Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 174
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Ethnopharmacol ; 248: 112308, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31622745

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium officinale polysaccharide (DOP) is the main active ingredient of Dendrobium officinale Kimura & Migo, which is a precious traditional Chinese medicine and often used in treatment of hepatitis, diabetes, obesity and rheumatoid arthritis. AIM OF THE STUDY: DOP exhibits significant hypoglycemic activity, while its mechanism remains unclear. The present study aims to investigate the hypoglycemic mechanisms of DOP based on the glucagon-mediated signaling pathways and the liver glycogen structure, which catalyze hepatic glucose metabolism, and provide new knowledge about the antidiabetic mechanism of DOP and further evidence for its clinical use for diabetes. MATERIALS AND METHODS: DOP were obtained from the dry stems of Dendrobium officinale by water extraction and alcohol precipitation method. T2DM mice model was established by high-fat diet combined with streptozotocin. Liver histopathological changes were observed by H&E and PAS straining. Pancreatic histology was studied by H&E staining and immunofluorescence analysis. The levels of glucagon and insulin were detected by Elisa Kit and the hepatic glycogen content was detected by GOPOD. The expressions of the hepatic glycogen-related metabolism enzymes, hepatic gluconeogenesis enzymes, and the related protein in cAMP-PKA and Akt/FoxO1 signaling pathways were detected by western blots. Liver glycogen was extracted from the liver tissues by sucrose density gradient centrifugation, and size exclusion chromatography (SEC) was used to analyze the structure of liver glycogen. RESULTS: DOP could significantly affect the glucagon-mediated signaling pathways, cAMP-PKA and Akt/FoxO1, to further promote hepatic glycogen synthesis, inhibit hepatic glycogen degradation and hepatic gluconeogenesis. Moreover, DOP could reverse the instability of the liver glycogen structure and thus probably suppressed glycogen degradation. Thus, DOP finally would ameliorate hepatic glucose metabolism via glucagon-mediated signaling pathways and modifying liver-glycogen structure in diabetic mice. CONCLUSIONS: The hypoglycemic mechanism of DOP might be associated with the regulation of glucagon-mediated hepatic glycogen metabolism and gluconeogenesis, and of liver glycogen structure, contributing to improved hepatic glucose metabolism in diabetic mice.

2.
Exp Cell Res ; 384(2): 111653, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31574286

RESUMO

Acute myeloid leukemia (AML) is a group of highly aggressive malignancies with a 5-year overall survival of less than 40%. Cell overgrowth with defective apoptosis is a hallmark of AML, but little is known about how it occurs. Here, we show that aberrant activation of the largest subunit of RNA polymerase II (RPB1) encoded by POLR2A gene is critically involved in this hallmark. We retrospectively analyzed the expression profiles of POLR2A and RPB1 in a panel of AML cell lines, primary AML patients and peripheral blood samples. Meanwhile, correlation analysis was used to explore the correlation between the expression of RPB1 with tumor burden and overall survival time in untreated AML samples. RNA-Seq approach was performed to identify the differentially expressed genes between RPB1 silencing AML cells with control cells after knocking out RPB1. Furthermore, orthotopic AML models were established with RPB1 silencing and control cells to investigate the effects of RPB1 protein level on leukemia cell growth. In most AML patients, RPB1 was aberrantly activated and closely associated with poor prognosis, but not in normal hematopoietic cells. Global transcriptomic analysis revealed that POLR2A knockout strongly impaired growth of AML cells by selectively depleting a substantial set of AML-related oncogenic and anti-apoptosis genes such as MYC, RUNX2, MEIS1, CDC25A and BCL-2. Silencing RPB1 by genetic technology led to a potent regression of human refractory AML in mouse models. These findings reveal that dysregulated RPB1 is a central oncogenic hub that drives overgrowth by hijacking an array of oncogenic and anti-apoptosis factors. Targeting RPB1 is a potential therapeutic for treating AML.

3.
Brain Res ; : 146509, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31626784

RESUMO

INTRODUCTION: Microglial activation plays a crucial role in the pathology of ischemic stroke. Recently, we demonstrated that fingolimod (FTY720) exerted neuroprotective effects via immunomodulation in ischemic white matter damage induced by chronic cerebral hypoperfusion, which was accompanied by robust microglial activation. In this study, we assessed the pro-angiogenic potential of FTY720 in a murine model of acute cortical ischemic stroke. METHODS: The photothrombotic (PT) method was used to induce cortical ischemic stroke in mice. We evaluated cortical damage, behavioral deficits, microglial polarization, and angiogenesis to identify the neuroprotective effects and possible molecular mechanisms of FTY720 in acute ischemic stroke. RESULTS: In vivo, a reduction in neuronal loss and improved motor function were observed in FTY720-treated mice after PT stroke. Immunofluorescence staining revealed that robust microglial activation and the associated neuroinflammatory response in the peri-infarct area were ameliorated by FTY720 via its ability to polarize microglia toward the M2 phenotype. Furthermore, both in vivo and in vitro, angiogenesis was enhanced in the microglial M2 phenotype state. Behaviorally, a significant improvement in the FTY720-treated group compared to the control group was evident from days 7 to 14. CONCLUSIONS: Our research indicated that FTY720 treatment promoted angiogenesis via microglial M2 polarization and exerted neuroprotection in PT ischemic stroke.

4.
Bioorg Chem ; 91: 103176, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31404797

RESUMO

Discrimination and quantification of intracellular biothiols, such as cysteine (Cys), homocysteine (Hcy), glutathione (GSH) under physiological conditions is significant for academic research and disease diagnosis. A new fluorescent probe (complex 1-Cu2+) for discriminate detection of GSH was prepared by copper ions coordinate with coumarin carbohydrazide Schiff base derivative 1. In suitable buffer solution (CH3CN: HEPES = 3:2, v/v) and under appropriate pH condition (pH = 7.2-7.4), the UV-vis spectroscopy experiments showed that compound 1 and copper ion exhibited a 1:1 ratio binding mode and moderate binding ability. Fluorescence quenching of compound 1 was observed when it complexed with Cu2+ ions. An obviously fluorescence restoration appeared after addition of GSH to the solution of probe, which also exhibited a highly selectivity relative to cysteine (Cys) and homocysteine (Hcy) in the amino acid competitive experiments. The minimum detection limit was calculated to 0.12 µM by fluorescent method, which was distinctly below the physiological concentration of GSH in live cells. Its biological application to detect the endogenous GSH was further proved by the HepG2 cell fluorescence image test.

5.
J Am Chem Soc ; 141(32): 12738-12743, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31328519

RESUMO

The ability to accurately identify and isolate cells is the cornerstone of precise disease diagnosis and therapies. A single-step cell identification method based on logic analysis of multiple surface markers will have unique advantages because of its accuracy and efficacy. Herein, using multiple DNA aptamers for cancer biomarker recognition and associative toehold activation for signal integration and amplification as two molecular keys, we have successfully operated a cell-surface device that can perform AND Boolean logic analysis of multiple biomarkers and precisely label the target cell subtype in large populations of similar cells via the presence or absence of different biomarkers. Our approach can achieve single-step cancer cell identification and isolation with excellent sensitivity and accuracy and thus will have broad applications in biological science, biomedical engineering, and personalized medicine.

6.
Sci Rep ; 9(1): 9805, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285446

RESUMO

mTOR signaling pathway is deregulated in most cancers and uncontrolled cell cycle progression is a hallmark of cancer cell. However, the precise molecular mechanisms of the regulation of DNA replication and chromatin metabolism by mTOR signaling are largely unknown. We herein report that mTOR signaling promotes the loading of MCM2-7 helicase onto chromatin and upregulates DNA replication licensing factor CDC6. Pharmacological inhibition of mTOR kinase resulted in CHK1 checkpoint activation and decreased MCM2-7 replication helicase and PCNA associated with chromatins. Further pharmacological and genetic studies demonstrated CDC6 is positively controlled by mTORC1-S6K1 and mTORC2 signaling. miRNA screening revealed mTOR signaling suppresses miR-3178 thereby upregulating CDC6. Analysis of TCGA data found that CDC6 is overexpressed in most cancers and associates with the poor survival of cancer patients. Our findings suggest that mTOR signaling may control DNA replication origin licensing and replisome stability thereby cell cycle progression through CDC6 regulation.

7.
Eur J Med Chem ; 178: 390-400, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202127

RESUMO

Two iridium(III) polypyridyl complexes [Ir(ppy)2(HPIP)](PF6) (Ir-1), [Ir(ppy)2(BHPIP)](PF6) (Ir-2) and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized by elemental analysis, IR, 1H NMR and 13C NMR. The anticancer activity in vitro and in vivo was evaluated. The cytotoxic activity in vitro of the complexes and their liposomes Ir-1-Lipo and Ir-2-Lipo against cancer cells was investigated by MTT methods. Ir-1 and Ir-2 show no cytotoxic activity, while Ir-1-Lipo and Ir-2-Lipo exhibit high cytotoxic effect. The IC50 values range from 5.2 ±â€¯0.8 to 22.3 ±â€¯1.8 µM. The apoptosis, reactive oxygen species, the change of mitochondrial membrane potential, intracellular Ca2+ levels and a release of cytochrome c were investigated. The effect of Ir-1-Lipo and Ir-2-Lipo on microtubules was also explored. In the C57BL/6 mice model, Ir-1 only displays a tumor inhibitory rate of 23.21%, while lr-1-Lipo exhibits satisfactory in vivo antitumor efficacy with tumor inhibitory rate of 72.55%. This study demonstrates that complexes encapsulated in liposomes induce apoptosis in B16 through ROS-mediated lysosomal-mitochondria dysfunction, inhibition of polymerization of microtubules and induce cell cycle arrest at S phase.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Irídio/farmacologia , Lipossomos/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Polímeros/química , Polímeros/farmacologia , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 178: 401-416, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202128

RESUMO

This work mainly introduces the synthesis and characterization of three iridium(III) complexes [Ir(ppy)2(adppz)](PF6) (Ir-1), [Ir(bzq)2(addpz)](PF6) (Ir-2) and [Ir(piq)2(adppz)](PF6) (Ir-3). The complexes are more cytotoxic than cisplatin against tumor cell lines such as SGC-7901, A549, HeLa, Eca-109, HepG2 and BEL-7402. The toxicity test results indicated that complexes Ir-1, Ir-2 and Ir-3 can effectively inhibit the cell growth of SGC-7901 cells, and the measured IC50 values are 1.8 ±â€¯0.4, 1.6 ±â€¯0.3 and 0.8 ±â€¯0.1 µM, respectively. AO/EB staining and flow apoptosis confirmed that SGC-7901 cells were caused apoptosis after being treated with the complexes. Along with the increase of endogenous ROS and Ca2+ levels, mitochondrial membrane potential collapse and massive release of cytochrome c, it is fully demonstrated that these complexes induce apoptosis through ROS-mediated mitochondrial pathway. At the same time, the complex Ir-3 is outstanding in the inhibition of tumor growth in vivo. Combined with the above results, it provides a favorable foundation for the future development of more effective anti-tumor drugs.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade
9.
Biomed Pharmacother ; 117: 109134, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247466

RESUMO

Proto-oncogene Myc, a key transcription factor, is frequently deregulated in human leukemia with aggressive and poor clinical outcome, but the development of MYC inhibitors remains challenging due to MYC helix-loop-helix topology lacking druggable domains. Here we describe a novel oral active small molecule analog of berbamine, tosyl chloride-berbamine (TCB), that efficiently eliminates MYC-positive leukemia in vitro and in vivo. Mechanistically, TCB potently reduced MYC protein by inhibiting CaMKIIγ, a critical enzyme that stabilizes MYC protein, and induces apoptosis of MYC-positive leukemia cells. In vivo, oral administration of TCB markedly eliminated lethal MYC-positive acute lymphoblastic leukemia (ALL) with well tolerability in orthotopic mouse model. Our studies identify CaMKIIγ/Myc axis as a valid target for developing small molecule-based new therapies for treating MYC-mediated leukemia and demonstrate that TCB is an orally active analog of berbamine that kills MYC-positive leukemia cells.

10.
Plant Cell Rep ; 38(9): 1181-1197, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165250

RESUMO

KEY MESSAGE: Drastic changes in soil water content can activate the short-term high expression of key enzyme-encoding genes involved in secondary metabolite synthesis thereby increasing the content of secondary metabolites. Bupleurum chinense DC. is a traditional medicinal herb that is famous for its abundant saikosaponins. In the current study, the effects of drought-re-watering-drought on the photosynthesis physiology and biosynthesis of saikosaponins were investigated in 1-year-old B. chinense. The results showed that alterations in soil moisture altered the photosynthesis physiological process of B. chinense. The dry weight and fresh weight of the roots, photosynthesis capacity, chlorophyll fluorescence parameters, and SOD, POD and CAT activities were significantly reduced, and the contents of SP, soluble sugars, PRO and MDA increased. There were strong correlations between different physiological stress indices. All indices promoted and restricted each other, responded to soil moisture changes synergistically, maintained plant homeostasis and guaranteed normal biological activities. It was found that RW and RD_1 were the key stages of the water-control experiment affecting the expression of saikosaponin-related genes. At these two stages, the expression of multiple genes was affected by changes in soil moisture, with their expression levels reaching several-fold higher than those at the previous stage. We noticed that the expression of saikosaponin synthesis genes (which were rapidly upregulated at the RW and RD_1 stages) did not coincide with the rapid accumulation of saikosaponins (at the RD-2 stage), which were found to correspond to each other at the later stages of the water-control experiment. This finding indicates that there is a time lag between gene expression and the final product synthesis. Rapid changes in the external environment (RW to RD_1) have a short-term promoting effect on gene expression. This study reveals that short-term stress regulation may be an effective way to improve the quality of medicinal materials.


Assuntos
Bupleurum/fisiologia , Ácido Oleanólico/análogos & derivados , Fotossíntese/fisiologia , Saponinas/biossíntese , Metabolismo Secundário , Água/fisiologia , Bupleurum/química , Secas , Ácido Oleanólico/biossíntese , Raízes de Plantas/química , Raízes de Plantas/fisiologia , Plantas Medicinais , Solo/química , Estresse Fisiológico
11.
Chem Commun (Camb) ; 55(53): 7691-7694, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31204742

RESUMO

We reported two simple rhodamine-based colourimetric sensors for the first time which can selectively and sensitively detect salicylic acid (SA) under naked-eye detection. We proposed two distinctly different modes to elucidate the possible mechanism for monitoring SA. The rationally designed probes can be well exploited in signalling SA in living cell lines.


Assuntos
Corantes Fluorescentes/química , Imagem Óptica , Rodaminas/química , Ácido Salicílico/análise , Corantes Fluorescentes/síntese química , Estrutura Molecular , Rodaminas/síntese química
12.
Clin Cancer Res ; 25(15): 4749-4760, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31097454

RESUMO

PURPOSE: Activating BRAF mutations, most commonly BRAFV600E, are a major oncogenic driver of many cancers. We explored whether BRAFV600E promotes radiation resistance and whether selectively targeting BRAFV600E with a BRAF inhibitor (vemurafenib, BRAFi) sensitizes BRAFV600E thyroid cancer cells to radiotherapy. EXPERIMENTAL DESIGN: Immunoblotting, neutral comet, immunocytochemistry, functional reporter, and clonogenic assays were used to analyze the outcome and molecular characteristics following radiotherapy with or without BRAFV600E or vemurafenib in thyroid cancer cells. RESULTS: BRAFV600E thyroid cancer cell lines were associated with resistance to ionizing radiation (IR), and expression of BRAFV600E into wild-type BRAF thyroid cancer cells led to IR resistance. BRAFi inhibited ERK signaling in BRAFV600E mutants, but not BRAF wild-type thyroid cancer cell lines. BRAFi selectively radiosensitized and delayed resolution of IR-induced γH2AX nuclear foci in BRAFV600E cells. Moreover, BRAFi impaired global DNA repair and altered the resolution of 53BP1 and RAD51 nuclear foci in BRAFV600E cells following IR. BRAFV600E mutants displayed enhanced nonhomologous end-joining (NHEJ) repair activity, which was abolished by BRAFi. Intriguingly, BRAFV600E mutation led to upregulation of XLF, a component of NHEJ, which was prevented by BRAFi. Importantly, BRAFi in combination with radiotherapy resulted in marked and sustained tumor regression of BRAFV600E thyroid tumor xenografts. CONCLUSIONS: BRAFV600E mutation promotes NHEJ activity leading to radioresistance and BRAFi selectively radiosensitizes BRAFV600E thyroid cancer cells through inhibiting NHEJ. Our findings suggest that combining BRAFi and radiation may improve the therapeutic outcome of patients with BRAFV600E-mutant thyroid cancer.

13.
Sci Rep ; 9(1): 6961, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061440

RESUMO

The Yiyuan hominin fossil site is one of the few localities in China where a partial skullcap and several loose teeth of Homo erectus have been discovered. Yiyuan was previously assigned broadly to the Middle Pleistocene by biostratigraphical correlation and ESR/U-series dating. Here, we report the first application of a radio-isotopic dating method to the site. 26Al/10Be burial dating results derived from two sand samples from the fossiliferous deposits show that the hominin fossils can be confidently dated to 0.64 ± 0.08 Ma (million years ago). The reliability of this age is supported by the zero age of modern fluvial sediment near the cave. Our result is consistent with the age estimation based on biostratigraphic correlation and supports the argument that the Yiyuan and Zhoukoudian Locality 1 H. erectus fossils are contemporaneous. The results presented here, along with other recent chronological studies on Chinese Middle Pleistocene hominin sites, indicate that the time span from 600-400 ka (thousand years ago) is a critical period for human evolution in East Asia. Importantly, this time bracket includes several major climatic changes that would have influenced hominins, both morphologically and behaviorally.

14.
Mol Cancer Ther ; 18(6): 1025-1035, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31015310

RESUMO

Targeting inhibitor of apoptosis proteins (IAP) with second mitochondria-derived activator of caspase (SMAC) mimetics may promote cancer cell death. We tested whether cIAP1 predicts poor prognosis in head and neck squamous cell carcinoma (HNSCC) and whether a novel Smac-mimetic, LCL161, could radiosensitize human papillomavirus-positive (HPV+) and -negative (HPV-) HNSCC. The association of BIRC2 (encoding cIAP1) mRNA level with HPV status in HNSCC was analyzed using The Cancer Genome Atlas (TCGA) database. cIAP1 was assessed by IHC on an HNSCC tissue microarray (TMA, n = 84) followed by correlation analysis with HPV status and patient outcomes. Human cell culture and animal models of HNSCC were used to analyze the outcome and molecular characteristics following radiotherapy in combination with LCL161. cIAP1 expression is increased in HPV- compared with HPV+HNSCC tumors in the TCGA database. In our TMA, cIAP1 was overexpressed in HNSCC compared with normal tissues (P = 0.0003) and associated with a poor overall survival (P = 0.0402). cIAP1 levels were higher in HPV- than that in HPV+HNSCC tumors (P = 0.004) and patients with cIAP1+/HPV- HNSCC had the worst survival. LCL161 effectively radiosensitized HPV- HNSCC cells, which was accompanied with enhanced apoptosis, but not HPV+ HNSCC cells. Importantly, LCL161 in combination with radiotherapy led to dramatic tumor regression of HPV- HNSCC tumor xenografts, accompanied by cIAP1 degradation and apoptosis activation. These results reveal that cIAP1 is a prognostic and a potential therapeutic biomarker for HNSCC, and targeting cIAP1 with LCL161 preferentially radiosensitizes HPV- HNSCC, providing justification for clinical testing of LCL161 in combination with radiation for patients with HPV- HNSCC.

15.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(4): 381-386, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31014433

RESUMO

OBJECTIVE: To study the etiology and genetic diagnosis of children with short stature. METHODS: A retrospective analysis was performed to study the etiological distribution and clinical features of 86 children with short stature. RESULTS: A total of 6 causes were observed in these children, among which idiopathic short stature (ISS, 41%) and growth hormone deficiency (GHD, 29%) were the most common causes, followed by genetic diseases (14%). There were no significant differences in age at the time of diagnosis, body height, body length and weight at birth, body height of parents and insulin-like growth factor-1 levels between the genetic disease group and the ISS/GHD groups (P>0.05). Compared with the ISS group, the genetic disease group had significantly lower deviation from the 3rd percentile for the height of children of the same age and sex (ΔP3) and height standard deviation score (P<0.05), while there were no significant differences between the genetic disease and GHD groups (P>0.05). The analysis of the clinical manifestations for the genetic disease group showed heterogeneity and phenotypic overlap in children with different genetic diseases. CONCLUSIONS: ISS, GHD and genetic diseases are major causes of short stature in children. For children with severe short stature, genetic testing should be performed to make a definitive diagnosis after GHD has been excluded.


Assuntos
Testes Genéticos , Estatura , Criança , Nanismo Hipofisário , Transtornos do Crescimento , Hormônio do Crescimento Humano , Humanos , Estudos Retrospectivos
16.
Exp Mol Pathol ; 108: 73-79, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30946843

RESUMO

BACKGROUND: Plakophilin 1 (PKP1) is an important plaque component of desmosomes, major intercellular adhesive junctions that act as anchorage points for intermediate filaments. Abnormal expression of PKP1 was observed in various types of cancer, however so far its function in lung cancer has not yet been elucidated. METHODS: The expression of PKP1 was analyzed by RT-PCR and western blotting in lung cancer cell lines. The protein expression of PKP1 was evaluated by immunohistochemistry in tissue microarray. The epigenetic mechanism of PKP1 was explored by demethylation test, bisulfite sequencing and Methylation-Specific-PCR. The function of PKP1 was investigated by stable transfection with an expression vector. RESULTS: We found that PKP1 was downregulated in 6 out of 8 lung cancer cell lines, and downregulation of PKP1 was associated with DNA hypermethylation. In advanced primary lung tumor samples, higher expression of PKP1 was significantly associated with favorable clinical outcome (p = .003). Ectopic expression of PKP1 inhibited cell proliferation, colony formation, migration/invasion and enhanced apoptosis. These phenomena are accompanied by increased caspase 3/7 activities and cleaved PARP-1 as well as decreased extracellular signal-regulated kinase (ERK) activity. CONCLUSION: Taken together, our data suggest that PKP1 is a novel tumor suppressor and its protein expression might be a potential prognostic marker for patients with advanced lung cancer.

17.
Transl Oncol ; 12(6): 801-809, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30953928

RESUMO

As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.

18.
Front Immunol ; 10: 297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941118

RESUMO

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

19.
Viruses ; 11(3)2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30841485

RESUMO

Herpesvirus infection is an orderly, regulated process. Among these viruses, the encapsidation of viral DNA is a noteworthy link; the entire process requires a powered motor that binds to viral DNA and carries it into the preformed capsid. Studies have shown that this power motor is a complex composed of a large subunit, a small subunit, and a third subunit, which are collectively known as terminase. The terminase large subunit is highly conserved in herpesvirus. It mainly includes two domains: the C-terminal nuclease domain, which cuts the viral concatemeric DNA into a monomeric genome, and the N-terminal ATPase domain, which hydrolyzes ATP to provide energy for the genome cutting and transfer activities. Because this process is not present in eukaryotic cells, it provides a reliable theoretical basis for the development of safe and effective anti-herpesvirus drugs. This article reviews the genetic characteristics, protein structure, and function of the herpesvirus terminase large subunit, as well as the antiviral drugs that target the terminase large subunit. We hope to provide a theoretical basis for the prevention and treatment of herpesvirus.


Assuntos
Endodesoxirribonucleases/metabolismo , Infecções por Herpesviridae/tratamento farmacológico , Herpesviridae/efeitos dos fármacos , Herpesviridae/enzimologia , Subunidades Proteicas/metabolismo , Proteínas Virais/metabolismo , Empacotamento do DNA , DNA Viral , Desenvolvimento de Medicamentos , Endodesoxirribonucleases/genética , Modelos Moleculares , Domínios Proteicos , Subunidades Proteicas/genética , Proteínas Virais/genética , Montagem de Vírus
20.
Angew Chem Int Ed Engl ; 58(23): 7600-7605, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-30843654

RESUMO

The synthesis of open-shell polycyclic hydrocarbons with large diradical characters is challenging because of their high reactivities. Herein, two diindeno-fused corannulene regioisomers DIC-1 and DIC-2, curved fragments of fullerene C104 , were synthesized that exhibit open-shell singlet ground states. The incorporation of the curved and non-alternant corannulene moiety within diradical systems leads to significant diradical characters as high as 0.98 for DIC-1 and 0.89 for DIC-2. Such high diradical characters can presumably be ascribed to the re-aromatization of the corannulene π system. Although the DIC compounds have large diradical characters, they display excellent stability under ambient conditions. The half-lives are 37 days for DIC-1 and 6.6 days for DIC-2 in solution. This work offers a new design strategy towards diradicaloids with large diradical characters yet maintain high stability.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA