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1.
Plant Physiol ; 192(2): 1483-1497, 2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-36810650

RESUMO

Glandular secretory trichomes (GSTs) can secrete and store a variety of specific metabolites. By increasing GST density, valuable metabolites can be enhanced in terms of productivity. However, the comprehensive and detailed regulatory network of GST initiation still needs further investigation. By screening a complementary DNA library derived from young leaves of Artemisia annua, we identified a MADS-box transcription factor, AaSEPALLATA1 (AaSEP1), that positively regulates GST initiation. Overexpression of AaSEP1 in A. annua substantially increased GST density and artemisinin content. The HOMEODOMAIN PROTEIN 1 (AaHD1)-AaMYB16 regulatory network regulates GST initiation via the jasmonate (JA) signaling pathway. In this study, AaSEP1 enhanced the function of AaHD1 activation on downstream GST initiation gene GLANDULAR TRICHOME-SPECIFIC WRKY 2 (AaGSW2) through interaction with AaMYB16. Moreover, AaSEP1 interacted with the JA ZIM-domain 8 (AaJAZ8) and served as an important factor in JA-mediated GST initiation. We also found that AaSEP1 interacted with CONSTITUTIVE PHOTOMORPHOGENIC 1 (AaCOP1), a major repressor of light signaling. In this study, we identified a MADS-box transcription factor that is induced by JA and light signaling and that promotes the initiation of GST in A. annua.


Assuntos
Artemisia annua , Tricomas , Tricomas/genética , Tricomas/metabolismo , Artemisia annua/genética , Artemisia annua/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ciclopentanos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
2.
Front Plant Sci ; 13: 982317, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119604

RESUMO

The plant Artemisia annua is well known for its production of artemisinin, a sesquiterpene lactone that is an effective antimalarial compound. Although remarkable progress has been made toward understanding artemisinin biosynthesis, the effect of MADS-box family transcription factors on artemisinin biosynthesis is still poorly understood. In this study, we identified a MADS transcription factor, AaSEP4, that was predominantly expressed in trichome. AaSEP4 acts as a nuclear-localized transcriptional activator activating the expression of AaGSW1 (GLANDULAR TRICHOME-SPECIFIC WRKY1). Dual-luciferase and Yeast one-hybrid assays revealed that AaSEP4 directly bound to the CArG motif in the promoter region of AaGSW1. Overexpression of AaSEP4 in A. annua significantly induced the expression of AaGSW1 and four artemisinin biosynthesis genes, including amorpha-4,11-diene synthase (ADS), cytochrome P450 monooxygenase (CYP71AV1), double-bond reductase 2 (DBR2) and aldehyde dehydrogenase 1 (ALDH1). Furthermore, the results of high-performance liquid chromatography (HPLC) showed that the artemisinin content was significantly increased in the AaSEP4-overexpressed plants. In addition, RT-qPCR results showed that AaSEP4 was induced by methyl jasmonic acid (MeJA) treatment. Taken together, these results explicitly demonstrate that AaSEP4 is a positive regulator of artemisinin biosynthesis, which can be used in the development of high-artemisinin yielding A. annua varieties.

3.
Bioresour Technol ; 357: 127248, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35500835

RESUMO

The rapid development of traditional Chinese medicine enterprises has put forward higher requirements for the resource utilization of traditional Chinese medicine residues (TCMR). Aerobic composting of TCMR to prepare bio-organic fertilizer is an effective resource utilization method. In this study, a back-propagation artificial neural network (BPNN) model using composting factors as inputs (C/N, initial moisture content, type of inoculant, composting days) and the humic acid content as the output was constructed based on the orthogonal test data. BPNN-GA (a genetic algorithm) was used for extreme value optimization, and the optimal composting process parameter combination was obtained and verified. The results show that the combination of orthogonal testing and BPNN can effectively establish the relationship between the composting process parameters and humic acid content. The R2 value was 0. 9064. The optimized parameter combination is as follows: C/N,37.42; moisture content,69.76%; bacteria,no; and composting time,50 d.


Assuntos
Compostagem , Reishi , Fertilizantes , Substâncias Húmicas/análise , Redes Neurais de Computação , Solo
4.
Chin J Nat Med ; 20(2): 102-110, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35279237

RESUMO

The infiltration of immune cells into the hepatocellular carcinoma microenvironment is the main reason why hepatocellular carcinoma patients are prone to carcinoma recurrence and the disease are incurable. Notably, the infiltration of Treg cells is the main trigger. Dahuang Zhechong pill (DHZCP) is a traditional Chinese herbal compound successful in the treatment of hepatitis and hepatocellular carcinoma. DHZCP can heal and nourish while slowing the onset of the disease, thereby strengthening the body's immune function. It can localize tumors and ultimately achieve the goal of eliminating tumors. In this study, an orthotopic liver cancer model of mice was used to explore the mechanism of DHZCP enhancing anti-tumor immunity, which showed more Th1 cells in the peripheral blood and spleen after DHZCP treatment, while more IFN-γ was secreted to activate CD8+ T cells and Treg cell production was inhibited, thereby suppressing the growth of HCC. Finally, we also analyzed the potential components of DHZCP from the perspective of modern targets using network pharmacology methods and experimental results.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Linfócitos T CD8-Positivos , Carcinoma Hepatocelular/tratamento farmacológico , Medicamentos de Ervas Chinesas , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Linfócitos T Reguladores , Microambiente Tumoral
5.
Int J Biol Macromol ; 192: 1021-1028, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34666131

RESUMO

Interleukin (IL)-11 is a multifunctional cytokine belonging to the IL-6 family, which plays essential roles in immune response. However, much less is known about the immunological functions of IL-11 in teleost. In this study, we investigated the immune properties of a teleost IL-11 homologue (CsIL-11) from tongue sole Cynoglossus semilaevis. CsIL-11 possesses four conserved α-helices and conserved CsIL-11 receptor binding residues L86 and R187, and shares 23.3%-80.1% identities with other IL-11 homologues. CsIL-11 expression was constitutive in tissues, with most abundant in blood and least abundant in spleen, and upregulated by bacterial challenge in blood, spleen, and head kidney. Recombinant CsIL-11 (rCsIL-11) in the native form of monomer, could bind to peripheral blood leukocytes (PBLs) membrane and enhance the activation and phagocytosis of PBLs. When administered in vivo, rCsIL-11 could markedly promote the host to defend against microbial infection. Overall, our findings show that CsIL-11 plays a pivotal role in regulating PBLs phagocytosis and antibacterial immunity.


Assuntos
Infecções Bacterianas/veterinária , Doenças dos Peixes/etiologia , Doenças dos Peixes/metabolismo , Peixes/fisiologia , Interleucina-11/metabolismo , Fagocitose/imunologia , Sequência de Aminoácidos , Animais , Resistência à Doença , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Interleucina-11/química , Interleucina-11/genética , Filogenia , Relação Estrutura-Atividade
6.
Front Endocrinol (Lausanne) ; 12: 802768, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34975771

RESUMO

Red pigment concentrating hormone (RPCH) and pigment dispersing hormone (PDH) are crustacean neuropeptides involved in broad physiological processes including body color changes, circadian rhythm, and ovarian growth. In this study, the full-length cDNA of RPCH and PDH were identified from the brain of the Chinese mitten crab Eriocheir sinensis. The deduced RPCH and PDH mature peptides shared identical sequence to the adipokinetic hormone/RPCH peptides family and the ß-PDH isoforms and were designated as Es-RPCH and Es-ß-PDH, respectively. Es-RPCH and Es-ß-PDH transcripts were distributed in the brain and eyestalks. The positive signals of Es-RPCH and Es-ß-PDH were localized in the neuronal clusters 6, 8, 9, 10, and 17 of the brain as revealed by in situ hybridization. The expression level of Es-RPCH and Es-ß-PDH mRNA in nervous tissues were all significantly increased at vitellogenic stage, and then decreased at the final meiotic maturation stage. The administrated with synthesized Es-RPCH peptide results in germinal vesicles shift toward the plasma membrane in vitellogenic oocyte, and significant decrease of the gonad-somatic index (GSI) and mean oocyte diameter as well as the expression of vitellogenin mRNA at 30 days post injection in vivo. Similar results were also found when injection of the Es-ß-PDH peptide. In vitro culture demonstrated that Es-RPCH and Es-ß-PDH induced germinal vesicle breakdown of the late vitellogenic oocytes. Comparative ovarian transcriptome analysis indicated that some reproduction/meiosis-related genes such as cdc2 kinase, cyclin B, 5-HT-R and retinoid-X receptor were significantly upregulated in response to Es-RPCH and Es-ß-PDH treatments. Taken together, these results provided the evidence for the inductive effect of Es-RPCH and Es-ß-PDH on the oocyte meiotic maturation in E. sinensis.


Assuntos
Braquiúros/fisiologia , Meiose/fisiologia , Oligopeptídeos/fisiologia , Oócitos/fisiologia , Peptídeos/fisiologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Química Encefálica , China , DNA Complementar/análise , Feminino , Expressão Gênica , Oligopeptídeos/genética , Oligopeptídeos/farmacologia , Oócitos/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Peptídeos/genética , Peptídeos/farmacologia , Ácido Pirrolidonocarboxílico/farmacologia , RNA Mensageiro/análise , Vitelogênese
7.
Front Microbiol ; 10: 2176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616396

RESUMO

The impact of gut microbiota and its metabolites on fat metabolism have been widely reported in human and animals. However, the critical mediators and the signal transductions are not well demonstrated. As ovipara, chicken represents a specific case in lipid metabolism that liver is the main site of lipid synthesis. The aim of this study is to elucidate the linkage of gut microbiota and fat synthesis in broiler chickens. The broilers were subjected to dietary treatments of combined probiotics (Animal bifidobacterium: 4 × 108 cfu/kg; Lactobacillus plantarum: 2 × 108 cfu/kg; Enterococcus faecalis: 2 × 108 cfu/kg; Clostridium butyrate: 2 × 108 cfu/kg, PB) and guar gum (1 g/kg, GG), respectively. Results showed that dietary supplementation of PB and GG changed the cecal microbiota diversity, altered short chain fatty acids (SCFAs) contents, and suppressed lipogenesis. In intestinal epithelial cells (IECs), SCFAs (acetate, propionate, and butyrate) up-regulated the expression of glucagon-like peptide-1 (GLP-1) via mitogen-activated protein kinase (MAPK) pathways, mainly via the phospho - extracellular regulated protein kinase (ERK) and phospho-p38 mitogen activated protein kinase (p38 MAPK) pathways. GLP-1 suppressed lipid accumulation in primary hepatocytes with the involvement of (AMP)-activated protein kinase/Acetyl CoA carboxylase (AMPK/ACC) signaling. In conclusion, the result suggests that SCFAs-induced GLP-1 secretion via MAPK pathway, which links the regulation of gut microbiota on hepatic lipogenesis in chickens.

8.
J Cell Physiol ; 234(12): 23202-23215, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31215650

RESUMO

Breast cancer (BC) is the most prevalent malignant cancer in the world, is the leading cause of cancer-related death female. Recently, there is accumulating evidence that long noncoding RNAs (lncRNAs) might as an important role in the progression of BC. (epithelial-mesenchymal transition (EMT) is considered to play a vital role in tumor cells migration and invasion. Nevertheless, the entire biological mechanisms and functions of lncRNAs in tumor migration, invasion, and EMT remain uncertain. In the present research, we observed that the expression of lncRNA AC073284.4 was downregulated in BC paclitaxel-resistant (PR) cells (MCF-7/PR) and tissues. Bioinformatics analysis predicted that miR-18b-5p was a direct target of AC073284.4, which has been validated by dual-luciferase reporter gene assay. We further proved that AC073284.4 could directly bind to miR-18b-5p and relieve the suppression for dedicator of cytokinesis protein 4 (DOCK4). Furthermore, the underlying functional experiments demonstrated that AC073284.4 might sponge miR-18b-5p to attenuate the invasion, metastasis, and EMT of BC cell through upregulating DOCK4 expression. In summary, AC073284.4 might serve as a competing endogenous RNA (ceRNA) in BC progression via modulating miR-18b-5p/DOCK4 axis, which weakens EMT and migration of BC. These results suggesting that AC073284.4 might function as a potential novel diagnostic biomarker in the progression of BC.


Assuntos
Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Invasividade Neoplásica/genética , Paclitaxel
9.
Food Chem ; 275: 688-695, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30724249

RESUMO

A novel solid phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) method was developed to quantify two new fungicide residuals (Y13149, Y12196) in mung bean sprouts. With a stable and biocompatible elcetrospinning nanofiber (polystyrene/graphene@silica, PS/G@SiO2) as coating, the SPME fiber was directly inserted into the stem of mung bean sprout to in-situ in-vivo sampling and extraction, followed by GC-MS analysis. Under the optimal conditions, satisfactory average recoveries of 99% and 72% were obtained for Y13149 and Y12196 with the relative standard deviations (RSDs) under 16.3%, indicating good precision and anti-matrix ability of the method. The result also exhibited low detection limit (0.06-0.08 µg·L-1) and wide liner range (0.3-100 µg·L-1) with the correlation coefficients (R2) of 0.9989. The established method was applied successfully to trace the accumulation and distribution of fungicides in mung bean sprouts, and it provides a simple, rapid and reliable quantitative method for food analysis.


Assuntos
Fungicidas Industriais/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Vigna/química , Análise de Alimentos , Fungicidas Industriais/isolamento & purificação , Grafite/química , Limite de Detecção , Nanofibras/química , Poliestirenos/química , Dióxido de Silício/química , Microextração em Fase Sólida , Vigna/metabolismo
10.
Oncotarget ; 8(23): 37448-37463, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28415580

RESUMO

NT21MP, a 21-residue peptide derived from the viral macrophage inflammatory protein II, competed effectively with the natural ligand of CXC chemokine receptor 4 (CXCR4), stromal cell-derived factor 1-alpha, to induce apoptosis and inhibit growth in breast cancer. Its role in tumor epithelial-to-mesenchymal transition (EMT) regulation remains unknown. In this study, we evaluated the reversal of EMT upon NT21MP treatment and examined its role in the inhibition of EMT in breast cancer. The parental cells of breast cancer (SKBR-3 and MCF-7) and paclitaxel-resistant (SKBR-3 PR and MCF-7 PR) cells were studied in vitro and in combined immunodeficient mice. The mice injected with SKBR-3 PR cells were treated with NT21MP through the tail vein or intraperitoneally with paclitaxel or saline. Sections from tumors were evaluated for tumor weight and EMT markers based on Western blot. In vitro, the effects of NT21MP, CXCR4 and PDGFRα on tumor EMT were assessed by relative quantitative real-time reverse transcription-polymerase chain reaction, western blot and biological activity in breast cancer cell lines expressing high or low levels of CXCR4. Our results illustrated that NT21MP could reverse the phenotype of EMT in paclitaxel-resistant cells. Furthermore, we found that NT21MP governed PR-mediated EMT partly due to controlling platelet-derived growth factors A and B (PDGFA and PDGFB) and their receptor (PDGFRα). More importantly, NT21MP down-regulated AKT and ERK1/2 activity, which were activated by PDGFRα, and eventually reversed the EMT. Together, these results indicated that CXCR4 overexpression drives acquired paclitaxel resistance, partly by activating the PDGFA and PDGFB/PDGFRα autocrine signaling loops that activate AKT and ERK1/2. Inhibition of the oncogenic EMT process by targeting CXCR4/PDGFRα-mediated pathways using NT21MP may provide a novel therapeutic approach towards breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quimiocina CXCL2/química , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Peptídeos/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos Nus , Peptídeos/química , Interferência de RNA , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Oncotarget ; 7(38): 61741-61754, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27557514

RESUMO

Long noncoding RNAs play a vital role in diverse biological processes such as embryonic development, cell growth, and tumorigenesis. In this study, we report that LncRNA ANRIL, which encodes a 3834-nt RNA that contains 19 exons at the antisense orientation of the INK4B-ARF-INK4A gene cluster, generally up-regulated in nasopharyngeal carcinoma [1]. In a cohort of 88 NPC patients, ANRIL was highly expressed in advanced-stage cancer. Multivariate analyses revealed that ANRIL expression could serve as an independent predictor of overall survival (P = 0.027) and disease-free survival (P = 0.033). Further investigation showed that knockdown of ANRIL significantly repressed NPC cell proliferation and transformation. We also found that ANRIL could induce the percentage of side population cells (SP cells) in NPC. To meet the urgent needs of energy provision, ANRIL can also reprogram glucose metabolism via increasing glucose uptake for glycolysis, which was regulated by the mTOR signal pathway to affect the expression of essential genes in glycolysis. We concluded that ANRIL could promote NPC progression via increasing cell proliferation, reprograming cell glucose metabolism and inducing side-population stem-like cancer cells. Our results also suggested that ANRIL may serve as a novel diagnostic or prognostic biomarker and a candidate target for new therapies in NPC.


Assuntos
Carcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Nasofaríngeas/metabolismo , RNA Longo não Codificante/genética , Células da Side Population/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Proliferação de Células , Transformação Celular Neoplásica , Progressão da Doença , Intervalo Livre de Doença , Éxons , Glucose/metabolismo , Glicólise , Humanos , Pessoa de Meia-Idade , Família Multigênica , Análise Multivariada , Carcinoma Nasofaríngeo , Células-Tronco Neoplásicas/citologia , Oligonucleotídeos Antissenso , Resultado do Tratamento , Regulação para Cima , Adulto Jovem
12.
Acta Pharmacol Sin ; 37(7): 984-93, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27238211

RESUMO

AIM: Fragment-based lead discovery (FBLD) is a complementary approach in drug research and development. In this study, we established an NMR-based FBLD platform that was used to screen novel scaffolds targeting human bromodomain of BRD4, and investigated the binding interactions between hit compounds and the target protein. METHODS: 1D NMR techniques were primarily used to generate the fragment library and to screen compounds. The inhibitory activity of hits on the first bromodomain of BRD4 [BRD4(I)] was examined using fluorescence anisotropy binding assay. 2D NMR and X-ray crystallography were applied to characterize the binding interactions between hit compounds and the target protein. RESULTS: An NMR-based fragment library containing 539 compounds was established, which were clustered into 56 groups (8-10 compounds in each group). Eight hits with new scaffolds were found to inhibit BRD4(I). Four out of the 8 hits (compounds 1, 2, 8 and 9) had IC50 values of 100-260 µmol/L, demonstrating their potential for further BRD4-targeted hit-to-lead optimization. Analysis of the binding interactions revealed that compounds 1 and 2 shared a common quinazolin core structure and bound to BRD4(I) in a non-acetylated lysine mimetic mode. CONCLUSION: An NMR-based platform for FBLD was established and used in discovery of BRD4-targeted compounds. Four potential hit-to-lead optimization candidates have been found, two of them bound to BRD4(I) in a non-acetylated lysine mimetic mode, being selective BRD4(I) inhibitors.


Assuntos
Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Ciclo Celular , Polarização de Fluorescência , Humanos , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
13.
J Mater Chem B ; 4(31): 5284-5288, 2016 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32263609

RESUMO

Hypoxia-inducible factor (HIF) highly expressed in most of the cancer cells. The Mn(ii)-aptamer based nanoclusters with 3D structures would be HIF-aptamer based targeted magnetic resonance imaging agents for cancer MRI diagnosis. Herein, a new class of contrast agent Mn(ii) silver-aptamer clusters (AdpaMn@DNA-Ag-DNAG1) were constructed based on the assembly of DNA-mediated Ag nanoclusters (DNA-AgNCs) with the Mn(ii) complex (AdpaMn) and DNAG1, the recognition sequence of GLUT-1. Then, the Mn(ii) silver-aptamer clusters (AdpaMn@DNA-Ag-DNAG1) are used as the MRI agents both in vitro and in vivo. The results show that the MRI signal is clearly presented in the tumor position. Consequently, the Mn(ii) silver-aptamer clusters can be used as a new class of contrast agents for targeted MR imaging of tumors.

14.
Sci Rep ; 5: 15388, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26472144

RESUMO

Supercapacitors fabricated by 3D porous carbon frameworks, such as graphene- and carbon nanotube (CNT)-based aerogels, have been highly attractive due to their various advantages. However, their high cost along with insufficient yield has inhibited their large-scale applications. Here we have demonstrated a facile and easily scalable approach for large-scale preparing novel 3D nitrogen-containing porous carbon frameworks using ultralow-cost commercial cotton. Electrochemical performance suggests that the optimal nitrogen-containing cotton-derived carbon frameworks with a high nitrogen content (12.1 mol%) along with low surface area 285 m(2) g(-1) present high specific capacities of the 308 and 200 F g(-1) in KOH electrolyte at current densities of 0.1 and 10 A g(-1), respectively, with very limited capacitance loss upon 10,000 cycles in both aqueous and gel electrolytes. Moreover, the electrode exhibits the highest capacitance up to 220 F g(-1) at 0.1 A g(-1) and excellent flexibility (with negligible capacitance loss under different bending angles) in the polyvinyl alcohol/KOH gel electrolyte. The observed excellent performance competes well with that found in the electrodes of similar 3D frameworks formed by graphene or CNTs. Therefore, the ultralow-cost and simply strategy here demonstrates great potential for scalable producing high-performance carbon-based supercapacitors in the industry.

15.
Acta Pharmacol Sin ; 34(9): 1243-50, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23770985

RESUMO

AIM: To study the conformational changes of Aß42 and discover novel inhibitors of both Aß42 aggregation and ß-secretase (BACE1). METHODS: A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of Aß42 monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both Aß42 aggregation and BACE1. Protein purification and in vitro activity assays were performed to validate the inhibition of the compounds identified via virtual screening. RESULTS: The initial α-helical conformation of Aß42, which was unstable in aqueous solution, turned into a ß-sheet mixed with a coil structure through a transient and fully random coil. The conformation of Aß42 mainly comprising ß-sheets and coils structure was used for further virtual screening. Five compounds were identified as inhibitors for Aß42 aggregation, and one of them, AE-848, was discovered to be a dual inhibitor of both Aß42 aggregation and BACE1, with IC50 values of 36.95 µmol/L and 22.70 µmol/L, respectively. CONCLUSION: A helical to ß-sheet conformational change in Aß42 occurred in a 1.8 microsecond MD simulation. The resulting ß-sheet structure of the peptide is an appropriate conformation for the virtual screening of inhibitors against Aß42 aggregation. Five compounds were identified as inhibitors of Aß42 aggregation by in vitro activity assays. It was particularly interesting to discover a dual inhibitor that targets both Aß42 aggregation and BACE1, the two crucial players in the pathogenesis of Alzheimer's disease.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Fragmentos de Peptídeos/metabolismo , Fatores de Tempo
16.
Hepatogastroenterology ; 60(123): 528-32, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23108087

RESUMO

BACKGROUND/AIMS: To describe survival rates and prognostic factors for colorectal cancer (CRC) operated in a district general hospital setting with a special focus on the number of lymph nodes examined. METHODOLOGY: Between December 2004 and December 2006, a total of 277 CRC patients who underwent surgical treatment in QHSU were included. All patients were followed up intensively from discharge until death or the end of the follow-up (December 31, 2010). RESULTS: The median follow-up period was 53 months (range, 1-72 months). Overall 3-year survival was 72.9%. In only 11.5% of the specimens were 12 or more lymph nodes retrieved, but this did not affect survival. A multivariate analysis identified that the significant prognostic factors were TNM stage III [adjusted hazard ratio (HR): 5.49; 95%CI: 1.64-18.41], TNM stage IV (adjusted HR: 7.55; 95%CI: 2.12-26.84), tumor histology (adjusted HR: 1.88; 95%CI: 1.16-3.04), hospital stay (adjusted HR: 1.03; 95%CI: 1.00-1.06) and lymph node ratio (LNR) (adjusted HR: 3.92; 95%CI: 1.79-8.55) for stage III. CONCLUSIONS: TNM stage, tumor histology and the length of hospital stay could prominently affect outcome overall. The lymph node count did not have a significant impact on survival, whereas the LNR proved significant for stage III. Nevertheless, a protocol using overall lymph node yield as a surrogate measure for more radical surgery seems warranted to improve the lymph node resected.


Assuntos
Colectomia , Neoplasias do Colo/cirurgia , Diferenciação Celular , China , Colectomia/efeitos adversos , Colectomia/mortalidade , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Feminino , Hospitais de Distrito , Hospitais Gerais , Humanos , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 29(6): 709-14, 2012 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-23225056

RESUMO

OBJECTIVE: To assess the association between single nucleotide polymorphisms (SNPs) of mannose-binding lectin 2 gene (MBL2) (rs1800450, rs1800451 and rs11003125) and protein kinase C-beta 1 gene (PRKC beta 1) (rs3700106, rs2575390) with diabetic macroangiopathy in northern Chinese Han population. METHODS: The samples have included 318 type 2 diabetes mellitus (T2DM) patients and 448 normoglycemic controls. The five SNPs were determined by a Multiplex SnaPshot method. Biochemical indices such as fasting plasma-glucose, triglyceride and total cholesterol were also measured. Linkage disequilibrium and haplotype analysis were carried out for all samples using Haploview 4.2. Additive model was applied to assess the effect of interaction between SNPs and environment factors on macrovascular complications. RESULTS: Genotypic frequencies of rs11003125 have differed significantly between the controls and patients with coronary heart disease and peripheral vascular disease (P=0.024 and 0.004, respectively). The allele frequency of rs11003125 was also statistically significant between the two groups (P=0.014 and 0.001, respectively). Compared with patients without macrovascular complications, the allele frequency of rs11003125 was significantly different in patients with peripheral vascular disease (P=0.031). No significant differences were found between the distribution of the genotype frequency and allele frequencies of other variants. Haplotype analysis indicated that, compared with controls and patients without macrovascular complications, individuals with G allele of rs1800450 and C allele of rs11003125 had a higher risk for macrovascular complications. CONCLUSION: The rs11003125 polymorphism located in the promoter region of MBL2 gene is associated with macrovascular complications of T2DM in northern Chinese Han population. G allele of rs1800450 and C allele of rs11003125 may be risk factors for macrovascular complications. There were additive interactive effects for rs11003125 polymorphism (GC+CC) and hypertension, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy on macrovascular complications.


Assuntos
Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/genética , Predisposição Genética para Doença , Lectina de Ligação a Manose/genética , Polimorfismo de Nucleotídeo Único , Proteína Quinase C/genética , Alelos , China/etnologia , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/etnologia , Frequência do Gene , Genótipo , Humanos , Regiões Promotoras Genéticas , Proteína Quinase C beta
18.
J Acupunct Meridian Stud ; 2(1): 71-4, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20633477

RESUMO

The aim of the present study was to investigate the effects of Fu Zi on changes in the body heat of dogs. Twelve clinically healthy dogs were divided into two groups: the control group (six dogs) and the experimental group (six dogs). The control group was made to ingest normal saline mixed with canned meat, while the experimental group was made to ingest the Fu Zi solution mixed with canned meat. The infrared thermographic system was used to determine the level of body heat generated by these dogs. These areas include the dorsocranial (DCr), dorsocaudal (DCd), ventrocranial (VCr), and ventrocaudal (VCd) regions at pretreatment and were determined at 10, 20, 30, 50, 90, 120, 240, and 360 minutes after treatment for each of these areas. The results showed a tendency toward increased body heat until 30 minutes after ingestion of the Fu Zi powder mixed with canned meat. The significant differences in the changes of body heat were detected at 360 minutes in the DCd regions, 20 minutes in the VCr regions, and 30 minutes in the VCd regions between the experimental and control groups (p < 0.05). Based from our results, we find that Fu Zi can increase and maintain the dogs' body heat for at least 6 hours.


Assuntos
Aconitum/química , Temperatura Corporal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Animais , Cães , Feminino , Temperatura Alta , Masculino
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