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1.
J Clin Invest ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32039918

RESUMO

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium-enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-ß signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti-programmed cell death protein 1 (anti-PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.

2.
mBio ; 11(1)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992625

RESUMO

Activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in antiviral responses to many DNA viruses. Sensing of cytosolic DNA by cGAS results in synthesis of the endogenous second messenger cGAMP that activates stimulator of interferon genes (STING) in infected cells. Critically, cGAMP can also propagate antiviral responses to uninfected cells through intercellular transfer, although the modalities of this transfer between epithelial and immune cells remain poorly defined. We demonstrate here that cGAMP-producing epithelial cells can transactivate STING in cocultured macrophages through direct cGAMP transfer. cGAMP transfer was reliant upon connexin expression by epithelial cells and pharmacological inhibition of connexins blunted STING-dependent transactivation of the macrophage compartment. Macrophage transactivation by cGAMP contributed to a positive-feedback loop amplifying antiviral responses, significantly protecting uninfected epithelial cells against viral infection. Collectively, our findings constitute the first direct evidence of a connexin-dependent cGAMP transfer to macrophages by epithelial cells, to amplify antiviral responses.IMPORTANCE Recent studies suggest that extracellular cGAMP can be taken up by macrophages to engage STING through several mechanisms. Our work demonstrates that connexin-dependent communication between epithelial cells and macrophages plays a significant role in the amplification of antiviral responses mediated by cGAMP and suggests that pharmacological strategies aimed at modulating connexins may have therapeutic applications to control antiviral responses in humans.

3.
Bioorg Med Chem Lett ; 30(2): 126849, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31831382

RESUMO

Honokiol is a natural bioactive neolignan and has been widely researched and structural modified as an anticancer agent. In this paper, 18 honokiol derivatives were synthesized and investigated for their antitumor activity. Among these, the promising compound 5a exhibited much higher anti-proliferative activity with IC50 value of 10.41 µM. Transwell assays showed that 5a could significantly inhibit the invasion and migration of I-10 cells at 2.5 µM, which was further confirmed by the western blotting experiments with down-regulation of the HIF-1α and its associated downstream proteins MMP-2 and MMP-9. Overall, these results provided useful suggestion for further structural optimization of honokiol derivatives.

4.
Chem Biodivers ; 16(12): e1900495, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31755643

RESUMO

Fifteen diterpenoids (1-15), including three undescribed ones with ent-atisane skeleton, eupnerias G-I (1-3), were obtained from Euphorbia neriifolia. Compounds 1-3 were established through comprehensive spectroscopic analysis. Compounds 4 and 5 exhibited obvious anti-HIV-1 effect, and their EC50 were 6.6±3.2 and 6.4±2.5 µg mL-1 , respectively. Compound 6 exhibited moderate cytotoxicity on HepG2 and HepG2/Adr cells with IC50 at 13.70 and 15.57 µm, respectively. In addition, compound 15 exhibited significant cytotoxicity on HepG2 cell lines (IC50 =0.01 µm), while it did not show any cytotoxicity against HepG2/Adr cell lines.


Assuntos
Fármacos Anti-HIV/química , Diterpenos/química , Euphorbia/química , Fármacos Anti-HIV/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Euphorbia/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Conformação Molecular , Relação Estrutura-Atividade
5.
Int J Biol Macromol ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31759029

RESUMO

This study focuses on preparing the monoclonal antibody (MAb) against subgroup A of avian leukosis virus (ALV-A) and identifying its antigenic epitope. The ALV-A gp85 gene with a size of 1005bp was amplified and expressed into a recombinant protein with a size of 46KD in E.coli. The products expressed after purification were inoculated into BALB/c mice for preparing antibody-secreting splenic lymphocytes and further obtaining hybridoma cells. Finally, one new hybridoma cell (A18GH) secreting MAb against ALV-A was screened, and the MAb was able to detect ALV-A/K strains in an indirect immunofluorescence assay (IFA), but not ALV-B/J strains. A total of 14 overlapping truncated ALV-A gp85 protein segments were expressed and eight peptides containing different antigenic amino acids were artificially synthesized for analyzing the antigenic epitope of the MAb using a western blot or an ELISA, and the results indicate that the antigenic epitope consists of seven amino acids within the 146-ATRFLLR -152 region of the ALV-A gp85 protein. A biological information analysis shows that the antigenic epitope has a high antigenic index and develops a curved linear spatial structure. Further, its 7 amino acids are completely within the 17 representative ALV-A strains, 4 are within the 11 ALV-K strains, and fewer are within the ALV-B/J/E strains. This study will significantly assist in a further understanding of the protein structure and function of ALV-A, and in the establishment of specific ALV-A detection methods.

6.
Drug Des Devel Ther ; 13: 3683-3692, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695335

RESUMO

Background: Widespread concern of the side effects and the broad-spectrum anticancer property of podophyllotoxin as an antitumor agent highlight the need for the development of new podophyllotoxin derivatives. Although some per-butyrylated glucosides of podophyllotoxin and 4ß-triazolyl-podophyllotoxin glycosides show good anticancer activity, the per-acetylated/free of podophyllotoxin glucosides and their per-acetylated are not well studied. Methods: A few glucoside derivatives of PPT were synthesized and evaluated for their in vitro cytotoxic activities against five human cancer cell lines, HL-60 (leukemia), SMMC-7721 (hepatoma), A-549 (lung cancer), MCF-7 (breast cancer), and SW480 (colon cancer), as well as the normal human pulmonary epithelial cell line (BEAS-2B). In addition, we investigated the structure-activity relationship and the physicochemical property-anticancer activity relationship of these compounds. Results: Compound 6b shows the highest cytotoxic potency against all five cancer cell lines tested, with IC50 values ranging from 3.27±0.21 to 11.37±0.52 µM. We have also found that 6b displays higher selectivity than the etoposide except in the case of HL-60 cell line. The active compounds possess similar physicochemical properties: MSA > 900, %PSA < 20, ClogP > 2, MW > 700 Da, and RB > 10. Conclusion: We synthesized several glucoside derivatives of PPT and tested their cytotoxicity. Among them, compound 6b showed the highest cytotoxicity. Further studies including selectivity of active compounds have shown that the selectivity indexes of 6b are much greater than the etoposide except in the case of HL-60 cell line. The active compounds possessed similar physicochemical properties. This study indicates that active glucoside analogs of podophyllotoxin have potential as lead compounds for developing novel anticancer agents.

7.
J Coll Physicians Surg Pak ; 29(10): 958-961, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31564270

RESUMO

OBJECTIVE: To explore the effect and safety of laparoscopic partial nephrectomy (LPN) and open partial nephrectomy (OPN) in the treatment of complex renal tumours and to compare renal function in the perioperative period. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Departments of Urology and Cardiovascular Medicine, Affiliated Hospital of Hebei University, from July 2016 to June 2018. METHODOLOGY: A total of 168 complex renal tumour patients with renal tumour scoring system scores (R.E.N.A.L) <7 and tumour stages of T1aN0M0~TlbN0M0 (diameter of tumour <7 cm without metastasis) were chosen. The patients were classified into the retroperitoneal laparoscopic partial nephrectomy (RLPN) group and open partial nephrectomy (OPN) group, comprising 84 patients in each group. Intraoperative and postoperative characteristics of both groups were compared. Statistical analysis of the occurrence rate of postoperative complications was conducted. Renal function indicators, including serum urea (UREA), creatinine (Cr), uric acid (UA) and glomerular filtration rate (GFR), were evaluated one day before the operation and one week after the operation. RESULTS: The differences between the two groups in intraoperative renal warm ischaemia time (WIT) and postoperative drainage time were not statistically significant. Compared with OPN group, RLPN group had shorter recovery time of gastrointestinal function, less use of analgesics and longer hospital stay. The difference in the recent occurrence rate of complications was not statistically significant. The differences between the two groups in UREA, Cr, UA and GFR one day before the operation and one week after the operation were not statistically significant (p>0.05). The Cr and UA levels of both groups improved significantly after the operation, and the GFR level declined significantly. The differences were statistically significant compared with preoperation levels (p<0.05). CONCLUSION: The effect and safety of RLPN in the treatment of complex renal tumours are equal to those of open operations. Laparoscopic surgery involves a small operative wound and contributes to renal function recovery, allowing patients to recover quickly; however, laparoscopic surgery has high technical requirements for its operators.

8.
Nat Commun ; 10(1): 3210, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324807

RESUMO

Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7, VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.


Assuntos
Fibroblastos/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Matriz Extracelular/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 7 de Crescimento de Fibroblastos/metabolismo , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Humanos , Interleucina-6 , Masculino , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Knockout , Recidiva Local de Neoplasia/metabolismo , Neoplasias Experimentais , Neoplasias Epiteliais e Glandulares/patologia , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
9.
J Bioenerg Biomembr ; 51(3): 239-248, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31062127

RESUMO

Hypoxia inducible factor-1α (HIF-1α) plays a central role in cell survival, invasion, metastasis and angiogenesis, and also is emerging as an important target in anti-cancer drug discovery. In the present study, bishonokiol A, a dimeric neolignan isolated from Magnolia grandiflora, was identified as a novel HIF-1α inhibitor. We here demonstrated that in a dose-dependent manner, bishonokiol A inhibited metastasis-related cell invasion and migration of cobalt chloride (CoCl2)-induced MCF-7 and MDA-MB-231 cells, associating with the reduction in HIF-1α levels. Transfection of MDA-MB-231 cells with HIF-1α small interfering ribonucleic acid (siRNA) resulted in a reduction in cell invasion and migration. Furthermore, we found that bishonokiol A not only inhibited the synthesis of HIF-1α protein and protein kinase B (AKT-473) phosphorylation without affecting the expression of HIF-1α mRNA or ubiquitination degradation, but also inhibited the expression of matrix metalloproteinase-9 (MMP-9) and promoter activity. Nude mice bearing MDA-MB-231 cells incubation were treated with bishonokiol A and results showed that bishonokiol A exhibited potent antitumor activity and low toxicity. Therefore, we suggest that bishonokiol A may be a potential inhibitor of HIF-1α and effective antitumor agent for breast cancer.

10.
Biomed Environ Sci ; 32(3): 169-176, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30987691

RESUMO

OBJECTIVE: We aimed to evaluate the combined effects of a high body shape index (ABSI) and a high serum C-reactive protein (CRP) level on the incidence of ischemic stroke in a Mongolian population in China. METHODS: A prospective cohort study was conducted among 2,589 participants from June 2002 to July 2012 in Inner Mongolia, China. The participants were categorized into 4 groups according to their level of ABSI and CRP. Cox proportional hazards models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) for ischemic stroke among all groups. RESULTS: The multivariate adjusted HRs (95% CI) of ischemic stroke for high ABSI and high CRP level were 1.46 (0.89-2.39) and 1.63 (0.95-2.79), respectively. Compared with the low ABSI/low CRP level group, the multivariate adjusted HRs (95% CI) of ischemic stroke in the low ABSI/high CRP, high ABSI/low CRP, and high ABSI/high CRP groups were 1.04 (0.46-2.35), 1.06 (0.58-1.95) and 2.52 (1.27-5.00), respectively. The HR of ischemic stroke for the high ABSI/high CRP level group was the highest and most statistically significant. CONCLUSION: We found that participants with simultaneously high ABSI and high CRP levels had the highest risk of ischemic stroke in the Mongolian population. Our findings suggest that the combination of high ABSI and high CRP levels may increase the risk of ischemic stroke.


Assuntos
Antropometria , Isquemia Encefálica/epidemiologia , Proteína C-Reativa/metabolismo , Acidente Vascular Cerebral/epidemiologia , Adulto , Idoso , Isquemia Encefálica/etiologia , China/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mongólia/etnologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/etiologia
11.
Zhongguo Zhong Yao Za Zhi ; 44(5): 1004-1009, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-30989862

RESUMO

Gastrodia elata B1.,a traditional Chinese medicine,was frequently applied as a cure for headache or migraine. Its effects include suppressing hyperactive liver,calming endogenous wind,dredging collateralsand relieving spasm. There has been a proportion that G. elata should be added to The List of Substances That Are Traditionally Both Food and Chinese Medicinal Materials. The dry G. elata was commonly used in clinic,which have some fundamental study on efficacy and mechanism. However,fresh G. elata,which was added to herbal cuisine very often,lacks corresponding research. The interaction of diet,microbiota and human is a hot issue and lots of scholars are focusing on it. This research sequenced the 16 S rRNA of mouse cecal contents on Mi Seq platform to understand the effect of taking fresh G. elata. As the results showing,multiple probiotics grew after taking fresh G. elata extract,including Ruminiclostridium,Butyricicoccus,and Parvibacter. To contrast,some pathogens or potential pathogens,such as Escherichia/Shigella,Parasutterella,decreased. This manifests that fresh G. elata performs a positive regulation on mouse gut microbiota,especially the low-dose fresh G. elata extraction could restructure the microbiota apparently. Our result reveals that microbiota might be a new target for G. elata extract and provides an important basis for further research on the interaction between gut microbiota and pharmacological activity of G. elata.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Gastrodia/química , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Medicina Tradicional Chinesa , Camundongos , Extratos Vegetais/farmacologia , Plantas Medicinais/química , RNA Ribossômico 16S/genética
12.
J Cardiovasc Pharmacol ; 73(3): 186-194, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30839512

RESUMO

OBJECTIVE: To investigate whether phenylephrine (PE) inhibits sepsis-induced cardiac dysfunction, cardiac inflammation, and mitochondrial injury through the PI3K/Akt signaling pathway. METHODS: A rat model of sepsis was established by cecal ligation and puncture. PE and/or wortmannin (a PI3K inhibitor) were administered to investigate the role of PI3K/Akt signaling in mediating the effects of PE on inhibiting sepsis-induced cardiac dysfunction, cardiac inflammation, and mitochondrial injury. Hematoxylin-eosin staining, echocardiography, and Langendorff system were used to examine the myocardial injury and function. The concentrations of TNF-α and IL-6 were analyzed by enzyme-linked immunosorbent assay. Intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), myeloperoxidase, mitochondria-related fusion/fission proteins, and PI3K/Akt signaling pathway-associated proteins were analyzed by Western blotting. RESULTS: PE improved the cardiac function and survival in septic rats. PE decreased TNF-α, IL-6, ICAM-1, VCAM-1, and myeloperoxidase contents in the myocardium of septic rats. Meanwhile, PE increased the fusion-related proteins and decreased the fission-related proteins in the myocardial mitochondria of septic rats. On the other hand, PE activated the PI3K/Akt signaling pathway in the cecal ligation and puncture-treated rats, and all the protective effects of PE were abolished by wortmannin. CONCLUSIONS: PE attenuated sepsis-induced cardiac dysfunction, cardiac inflammation, and mitochondrial injury through the PI3K/Akt signaling pathway.

13.
Chem Biodivers ; 16(5): e1800474, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30801931

RESUMO

Twelve 3,8-epoxy iridoids, including four new compounds, jatamanins R-U (1-4), and eight known compounds (5-12), were obtained from the roots and rhizomes of Valeriana jatamansi. The structures were elucidated from analysis of spectroscopic data. The absolute configurations of 1-4 were determined by comparison of experimental and literature ECD spectra. Moreover, the compounds were evaluated for cytotoxic effects against glioma stem cells, inhibition of NO production, activity against influenza A virus and reversal of multidrug resistance of HepG2/ADR cells. Compounds 9 and 12 showed significant cytotoxic potency against GSC-18# (IC50 =1.351 and 4.439 µg ml-1 , respectively) and GSC-3# (IC50 =10.88 and 6.348 µg ml-1 , respectively) glioma stem cells, while compound 12 was also slightly less potent against GSC-12# (IC50 =13.45 µg ml-1 ) glioma stem cell growth. In addition, compounds 9 and 12 displayed obvious inhibition of NO production (IC50 =4.6 and 15.8 µm, respectively).


Assuntos
Iridoides/química , Valeriana/química , Animais , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Hep G2 , Humanos , Iridoides/isolamento & purificação , Iridoides/farmacologia , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Óxido Nítrico/metabolismo , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Valeriana/metabolismo
14.
Nat Prod Res ; : 1-9, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30691300

RESUMO

Six new compounds, including three terpenoids (1-3) and three lignans (4-6), were isolated from the 95% EtOH extract of the twigs of Tripterygium hypoglaucum. Their structures were determined on the basis of extensive spectroscopic analysis. 9'-O-benzoyl-lariciresinol (4) showed weak cytotoxicity against HepG2/Adr cells, with an IC50 value of 30.1 µM in vitro.

15.
J Immunol ; 202(2): 527-538, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30530591

RESUMO

G2A is a GPCR abundantly expressed in immune cells. G2A-/- mice showed higher lethality, higher plasma cytokines, and an impaired bacterial clearance in response to a murine model of sepsis (cecal ligation and puncture), which were blocked by GdCl3, an inhibitor of Kupffer cells. Anti-IL-10 Ab reversed the impaired bacterial clearance in G2A-/- mice. Indomethacin effectively blocked both the increased i.p. IL-10 levels and the impaired bacterial clearance, indicating that disturbed PG system is the proximal cause of these phenomena. Stimulation with LPS/C5a induced an increase in Escherichia coli phagocytosis and intracellular cAMP levels in G2A+/+ peritoneal macrophages but not G2A-/- cells, which showed more PGE2/nitrite release and intracellular reactive oxygen species levels. Heterologous coexpression of G2A and adenosine receptor type 2b (A2bAR) induced a synergistic increase in cAMP signaling in a ligand-independent manner, with the evidence of physical interaction of G2A with A2bAR. BAY 60-6583, a specific agonist for A2bAR, increased intracellular cAMP levels in Kupffer cells from G2A+/+ but not from G2A-/- mice. Both G2A and A2bAR were required for antiseptic action of lysophosphatidylcholine. These results show inappropriate activation of G2A-/- Kupffer cells to septic insults due to an impaired cAMP signaling possibly by lack of interaction with A2bAR.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Infecções por Escherichia coli/imunologia , Escherichia coli/fisiologia , Macrófagos do Fígado/imunologia , Macrófagos Peritoneais/fisiologia , Receptor A2B de Adenosina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sepse/metabolismo , Animais , Anticorpos Bloqueadores , Proteínas de Ciclo Celular/genética , Células Cultivadas , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Receptor Cross-Talk , Receptor A2B de Adenosina/genética , Receptores Acoplados a Proteínas-G/genética , Sepse/genética , Transdução de Sinais
16.
Bone Marrow Transplant ; 54(6): 894-902, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30337697

RESUMO

To compare the efficacy and toxicity of a novel regimen called FBA, consisting of fludarabine, busulfan, and cytarabine, with the standard BuCy2 regimen for younger adult patients with acute myeloid leukemia, we conducted a prospective randomized phase II study. Patients in complete remission were randomly assigned to receive either the FBA (n = 56) or the BuCy2 regimen (n = 55). The difference in 100-day transplant-related mortality (TRM) was not statistically significant between the two arms (1.79% for FBA versus 5.45% for BuCy2, P = 0.260), as were the cumulative incidences of relapse, TRM, overall survival (OS) and event-free survival (EFS) at 3 years. However, the 100-day cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease (aGVHD) were lower in the FBA group [(8.93% versus 21.86%, P = 0.032) (1.79% versus 9.09%, P = 0.025)]. The 3-year GVHD and relapse-free survival (GRFS) was 31.20% for the FBA group and 14.96% for the BuCy2 group (P = 0.004). The incidences of diarrhea and severe oral mucositis within the first 30 days post-transplantation were lower in the FBA group [(28.57% versus 65.45%; P < 0.001) (51.79% versus 70.91%; P = 0.039)]. In conclusion, allogenic transplantation with the FBA regimen achieved similar TRM, relapse rate, OS and EFS, as that with the BuCy2 regimen but with less frequent and less severe complications in early stage after transplantation and a trend toward higher GRFS.

17.
Nat Prod Res ; 33(21): 3083-3088, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30427740

RESUMO

A new protostane-type triterpenoid bearing an oxetane ring in the side-chain, named alisol W (1), has been obtained from the dried rhizome of Alisma plantago-aquatica subsp. orientale. The structure and absolute configuration of compound 1 was determined from extensive spectroscopic analysis. In addition, the vasorelaxant activity and the inhibition on 11ß-HSD1 of compound 1 were also evaluated, however, it didn't show remarkable effects.


Assuntos
Alisma/química , Triterpenos/isolamento & purificação , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Humanos , Estrutura Molecular , Rizoma/química , Análise Espectral , Triterpenos/química , Vasodilatadores/análise
18.
Food Chem ; 276: 50-56, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30409625

RESUMO

In this paper, we employed a direct analysis in real time (DART) ion source coupled to QTRAP mass spectrometry for the analysis of chloramphenicol (CAP) in honey. The accuracy of the DART-MS/MS method for the analysis of CAP in honey was evaluated by comparison with data generated by a validated HPLC-MS/MS method. The sample preparation procedure was optimized to obtain sensitive and accurate determination of trace CAP residue in honey at concentrations less than 1.0 µg/kg. The DART-MS/MS method offers faster analysis time, lower cost per analysis, and reduced matrix effects and simplicity compared to HPLC-MS/MS method. Fifty-two honey samples collected from a Chinese market were analyzed using two methods. The results of the two methods are in good agreement, suggesting DART-MS/MS as a potential technique for the direct detection of trace amounts of veterinary drugs in complex matrixes.


Assuntos
Cloranfenicol/análise , Análise de Alimentos/métodos , Mel/análise , Limite de Detecção , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo
19.
Biomed Environ Sci ; 31(6): 463-466, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30025560

RESUMO

The objective of this study was to evaluate the usefulness of the China-PAR equations in predicting the 10-year risk of cardiovascular disease (CVD) in the Inner Mongolians population. A population-based, prospective cohort of 2,589 Mongolians were followed up from 2003 to 2012. Participants were categorized into 4 subgroups according to their 10-year CVD risks calculated using the China-PAR equations: < 5%, 5%-9.9%, 10%-19.9%, and ⪖ 20%. The China-PAR equations discriminated well with good C statistics (range, 0.76-0.86). The adjusted hazard ratios for CVD showed an increasing trend among the 4 subgroups (P for trend < 0.01). However, the China-PAR equations underestimated the 10-year CVD risk in Mongolians, and the calibration was unsatisfactory (Hosmer-Lemeshow χ2 = 19.98, P < 0.01 for men, χ2 = 46.58, P < 0.001 for women). The performance of the China-PAR equations warrants further validation in other ethnic groups in China.


Assuntos
Grupo com Ancestrais do Continente Asiático , Doenças Cardiovasculares/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mongólia/etnologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco
20.
Br J Pharmacol ; 175(14): 3034-3049, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29722898

RESUMO

BACKGROUND AND PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. However, the antitumour efficacy of existing small-molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small-molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models. EXPERIMENTAL APPROACH: C57BL6 mice, athymic nude mice or Ido1-/- mice were inoculated with IDO1-expressing and -nonexpressing tumour cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted tumours, plasma, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses. KEY RESULTS: LW106 dose-dependently inhibited the outgrowth of xenografted tumours that were inoculated in C57BL6 mice but not nude mice or Ido1-/- mice, showing a stronger antitumour efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoural infiltration of proliferative Teff cells, while reducing recruitment of proliferative Treg cells and non-haematopoietic stromal cells such as endothelial cells and cancer-associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumours in which fewer proliferative/invasive tumour cells and more apoptotic tumour cells were observed. CONCLUSIONS AND IMPLICATIONS: LW106 inhibits tumour outgrowth by limiting stroma-immune crosstalk and CSC enrichment in the tumour micro-environment. LW106 has potential as a immunotherapeutic agent for use in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Dioxigenases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dioxigenases/genética , Dioxigenases/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Neoplasias/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
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