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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(10): 1049-1054, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31642443

RESUMO

OBJECTIVE: To study the changes and significance of apoptosis signal-regulating kinase 1 (ASK1) in left ventricular remodeling in FVB/N mice. METHODS: A total of 54 FVB/N mice were randomly divided into 4 groups: 0 d group with 8 mice, 7 d group with 10 mice, 14 d group with 16 mice, and 21 d group with 20 mice. A model of cardiac remodeling was established by intraperitoneal injection of isoproterenol (ISO) at a daily dose of 30 mg/kg, and the 7 d, 14 d, and 21 d groups were injected for 7, 14, and 21 consecutive days respectively. The 0 d group was given intraperitoneal injection of an equal volume of normal saline. Echocardiography was used to measure left ventricular posterior wall thickness at end diastole (dLVPW) and the ratio of heart weight to tibia length (HW/TL) was measured. Hematoxylin-eosin staining was used to measure left ventricular myocardial fiber diameter. Picric-Sirius red staining was used to measure myocardial collagen deposition area in the left ventricle. Quantitative real-time PCR was used to measure the mRNA expression of ASK1, type I collagen (collagen I), and B-type natriuretic peptide (BNP). The mortality rate was observed for each group. RESULTS: There were gradual increases in HW/TL, myocardial fiber diameter, and dLVPW after 0, 7, and 14 days of ISO injection (P<0.05). There were no significant changes in HW/TL ratio and dLVPW from days 14 to 21 of ISO injection (P>0.05), while there was a significant reduction in myocardial fiber diameter (P<0.05), which was similar to the value on day 7 (P>0.05). There were significant increases in myocardial collagen deposition area and the mRNA expression of collagen I, ASK1, and BNP after 0, 7, 14, and 21 days of ISO injection, which reached the peaks on day 21 (P<0.01). The mRNA expression of ASK1 was positively correlated with myocardial collagen deposition area and the mRNA expression of collagen I and BNP and had a weak correlation with HW/TL, myocardial fiber diameter, and dLVPW. There was a significant increase in the mortality rate of the mice over the time of ISO injection. CONCLUSIONS: The expression of ASK1 in the myocardium is closely associated with left ventricular remodeling. The increase of ASK1 expression may lead to the aggravation of left ventricular remodeling, and the mechanism of which needs further study.


Assuntos
Remodelação Ventricular , Animais , Isoproterenol , MAP Quinase Quinase Quinase 5 , Camundongos , Miocárdio , Miócitos Cardíacos
2.
Int J Mol Sci ; 20(20)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31627272

RESUMO

Aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impedes antitumor immunity and instigates immune evasion. The remarkable efficacy of immune checkpoint blockade has been confirmed in various solid tumors. However, the correlation between PD-L1 expression and host immunological landscape remains of considerable controversy in non-small cell lung cancer (NSCLC). In the present study, PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) infiltration levels were determined by immunohistochemistry (IHC) in tumor sections of 138 NSCLC patients. The expression level of PD-L1 was positively correlated with the abundance of CD8 + TILs (p < 0.0001). Furthermore, no constitutive expression of PD-L1 was observed in the majority of six NSCLC cell lines detected by Western blot; but exposure to interferon-γ (IFN-γ), a primary cytokine secreted by activated CD8+ T cells, prominently increased PD-L1 expression. Notably, a significantly positive association was determined within PD-L1, CD8 and IFN-γ gene expression by qRT-PCR, which was corroborated by RNA-sequencing from TCGA lung cancer dataset. These findings demonstrate that PD-L1 expression indicates an adaptive immune resistance mechanism adopted by tumor cells in the aversion of immunogenic destruction by CD8+ TILs. Both higher expression of PD-L1 and infiltration of CD8+ TILs were correlated with superior prognosis (p = 0.044 for PD-L1; p = 0.002 for CD8). Moreover, Cox multivariate regression analysis showed that the combination of PD-L1 and CD8 were independent prognostic factors, which was more accurate in prediction of prognosis in NSCLC than individually. Finally, we found that IFN-γ induced the upregulation of PD-L1 in NSCLC cells, mainly through the JAK/STAT1 signaling pathway. In conclusion, PD-L1 expression is mainly induced by activated CD8+ TILs via IFN-γ in the immune milieu and indicates pre-existing adaptive immune response in NSCLC.

3.
ANZ J Surg ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31364259

RESUMO

BACKGROUND: Electronic health records (EHR) systems have been utilized in New South Wales for more than a decade; however, there is no agreement as to what clinical benefits they provide. This study aims at determining whether the introduction of EHR systems resulted in changes in documentation quality and other markers of clinical performance such as post-operative length of stay (PO LOS), use of imaging modality, rates of readmission and morbidity. METHODS: A before and after study was conducted utilizing both written and electronic patient documentation in a single surgical ward. Patients who underwent appendicectomy at Blacktown Hospital had inpatient documentation collated at three distinct time-points. Documentation was then assessed against the QNOTE assessment criteria. Other markers of clinical performance assessed included PO LOS, ultrasound use, computed tomography use, rate of readmission, rate of morbidity and rate of positive histological findings. RESULTS: There was a significant (P = 0.001) improvement in QNOTE score between group 1 (6 months prior to the implementation of EHR) and group 3 (12 months after the implementation of EHR) of 9 points. PO LOS was reduced following the implementation of EHR from 1.94 to 1.37 days (P = 0.001). CONCLUSION: This study demonstrated that following the implementation of EHR system in an inpatient surgical ward, notation quality improved. It was also found that the implementation of EHR was associated with a decrease in PO LOS.

5.
Theranostics ; 9(12): 3659-3673, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281505

RESUMO

Rationale: Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3). RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression. We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice. Methods: Tissues from colorectal cancer patients were examined for RIP3 expression. CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice. Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses. Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively. Results: RIP3 expression was upregulated in mouse CAC and human colon cancer. RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis. Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype. RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis. RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC. The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3-/- mice. Conclusion: Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression. These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.

6.
Nephron ; 143(2): 135-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31216555

RESUMO

BACKGROUND: Acute kidney injury (AKI) is a complex clinical disorder with sudden decay in renal function. Ischemia-reperfusion injury (IRI) has been regarded as the main etiology for the occurrence of AKI. MicroRNAs have been consistently shown to be involved AKI. OBJECTIVES: We aimed to investigate the role of miR-155 in AKI and its underlying mechanism. METHODS: Ischemia-reperfusion (I/R)-induced AKI rat model and hypoxia-reoxygeneration (H/R)-induced NRK-52E cell model were established. The concentrations of serum creatinine and blood urea nitrogen were measured to evaluate renal function. Hematoxylin and eosin staining and TUNEL assay were performed to assess the severity of kidney injury. Additionally, quantitative real-time-PCR and western blot analysis were subjected to determine the expression of miR-155, TCF4, and apoptosis-related proteins, respectively. Moreover, cell proliferation and apoptosis were evaluated by Cell Counting Kit-8, bromodeoxyuridine, and flow cytometry analyses, respectively. Luciferase reporter assay was used to validate the direct targeting of TCF4 with miR-155. The protein levels of TCF4 and its downstream proteins in cells were measured by western blot. RESULTS: The expression level of miR-155 was upregulated in both I/R-induced AKI rat model and H/R-treated NRK-52E cells. Moreover, overexpression of miR-155 promoted H/R-induced NRK-52E cells apoptosis and suppressed cell proliferation, while inhibition of miR-155 expression exerted opposite effects. Additionally, TCF4 was identified as a target of miR-155, of which expression was downregulated both in vivo and in vitro. Furthermore, the activity of Wnt/ß-catenin signaling pathway was promoted following overexpression of TCF4 in NRK-52E cells, and this effect was attenuated by the increasing miR-155 expression. CONCLUSION: We demonstrated that miR-155 exacerbated AKI involving the targeting and regulation of TCF4/Wnt/ß-catenin signaling pathway, indicating a novel regulatory network and elucidating a potential target for IRI-induced AKI treatment.

7.
Hepatology ; 70(5): 1564-1581, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31021443

RESUMO

Receptor-interacting protein kinase 3 (RIP3) is the core regulator that switches cell death from apoptosis to necrosis. However, its role in tumor immunity is unknown. In this study, decreased RIP3 expression was observed in patients with hepatocellular carcinoma (HCC), which correlates with myeloid-derived suppressor cell (MDSC) accumulation. Moreover, RIP3 is a prognosis factor for patients with HCC. We further found that RIP3 knockdown results in an increase of MDSCs and a decrease of interferon gamma-positive (IFN-γ+ ) cluster of differentiation 8-positive (CD8+ ) tumor-infiltrating lymphocytes (IFN-γ+ CD8+ T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65Ser536 and promoting phosphorylated P65Ser536 nuclear translocation, RIP3 knockdown increases the expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in HCC cells. RIP3 knockdown induces MDSC recruitment through the CXCL1-chemokine (C-X-C motif) receptor 2 (CXCR2) axis. Furthermore, a CXCR2 antagonist substantially suppresses MDSC chemotaxis and HCC growth in RIP3 knockout mice. Conclusion: RIP3 deficiency is an essential factor directing MDSC homing to HCC and promoting CXCL1/CXCR2-induced MDSC chemotaxis to facilitate HCC immune escape and HCC progression; blocking the CXCL1-CXCR2 chemokine axis may provide an immunological therapeutic approach to suppress progression of RIP3 deficiency HCC.

8.
Curr Med Sci ; 39(1): 59-66, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30868492

RESUMO

Chronic nerve compression (CNC) neuropathy is a common disease in the clinic and provokes paraesthesia, or numbness at early stage. The changes in muscle fiber composition and motor nerve terminal morphology in distal muscles were studied in this study. A well-established CNC model was used to assess the changes in the muscles. Behaviors were measured by von Frey filament test. The myosin heavy chain isoforms and neuromuscular junctions (NMJs) were stained by immunofluorescence to show the muscle fiber types composition and motor nerve terminals morphologic changes in the flexor digitorum longus (FDL) and lumbrical muscle. The fiber cross-sectional areas of different muscle fiber types were measured. The small-fiber degeneration of cutaneous nerve fibers was examined by detecting the protein gene product 9.5 (PGP9.5) with immunofluorescence. At 2nd month after compression, the proportion of type I and type II B fibers was markedly decreased, and that of type II A fibers was increased in the lumbrical muscle. There was no significant change in composition of muscle fiber types in FDL and NMJ morphology of FDL and lumbrical muscles. Intra-epidermal nerve fibre density (IENFD) declined at 2nd month after the compression. Our study reveals the morphological changes of the FDL and lumbrical muscle at an early stage of CNC. These findings may be helpful to understand muscle damage and pathophysiological development of the nerve compression, and provide new evidence for early treatment of CNC.


Assuntos
Síndrome do Túnel Carpal/fisiopatologia , Neurônios Motores/fisiologia , Fibras Musculares Esqueléticas/classificação , Ubiquitina Tiolesterase/metabolismo , Animais , Síndrome do Túnel Carpal/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Modelos Biológicos , Fibras Musculares Esqueléticas/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Condução Nervosa , Junção Neuromuscular , Ratos , Ratos Sprague-Dawley
9.
Int J Mol Sci ; 20(1)2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30609841

RESUMO

Blockade of the immunosuppressive checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed death 1 (PD-1) and its cognate ligand, programmed death 1 ligand (PD-L1), has altered the landscape of anti-tumor immunotherapy. B7 family and tumor necrosis factor receptor (TNFR) superfamily play a crucial role in T cell activation, tolerance, and anergy through co-stimulatory and inhibitory signal transduction. Investigating the immune molecular landscapes of the B7 and TNFR families is critical in defining the promising responsive candidates. Herein, we performed comprehensive alteration analysis of the B7 and TNFR family genes across six hepatocellular carcinoma (HCC) datasets with over 1000 patients using cBioPortal TCGA data. About 16% of patients had both B7 and TNFR gene alterations. TNFR gene amplifications were relatively more common (1.73⁻8.82%) than B7 gene amplifications (1.61⁻2.94%). Analysis of 371 sequenced samples revealed that all genes were upregulated: B7 and TNFR mRNA were upregulated in 23% of cases (86/371) and 28% of cases (105/371), respectively. Promoter methylation analysis indicated an epigenetic basis for B7 and TNFR gene regulation. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. B7-H6 expression was significantly associated with worse overall survival, and B7-H6 mRNA was increased gradually in cases with gene copy number alterations. B7-H6 overexpression was associated with aggressive clinicopathologic features and poor prognosis in HCC. Downregulation of B7-H6 in HCC cells significantly inhibited cell adhesion, proliferation, migration, and invasion. Knockdown of B7-H6 in HCC cells inhibited tumor growth and metastasis in vivo. B7-H6 promoted HCC metastasis via induction of MMP-9 expression and STAT3 activation. B7-H6 and STAT3 performed functional overlapping roles on enhancing the MMP-9 promoter activity in HCC cells. These results suggest that alterations of the immunologic co-stimulator B7 and TNFR families correlate with HCC metastasis and prognosis, and especially B7-H6 plays a critical role in promoting metastasis of HCC.


Assuntos
Antígenos B7/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antígenos B7/antagonistas & inibidores , Antígenos B7/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores do Fator de Necrose Tumoral/genética
10.
Sci Rep ; 8(1): 14059, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232461

RESUMO

The salicylic acid (SA) plays a critical role during the establishment of systemic acquired resistance (SAR) in uninfected plant tissues after localised exposure to a pathogen. Here, we studied SA in Populus tomentosa infected by the plant pathogen Botryosphaeria dothidea. The accumulation of SA and methyl salicylate (MeSA) occurred in chronological order in P. tomentosa. The SA and MeSA contents were greater at infected than uninfected sites. Additionally, a gene expression analysis indicated that SA might be accumulated by phenylalanine ammonialyase (PAL) and converted to MeSA by SA carboxyl methyltransferase (SAMT), while MeSA might convert to SA by SA-binding protein 2 (SABP2). The expressions of SAMT at infected sites and SABP2 at uninfected sites, respectively, were significantly up-regulated. Thus, SA might be converted to MeSA at infected sites and transported as a signalling molecule to uninfected sites, where it is converted to SA for SAR. Moreover, the expressions of pathogenesis-related genes PR-1, PR-2 and PR-5 in P. tomentosa were up-regulated by the B. dothidea infection. Our study determined that variations in SA and MeSA contents occur at infected and uninfected sites in poplar after pathogen infection and contributed to the remote signals for poplar SAR.


Assuntos
Proteínas de Plantas/genética , Populus/microbiologia , Saccharomycetales/patogenicidade , Ácido Salicílico/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Metiltransferases/genética , Metiltransferases/metabolismo , Fenilalanina Amônia-Liase/genética , Fenilalanina Amônia-Liase/metabolismo , Proteínas de Plantas/metabolismo , Populus/genética , Populus/metabolismo , Salicilatos/metabolismo , Transdução de Sinais
11.
Neural Regen Res ; 13(8): 1477-1485, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30106062

RESUMO

Current animal models of chronic peripheral nerve compression are mainly silicone tube models. However, the cross section of the rat sciatic nerve is not a perfect circle, and there are differences in the diameter of the sciatic nerve due to individual differences. The use of a silicone tube with a uniform internal diameter may not provide a reliable and consistent model. We have established a chronic sciatic nerve compression model that can induce demyelination of the sciatic nerve and lead to atrophy of skeletal muscle. In 3-week-old pups and adult rats, the sciatic nerve of the right hind limb was exposed, and a piece of surgical latex glove was gently placed under the nerve. N-butyl-cyanoacrylate was then placed over the nerve, and after it had set, another piece of glove latex was placed on top of the target area and allowed to adhere to the first piece to form a sandwich-like complex. Thus, a chronic sciatic nerve compression model was produced. Control pups with latex or N-butyl-cyanoacrylate were also prepared. Functional changes to nerves were assessed using the hot plate test and electromyography. Immunofluorescence and electron microscopy analyses of the nerves were performed to quantify the degree of neuropathological change. Masson staining was conducted to assess the degree of fibrosis in the gastrocnemius and intrinsic paw muscles. The pup group rats subjected to nerve compression displayed thermal hypoesthesia and a gradual decrease in nerve conduction velocity at 2 weeks after surgery. Neuropathological studies demonstrated that the model caused nerve demyelination and axonal irregularities and triggered collagen deposition in the epineurium and perineurium of the affected nerve at 8 weeks after surgery. The degree of fibrosis in the gastrocnemius and intrinsic paw muscles was significantly increased at 20 weeks after surgery. In conclusion, our novel model can reproduce the functional and histological changes of chronic nerve compression injury that occurs in humans and it will be a useful new tool for investigating the mechanisms underlying chronic nerve compression.

12.
Genome Announc ; 6(21)2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29798912

RESUMO

Bacillus velezensis PEBA20 is a poplar endophyte with biocontrol activities and plant growth-promoting effects. The genome of B. velezensis PEBA20 was sequenced and the draft genome assembled, with a length of 4,249,176 bp and 4,487 genes.

13.
J Pathol ; 245(1): 41-52, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29431199

RESUMO

While the importance of protein N-glycosylation in cancer cell migration is well appreciated, the precise mechanisms by which N-acetylglucosaminyltransferase V (GnT-V) regulates cancer processes remain largely unknown. In the current study, we report that GnT-V-mediated N-glycosylation of CD147/basigin, a tumor-associated glycoprotein that carries ß1,6-N-acetylglucosamine (ß1,6-GlcNAc) glycans, is upregulated during TGF-ß1-induced epithelial-to-mesenchymal transition (EMT), which correlates with tumor metastasis in patients with hepatocellular carcinoma (HCC). Interruption of ß1,6-GlcNAc glycan modification of CD147/basigin decreased matrix metalloproteinase (MMP) expression in HCC cell lines and affected the interaction of CD147/basigin with integrin ß1. These results reveal that ß1,6-branched glycans modulate the biological function of CD147/basigin in HCC metastasis. Moreover, we showed that the PI3K/Akt pathway regulates GnT-V expression and that inhibition of GnT-V-mediated N-glycosylation suppressed PI3K signaling. In summary, ß1,6-branched N-glycosylation affects the biological function of CD147/basigin and these findings provide a novel approach for the development of therapeutic strategies targeting metastasis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Basigina/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Glicosilação/efeitos dos fármacos , N-Acetilglucosaminiltransferases/farmacologia , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Metástase Neoplásica/patologia
14.
Nat Med ; 24(1): 73-83, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29227475

RESUMO

Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.


Assuntos
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Araquidonato 12-Lipoxigenase/metabolismo , Fígado/irrigação sanguínea , Receptores Acoplados a Proteínas-G/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/antagonistas & inibidores , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/biossíntese , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Metabolismo dos Lipídeos , Camundongos , Traumatismo por Reperfusão/parasitologia , Suínos
15.
ACS Nano ; 11(11): 11701-11713, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29091396

RESUMO

Electron-rich (donor) and electron-deficient (acceptor) units to construct donor-acceptor (D-A) conjugated macrocycles were investigated to elucidate their interactions with electron-deficient fullerene. Triphenylamine and 4,7-bisthienyl-2,1,3-benzothiadiazole were alternately linked through acetylene, as the donor and acceptor units, respectively, for pentagonal 3B2A and hexagonal 4B2A macrocycles. As detected by scanning tunneling microscopy, both D-A macrocycles were found to form an interesting concentration-controlled nanoporous monolayer on highly oriented pyrolytic graphite, which could effectively capture fullerene. Significantly, the fullerene filling was cavity-size-dependent with only one C70 or PC71BM molecule accommodated by 3B2A, while two were accommodated by 4B2A. Density functional theory calculations were also utilized to gain insight into the host-guest systems and indicted that the S···π contact is responsible for stabilizing these host-guest systems. Owing to the ellipsoidal shape of C70, C70 molecules are standing or lying in molecular cavities depending on the energy optimization. For the 3B2A/PC71BM blended film, PC71BM was intercalated into the cavity formed by the macrocycle 3B2A and provided excellent power conversion efficiency despite the broad band gap (2.1 eV) of 3B2A. This study of D-A macrocycles incorporating fullerene provides insights into the interaction mechanism and electronic structure in the host-guest complexes. More importantly, this is a representative example using D-A macrocycles as a donor to match with the spherical fullerene acceptor for photovoltaic applications, which offer a good approach to achieve molecular scale p-n junctions for substantially enhanced efficiencies of organic solar cells through replacing linear polymer donors by cyclic conjugated oligomers.

16.
Cell Death Dis ; 8(7): e2925, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28703811

RESUMO

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers worldwide. CD147 (EMMPRIN or basigin) is a leading gene relating to hepatocarcinogenesis and metastasis, and is detected in transmembrane, exosome or circulating forms in HCC patients. The endosome recycling of CD147 further enhances the function of this oncoprotein from a dynamic perspective. However, previous studies about CD147 mainly focused on one separate form, and little attention has been paid to how the different forms of tumor-derived CD147 changes. Moreover, uncovering the roles of the residual C-terminal portion of CD147 after shedding is inevitable to fully understand CD147 promoting tumor progression. In this study, we discovered that under low-cholesterol condition, CD147 endocytosis is inhibited but its shedding mediated by ADAM10 is enhanced. Further procession of residual CD147 in the lysosome produces nuclear-localized CD147-ICD (intracellular domain of CD147), which contributes to autophagy through NF-κB-TRAIL-caspase8-ATG3 axis. As autophagy endows cancer cells with increased adaptability to chemotherapy, and HAb 18 (a specific antibody targeting CD147) inhibits CD147 shedding and sequential CD147-ICD enhances autophagy, we found the combination of HAb 18 and cisplatin exhibited marked antitumor efficiency.


Assuntos
Autofagia , Basigina/metabolismo , Proteína ADAM10/antagonistas & inibidores , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Fatores de Ribosilação do ADP/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Autofagia/efeitos dos fármacos , Basigina/química , Basigina/imunologia , Proteína Beclina-1/antagonistas & inibidores , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Cisplatino/toxicidade , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Leupeptinas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Proteólise/efeitos dos fármacos , Sinvastatina/farmacologia , beta-Ciclodextrinas/farmacologia
17.
CNS Neurosci Ther ; 23(3): 233-240, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28145081

RESUMO

AIMS: To clarify the correlation between chronic sleep restriction (CSR) and sporadic Alzheimer disease (AD), we determined in wild-type mice the impact of CSR, on cognitive performance, beta-amyloid (Aß) peptides, and its feed-forward regulators regarding AD pathogenesis. METHODS: Sixteen nine-month-old C57BL/6 male mice were equally divided into the CSR and control groups. CSR was achieved by application of a slowly rotating drum for 2 months. The Morris water maze test was used to assess cognitive impairment. The concentrations of Aß peptides, amyloid precursor protein (APP) and ß-secretase 1 (BACE1), and the mRNA levels of BACE1 and BACE1-antisense (BACE1-AS) were measured. RESULTS: Following CSR, impairments of spatial learning and memory consolidation were observed in the mice, accompanied by Aß plaque deposition and an increased Aß concentration in the prefrontal and temporal lobe cortex. CSR also upregulated the ß-secretase-induced cleavage of APP by increasing the protein and mRNA levels of BACE1, particularly the BACE1-AS. CONCLUSIONS: This study shows that a CSR accelerates AD pathogenesis in wild-type mice. An upregulation of the BACE1 pathway appears to participate in both cortical Aß plaque deposition and memory impairment caused by CSR. BACE1-AS is likely activated to initiate a cascade of events that lead to AD pathogenesis. Our study provides, therefore, a molecular mechanism that links CSR to sporadic AD.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Córtex Cerebral/metabolismo , Transtornos Cognitivos/etiologia , Privação do Sono/complicações , Privação do Sono/patologia , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , DNA Antissenso/farmacologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Tempo de Reação/efeitos dos fármacos , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia
18.
Int J Mol Sci ; 18(1)2017 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-28117675

RESUMO

Drug resistance remains a major clinical obstacle to successful treatment of cancer. As posttranslational modification is becoming widely recognized to affect the function of oncoproteins, targeting specific posttranslational protein modification provides an attractive strategy for anticancer drug development. CD147 is a transmembrane glycoprotein contributing to chemo-resistance of cancer cells in a variety of human malignancies. Ubiquitination is an important posttranslational modification mediating protein degradation. Degradation of oncoproteins, CD147 included, emerges as an attractive alternative for tumor inhibition. However, the ubiquitination of CD147 remains elusive. Here in this study, we found that deletion of the CD147 intracellular domain (CD147-ICD) prolonged the half-life of CD147 in HEK293T cells, and we identified that CD147-ICD interacts with FBXO22 using mass spectrometry and Western blot. Then, we demonstrated that FBXO22 mediates the polyubiquitination and degradation of CD147 by recognizing CD147-ICD. While knocking down of FBXO22 prolonged the half-life of CD147 in HEK293T cells, we found that FBXO22 regulates CD147 protein turnover in SMMC-7721, Huh-7 and A549 cells. Moreover, we found that the low level of FBXO22 contributes to the accumulation of CD147 and thereafter the cisplatin resistance of A549/DDP cells. To conclude, our study demonstrated that FBXO22 mediated the polyubiquitination and degradation of CD147 by interacting with CD147-ICD, and CD147 polyubiquitination by FBXO22 reversed cisplatin resistance of tumor cells.


Assuntos
Basigina/metabolismo , Cisplatino/farmacologia , Proteínas F-Box/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Ubiquitinação , Células A549 , Antineoplásicos/farmacologia , Basigina/genética , Sítios de Ligação/genética , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas F-Box/genética , Deleção de Genes , Células HEK293 , Humanos , Espectrometria de Massas , Microscopia Confocal , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Poliubiquitina/metabolismo , Ligação Proteica , Proteólise , Interferência de RNA , Receptores Citoplasmáticos e Nucleares/genética
19.
Molecules ; 21(12)2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27916955

RESUMO

A multi-residue method for the determination of 54 pesticide residues in pollens has been developed and validated. The proposed method was applied to the analysis of 48 crude pollen samples collected from eight provinces of China. The recovery of analytes ranged from 60% to 136% with relative standard deviations (RSDs) below 30%. Of the 54 targeted compounds, 19 pesticides were detected. The major detection rates of each compound were 77.1% for carbendazim, 58.3% for fenpropathrin, 56.3% for chlorpyrifos, 50.0% for fluvalinate, 31.3% for chlorbenzuron, and 29.2% for triadimefon in crude pollen samples. The maximum values of each pesticide were 4516 ng/g for carbendazim, 162.8 ng/g for fenpropathrin, 176.6 ng/g for chlorpyrifos, 316.2 ng/g for fluvalinate, 437.2 ng/g for chlorbenzuron, 79.00 ng/g for triadimefon, and so on. This study provides basis for the research on the risks to honeybee health.


Assuntos
Praguicidas/análise , Pólen/química , China , Praguicidas/química
20.
Int J Mol Sci ; 17(11)2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27834933

RESUMO

Hepatocellular carcinoma (HCC) is currently the third most common cause of cancer-related death in the Asia-Pacific region. Our previous work showed that knockdown of CD98 significantly inhibits malignant HCC cell phenotypes in vitro and in vivo. The level of CD98 in the membrane is tightly regulated to mediate complex processes associated with cell-cell communication and intracellular signaling. In addition, the intracellular domain of CD98 (CD98-ICD) seems to be of vital importance for recycling CD98 to the membrane after it is endocytosed. The intracellular and transmembrane domains of CD98 associate with ß-integrins (primarily ß1 but also ß3), and this association is essential for CD98 mediation of integrin-like signaling and complements dominant suppression of ß1-integrin. We speculated that isolated CD98-ICD would similarly suppress ß1-integrin activation and inhibit the malignant behaviors of cancer cells. In particular, the exact role of CD98-ICD has not been studied independently in HCC. In this study, we found that ectopic expression of CD98-ICD inhibited the malignant phenotypes of HCC cells, and the mechanism possibly involves ß1-integrin suppression. Moreover, the expression levels of CD98, ß1-integrin-A (the activated form of ß1-integrin) and Ki-67 were significantly increased in HCC tissues relative to those of normal liver tissues. Therefore, our preliminary study indicates that ectopic CD98-ICD has an inhibitory role in the malignant development of HCC, and shows that CD98-ICD acts as a dominant negative mutant of CD98 that attenuates ß1-integrin activation. CD98-ICD may emerge as a promising candidate for antitumor treatment.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteína-1 Reguladora de Fusão/metabolismo , Integrina beta1/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Sítios de Ligação/genética , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Progressão da Doença , Citometria de Fluxo , Proteína-1 Reguladora de Fusão/genética , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Confocal , Transfecção , Transplante Heterólogo , Carga Tumoral
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