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1.
Mar Drugs ; 18(2)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32054048

RESUMO

Latrunculia sponges represent a rich source of discorhabdin-type pyrroloiminoquinone alkaloids, a few of which comprise a dimeric structure. The anticancer-activity-guided isolation of the n-hexane subextract of the Antarctic deep-sea sponge Latrunculia biformis yielded the known compound (-)-(1R,2R,6R,8S,6'S)-discorhabdin B dimer (1) and two new derivatives, (-)-(1S,2R,6R,8S,6'S)-discorhabdin B dimer (2) and (-)-(1R,2R,6R,8S,6'S)-16',17'-dehydrodiscorhabdin B dimer (3). The chemical structures of compounds 1-3 were elucidated by means of HR-ESIMS, NMR, [], ECD spectroscopy, and a comparison with the previously reported discorhabdin analogs. Compounds 1 and 2 showed significant in vitro anticancer activity against the human colon cancer cell line (HCT-116), with IC50 values of 0.16 and 2.01 µM, respectively. Compared to monomeric discorhabdins, dimeric discorhabdins are very rare in Nature. This study adds two new discorhabdin dimers (2 and 3) to this small pyrroloiminoquinone subfamily. This is also the first report of compound 1 as a natural product and the first assessment of its in vitro anticancer activity.

2.
Plant Dis ; : PDIS08191628RE, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31951509

RESUMO

Chili anthracnose caused by Colletotrichum spp. is an annual production concern for growers in China. Sterol C14-demethylation inhibitors (DMIs, such as tebuconazole) have been widely used to control this disease for more than three decades. In the current study, of 48 isolates collected from commercial chili farms in Jiangsu Province of China during 2018 and 2019, 8 single-spore isolates were identified as Colletotrichum gloeosporioides and the rest were identified as C. acutatum. To determine whether the DMI resistance of isolates develops in the field, mycelial growth of the 48 isolates was measured in culture medium with and without tebuconazole. In all, 6 of the 8 C. gloeosporioides isolates were resistant to tebuconazole, but all 40 of the C. acutatum isolates were sensitive to tebuconazole. The fitness cost of resistance was low based on a comparison of fitness parameters between the sensitive and resistant isolates of C. gloeosporioides. Positive cross-resistance was observed between tebuconazole and difenconazole or propiconazole, but not prochloraz. Alignment results of the CgCYP51 amino acid sequences from the sensitive and resistant isolates indicated that mutations can be divided into three genotypes. Genotype I possessed four substitutions (V18F, L58V, S175P, and P341A) at the CgCYP51A gene but no substitutions at CgCYP51B, while genotype II had five substitutions (L58V, S175P, A340S, T379A, and N476T) at CgCYP51A, concomitant with three substitutions (D121N, T132A, and F391Y) at CgCYP51B. In addition, genotype III contained two substitutions (L58V and S175P) at CgCYP51A, concomitant with one substitution (T262A) at CgCYP51B. Molecular docking models illustrated that the affinity of tebuconazole to the binding site of the CgCYP51 protein from the resistant isolates was decreased when compared with binding site affinity of the sensitive isolates. Our findings provide not only novel insights into understanding the resistance mechanism to DMIs, but also some important references for resistance management of C. gloeosporioides on chili.

3.
Mar Drugs ; 18(1)2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940767

RESUMO

Marine algae represent a prolific source of filamentous fungi for bioprospecting. In continuation of our search for new anticancer leads from fungi derived from the brown alga Fucus vesiculosus, an endophytic Pyrenochaetopsis sp. FVE-001 was selected for an in-depth chemical analysis. The crude fungal extract inhibited several cancer cell lines in vitro, and the highest anticancer activity was tracked to its CHCl3-soluble portion. A bioactivity-based molecular networking approach was applied to C18-SPE fractions of the CHCl3 subextract to predict the bioactivity scores of metabolites in the fractions and to aid targeted purification of anticancer metabolites. This approach led to a rapid isolation of three new decalinoylspirotetramic acid derivatives, pyrenosetins A-C (1-3) and the known decalin tetramic acid phomasetin (4). The structures of the compounds were elucidated by extensive NMR, HR-ESIMS, FT-IR spectroscopy, [α]D and Mosher's ester method. Compounds 1 and 2 showed high anticancer activity against malignant melanoma cell line A-375 (IC50 values 2.8 and 6.3 µM, respectively), in line with the bioactivity predictions. This is the first study focusing on secondary metabolites of a marine-derived Pyrenochaetopsis sp. and the second investigation performed on the member of the genus Pyrenochaetopsis.

4.
Proc Natl Acad Sci U S A ; 116(41): 20511-20516, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31548420

RESUMO

Resistance to ionizing radiation (IR), which is a conventional treatment for osteosarcoma that cannot be resected, undermines the efficacy of this therapy. However, the mechanism by which IR induces radioresistance in osteosarcoma is not defined. Here, we report that CR6-interacting factor-1 (CRIF1) is highly expressed in osteosarcoma and undergoes nuclear-cytoplasmic shuttling of cyclin-dependent kinase 2 (CDK2) after IR. Osteosarcoma cells lacking CRIF1 show increased sensitivity to IR, which is associated with delayed DNA damage repair, inactivated G1/S checkpoint, and mitochondrial dysfunction. CRIF1 interacts with the DNA damage checkpoint regulator CDK2, and CRIF1 and CDK2 colocalize in the nucleus after IR. Nuclear localization of CDK2 is associated with phosphorylation changes that promote DNA repair and activation of the G1/S checkpoint. CRIF1 knockdown synergized with IR in an in vivo osteosarcoma model, leading to tumor regression. Based on these findings, we identify CRIF1 as a potential therapeutic target in osteosarcoma that can increase the efficacy of radiotherapy. More broadly, our findings may provide insights into the mechanism for other types of radioresistant cancers and be exploited for therapeutic ends.

5.
Mar Drugs ; 17(8)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349703

RESUMO

The sponge genus Latrunculia is a prolific source of discorhabdin type pyrroloiminoquinone alkaloids. In the continuation of our research interest into this genus, we studied the Antarctic deep-sea sponge Latrunculia biformis that showed potent in vitro anticancer activity. A targeted isolation process guided by bioactivity and molecular networking-based metabolomics yielded three known discorhabdins, (-)-discorhabdin L (1), (+)-discorhabdin A (2), (+)-discorhabdin Q (3), and three new discorhabdin analogs (-)-2-bromo-discorhabdin D (4), (-)-1-acetyl-discorhabdin L (5), and (+)-1-octacosatrienoyl-discorhabdin L (6) from the MeOH-soluble portion of the organic extract. The chemical structures of 1-6 were elucidated by extensive NMR, HR-ESIMS, FT-IR, [α]D, and ECD (Electronic Circular Dichroism) spectroscopy analyses. Compounds 1, 5, and 6 showed promising anticancer activity with IC50 values of 0.94, 2.71, and 34.0 µM, respectively. Compounds 1-6 and the enantiomer of 1 ((+)-discorhabdin L, 1e) were docked to the active sites of two anticancer targets, topoisomerase I-II and indoleamine 2,3-dioxygenase (IDO1), to reveal, for the first time, the binding potential of discorhabdins to these proteins. Compounds 5 and 6 are the first discorhabdin analogs with an ester function at C-1 and 6 is the first discorhabdin bearing a long-chain fatty acid at this position. This study confirms Latrunculia sponges to be excellent sources of chemically diverse discorhabdin alkaloids.


Assuntos
Alcaloides/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Poríferos/química , Quinonas/química , Compostos de Espiro/química , Tiazepinas/química , Células A549 , Animais , Regiões Antárticas , Antineoplásicos/química , Linhagem Celular Tumoral , Células HCT116 , Células HT29 , Células Hep G2 , Humanos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Estereoisomerismo
6.
Theranostics ; 9(8): 2198-2208, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31149038

RESUMO

Irradiation can greatly inhibit osteogenesis of bone marrow mesenchymal stem cells (BM-MSCs). However, the mechanism remains unclear. Methods: We analyzed the expression profile of long noncoding RNAs (lncRNAs) in BM-MSCs using microarray data. LncRNA TUG1 (Taurine Upregulated Gene 1) was selected and tested in radiated BM-MSCs and non-radiated BM-MSCs. Functional analyses (in vitro) were performed to confirm the role of TUG1 in the osteogenic inhibition induced by irradiation. A RIP (RNA immunoprecipitation) assay was performed to detect the interaction of TUG1 and Smad5. Smad5 and the phosphorylated Smad5 (p-Smad5) were tested by western blot. The nuclear translocation of p-Smad5 were tested by immunofluorescence analysis. Furthermore, a series of Smad5 deletions was constructed to identify the TUG1 binding site of Smad5. Results: We found that numerous lncRNAs, including TUG1, exhibit significant expression differences after irradiation. After irradiation TUG1 was significantly increased in BM-MSCs and inhibited osteogenesis. Furthermore, TUG1 directly bound to Smad5, an osteogenic enhancer. Although the phosphorylation level of Smad5 was increased following irradiation, osteogenesis of BM-MSCs was decreased. Mechanistically, TUG1 interacting with the 50-90 aa region of Smad5 and blocks the nuclear translocation of p-Smad5, abolishing osteogenic signalling after irradiation. Conclusion: These results indicate that TUG1 is a negative regulator of Smad5 signalling and suppresses osteogenesis of BM-MSCs after irradiation.

7.
BMB Rep ; 52(3): 226, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30909989

RESUMO

The BMB Reports would like to correct in the Supplementary Figure 1 of BMB Rep. 51(9): 456-461 titled "MiR-363 inhibits cisplatin chemoresistance of epithelial ovarian cancer by regulating snail-induced epithelial-mesenchymal transition."

8.
Stem Cell Res Ther ; 10(1): 82, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850008

RESUMO

BACKGROUND: Bone marrow stromal cells (BMSCs) are extensively used in regeneration therapy and cytology experiments simulate how BMSCs respond to radiation. Due to the small number and the heterogeneity of primary isolated BMSCs, extensive in vitro expansion is usually required before application, which affects the cellular characteristics and gene expression of BMSCs. However, whether the radiation response of BMSCs changes during in vitro expansion is unclear. METHODS: In this study, BMSCs were passaged in vitro and irradiated at passage 6 (P6) and passage 10 (P10). Then, apoptosis, the cell cycle, senescence, the cytokine secretion and the gene expression profile were analysed for the P6, P10, and non-irradiated (control) BMSCs at different post-irradiation time points. RESULTS: The P6 BMSCs had a lower percentage of apoptotic cells than the P10 BMSCs at 24 and 48 h post-irradiation but not compared to that of the controls at 2 and 8 h post-irradiation. The P6 BMSCs had a lower percentage of cells in S phase and a higher percentage in G1 phase than the P10 BMSCs at 2 and 8 h post-irradiation. The radiation had similar effects on the senescent cell level and impaired immunomodulation capacity of the P6 and P10 BMSCs. Regardless of whether they were irradiated, the P6 and P10 BMSCs always expressed a distinctive set of genes. The upregulated genes were enriched in pathways including the cell cycle, DNA replication and oocyte meiosis. Then, a subset of conserved irradiation response genes across the BMSCs was identified, comprising 12 differentially upregulated genes and 5 differentially downregulated genes. These genes were especially associated with the p53 signaling pathway, DNA damage and DNA repair. Furthermore, validation experiments revealed that the mRNA and protein levels of these conserved genes were different between the P6 and P10 BMSCs after irradiation. Weighted gene co-expression network analysis supported these findings and further revealed the effects of cell passage on the irradiation response in BMSCs. CONCLUSION: The results indicated that cell passage in vitro affected the irradiation response of BMSCs via molecular mechanisms that mediated differences in apoptosis, the cell cycle, senescence and the cytokine secretion. Thus, accurate cell passage information is not only important for transplantation therapy but also for future studies on the radiation response in BMSCs.

9.
Curr Genet ; 65(1): 293-300, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30167777

RESUMO

Autophagy serves as a survival mechanism against starvation and has been reported to be important for cell growth and differentiation in eukaryotes. Here, we investigated the function of a cysteine protease BcAtg4 in the gray mold fungus Botrytis cinerea. Yeast complementation experiments revealed that Bcatg4 can functionally replace the counterpart of yeast. Subcellular localization exhibited that BcAtg4 diffused in cytoplasm at different developmental stages. Targeted gene deletion of Bcatg4 (ΔBcatg4) led to autophagy blocking and a significant retardation in growth and conidiation. In addition, ΔBcatg4 failed to form sclerotia. Infection tests demonstrated that ΔBcatg4 was severely attenuated in virulence on different host plant tissues. All of the phenotypic defects were restored by reintroducing an intact copy of Bcatg4 into ΔBcatg4. These results indicate that Bcatg4 plays multiple roles in the developmental processes and pathogenesis of B. cinerea.


Assuntos
Botrytis/genética , Cisteína Proteases/genética , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Sequência de Aminoácidos , Autofagia/genética , Botrytis/metabolismo , Botrytis/patogenicidade , Cucumis sativus/microbiologia , Cisteína Proteases/classificação , Cisteína Proteases/metabolismo , Proteínas Fúngicas/classificação , Proteínas Fúngicas/metabolismo , Interações Hospedeiro-Patógeno , Mutação , Filogenia , Folhas de Planta/microbiologia , Homologia de Sequência de Aminoácidos , Esporos Fúngicos/genética , Esporos Fúngicos/metabolismo , Virulência/genética
10.
J Nippon Med Sch ; 85(6): 302-308, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30568055

RESUMO

BACKGROUND: Antibiotic resistance of pathogenic bacteria is well recognized among clinicians; however, studies that directly evaluate the bacterial resistance to commonly used disinfectants in clinical settings are lacking. Currently available reports focus on the resistance of single strains to single disinfectants and do not adequately examine the degree of resistance and cross-resistance to antimicrobials in the large-scale clinical use of disinfectants. METHODS: We investigated the resistance capacity to 11 antibiotics and 7 chemical disinfectants by bacterial strains collected from body fluids of patients in 10 hospitals in Beijing, China over a 1-year period. Bacterial resistance to disinfectants was tested using minimum inhibitory concentration and minimum bactericidal concentration using agar dilution methods based on commercially available reference strains. RESULTS: A total of 1,104 pathogenic strains were identified, of which 23% were Gram-positive bacteria, 74% were Gram-negative bacteria, and 3% were fungi. Overall, resistance to antibiotics for the most common strains was significantly higher than their resistance to disinfectants. The least effective antibiotics and disinfectants were aztreonam and glutaral, respectively, exhibiting the highest overall resistance rates; while amikacin and alcohol had the lowest resistance rates. Consistently, Acinetobacter baumannii exhibited the most resistance, while Escherichia coli had the least resistance for both antibiotics and disinfectants. CONCLUSIONS: Based on the pathogen spectrum for bacterial infective pathogens evaluated in this study, as well as the status quo of their resistance to antimicrobial agents and common clinical disinfectants, it is essential for healthcare professionals to pay attention not only to the standardized use of antimicrobial agents but also to the rational application of disinfectants.


Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/prevenção & controle , Desinfetantes/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Anti-Infecciosos/classificação , Bactérias/classificação , Bactérias/patogenicidade , Infecções Bacterianas/microbiologia , Pequim , Líquidos Corporais/microbiologia , Desinfetantes/classificação , Humanos , Testes de Sensibilidade Microbiana , Virulência
11.
Cell Physiol Biochem ; 51(6): 2564-2574, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30562733

RESUMO

BACKGROUNDS/AIMS: Ovarian cancer is the most lethal gynaecologic malignancy and is difficult to detect early. The inefficient early diagnosis of ovarian cancer is the main contributor to its high mortality rate. Aptamers, as chemical antibodies, are single-stranded DNA or RNA oligonucleotides that target cells or molecules with high affinity. METHODS: Binding ability of R13 was measured by flow cytometry analysis. Stability of R13 was tested in blood serum of an ovarian cancer patient. Internalization of R13 was verified by confocal microscope imaging. 80 cases ovarian cancer tissues, 10 cases normal ovary tissues in a microarray and 6 fallopian tube tissues were prepared for this study. R13's target ability was further confirmed in vivo tumor models in NOD/SCID mice. RESULTS: In this study, we found aptamer R13 bound to ovarian cancer cells with dissociation constants in the nanomolar range. Moreover, these results were further confirmed by tissue imaging. Next we demonstrated that the targets of R13 are membrane proteins and that its internalization occurs in a caveolae-mediated and clathrin-mediated manner. The target function of R13 was determined by imaging A2780 tumours in mouse models. CONCLUSION: These findings suggest that R13 is a promising novel tool to diagnose and deliver drugs to treat ovarian cancer.


Assuntos
Aptâmeros de Nucleotídeos/química , Imagem Óptica/métodos , Neoplasias Ovarianas/diagnóstico por imagem , Animais , Sequência de Bases , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Imagem Corporal Total/métodos
12.
Mar Drugs ; 16(8)2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072656

RESUMO

The Antarctic deep-sea sponge Latrunculia (Latrunculia) biformis Kirkpatrick, 1908 (Class Demospongiae Sollas, Order Poecilosclerida Topsent, Latrunculiidae Topsent) was selected for chemical analyses due to its potent anticancer activity. Metabolomic analysis of its crude extract by HRMS/MS-based molecular networking showed the presence of several clusters of pyrroloiminoquinone alkaloids, i.e., discorhabdin and epinardin-type brominated pyridopyrroloquinolines and tsitsikammamines, the non-brominated bis-pyrroloiminoquinones. Molecular networking approach combined with a bioactivity-guided isolation led to the targeted isolation of the known pyrroloiminoquinone tsitsikammamine A (1) and its new analog 16,17-dehydrotsitsikammamine A (2). The chemical structures of the compounds 1 and 2 were elucidated by spectroscopic analysis (one-dimensional (1D) and two-dimensional (2D) NMR, HR-ESIMS). Due to minute amounts, molecular modeling and docking was used to assess potential affinities to potential targets of the isolated compounds, including DNA intercalation, topoisomerase I-II, and indoleamine 2,3-dioxygenase enzymes. Tsitsikammamines represent a small class of pyrroloiminoquinone alkaloids that have only previously been reported from the South African sponge genus Tsitsikamma Samaai & Kelly and an Australian species of the sponge genus Zyzzya de Laubenfels. This is the first report of tsitsikammamines from the genus Latrunculia du Bocage and the successful application of molecular networking in the identification of comprehensive chemical inventory of L.biformis followed by targeted isolation of new molecules. This study highlights the high productivity of secondary metabolites of Latrunculia sponges and may shed new light on their biosynthetic origin and chemotaxonomy.


Assuntos
Antineoplásicos/farmacologia , Poríferos/química , Pirróis/química , Pirróis/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I , Doxorrubicina/farmacologia , Humanos , Queratinócitos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica
13.
BMB Rep ; 51(9): 456-461, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30037365

RESUMO

Chemoresistance is a major barrier to successful cisplatinbased chemotherapy for epithelial ovarian cancer (EOC), and emerging evidences suggest that microRNAs (miRNAs) are involved in the resistance. In this study, it was indicated that miR-363 downregulation was significantly correlated with EOC carcinogenesis and cisplatin resistance. Moreover, miR-363 overexpression could resensitise cisplatin-resistant EOC cells to cisplatin treatment both in vitro and in vivo. In addition, data revealed that EMT inducer Snail was significantly upregulated in cisplatin-resistant EOC cell lines and EOC patients and was a functional target of miR-363 in EOC cells. Furthermore, snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells. Taken together, findings suggest that miR-363 may be a biomarker for predicting responsiveness to cisplatin-based chemotherapy and a potential therapeutic target in EOC. [BMB Reports 2018; 51(9): 456-461].


Assuntos
Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MicroRNAs/farmacologia , Fatores de Transcrição da Família Snail/metabolismo , Animais , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Células Tumorais Cultivadas
14.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 30(6): 558-563, 2018 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-30009731

RESUMO

OBJECTIVE: To investigate the accuracy of sequential organ failure assessment (SOFA) scoring in emergency physicians in Beijing. METHODS: Emergency physicians from 8 hospitals in Beijing in January 2018 were demanded to complete a SOFA questionnaire which was developed on "wenjuanxing" website and submit via cell phone. All participants were divided into urban center group (UC group) and no-urban center group (NUC group) based on the hospital's location. The accuracy rate of components and total score of SOFA along with the mistakes were evaluated, and the results of the two groups were compared. RESULTS: (1) The questionnaire was sent to 217 emergency physicians of the 8 hospitals, and 197 qualified questionnaires were received with 109 of NUC group and 88 of UC group, respectively, the total response rate was 90.8%. Compared with those from NUC group, UC physicians had older ages [years: 37 (32, 42) vs. 34 (29, 40), Z = -2.554, P = 0.011] and higher education level [postgraduate degree 76.1% (67/88) vs. 40.4% (44/109), χ2 = 25.327, P < 0.001], and more of them experienced SOFA scoring [62.5% (55/88) vs. 45.9% (50/109), χ2 = 5.409, P = 0.020]. Other baseline characteristics such as gender, working years, professional title and training experience were not different between the two groups. (2) The accuracy rate of total SOFA score was 62.4% (123/197) in the whole cohort, and UC group was lower than that of NUC group, but the difference was not significant [56.8% (50/88) vs. 67.0% (73/109), χ2 = 2.141, P = 0.143]. While comparing the accuracy of individual variable/system of SOFA, the accuracy rate of norepinephrine of UC group was much higher than NUC group [80.7% (71/88) vs. 66.1% (72/109), χ2 = 5.235, P = 0.022], but the accuracy of Glasgow coma scale (GCS) was much lower in NUC group [38.6% (27/70) vs. 81.6% (71/87), χ2 = 30.629, P < 0.001]. Other variables of SOFA were not different between the two groups. Based upon the results of all submitted questionnaires, 566 mistakes were identified. It was indicated that the mistakes per capital was 2.9 in the whole cohort and in the two groups. The first type mistakes which caused by carelessness (including calculating error, filling error, choosing error) were 233 times. The calculating error in norepinephrine from NUC physicians was higher than the UC group [33.9% (37/109) vs. 19.3% (17/88), χ2 = 5.235, P = 0.022], there was no significant difference in any other first type mistakes between the two groups. The total second type mistakes caused by misunderstanding of SOFA (including using wrong variables, not using the worst value within 24 hours, and incorrect GCS score) were 333 times in the whole cohort. GCS error [61.8% (42/88) vs. 16.9% (14/109), χ2 = 32.292, P < 0.001], and using urine output per hour instead of urine output per 24 hours [15.9% (14/88) vs. 4.6% (5/109), χ2 = 7.162, P = 0.007] were much higher in UC group than NUC group. CONCLUSIONS: The total accuracy of SOFA scoring in the investigated emergency physicians of 8 hospitals in Beijing was not good. Mistakes causing by carelessness or misunderstanding of score rules were similar. It is necessary to apply strict training in SOFA scoring.


Assuntos
Serviço Hospitalar de Emergência , Escala de Coma de Glasgow , Humanos , Unidades de Terapia Intensiva , Escores de Disfunção Orgânica , Médicos , Prognóstico
15.
Am J Transl Res ; 10(6): 1583-1599, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018702

RESUMO

Nuclear receptor-related factor 1 (Nurr1) has a crucial role in the development and maturation of mesencephalic dopamine (DA) neurons and also plays a protective role in maintenance of DA neurons by inhibiting the activation of microglia and astrocyte. Moreover, the mutations in Nurr1 gene are associated with familial Parkinson's disease (PD), suggested that Nurr1 modulation is a potential therapeutic target for PD. This study examines the therapeutic effects of transplantation of Nurr1 gene-modified bone marrow mesenchymal stem cells (MSCs) on 6-hydroxydopamine (6-OHDA)-induced PD rat models. MSCs were transduced with lentivirus expressing Nurr1 gene and then intrastriatally transplanted into PD rats. Our results showed that Nurr1 gene-modified MSCs overexpress and secrete Nurr1 protein in vitro and also survive and migrate in the brain. Four weeks after transplantation Nurr1 gene-modified MSCs dramatically ameliorated the abnormal behavior of PD rats and increased the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) and TH-positive fibers in the striatum, inhibited the activation of glial cells, and reduced the expression of inflammatory factors in the SN. Taken together, these findings suggest that intrastriatal transplantation of lentiviral vector mediated Nurr1 gene-modified MSCs has notable therapeutic effect for PD rats.

16.
Angew Chem Int Ed Engl ; 57(29): 8994-8997, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-29923269

RESUMO

Automated attachment of chemotherapeutic drugs to oligonucleotides through phosphoramidite chemistry and DNA synthesis has emerged as a powerful technology in constructing structure-defined and payload-tunable oligonucleotide-drug conjugates. In practice, however, in vivo delivery of these oligonucleotides remains a challenge. Inspired by the systemic transport of hydrophobic payloads by serum albumin in nature, we report the development of a lipid-conjugated floxuridine homomeric oligonucleotide (LFU20) that "hitchhikes" with endogenous serum albumin for cancer chemotherapy. Upon intravenous injection, LFU20 immediately inserts into the hydrophobic cave of albumin to form an LFU20/albumin complex, which accumulates in the tumor by the enhanced permeability and retention (EPR) effect and internalizes into the lysosomes of cancer cells. After degradation, cytotoxic floxuridine monophosphate is released to inhibit cell proliferation.


Assuntos
Antimetabólitos Antineoplásicos/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Sistemas de Liberação de Medicamentos , Floxuridina/análogos & derivados , Floxuridina/farmacocinética , Albumina Sérica/metabolismo , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Floxuridina/metabolismo , Floxuridina/uso terapêutico , Interações Hidrofóbicas e Hidrofílicas , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Oligonucleotídeos/metabolismo , Oligonucleotídeos/farmacocinética , Oligonucleotídeos/uso terapêutico , Ligação Proteica
17.
Int J Cancer ; 142(9): 1786-1796, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29226320

RESUMO

In the last decade, mitochondrial DNA (mtDNA) haplogroups have been associated with the occurrence of breast cancer. However, the underlying mechanism is not known. Combining a case-control study with a large cohort of women from Southern China with breast cancer and functional analyses with trans-mitochondrial technology, we demonstrate that the D5 haplogroup is associated with an increased risk of breast cancer [odds ratio (OR) = 2.789; 95% confidence interval (CI) [1.318, 5.901]; p = 0.007]. Furthermore, mitochondrial respiration, mitochondrial ATP content and membrane potential, were lower in both bone osteosarcoma and breast cancer cell models of cytoplasmic hybrids (cybrids) containing the mtDNA D5 haplogroup than in those with non-D5 haplogroups. Using in vitro and in vivo tumorigenicity assays, we found that cells with the D5 haplogroup were more susceptible to tumorigenesis compared to cells with non-D5 haplogroups. Mechanistically, the D5 haplogroup may promote tumorigenesis at least partially through activation of the v-AKT murine thymoma viral oncogene (AKT) via phosphorylation of threonine 308, which is mediated by increased reactive oxygen species generation in D5 cybrids. Our findings demonstrate that there is decreased mitochondrial function in cells with the D5 haplogroup compared to cells with non-D5 haplogroups, which may be associated with increased neoplastic growth in breast cancer.


Assuntos
Neoplasias da Mama/genética , DNA Mitocondrial/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Estudos de Coortes , DNA Mitocondrial/metabolismo , Ativação Enzimática , Feminino , Predisposição Genética para Doença , Haplótipos , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Adulto Jovem
18.
Zhongguo Zhong Yao Za Zhi ; 42(6): 1011-1014, 2017 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-29027409

RESUMO

Safety issues of traditional Chinese medicine injections has been heated debate. There are two diametrically opposed views: it should be used reasonable and developed healthily or be forbidden to use. Some people have many misunderstandings and prejudices about the safety of traditional Chinese medicine injections. Compared with western medicine,traditional Chinese medicine has its own particularity. Traditional Chinese medicine has complex components. Its research and clinical application is different from western medicine. Adverse reactions of traditional Chinese medicine injections are related to many factors,such as a large number of irrational use,blind use of traditional Chinese medicine injections and western medicine injections,counterfeit and substandard drugs,incorrect methods of intravenous infusion,toxicity of supplementary materials,drug ingredients. Developing traditional Chinese medicine injection is the need for curing sickness to save patients. The purposeful, targeted, organized and planned systematic research of traditional Chinese medicine injections should be strengthened,especially the safety of traditional Chinese medicine. Strengthen supervision and control of rational drug use.Strengthen the examination and approval,supervision and management of all aspects to ensure the safety of patients.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/normas , Medicina Tradicional Chinesa , Humanos , Injeções , Projetos de Pesquisa
19.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 42(8): 882-888, 2017 Aug 28.
Artigo em Chinês | MEDLINE | ID: mdl-28872078

RESUMO

OBJECTIVE: To study the relationship between alpha seine/threonine-protein kinase (p-Akt)-serine/threonine-protein kinase (mTOR)-ribosomal protein S6 kinase (p70S6K) signaling pathway and clinicopathological features or chemoresistance of ovarian cancer.
 Methods: We checked the p-Akt, mTOR and p70S6K protein levels in 18 tissues with chemoresistance or 25 with chemosensitivity of ovarian cancer by immunohistochemistry technique, and analyzed the relationship between those proteins and clinicopathological features or chemoresistance of ovarian cancer.
 Results: The levels of p-Akt protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 77.14%, 50.00% and 66.67%, respectively, with no significant difference (P>0.05). The levels of these proteins in well-middle differentiated carcinoma and low differentiated carcinoma were 73.33% and 75.00%, respectively, with no significant difference (P>0.05). The levels of these proteins in I-II stage carcinoma, and III-IV stage carcinoma were 18.18% and 93.75%, respectively, with significant difference (P<0.05). The levels of mTOR protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 77.14%, 100.00% and 83.33%, respectively, with no significant difference (P>0.05). The levels of this protein in well-middle differentiated carcinoma and low differentiated carcinoma were 80.00% and 78.57%, respectively, with no significant difference (P>0.05). The levels of this protein in I-II stage carcinoma, and III-IV stage carcinoma were 27.27% and 96.88%, respectively, with significant difference (P<0.05). The levels of p70S6K protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 80.00%, 100.00% and 100.00%, respectively, with no significant difference (P>0.05). The levels of this protein in well-middle differentiated carcinoma and low differentiated carcinoma were 93.33% and 78.57%, respectively, with no significant difference (P>0.05). The levels of this protein in I-II stage carcinoma, and III-IV stage carcinoma were 45.45% and 96.88%, respectively, with significant difference (P<0.05). The levels of p-Akt protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 88.89% and 64.00%, respectively, with significant difference (P<0.05). The levels of mTOR protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 94.44% and 68.00%, respectively, with significant difference (P<0.05). The levels of p70S6K protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 100.00% and 72.00%, respectively, with significant difference (P<0.05).
 Conclusion: The p-Akt-mTOR-p70S6K signaling pathway may take part in invasion and metastasis of ovarian cancer. The up-regulation of these proteins may be associated with the chemoresistance of ovarian cancer, and these proteins may have potential to be the prognostic markers for the chemoresistance of ovarian cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Ovarianas , Fosforilação , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases S6 Ribossômicas 70-kDa , Serina-Treonina Quinases TOR
20.
Cell Death Discov ; 3: 17046, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28845294

RESUMO

[This corrects the article DOI: 10.1038/cddiscovery.2017.21.].

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