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1.
Phytomedicine ; 67: 153154, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31926475

RESUMO

BACKGROUND: Kanglaite injection (KLT) is a broad-spectrum anti-tumor drug, which is extracted from the seeds of the Chinese medicinal herb Coix lacryma-jobi, and has been widely used for the treatment of advanced lung cancer. PURPOSE: To evaluate the combined effects of Kanglaite injection plus platinum-based chemotherapy (PBC) on patients with stage III/IV non-small cell lung cancer (NSCLC). STUDY DESIGN: A systematic review and meta-analysis of randomized clinical trials (RCTs). MATERIALS AND METHODS: Twelve databases were searched from their inceptions until July 05, 2019. All the RCTs comparing the efficacy and safety of Kanglaite injection plus PBC versus PBC alone were selected. Analyses were performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis (TSA). Disease control rate (DCR) was defined as the primary endpoint, objective response rate (ORR), survival rate, quality of life (QOL), cellular immunity function, and toxicities were defined as the secondary endpoints. RESULTS: Twenty-seven RCTs recruiting 2,243 patients with stage III/IV NSCLC were included. The results showed that, compared with PBC alone, Kanglaite injection plus PBC improved DCR (RR = 1.20, 95% CI 1.15-1.26, p < 0.00001), ORR (RR = 1.45, 95% CI 1.31-1.60, p < 0.00001), 1-year survival rate (RR = 1.20, 95% CI 1.02-1.43, p = 0.03), QOL (RR = 1.32, 95% CI 1.25-1.40, p < 0.00001), CD4+T cells (WMD = 4.86, 95% CI 4.00-5.73, p < 0.00001), CD4+/CD8+ ratio (WMD = 0.19, 95% CI 0.07-0.31, p < 0.002), and reduced severe toxicities by 59% (RR = 0.41, 95% CI 0.33-0.51, p < 0.00001). Most results were robust and the quality of evidence was from moderate to low. CONCLUSIONS: Kanglaite injection in combination with PBC showed significantly higher efficacy than PBC alone in the treatment of stage III/IV NSCLC. Moreover, the combination therapy can improve cellular immunity and attenuate the severe toxicities caused by chemotherapy. However, high-quality RCTs are warranted to further assess the effects of the combined therapy.

3.
J Ethnopharmacol ; 246: 112231, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31520671

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liangxue Tongyu Prescription (LTP) is a traditional Chinese medicine formula composed of 8 crude drugs that is widely used to treat acute intracerebral hemorrhage (AICH). AIM OF THE STUDY: To verify the efficacy of LTP on the survival time in the treatment of acute intracerebral hemorrhagic rats (AICHs), and to elucidate its network pharmacodynamic mechanism of multi-component, multi-target, and multi-signaling pathways. MATERIALS AND METHODS: Survival analysis was used to evaluate the survival time of AICH rats induced by different doses of collagenase and the efficacy of three doses of LTP in the treatment of AICH rats. The Kaplan-Meier curves for survival time were produced and compared with the Log-rank test and Wilcoxon (Gehan) χ2. Differential mRNA-seq combined with network pharmacology was used to disclose the network effect mechanism of LTP on AICH, and the obtained differential genes were mapped into the predictive empirical compound-target network model (ECT network model) and the empirical compound-target-pathogenesis (disease) network model (ECTP network model). RESULTS: The median survival time of four different doses of LTP-treated groups (0.00 g/kg, 5.78 g/kg, 11.55 g/kg, 23.10 g/kg) for adult AICH rats by 0.18 U collagenase was 14 h, 37 h, 150 h, and 51 h respectively, and the 7-day survival rates were 33.3%, 41.7%, 50.0%, and 38.5%, of which the medium-dose group (MD) had a longer survival time and higher survival rate. Through further validation experiments, the MD group had a better efficacy trend with a median survival time of 168 h vs 23 h in the model control group (MC) (Wilcoxon Gehan Test, χ2 = 3.478, P = 0.062). The transcriptomic analysis of mRNA showed that 583 significant differential genes were found between the MC and MD group and 7 key therapeutic targets regulated by 29 compounds in LTP on AICH were screened out by VCT and VCTP network model. These targets were involved in 5 regulatory models or pathways. CONCLUSION: Our study confirmed the exact efficacy of the LTP in the treatment of AICH and revealed the potential pharmacodynamic components and mode of action of the LTP on AICH. Using differential transcriptome of mRNA combined with network pharmacology, we screened out 29 chemical compounds as the potential effective ingredients of LTP which acted on 7 targets of AICH involving 5 pathological pathways, mainly including repairing the brain function defect, improving neural function, protecting blood-brain barrier from damage, reducing inflammatory factors, and inhibiting apoptosis. The present study not only provides a new explanation for the 'multi-component, multi-target, multi-pathway' effects of the LTP on AICH but also screened out some major compounds of LTP and their potential targets which will facilitate the development of new drugs for AICH.

4.
Medicine (Baltimore) ; 98(52): e18552, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876753

RESUMO

BACKGROUND: Compound Kushen injection (CKI) is a commonly used anti-tumor Chinese patent medicine, which is extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Smilacis Glabrae) and has been widely prescribed as an add-on therapy to platinum-based chemotherapy (PBC) for advanced non-small cell lung cancer (NSCLC). However, the efficacy and safety of this combination therapy remain controversial. METHODS AND ANALYSIS: A systematic review and meta-analysis will be performed following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. All randomized controlled trials (RCTs) comparing CKI in combination with PBC versus PBC alone will be retrieved and assessed for inclusion. Analyses will be performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis software. The disease control rate (DCR) will be defined as the primary outcome, and the objective response rate (ORR), quality of life (QOL), survival rate, and toxicities will be the secondary outcomes. RESULTS: This study will systematically evaluate the efficacy and safety of Compound Kushen injection combined with platinum-based chemotherapy in the treatment of stage III/IV NSCLC. The results of this study will be published in a peer-reviewed journal. CONCLUSIONS: This systematic review and meta-analysis of eligible randomized controlled trials will evaluate the effects of Compound Kushen injection as adjunctive therapy to platinum-based chemotherapy in patients with stage III/IV non-small cell lung cancer, thus providing evidence to the clinical use of this combination therapy for the specific subsets of patients. PROSPERO REGISTRATION NUMBER: CRD42019134892.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Platina/uso terapêutico , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/uso terapêutico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Compostos de Platina/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
J Cancer ; 10(25): 6207-6216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772653

RESUMO

Purpose: To determine whether p53, PCDH17, Beclin-1 expression is associated with clinicopathological characteristics of bladder cancer. Materials and Methods: 75 patients with non-muscle-invasive and muscle-invasive bladder cancer were included. Immunohistochemical staining for p53, PCDH17 and Beclin-1 were carried out on the same paraffin-embedded blocks serial sections of these patients who underwent surgery between 2010 and 2015. In addition, p53 gene mutations in these tumors were screened by DNA sequencing. Results: Forty-nine (66.7%) of 75 tumors had p53 gene mutations detected by DNA sequencing method. Of these tumors, 43 (86.0%) exhibited p53 high expression. Furthermore, p53 mutation and low expression of PCDH17 were significantly associated with muscle-invasive bladder cancer. Beclin-1 was also strongly associated with T stage. The p53 mutation, the expression of p53 and PCDH17 were significantly associated with survival from bladder cancer. In addition, patients with p53 high-expression or p53 mutation, PCDH17 low-expression and Beclin-1 low-expression significantly had a poor prognosis. Conclusions: Use of a DNA sequencing method to detect p53 gene mutations was consistent with an immunohistochemical method to detect p53 alterations. In conjunction with levels of p53/PCDH17/Beclin-1, p53 and PCDH17 were independently associated with prognosis; Beclin-1 only had a tendency towards overall survival. p53/PCDH17/Beclin-1 phenotype seems to play a more important role than p53 expression in bladder cancer outcome. It is also identified that p53/PCDH17, p53/Beclin-1 or PCDH17/Beclin-1 all have a cooperative and synergistic effect, which may provide us the potential biomarker for bladder cancer patients.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31673755

RESUMO

Dr. Tarek Haykal et al. (145:1795-1809, 2019) reported a meta-analysis of aspirin for the primary prevention of cancer in individuals without known cancer. The authors found that aspirin use was not associated with significant reduction in cancer mortality or incidence, but with higher rates of bleeding. The findings of this study added some evidence to the clinical practice. However, several issues might have compromised the strength of the evidence of this systematic review. If the investigators could have further clarified the inclusion and exclusion criteria, included all eligible studies, extracted data more meticulously, and performed more necessary sensitivity analyses to confirm the robustness of their findings, the strength of evidence of this meta-analysis would have been stronger.

7.
Cell Death Dis ; 10(11): 821, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659154

RESUMO

MicroRNAs regulate post-transcriptional gene expression and play important roles in multiple cellular processes. In this study, we found that miR-421 suppresses kelch-like ECH-associated protein 1(KEAP1) expression by targeting its 3'-untranslated region (3'UTR). A Q-PCR assay demonstrated that miR-421 is overexpressed in non-small cell lung cancer (NSCLC), especially in A549 cells. Consistently, the level of miR-421 was higher in clinical blood samples from lung cancer patients than in those from normal healthy donors, suggesting that miR-421 is an important lung cancer biomarker. Interestingly, overexpression of miR-421 reduced the level of KEAP1 expression, which further promoted lung cancer cell migration and invasion, as well as inhibited cell apoptosis both in vivo and in vitro. Furthermore, knockdown of miR-421 expression with an antisense morpholino oligonucleotide (AMO) increased ROS levels and treatment sensitivity to paclitaxel in vitro and in vivo, indicating that high miR-421 expression may at least partly account for paclitaxel tolerance in lung cancer patients. To find the upstream regulator of miR-421, one of the candidates, ß-catenin, was knocked out via the CRISPR/Cas9 method in A549 cells. Our data showed that inhibiting ß-catenin reduced miR-421 levels in A549 cells. In addition, ß-catenin upregulation enhanced miR-421 expression, indicating that ß-catenin regulates the expression of miR-421 in lung cancer. Taken together, our findings reveal the critical role of miR-421 in paclitaxel drug resistance and its upstream and downstream regulatory mechanisms. Therefore, miR-421 may serve as a potential molecular therapeutic target in lung cancer, and AMOs may be a potential treatment strategy.

8.
Medicine (Baltimore) ; 98(39): e17350, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574877

RESUMO

BACKGROUND: Shenqi Fuzheng injection (SFI) is a commonly used anti-cancer Chinese patent medicine and has long been prescribed as adjunctive treatment to platinum-based chemotherapy (PBC) in patients with stage III/IV non-small cell lung cancer (NSCLC). However, the efficacy and safety of this combination therapy remain unclear. METHODS: A systematic review and meta-analysis will be conducted following the Preferred Reported Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Seven databases will be searched for relevant studies from their inception to the present date: PubMed, Web of Science, Cochrane Library, EMBASE, ClinicalTrials.gov, China National Knowledge Infrastructure (CNKI), and Wanfang Databases. All randomized clinical trials comparing SFI in combination with PBC versus PBC alone will be retrieved and assessed for inclusion. Two researchers will independently perform the selection of the studies, data extraction, and synthesis. The Cochrane Risk of Bias Tool will be used to evaluate the risk of bias of the RCTs. The primary endpoint is the disease control rate (DCR), the secondary outcomes are the objective response rate (ORR), survival rate, quality of life (QOL), cellular immune function, and toxicities. Review Manager 5.3 (Nordic Cochrane Centre, Cochrane Collaboration, 2014 Copenhagen, Denmark) will be used to analyze the outcomes. RESULTS: This study will systematically evaluate the efficacy and safety of SFI combined with platinum-based chemotherapy in the treatment of stage III/IV NSCLC. The results will be published in a peer-reviewed journal. CONCLUSION: This systematic review will evaluate the effects of SFI as adjunctive treatment to platinum-based chemotherapy in the patients with stage III/IV non-small cell lung cancer, thus providing evidence to the clinical application of this combination therapy. PROSPERO REGISTRATION NUMBER: CRD42019137196.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Platina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Injeções , Neoplasias Pulmonares/patologia , Metanálise como Assunto , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisão Sistemática como Assunto , Resultado do Tratamento
9.
Medicine (Baltimore) ; 98(39): e17382, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574890

RESUMO

BACKGROUND: Long-term use of aspirin for primary prevention of cancer remains inconclusive, and variation in the effects of aspirin use on cancer outcomes by cancer site, aspirin dose, follow-up duration, or different populations has never been systematically evaluated. METHODS: Seven electronic databases (PubMed, EMBASE, ClinicalTrials.gov, etc) will be searched from inception to September 30, 2019. Randomized clinical trials (RCTs) comparing aspirin versus no aspirin in participants without pre-existing cancer and reporting cancer incidence, and/or cancer mortality outcomes will be selected and assessed for inclusion. The Cochrane's Risk of Bias Tool and the Jadad scale will be used to evaluate the risk of bias and the methodologic quality of the RCTs. Data will be screened and extracted by independent investigators. Total cancer incidence will be defined as the primary clinical endpoint, and total cancer mortality, all-cause mortality, and the risk of major bleeding will be the secondary outcomes. Subgroup analyses based on cancer site, aspirin dose, follow-up duration, or different populations will be conducted. Analyses will be performed using Review Manager 5.3, Comprehensive Meta-Analysis 2.0, and Trial Sequential Analysis (TSA) software. RESULTS: This study will systematically evaluate the effects of long-term aspirin use on total cancer incidence, cancer mortality, all-cause mortality, and the risk of major bleeding. Subgroup analyses will indicate whether the effects of aspirin on cancer outcomes are associated with cancer site, daily dose of aspirin, follow-up duration, or different subgroup of participants. The results will be submitted and published in a peer-reviewed scientific journal. CONCLUSIONS: This systematic review will systematically evaluate the efficacy and safety of long-term use of aspirin for primary prevention of cancer and determine whether there are some potential influencing factors affecting the effects of aspirin on cancer outcomes, thus strengthening the evidence base for the clinical practice and future research of this intervention.


Assuntos
Aspirina/uso terapêutico , Neoplasias/prevenção & controle , Prevenção Primária/métodos , Humanos , Incidência , Metanálise como Assunto , Neoplasias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisão Sistemática como Assunto , Fatores de Tempo
10.
World J Clin Cases ; 7(16): 2287-2301, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31531322

RESUMO

BACKGROUND: Perioperative shivering is clinically common during cesarean sections under neuraxial anesthesia, and several neuraxial adjuvants are reported to have preventive effects on it. However, the results of current studies are controversial and the effects of these neuraxial adjuvants remain unclear. AIM: To evaluate the effects of neuraxial adjuvants on perioperative shivering during cesarean sections, thus providing an optimal choice for clinical application. METHODS: A systematic review and network meta-analysis were conducted following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. Analyses were performed using Review Manager 5.3 and Stata 14.0. We searched PubMed, EMBASE, Web of Science, and Cochrane Central databases for eligible clinical trials assessing the effects of neuraxial adjuvants on perioperative shivering and other adverse events during cesarean sections. Perioperative shivering was defined as the primary endpoint, and nausea, vomiting, pruritus, hypotension, and bradycardia were the secondary outcomes. RESULTS: Twenty-six studies using 9 neuraxial adjuvants for obstetric anesthesia during caesarean sections were included. The results showed that, compared with placebo, pethidine, fentanyl, dexmedetomidine, and sufentanil significantly reduced the incidence of perioperative shivering. Among the four neuraxial adjuvants, pethidine was the most effective one for shivering prevention (OR = 0.15, 95%CI: 0.07-0.35, surface under the cumulative ranking curve 83.9), but with a high incidence of nausea (OR = 3.15, 95%CI: 1.04-9.57) and vomiting (OR = 3.71, 95%CI: 1.81-7.58). The efficacy of fentanyl for shivering prevention was slightly inferior to pethidine (OR = 0.20, 95%CI: 0.09-0.43), however, it significantly decreased the incidence of nausea (OR = 0.34, 95%CI: 0.15-0.79) and vomiting (OR = 0.25, 95%CI: 0.11-0.56). In addition, compared with sufentanil, fentanyl showed no impact on haemodynamic stability and the incidence of pruritus. CONCLUSION: Pethidine, fentanyl, dexmedetomidine, and sufentanil appear to be effective for preventing perioperative shivering in puerperae undergoing cesarean sections. Considering the risk-benefit profiles of the included neuraxial adjuvants, fentanyl is probably the optimal choice.

11.
Pharmacol Res ; 149: 104440, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31479750

RESUMO

Targeting on the IKKß to discover anti-inflammatory drugs has been launched for ten years, due to its predominant role in canonical NF-κB signaling. In the current study, we identified a novel IKKß inhibitor, ellipticine (ELL), an alkaloid isolated from Ochrosia elliptica and Rauvolfia sandwicensis. We found that ELL reduced the secretion and mRNA expression of TNF-α and IL-6 and decreased the protein expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in bone marrow derived macrophages (BMDMs) stimulated with LPS. In coincided with the results, ELL suppressed PGE2 and NO production in BMDMs. Underlying mechanistic study showed that ELL inhibited IκBα phosphorylation and degradation as well as NF-κB nuclear translocation, which was attributed to suppression of IKKα/ß activation. Furthermore, kinase assay and binding assay results indicated that ELL inhibited IKKß activity via directly binding to IKKß and in turn resulted in suppression of NF-κB signaling. To identify the binding sites of ELL on IKKß, IKKßC46A plasmid was prepared and the kinase assay was performed. The results demonstrated that the inhibitory effect of ELL on IKKß activity was impaired in the mutation, implying that anti-inflammatory effect of ELL was partially attributed to binding on cysteine 46. Furthermore, ELL up-regulated LC3 II expression and reduced p62 expression, suggesting that autophagy induction contributed to the anti-inflammatory effect of ELL as well. In coincided with the in vitro results, ELL increased the survival and antagonized the hypothermia in the mice with LPS-induced septic shock. Consistently, ELL reduced TNF-α and IL-6 production in the serum of the mice treated with LPS. Collectively, our study provides evidence that ELL is an IKKß inhibitor and has potential to be developed as a lead compound for treatment inflammatory diseases in the future.

12.
J Cancer ; 10(18): 4264-4269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413745

RESUMO

Insulin-like growth factor-1 (IGF-1) -induced epithelial-mesenchymal transition (EMT) plays a key role in the metastasis and drug resistance of non-small cell lung cancer (NSCLC). Sphingosine kinase-1 (SphK1) is also involved in EMT of NSCLC. However, the interaction between SphK1 and IGF-1 in the EMT of NSCLC is largely unknown. To clarify this issue, we examined the involvement of SphK1 in IGF-1-induced EMT using human lung cancer cell line A549, and its paclitaxel-resistant subline. Cell viability was evaluated by cell counting kit-8 assay; Migratory ability was examined using scratch wound healing test; Protein expression levels of SphK1, vimentin, fibronectin, N-cadherin and E-cadherin were detected by western blot analysis, respectively. The results showed that, IGF-1 treatment of A549 cells stimulated the expression of SphK1, the activation of ERK and AKT, the cell migration, and the expression of EMT hallmark proteins, while inhibition of SphK1 by its specific inhibitor SKI-II suppressed all the above changes and increased the sensitivity of A549 cells to paclitaxel. Our data demonstrate that SphK1 acts as a downstream effector of IGF-1 and plays a critical role in IGF-1-induced EMT, cell migration and paclitaxel resistance of A549 cells, suggesting that SphK1 might be a potential therapeutic target for NSCLC.

13.
Front Oncol ; 9: 749, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456940

RESUMO

This meta analysis evaluated the comparative safety and efficacy for the addition of Astragalus-based Chinese medicines combined with chemotherapy and chemotherapy alone for colorectal cancer (CRC) treatment. Systematic literature search was performed by PubMed, EMBSAE, Ovid, Web of Science, Cochrane Library, Chinese Science and Technology Journals (CQVIP), China Academic Journals (CNKI), and Chinese Biomedical Literature database. A total of 22 studies which reported on 1,409 subjects were identified. This meta-analysis indicated that the combination of Astragalus-based Chinese medicines and chemotherapy may increase the efficiency of tumor response rate (TRR) for the treatment of CRC patients (RR: 1.52; 95% CI: 1.24-1.87; p < 0.0001), improve their life quality based on KPS (RR: 2.51; 95% CI: 1.85-3.42; p < 0.00001 and WMD: 10.96; 95% CI: 9.45-12.47; p < 0.00001), and reduce the adverse reactions, including neutropenia (RR: 0.52; 95% CI: 0.44-0.62; p < 0.00001), anemia (RR: 0.49; 95% CI: 0.34-0.70; p < 0.0001), thrombocytopenia (RR: 0.59; 95% CI: 0.46-0.77; p = 0.0001), nausea and vomiting (RR: 0.56; 95% CI: 0.46-0.68; p < 0.00001), diarrhea (RR: 0.55; 95% CI: 0.40-0.75; p = 0.0001), and neurotoxicity (RR: 0.56; 95% CI: 0.49-0.65; p < 0.00001). Hepatic dysfunction (RR: 0.76; 95% CI: 0.53-1.09; p = 0.13) and renal dysfunction (RR: 0.95; 95% CI: 0.51-1.76; p = 0.87) were similar between two groups. The results showed that Astragalus-based Chinese medicines combined with chemotherapy in the treatment of CRC may increase the efficiency of TRR, reduce chemotherapeutic agents-associated adverse reactions, and improve their life quality when compared with chemotherapy alone, but further randomized studies are warranted.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31234281

RESUMO

Background: Non-alcoholic fatty liver disease (NAFLD) is a serious health problem, but the dose-response relationship between sugar-sweetened beverages (SSBs) and NAFLD remains uncertain. Methods: A systematic review and dose-response meta-analysis were conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Review Manager 5.3 and Stata 14.0 were used to combine trials and analyze data. The dose-response meta-analysis was performed by non-linear trend regression. Results: Twelve studies recruiting a total of 35,705 participants were included. The results showed that the consumption of SSBs was associated with 1.39-fold increased odds of NAFLD (95% CI: 1.29-1.50, p < 0.00001). The risk of NAFLD rose with an increased consumption of SSBs, while the consumptions of low doses (<1 cup/week), middle doses (1-6 cups/week) and high doses (≥7 cups/week) of SSBs increased the relative risk of NAFLD by 14%, 26% and 53%, respectively (p = 0.01, p < 0.00001, p = 0.03, respectively). Conclusions: This study demonstrates that consumers of SSBs are at significantly increased risk of NAFLD, and the consumption of SSBs has a dose-dependent effect on the risk of NAFLD. The findings of this study strengthen the evidence base for healthy dietary patterns and are meaningful for the primary prevention of NAFLD.


Assuntos
Bebidas , Sacarose na Dieta/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
15.
Front Med ; 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31104301

RESUMO

Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.

16.
Phytomedicine ; 59: 152787, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005810

RESUMO

BACKGROUND: Elemene injection is an anticancer Chinese patent medicine that is widely used for the treatment of advanced lung cancer. Its active ingredients are ß-, γ- and δ-elemene, which are extracted from Curcumaaromatica Salisb. (Curcumawenyujin Y.H. Chen & C. Ling). PURPOSE: To evaluate the effects of Elemene injection as adjunctive treatment to platinum-based chemotherapy (PBC) in patients with stage III/IV non-small cell lung cancer. STUDY DESIGN: A systematic review and meta-analysis of randomized clinical trials (RCTs). MATERIALS AND METHODS: A systematic review and meta-analysis were conducted following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. Analyses were performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis software. All RCTs comparing Elemene injection combined with PBC vs. PBC alone were selected and assessed for inclusion. The disease control rate (DCR) was defined as the primary endpoint, and the objective Response rate (ORR), survival rate, quality of life (QOL), cellular immune function and toxicities were the secondary outcomes. RESULTS: 15 RCTs recruiting 1,410 patients with stage III/IV NSCLC were included. The methodological quality of most included trials was low to moderate. Compared with PBC alone, Elemene injection plus PBC can improve DCR (RR = 1.23, 95% CI 1.16 to 1.31, p < 0.00001), ORR (RR = 1.62, 95% CI 1.44 to 1.82, p < 0.00001), 1- and 2-year survival rates (RR = 1.33, 95% CI 1.11 to 1.59, p = 0.002; RR = 1.73, 95% CI 1.21 to 2.46, p = 0.002, respectively), QOL (RR = 1.91, 95% CI 1.58 to 2.32, p < 0.00001), CD4+T cell counts (WMD = 10.43, 95% CI 8.25 to 12.62, p < 0.00001), and the CD4+/CD8+ratio (WMD = 0.78, 95% CI 0.42 to 1.14, p < 0.0001) and can reduce severe toxicities by 58% (RR = 0.42, 95% CI 0.34 to 0.52, p < 0.00001). CONCLUSION: Elemene injection is a safe and effective adjunctive treatment to platinum-based chemotherapy in patients with stage III/IV NSCLC. Elemene injection can improve clinical efficacy, enhance cellular immune function and alleviate the toxicity of chemotherapy. High-quality RCTs with significant survival outcomes and longer follow-ups are warranted to confirm the results further.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Injeções , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Compostos de Platina/administração & dosagem , Compostos de Platina/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Sesquiterpenos/administração & dosagem , Taxa de Sobrevida , Resultado do Tratamento
17.
J Clin Invest ; 129(3): 972-987, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30688657

RESUMO

Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1-/- Trp53-/- SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin ß1, which stabilized integrin ß1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin ß1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated integrin ß1 turnover in controlling SCLC metastasis, which might have therapeutic implications.

19.
Mol Pharm ; 16(2): 798-807, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30592425

RESUMO

RORγt is the master transcription factor of IL-17 cytokine expression and Th17 lymphocyte differentiation, which are responsible for the induction of many autoimmune diseases. Recently, RORγt has become an attractive target for drug development to treat these types of diseases, and the field of RORγt antagonist research is now extremely competitive. In our current study, molecular docking was applied to demonstrate that cardenolides, including uscharin, calactin, and calotropin derived from Calotropis gigantea, probably directly bind to RORγt. Therefore, the inhibitory effect was further validated using a luciferase reporter assay. Because RORγt is the key transcriptional factor for Th17 differentiation, the effects of these compounds on Th17 differentiation were studied by flow cytometry. The results showed that uscharin, calactin, and calotropin inhibited Th17 differentiation from 100 to 500 nM. Furthermore, uscharin had a better effect than digoxin, a well-known inverse agonist of RORγt, in reducing Th17 polarization. Additionally, the effects of the cardenolides on the differentiation of other Th lineages, including Th1, Th2, and Treg, were investigated. Uscharin suppressed Th1, Th2, and Treg cell differentiation, while calactin suppressed the differentiation of Th1 cells, and calotropin did not influence the other T cell subsets, indicating that calactin suppressed Th1 and Th17 differentiation, and calotropin selectively quenched Th17 polarization. Structural analysis of the three compounds showed that the selectivity of uscharin, calactin, and calotropin on the suppression of the different subsets of T cells is correlated to the minor differences in their chemical structures. Collectively, calactin and calotropin have greater potential to be developed as lead compounds than uscharin to treat autoimmune diseases mediated by Th17 and/or Th1 cells.


Assuntos
Calotropis/química , Cardenolídeos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Receptores do Ácido Retinoico/antagonistas & inibidores , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Animais , Western Blotting , Citometria de Fluxo , Células HEK293 , Humanos , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Células Th1/citologia , Células Th1/efeitos dos fármacos , Células Th17/citologia , Células Th17/efeitos dos fármacos
20.
Proc Natl Acad Sci U S A ; 115(17): E3978-E3986, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29632194

RESUMO

Lung cancer is the leading cause of cancer-related death worldwide. Inactivation of tumor suppressor genes (TSGs) promotes lung cancer malignant progression. Here, we take advantage of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated somatic gene knockout in a KrasG12D/+ mouse model to identify bona fide TSGs. From individual knockout of 55 potential TSGs, we identify five genes, including Utx, Ptip, Acp5, Acacb, and Clu, whose knockout significantly promotes lung tumorigenesis. These candidate genes are frequently down-regulated in human lung cancer specimens and significantly associated with survival in patients with lung cancer. Through crossing the conditional Utx knockout allele to the KrasG12D/+ mouse model, we further find that Utx deletion dramatically promotes lung cancer progression. The tumor-promotive effect of Utx knockout in vivo is mainly mediated through an increase of the EZH2 level, which up-regulates the H3K27me3 level. Moreover, the Utx-knockout lung tumors are preferentially sensitive to EZH2 inhibitor treatment. Collectively, our study provides a systematic screening of TSGs in vivo and identifies UTX as an important epigenetic regulator in lung tumorigenesis.


Assuntos
Sistemas CRISPR-Cas , Transformação Celular Neoplásica/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Experimentais/metabolismo , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Histona Desmetilases/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
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