID) use on the HR and aHR of RC surgery risk were analysed. RESULTS: We enrolled 5019 ACTD patients and 25 095 controls in the ACTD and control cohorts, respectively. RC surgery incidence was 49 and 24 per 100 000 person-years in the ACTD and control cohorts, respectively. In the ACTD cohort, the crude HR for RC surgery was 2.08 (95% CI , 1.08 to 4.02, p<0.05), and the aHR was 1.97 (95% CI, 1.01 to 3.82, p<0.05). The ACTD patients who used NSAIDs had an aHR of 3.13 (95% CI, 1.21 to 8.07, p<0.05) compared with the controls, but the ACTD patients who used steroids did not have a significantly higher aHR than the controls. CONCLUSIONS: ACTD patients had an increased risk of RC repair surgery. However, no difference was found in RC surgery risk when steroids were used compared with the control cohort. This could indicate that inflammation control may be a strategy for managing subsequent RC lesions.

13.
Hepatology ; 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737831

RESUMO

Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/ß-Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/ß-catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c-MET activation and AXIN1 mutations occur concomitantly in ~3%-5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9-based gene deletion of Axin1 (sgAxin1) in combination with transposon-based expression of c-Met in the mouse liver (c-Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1, and HCCs induced by c-Met/∆N90-ß-Catenin revealed activation of the Wnt/ß-Catenin and Notch signaling in c-Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/ß-Catenin target genes were induced in c-Met/sgAxin1 HCC when compared with corresponding lesions from c-Met/∆N90-ß-Catenin mice. To study whether endogenous ß-Catenin is required for c-Met/sgAxin1-driven HCC development, we expressed c-Met/sgAxin1 in liver-specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of ß-Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal-binding protein for immunoglobulin kappa J region (RBP-J) or the ablation of Notch2 did not significantly affect c-Met/sgAxin1-driven hepatocarcinogenesis. Conclusion: We demonstrated here that loss of Axin1 cooperates with c-Met to induce HCC in mice, in a ß-Catenin signaling-dependent but Notch cascade-independent way.

14.
Am J Pathol ; 189(5): 1077-1090, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30794805

RESUMO

Hepatoblastoma (HB) is the most common type of pediatric liver cancer. Activation of yes-associated protein (YAP) has been implicated in HB molecular pathogenesis. The transcriptional co-activator Yap regulates downstream gene expression through interaction with the TEA domain (TEAD) proteins. Nonetheless, YAP also displays functions that are independent of its transcriptional activity. The underlying molecular mechanisms by which Yap promotes HB development remain elusive. In the current study, we demonstrated that blocking TEAD function via the dominant-negative form of TEAD2 abolishes Yap-driven HB formation in mice and restrains human HB growth in vitro. When TEAD2 DNA-binding domain was fused with virus protein 16 transcriptional activation domain, it synergized with activated ß-catenin to promote HB formation in vivo. Among TEAD genes, silencing of TEAD4 consistently inhibited tumor growth and Yap target gene expression in HB cell lines. Furthermore, TEAD4 mRNA expression was significantly higher in human HB lesions when compared with corresponding nontumorous liver tissues. Human HB specimens also exhibited strong nuclear immunoreactivity for TEAD4. Altogether, data demonstrate that TEAD-mediated transcriptional activity is both sufficient and necessary for Yap-driven HB development. TEAD4 is the major TEAD isoform and Yap partner in human HB. Targeting TEAD4 may represent an effective treatment option for human HB.

15.
Eur J Phys Rehabil Med ; 55(4): 480-487, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30543266

RESUMO

BACKGROUND: Rotator cuff lesions are common causes of shoulder pain. Although patients with symptoms caused by chronic rotator cuff tendinopathy can be treated using conservative treatments, some of them may still experience refractory symptoms. Hypertonic dextrose prolotherapy (DPT) may be another treatment choice for these refractory symptoms. AIM: The aim of this study was to evaluate the effects of an ultrasound-guided hypertonic dextrose injection for patients with chronic supraspinatus tendinopathy. DESIGN: Randomized double-blind placebo-controlled trial. SETTING: Academic medical center. POPULATION: Outpatients patients (N.=31) with chronic supraspinatus tendinopathy and shoulder pain for more than six months. METHODS: Study group treated with one dose of an ultrasound-guided hypertonic dextrose (20%) injection at the supraspinatus enthesis site, whereas control patients received one dose of 5% normal saline through the same method. The Visual Analog Scale (VAS), Shoulder Pain And Disability Index (SPADI), shoulder active range of motion (AROM) and ultrasonographic thickness and histogram results of the supraspinatus tendon were evaluated before intervention and at two and six weeks after intervention. The outcome differences between the study and control groups were analyzed by using repeated-measures analysis of variance (ANOVA). RESULTS: In total, 31 patients completed the study. The study group indicated a significant improvement in the VAS (P=0.001), SPADI scores (P=0.017), shoulder AROM of flexion (P=0.039), and abduction (P=0.043) compared with the control group at two weeks after the injection. However, the effect did not sustain until six weeks after the injection. No differences in the histograms and morphological changes (thickness) were noted before and after injection in both groups. CONCLUSIONS: This study revealed that the ultrasound-guided hypertonic dextrose injection relieved pain, disability, and improved shoulder AROM for a short period in patients with chronic supraspinatus tendinopathy. CLINICAL REHABILITATION IMPACT: For patients with chronic shoulder pain and supraspinatus tendinopathy, ultrasound-guided hypertonic dextrose injections can provide relief from pain, disability, and shoulder range of motion for up to two weeks after intervention.

16.
J Cell Physiol ; 234(7): 10655-10670, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30536889

RESUMO

The diabetes mellitus (DM)-induced reduction of neurogenesis in the hippocampus is consequently accompanied by cognitive decline. The present study set out to define the critical role played by long noncoding RNA H19 (lncRNA H19) in the apoptosis of hippocampal neurons, as well as oxidative stress (OS) in streptozotocin (STZ)-induced DM mice through regulation of insulin-like growth factor 2 (IGF2) methylation. The expression of lncRNA H19 in the hippocampal neurons and surviving neurons were detected. Hippocampal neurons were cultured and transfected with oe-H19, sh-H19, oe-IGF2, or sh-IGF2, followed by detection of the expressions of IGF2 and apoptosis-related genes. Determination of the lipid peroxide and glutathione levels was conducted, while antioxidant enzyme activity was identified. The IGF2 methylation, the binding of lncRNA H19 to DNA methyltransferase, and the binding of lncRNA H19 to IGF2 promoter region were detected. DM mice exhibited high expressions of H19, as well as a decreased hippocampal neurons survival rate. Higher lncRNA H19 expression was found in DM. Upregulated lncRNA H19 significantly increased the expression of Bax and caspase-3 but decreased that of Bcl-2, thus promoting the apoptosis of hippocampal neuron. Besides, upregulation of lncRNA H19 induced OS. LncRNA H19 was observed to bind specifically to the IGF2 gene promoter region and promote IGF2 methylation by enriching DNA methyltransferase, thereby silencing IGF2 expression. Taken together, downregulated lncRNA H19 reduces IGF2 methylation and enhances its expression, thereby suppressing hippocampal neuron apoptosis and OS in STZ-induced (DM) mice.

17.
Nutrients ; 10(11)2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30453643

RESUMO

Isolated soy protein (ISP) is a well-known supplement and has been reported to improve health, exercise performance, body composition, and energy utilization. ISP exhibits multifunctional bioactivities and also contains branched-chain amino acids (BCAAs), which have been confirmed to positively affect body weight (BW) regulation and muscle protein synthesis. The combined effects of BCAA supplements and exercise in older postmenopausal women with osteoporosis, sarcopenia, and obesity have been inadequately investigated. Therefore, in this study, we evaluated the potential beneficial effects of soy protein supplementation and exercise training on postmenopausal mice. Forty mice (14 weeks old) with ovariectomy-induced osteosarcopenic obesity were divided into five groups (n = 8), namely sham ovariectomy (OVX, control), OVX, OVX with ISP supplementation (OVX+ISP), OVX with exercise training (ET, OVX+ET), and OVX with ISP and ET (OVX+ISP+ET). The mice received a vehicle or soy protein (3.8 g/kg BW) by oral gavage for four weeks, and the exercise performance (forelimb grip strength and exhaustive swimming time) was evaluated. In the biochemical profiles, we evaluated the serum glucose level and tissue damage markers, such as lactate, ammonia, glucose, blood urine nitrogen (BUN), and creatinine phosphate kinase (CPK). The body composition was determined by evaluating bone stiffness and muscle mass. All data were analyzed using one-way repeated measures analysis of variance. The physical performance of the OVX+ISP+ET group did not differ from that of the other groups. The OVX+ISP+ET group exhibited lower levels of serum lactate, ammonia, CPK, and BUN as well as economized glucose metabolism after an acute exercise challenge. The OVX+ISP+ET group also exhibited higher muscle mass and bone strength than the OVX group. Our study demonstrated that a combination of ISP supplementation and exercise reduced fatigue and improved bone function in OVX mice.

18.
Cell Physiol Biochem ; 51(3): 1069-1086, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30476906

RESUMO

BACKGROUND/AIMS: Cerebral ischemia is considered to be the most common cause of stroke with high mortality. It occurs as a result of the damage of the hippocampal neurons with lymphocyte function-associated antigen (LFA)-1 being emphasized to play a role in the biological functions of hippocampal neurons. This study was conducted in order to investigate the effects of specific knockdown of LFA-1 expression by lentivirus had on the apoptosis of the hippocampal neurons, simulated by rat models of acute cerebral ischemia after cerebral lymphatic blockage. METHODS: A total of 60 Wistar rats were selected as subjects, among which 50 were used to establish models of the acute cerebral ischemia after cerebral lymphatic blockage, while the remaining 10 rats were treated with the sham operation. The underlying regulatory mechanisms regarding LFA-1 were analyzed with the treatment of si-LFA-1 and LFA-1 vector in the hippocampal CA1 area of brain tissues isolated from the rats with acute cerebral ischemia. The brain water content, electrolyte content, and blood-brain barrier permeability located in ischemic area of rats were measured. TUNEL staining and immunochemistry methods were employed in order to determine the apoptosis rate and positive levels of LFA-1, MMP-9, and Caspase-3. The mRNA and protein levels of related genes were also detected by means of RT-qPCR and western blot assay. RESULTS: The brain water content, Na+ and Ca+ contents, blood-brain barrier permeability, apoptosis rate, positive levels of LFA-1, MMP-9, and Caspase-3 were decreased, and the K+ content was increased in ischemic tissues treated with si-LFA-1. The mRNA and protein levels of LFA-1, MMP-9, Caspase-3, and Bax had all decreased, while the mRNA and protein levels of Bcl-2 were elevated in the hippocampal CA1 area of rat brain tissues treated with si-LFA-1. These situations could be reversed through the up-regulation of LFA-1. CONCLUSION: In conclusion, LFA-1 gene silencing could improve the acute cerebral ischemia after cerebral lymphatic blockage by inhibiting apoptosis of the hippocampal neurons in rats.

19.
BMC Cancer ; 18(1): 1093, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30419856

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with limited treatment options. Mutation of ß-catenin is one of the most frequent genetic events along hepatocarcinogenesis. ß-catenin mutations can be in the form of point mutation or large N-terminal deletion. Studies suggested that different ß-catenin mutations might have distinct oncogenic potential. METHODS: We tested the oncogenic activity of ß-cateninS45Y, one of the most frequent point mutations of ß-catenin, and ∆N90-ß-catenin, a form of ß-catenin with a large N-terminal deletion, in promoting HCC development in mice. Thus, we co-expressed ß-cateninS45Y or ∆N90-ß-catenin together with c-Met into the mouse liver using hydrodynamic injection. RESULTS: We found that both ß-catenin mutations were able to induce HCC formation in combination with c-Met at the same latency and efficiency. Tumors showed similar histological features and proliferation rates. However, immunohistochemistry showed predominantly nuclear staining of ß-catenin in c-Met/∆N90-ß-catenin HCC, but membrane immunoreactivity in c-Met/ß-cateninS45Y HCC. qRT-PCR analysis demonstrated that both ∆N90-ß-catenin and ß-cateninS45Y induced the same effectors, although at somewhat different levels. In cultured cells, both ∆N90-ß-catenin and ß-cateninS45Y were capable of inducing TCF/LEF reporter expression, promoting proliferation, and inhibiting apoptosis. CONCLUSIONS: Our study suggests that ß-cateninS45Y and ∆N90-ß-catenin, in combination with the c-Met proto-oncogene, have similar oncogenic potential. Furthermore, nuclear staining of ß-catenin does not always characterize ß-catenin activity.

20.
Cancer Med ; 2018 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-30370649

RESUMO

Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Recently, it was found that Dasatinib treatment led to synthetic lethality in c-Myc high-expressing human cancer cells due to inhibition of p-Lyn. Overexpression of c-Myc is frequently seen in human HCC. We investigated the sensitivity to Dasatinib in vitro using HCC cell lines and in vivo using c-Myc mouse HCC model. We found that HCC cell line responsiveness to Dasatinib varied significantly. However, there was no correlation between c-Myc expression and IC50 to Dasatinib. In c-Myc-induced HCC in mice, tumors continued to grow despite Dasatinib treatment, although the eventual tumor burden was lower in Dasatinib treatment cohort. Molecular analyses revealed that Dasatinib was effective in inhibiting p-Src, but not p-Lyn, in HCC. Importantly, we found that in HCC cell lines as well as c-Myc mouse HCC, Dasatinib treatment induced up regulation of activated/phosphorylated (p)-focal adhesion kinase(FAK). Concomitant treatment of HCC cell lines with Dasatinib and FAK inhibitor prevented Dasatinib-induced FAK activation, leading to stronger growth restraint. Altogether, our results suggest that Dasatinib may have limited efficacy as single agent for HCC treatment. Combined treatment with Dasatinib with FAK inhibitor might represent a novel therapeutic approach against HCC.

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