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1.
Medicine (Baltimore) ; 99(9): e19280, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118739

RESUMO

BACKGROUND: Lumbar disc herniation (LDH) is a disease commonly seen in clinical practice. In the majority of such patients presenting in clinic, the symptoms can be relieved or even abolished after non-surgical treatment. Floating needle therapy has attracted considerable attention as a promising non-surgical technique to treat LDH, as demonstrated in previous studies. The purpose of the present study was to evaluate the outcomes of patients treated using this therapy in a single blind and randomized controlled trial by recording patient report questionnaires and objective test data, and to explore the feasibility and preliminary effects of floating needle therapy for patients with LDH. METHODS: A total of 80 patients who fulfilled the inclusion criteria were randomly divided into a Fu's subcutaneous needling (FSN) group and an acupuncture group then treated in accordance with procedures appropriate for a single blind and randomized controlled trial. The FSN group received 12 FSN therapy sessions over a 3-week period, and the acupuncture group received acupuncture therapy at specified points using acupuncture needles. The principal measurements were scored using the visual analogue scale (VAS), Japanese Orthopedic Association (JOA) Score, and Oswestry disability index (ODI) before and 3 weeks after treatment. Secondary measurements included immune function IgG and IgM measurements performed at the same time and adverse reactions during treatment. RESULTS: The results of this trial will be published on the website of China Clinical Trial Registration Center (http://www.chictr.org.cn/searchprojen.aspx) and in peer-reviewed journals or academic conferences. CONCLUSIONS: This study will explore the feasibility and preliminary effects of floating needle therapy for the treatment of patients with LDH. REGISTRATION: PROSPERO (registration number ChiCTR1900024045).


Assuntos
Terapia por Acupuntura , Degeneração do Disco Intervertebral/terapia , Deslocamento do Disco Intervertebral/terapia , Dor Intratável/terapia , Adulto , Idoso , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Degeneração do Disco Intervertebral/sangue , Deslocamento do Disco Intervertebral/sangue , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Medição da Dor , Projetos de Pesquisa , Método Simples-Cego , Resultado do Tratamento , Escala Visual Analógica , Adulto Jovem
2.
Artigo em Inglês | MEDLINE | ID: mdl-32162453

RESUMO

Most of current nanomedicines are administrated intravenously to favour tumor accumulation via enhanced permeability and retention (EPR) effect, which, however, suffers from a number of drawbacks such as low drug bioavailability and severe side effect. Inspired from the advances in nutriology, in this work, we have constructed a doxorubicin(Dox)-based liposomal nanosystem, whose component is analogous to that of FDA-approved cancer nanomedicine Doxil ® , for tumor-specific chemotherapy by enabling differential stress sensitization between cancer and normal cells for restricting the chemodrug toxicity exclusively in tumor regions. In detail, 2-Deoxy-D-glucose (2DG) was loaded in the nanoliposome to inhibit glycolysis of cancer cells, which works in synergy with the co-loaded chemodrug Dox to promote mitochondrial depolarization and subsequent apoptosis. In the meantime, the starvation effect of 2DG is able to counteract the toxicity of Dox in normal cells and thus mitigates the harmful side effect of chemotherapy. In vivo results also evidence that this engineered nanosystem features largely elevated therapeutic efficacy, mitigated side effects, as well as distinct anti-metastasis function. It is expected that such a differential stress sensitization strategy may greatly benefit future nanomedicine design.

3.
Cell Commun Signal ; 18(1): 48, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32213179

RESUMO

BACKGROUND: Recent findings suggested that premetastatic niche (PMN) is a prerequisite in mediating cancer metastasis. Previously we demonstrated that XIAOPI formula could inhibit breast cancer lung metastasis via inhibiting tumor associated macrophages (TAMs)-secreted CXCL1. Herein, we aimed to explore the effects of XIAOPI formula on preventing breast cancer PMN formation and its underlying molecular mechanisms. METHODS: CXCL1 expression of TAMs was detected by qPCR and Western blotting assay. The influences of XIAOPI formula on the proliferation of TAMs and 4 T1 in the co-culture system were tested by CCK8 or EdU staining. Transwell experiment was applied to determine the effects of XIAOPI formula on the invasion ability of HSPCs and 4 T1. Breast cancer xenografts were built by inoculating 4 T1 cells into the mammary pads of Balb/c mice and lung metastasis was monitored by luciferase imaging. Immune fluorescence assay was used to test the epithelial-mesenchymal transition process and PMN formation in the lung tissues. The effects of XIAOPI formula on TAMs phenotype, hematopoietic stem/progenitor cells (HSPCs) and myeloid-derived suppressor cells (MDSCs) were determined by flow cytometry. RESULTS: It was found that XIAOPI formula could inhibit the proliferation and polarization of M2 phenotype macrophages, and reduce CXCL1 expression in a dose-dependent manner. However, M1 phenotype macrophages were not significantly affected by XIAOPI formula. TAMs/CXCL1 signaling was subsequently found to stimulate the recruitment of c-Kit+/Sca-1+ HSPCs and their differentiation into CD11b+/Gr-1+ MDSCs, which were symbolic events accounting for PMN formation. Moreover, XIAOPI formula was effective in inhibiting HSPCs activation and suppressing the proliferation and metastasis of breast cancer cells 4 T1 induced by HSPCs and TAMs co-culture system, implying that XIAOPI was effective in preventing PMN formation in vitro. Breast cancer xenograft experiments further demonstrated that XIAOPI formula could inhibit breast cancer PMN formation and subsequent lung metastasis in vivo. The populations of HSPCs in the bone marrow and MDSCs in the lung tissues were all remarkably declined by XIAOPI formula treatment. However, the inhibitory effects of XIAOPI formula could be relieved by CXCL1 overexpression in the TAMs. CONCLUSIONS: Taken together, our study provided preclinical evidence supporting the application of XIAOPI formula in preventing breast cancer PMN formation, and highlighted TAMs/CXCL1 as a potential therapeutic strategy for PMN targeting therapy. Video Abstract.

4.
Aging (Albany NY) ; 12(4): 3190-3204, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32112552

RESUMO

We developed and validated a nomogram to predict coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) in northern China. We analyzed a cohort of RA patients admitted to the Department of Rheumatology and Immunology of the First Affiliated Hospital of China Medical University from 2011 to 2017. To select a high-performance model for clinical data prediction, we evaluated the F1-scores of six machine learning models. Based on the results, we selected multivariable logistic regression analysis for the development of a prediction model. We then generated an individualized prediction nomogram that included age, sex, hypertension, anti-cyclic citrullinated peptide antibody positivity, the erythrocyte sedimentation rate, and serum LDL-cholesterol, triglyceride and HDL-cholesterol levels. The prediction model exhibited better discrimination than the Framingham Risk Score in predicting CHD in RA patients. The area under the curve of the prediction model was 0.77, with a sensitivity of 63.9% and a specificity of 77.2%. The nomogram exhibited good calibration and clinical usefulness. In conclusion, our prediction model was more accurate than the Framingham Risk Score in predicting CHD in RA patients. Our nomogram combining various risk factors can be used for the individualized preoperative prediction of CHD in patients with RA.

5.
Medicine (Baltimore) ; 99(9): e19310, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118755

RESUMO

BACKGROUND: Lumbar disc herniation (LDH) is 1 of the most common diseases in orthopedics, which seriously affects people's daily life and brings a heavy burden on society and families. Chinese herbal medicine has been used in clinical practice for a long time and Duhuo Jisheng Decoction (DHJSD) is believed to help alleviate the symptoms of LDH. This systematic review aims to collect evidences from randomized clinical trials and evaluate the efficacy of DHJSD on LDH in order to provide a reference for clinicians and researchers. METHODS: We will comprehensively search the 8 electronic databases until December 2019 to identify related randomized controlled trials, including 4 foreign databases (PubMed, MEDLINE, EMBASE, Cochrane Library) and 4 Chinese databases (China National Knowledge Infrastructure Database, VIP Database, Wanfang Database and China Biology Medicine disc). The data of the World Health Organization International Clinical Trial Registry Platform and the Chinese Clinical Trial Registry also will be searched. The primary outcomes are Japanese Orthopaedic Association scores and visual analog scale scores. The risk of bias will be assessed using the Cochrane Collaboration tool. RevMan (V.5.3) software will be used for meta-analysis. RESULTS: This study will report the results of DHJSD for the treatment of LDH from the literature screening, the basic information of the included studies, the risk of bias of the included studies, treatment effects, safety, and so on. CONCLUSION: This systematic review will evaluate the effectiveness and safety of DHJSD for the treatment of LDH and provide the latest evidence for its clinical application. ETHICS AND DISSEMINATION: This is a literature-based study, therefore it does not require ethical approval. PROSPERO REGISTRATION NUMBER: CRD42019147302.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Deslocamento do Disco Intervertebral/tratamento farmacológico , Região Lombossacral/lesões , Medicina Tradicional Chinesa/normas , Protocolos Clínicos , Medicamentos de Ervas Chinesas/normas , Humanos , Deslocamento do Disco Intervertebral/fisiopatologia , Medicina Tradicional Chinesa/métodos , Resultado do Tratamento
6.
Nano Lett ; 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202802

RESUMO

We report on nanosecond long, gate-dependent valley lifetimes of free charge carriers in monolayer WSe2, unambiguously identified by the combination of time-resolved Kerr rotation and electrical transport measurements. While the valley polarization increases when tuning the Fermi level into the conduction or valence band, there is a strong decrease of the respective valley lifetime consistent with both electron-phonon and spin-orbit scattering. The longest lifetimes are seen for spin-polarized bound excitons in the band gap region. We explain our findings via two distinct, Fermi level-dependent scattering channels of optically excited, valley polarized bright trions either via dark or bound states. By electrostatic gating we demonstrate that the transition metal dichalcogenide WSe2 can be tuned to be either an ideal host for long-lived localized spin states or allow for nanosecond valley lifetimes of free charge carriers (> 10 ns).

7.
Adv Mater ; 32(12): e1907152, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32053261

RESUMO

Nanocatalytic medicine has been developed recently to trigger intratumoral generation of highly toxic reactive oxygen species (ROS) for cancer therapy, which, unfortunately, suffers from compromised therapeutic efficacy due to a self-protective mechanism, autophagy, of cancer cells to mitigate oxidative damage. In this work, during the efforts of ROS generation by nanocatalytic medicine, a pharmacological autophagy inhibition strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. An iron-containing metal-organic framework [MOF(Fe)] nanocatalyst as a peroxidase mimic is used to catalyze the generation of highly oxidizing •OH radicals specifically within cancer cells, while chloroquine is applied to deacidify lysosomes and inhibit autophagy, cutting off the self-protection pathway under severe oxidative stress. Cancer cells fail to extract their components to detoxicate and strengthen themselves, finally succumbing to the ROS-induced oxidative damage during nanocatalytic therapy. Both in vitro and in vivo results demonstrate the synergy between nanocatalytic therapy and autophagy inhibition, suggesting that such a combined strategy is applicable to amplify tumor-specific oxidative damage and may be informative to future design of therapeutic regimen.

8.
Adv Mater ; : e1907757, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068922

RESUMO

Passivation of interfacial defects serves as an effective means to realize highly efficient and stable perovskite solar cells (PSCs). However, most molecular modulators currently used to mitigate such defects form poorly conductive aggregates at the perovskite interface with the charge collection layer, impeding the extraction of photogenerated charge carriers. Here, a judiciously engineered passivator, 4-tert-butyl-benzylammonium iodide (tBBAI), is introduced, whose bulky tert-butyl groups prevent the unwanted aggregation by steric repulsion. It is found that simple surface treatment with tBBAI significantly accelerates the charge extraction from the perovskite into the spiro-OMeTAD hole-transporter, while retarding the nonradiative charge carrier recombination. This boosts the power conversion efficiency (PCE) of the PSC from ≈20% to 23.5% reducing the hysteresis to barely detectable levels. Importantly, the tBBAI treatment raises the fill factor from 0.75 to the very high value of 0.82, which concurs with a decrease in the ideality factor from 1.72 to 1.34, confirming the suppression of radiation-less carrier recombination. The tert-butyl group also provides a hydrophobic umbrella protecting the perovskite film from attack by ambient moisture. As a result, the PSCs show excellent operational stability retaining over 95% of their initial PCE after 500 h full-sun illumination under maximum-power-point tracking under continuous simulated solar irradiation.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32106644

RESUMO

Objective: The purpose of this experiment was to investigate the effects of the Agaricus bisporus stem residue (ABSR) on the performance, nutrients digestibility, antioxidant activity of laying hens, and its effects on egg storage to determine the appropriate dosage of ABSR, so as to provide a scientific basis for the effective utilization of ABSR. Methods: A total of 384 53-wk-old Nongda Ⅲ layers were randomly divided into six treatments, four replicates in each treatment and 16 birds in each replicate. The control treatment was fed with basic diet, while experimental treatments were fed with diets of 2%, 4%, 6%, 8%, and 10% ABSR respectively. The experimental period was 56 d. Results: The results showed that compared with the control treatment, ABSR had no significant effect on laying performance (p>0.05). The crude protein and total energy digestibility of experimental treatments was significantly higher than those of control treatment (p<0.05). When eggs were stored for 1 wk, 2 wk, and 3 wk at 25℃, there were no significant differences in egg storage between the experimental treatments and the control treatment (p>0.05). The superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity in the serum of the experimental treatments were significantly higher than those of the control treatment (p<0.05), and the malonaldehyde (MDA) content did not change dramatically. SOD activity in yolk of experimental treatments was significantly higher than that in control treatment (p<0.05); MDA content in yolk was markedly lower than that in control treatment (p<0.05). The activity of GSH-Px and SOD in yolk of experimental treatments was significantly higher than that of control treatment stored at 25℃ for 21 d, and the content of MDA was significantly lower than that of control treatment (p<0.05). Conclusion: ABSR can be used to improve the antioxidant activity of laying hens without affecting laying performance.

10.
Nanotechnology ; 31(18): 185404, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952060

RESUMO

Recently, two-dimensional (2D) monolayers C3B and C3N attract growing research interest due to the excellent physical properties. In this work, the thermal conductivities (k) of the monolayer C3B x N1-x alloy and the special C3B0.5N0.5 superlattice (C3B0.5N0.5-SL) alloy are systematically evaluated by using molecular dynamic simulation. First, the k of monolayer C3B x N1-x alloy presents a U-shaped profile with the increasing random doping ratio (x), in which the lowest k exists in x = 0.5. Second, we further calculate the thermal conductivity of C3B0.5N0.5-SL. The result shows an initial decreasing and then rising trend, and the coherent length is 5.11 nm which occupies the minimum thermal conductivity. Furthermore, to uncover the phonon thermal transport mechanism, we calculate the spatiotemporal thermal transport, phonon density of states, phonon group velocity, participation ratio and the phonon wave packet simulations in monolayer alloy system. We note that on account of the random doping atoms, the enhancive phonon-impurity scattering and phonon localization reduce the thermal conductivity in monolayer C3B x N1-x alloy. In C3B0.5N0.5-SL, when the period length is smaller than the coherent length, coherent phonon modes emerge because of the phonon interference, in which the superlattice can be regarded as a 'newly generated material'. However, when the period length is larger than the coherent length, the decreasing number of the interface in superlattice lessens phonon-interface scattering and cause the increasing thermal conductivity. This work contributes the fundamental knowledge for thermal management in 2D monolayer C3B x N1-x alloy based nanoelectronics.

11.
Eur J Med Chem ; 188: 112024, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923858

RESUMO

A series of 2,7-disubstituted-thieno[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated as novel focal adhesion kinase (FAK) inhibitors. The novel 2,7-disubstituted-thieno[3,2-d]pyrimidine scaffold has been designed as a new kinase inhibitor platform that mimics the bioactive conformation of the well-known diaminopyrimidine motif. Most of the compounds potently suppressed the enzymatic activities of FAK and potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cancer cell lines. Among these derivatives, the optimized compound 26f potently inhibited the enzyme (IC50 = 28.2 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.16, 0.27, and 0.19 µM, respectively. Compound 26f also exhibited relatively less cytotoxicity (IC50 = 3.32 µM) toward a normal human cell line, HK2. According to the flow cytometry results, compound 26f induced the apoptosis of MDA-MB-231 cells in a dose-dependent manner and effectively arrested MDA-MB-231 cells in G0/G1 phase. Further investigations revealed that compound 26f potently suppressed the migration of MDA-MB-231 cells. Collectively, these data support the further development of compound 26f as a lead compound for FAK-targeted anticancer drug discovery.

12.
Int J Biol Macromol ; 146: 875-886, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31726131

RESUMO

De novo transcriptome assembly and shotgun proteome analysis of Dictyophora indusiata fruiting bodies were performed. A total of 19,704 unigenes were sequenced, and 4380 proteins were identified. Annotation and functional analysis of the identified proteins were significantly enriched in small molecule synthetic and metabolic processes, protein modification regulation (phosphorylation and ubiquitination), and vesicle transport. Furthermore, quantitative developmental transcriptome analysis was performed between the peach-shaped and mature fruiting bodies, and the results revealed that the metabolism and transport activities were upregulated in the mature stage, while protein translation was downregulated; this regulation is likely the main reason for the significant changes in the nutrients of fruiting bodies. Furthermore, the cell wall stress-dependent MAPK sub-pathway was activated in the mature stage, and fungal cell wall degradation-related genes were upregulated, which could promote reconstruction of the cell wall and might play a key role in the morphological development of D. indusiata fruiting bodies.

13.
Biofabrication ; 12(2): 025011, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31805544

RESUMO

During the bioprinting processes that employ either pneumatic or screw-driven mechanisms, living cells are subject to process-induced forces, which may cause cell injury or damage. However, the similarities and differences between these two mechanisms have not been discovered and documented in terms of process-induced forces and cell damage. In this paper, we examined the process-induced forces, including hydrostatic pressure, shear stress, extensional stress, and tensile/compressive forces that the cells experienced during the bioprinting processes by means of these two mechanisms; we also experimentally investigated the process-induced cell damage (featured by the rupture of the cell membrane) under various printing conditions or factors, including the volumetric flow rates, cell types, bioink solutions, needle types and sizes, and printing head-movement speeds. On this basis, we correlated the percent of cell damage to the process-induced forces, which were considered mainly responsible for the rupture of the cell membrane. Our results illustrate that compared to the pneumatic bioprinting process, the screw-driven bioprinting process generally induces more cell damage, varying with the printing conditions. This study, for the first time, discovers the similarities and differences between the pneumatic and screw-driven bioprinting processes and further demonstrates their merits and demerits for bioprinting in terms of printing-process control, process-induced forces, and cell damage.

14.
Appl Microbiol Biotechnol ; 104(1): 225-239, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31788711

RESUMO

Actinobacteria are one of the most important sources of pharmaceutically valuable and industrially relevant secondary metabolites. Modern genome mining reveals that the potential for secondary metabolite production of actinomycetes has been underestimated. Recently, the establishment of CRISPR/Cas9-based genetic manipulation approaches in actinomycetes opened a new era for genome engineering of this type of organism. Compared with the traditional methods, the application of CRISPR/Cas9 shows several advantages in actinomycetes including higher efficiency and ease of operation. However, the screening process for the correctly edited mutants and the plasmid curing are still time- and labor-intensive. To address this problem, we developed an updated version of the CRISPR/Cas9 genome editing system for actinomycetes, based on two chromogenic reporter systems (GusA and IdgS). Our system facilitates both processes of positive clone screening and plasmid curing. Here, we demonstrate by three case studies in both model actinomycetes and non-model actinomycetes that this system is faster and more efficient. We performed the deletion of one single gene, actIORFI (SCO5087 of the actinorhodin gene cluster) in Streptomyces coelicolor M145, one small-size (5.5 kb) gene cluster (orange-pigmented carotenoid gene cluster), and one relatively large-size (61 kb) gene cluster (abyssomicin gene cluster) in Verrucosispora sp. MS100137. The results presented in this study indicate that this updated CRISPR/Cas9 system employing chromogenic reporters is versatile and broadly applicable in genome engineering of actinomycetes, not only for the largest genus Streptomyces.

15.
Adv Mater ; 32(2): e1905433, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31647588

RESUMO

Memristive devices whose resistance can be hysteretically switched by electric field or current are intensely pursued both for fundamental interest as well as potential applications in neuromorphic computing and phase-change memory. When the underlying material exhibits additional charge or spin order, the resistive states can be directly coupled, further allowing electrical control of the collective phases. The observation of abrupt, memristive switching of tunneling current in nanoscale junctions of ultrathin CrI3 , a natural layer antiferromagnet, is reported here. The coupling to spin order enables both tuning of the resistance hysteresis by magnetic field and electric-field switching of magnetization even in multilayer samples.

16.
Water Res ; 168: 115211, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669780

RESUMO

It has been long desired but challenging to forward the advanced treatment of wastewater from empirical trials towards scientific design due to the lack of molecular insight into the pollutants of concern. Herein, we first established a systematic methodology to identify the ligands of Ni(II)-complexes in an electroless nickel (EN) plating effluent. The presence of N-containing groups in the ligands of most Ni(II)-complexes was verified by time-aligned ICP-MS and ESI-HRMS, implying the suitability of autocatalytic ozonation for efficient decomplexation. Thereby, a combined process was proposed on the basis of ozonation to achieve over 83% decomplexation of Ni(II) (initially at 0.36 mg/L), followed by selective Ni(II) sequestration for resource recovery. Combinational LC-MS systems revealed the ozonation-induced fragmentation or elimination of most Ni(II)-complexes as well as the structural change of the residual complexed molecules. The released free Ni(II) was further sequestrated by a nanocomposite of hydrated Zr(IV) oxide confined in a polymeric cation exchanger (nHZO@PCE). The fixed-bed working capacity of nHZO@PCE (∼550 BV) for the ozonated EN plating effluent was over 18 times that of the cation exchanger host (∼30 BV) at the breakthrough point of 0.10 mg Ni/L. More attractively, five adsorption-regeneration cycles demonstrated the great potential of the hybrid adsorbent for sustainable utilization. This study is believed to shed new light on how to design rational processes for advanced treatment of real wastewater based on molecular identification.


Assuntos
Nanocompostos , Poluentes Químicos da Água , Adsorção , Níquel , Águas Residuárias
17.
Biomed Pharmacother ; 121: 109569, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31739163

RESUMO

XIAOPI formula has been approved for mammary hyperplasia treatment by National Medical Products Administration in China. However, the absorbed substances of XIAOPI formula and their influences on metabolic pathways are largely remained unknown. Liquid chromatography coupled with mass spectrometry was used to identify the substances existing in the serum. Network pharmacology was utilized to explore the underlying metabolic targets and pathways involved in. Western blotting and immunofluorescence assays were carried out for target validation. The exogenous results demonstrated 196 compounds were filtered as absorbed substances, among which 63 constituents or metabolites were tentatively identified in rat serum, and the metabolites of tanshinone II and tanshinone I were found to act as the major metabolic pathways. Subsequently, the endogenous results revealed that XIAOPI formula could significantly regulate serum biochemical indices and the bile acid secretion signaling ranks as top1 among all the involved pathways. The levels of intermediates including cholic acid, glycocholic acid, taurochenodeoxycholic acid and taurocholic acid were significantly upregulated following XIAOPI treatment, accompanied by increased expression of key enzyme CYP7A1, indicating that XIAOPI formula could accelerate the bile acid metabolism pathway. Our study presented a comprehensive metabolic profile of XIAOPI formula in vivo for the first time, and bile acid synthesis pathway might be one of the key mechanisms contributing to the pharmacological function of the formula.

18.
Bioorg Chem ; 94: 103474, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31859010

RESUMO

A class of 3-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were designed, synthesized and evaluated for their in vitro biological activities against maternal embryonic leucine zipper kinase (MELK). Among these derivatives, the optimized compound 16h exhibited potent enzyme inhibition (IC50 = 32 nM) and excellent anti-proliferative effect with IC50 values from 0.109 µM to 0.245 µM on A549, MDA-MB-231 and MCF-7 cell lines. The results of flow cytometry indicated that 16h promoted apoptosis of A549 cells in a dose-dependent manner and effectively arrested A549 cells in the G0/G1 phase. Further investigation indicated that compound 16h potently suppressed the migration of A549 cells, had moderate stability in rat liver microsomes and showed moderate inhibitory activity against various subtypes of human cytochrome P450. However, compound 16h is a multi-target kinase inhibitor and recently several studies reported MELK expression is not required for cancer growth, suggesting that compound 16h suppressed the proliferation and migration of cancer cells should through an off-target mechanism. Collectively, compound 16h has the potential to serve as a new lead compound for further anticancer drug discovery.

19.
Front Oncol ; 9: 1243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803620

RESUMO

Gastric cancer (GC), with high heterogeneity, can be mainly classified into intestinal type and diffuse type according to the Lauren classification system. Although a number of differences were reported between these two types, no study on the Lauren subtype-specific multi-gene signature for evaluation of GC prognosis has been conducted, and the molecular mechanism underlying its poor prognosis has still remained elusive. Therefore, this study aimed to explore subtype-specific multi-gene signature for prognostic prediction in different subtypes of Lauren classification. With combination of the least absolute shrinkage and selection operator (LASSO) algorithm and the Akaike information criterion (AIC), the 3-gene subtype-specific prognostic signature was successfully established in diffuse type GC using GSE62254 dataset. Following the calculation of risk score (RS) based on 3-gene signature, the nomogram models were established to predict 1-, 3-, and 5-year overall survival in diffuse type GC. Moreover, the prognostic predictive nomogram model of diffuse type GC was also proved to be effective for validation of GSE1549 dataset and by a Gene Expression Omnibus (GEO)-based meta-analysis. In the analysis of the correlation between RS and clinical-pathological characteristics, RS and two genes of the 3-gene signature (EMCN and COL4A5) were found to be positively correlated with peritoneal metastasis. Furthermore, EMCN and COL4A5, rather than CCL11, were proved to be able to enhance the adhesion ability of MKN45 and NUGC4 cells to peritoneal mesothelial cell line HMR-SV5. Eventually, it was proved that COL4A5 promoted peritoneal metastasis by activating Wnt signaling pathway, whereas the upregulation of integrin family genes mediated by FAK-AKT/ERK/STAT3 signaling pathway activation is involved in peritoneal metastasis promotion function of EMCN. Taken together, our study identified the subtype-specific 3-gene signature in diffuse type GC, which could effectively predict the patients' OS and might explain the molecular mechanisms in presence of its poor prognosis.

20.
Front Pharmacol ; 10: 1371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803057

RESUMO

Macrophages are the most abundant stromal cells associated with the host immune system in multiple malignancies including breast cancer. With proven clinical efficacy and no noticeable adverse effects, XIAOPI formula (XPS) has been approved for breast hyperplasia treatment by the State Food and Drug Administration of China (SFDA) in 2018. The existing knowledge about the anti-breast cancer activities and mechanisms of XPS has been very limited. The present study aimed to investigate whether XPS could exert an anti-breast cancer effect by regulating tumor-associated macrophages (TAMs) in tumor microenvironment. Herein, breast cancer cells and TAMs were co-cultured using the transwell co-culture system to simulate the coexistence of them. XPS could significantly inhibit the proliferation, colony formation, breast cancer stem cells (CSCs) subpopulation, mammosphere formation abilities as well as stemness-related genes expression in both human and mouse breast cancer cells in the co-culture system. Additionally, XPS could suppress M2 phenotype polarization as well as C-X-C motif chemokine ligand 1 (CXCL1) expression and secretion of TAMs. Notably, further mechanistic explorations verified TAMs/CXCL1 as the critical target of XPS in inhibiting breast CSCs self-renewal in the co-culture system as the exogenous CXCL1 administration could abrogate the inhibitory effect of XPS on breast CSCs self-renewal. More importantly, XPS significantly inhibited mammary tumor growth, breast CSCs subpopulation, and TAMs/CXCL1 activity in mouse 4T1-Luc xenografts in vivo without any detectable side effects. Taken together, this study not only uncovers the immunomodulatory mechanism of XPS in treating breast cancer but also sheds novel insights into TAMs/CXCL1 as a potential molecular target for breast CSCs elimination.

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