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1.
J Ethnopharmacol ; : 112929, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32416245

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Scutellaria barbata and Hedyotis diffusa (SH) herb pair is extensively used in Traditional Chinese Medicine for both efficacy enhancement and toxicity reduction, of TCM widely using for efficacy enhancing and toxicity reducing in breast cancer treatment in China and Asian countries. Superior clinical efficacy observations based on high dosages (≥60 g) motivated us to explore appropriate dosages and the underlying mechanisms of action. AIM OF THE STUDY: To explore the efficacy and potential mechanisms of actions of SH through in vitro and in vivo experiments and network pharmacology. MATERIALS AND METHODS: SH lyophilized powder (SHLP) was prepared from decoctions and the active ingredients were identified using high performance liquid chromatography (HPLC). Proliferation and migration experiments in vitro and tumor growth in vivo were performed to evaluate the effects of SHLP on breast cancer. Corresponding potential target genes for SHLP components and breast cancer were extracted from established databases and the Protein-Protein Internetwork of shared genes were constructed using STRING database. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation clusters were acquired and the top 30 pathways were presented. At last, as one of pathways indicated by enriched results, apoptosis was validated with flow cytometric analysis and caspase-3, 8, 9 activities. RESULTS: Seventy-five ingredients were identified from SHLP by HPLC. High SHLP doses inhibited proliferation and migration of three types of breast cancer cells in vitro and tumor growth in nude mice. After target genes extraction and intersection, the top 30 KEGG clusters were enriched, including VEGF, Micro-RNAs and cell cycle, besides, key genes in apoptosis were mapped. In the last, apoptosis was validated with flow cytometric analysis and caspase-3, 8, 9 activities after SHLP treatment. CONCLUSION: High SHLP dosages inhibited breast cancer in vitro and in vivo, enriched by network pharmacology and confirmed by flow cytometric analysis and caspase activation, with apoptosis identified as one of the mechanisms of action of SHLP. SHLP administration with higher doses is recommended for clinical usage.

2.
Brain Imaging Behav ; 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32314197

RESUMO

Recent studies have demonstrated that hemodialysis patients exhibit disruptions in functional networks with invisible cerebral alterations. We explored the alterations of functional connectivity in hemodialysis patients using the graph-theory method. A total of 46 hemodialysis patients (53.11 ± 1.58 years, 28 males) and 47 healthy controls (55.57 ± 0.86 years, 22 males) were scanned by using resting-state functional magnetic resonance imaging. The brains of these patients were divided into 90 regions and functional connectivity was constructed with the automatic anatomical labeling atlas. In the defined threshold range, the graph-theory analysis was performed to compare the topological properties including global, regional and edge parameters between the hemodialysis and the healthy control groups. Both hemodialysis patients and healthy control subjects demonstrated common small-world property of the brain functional connections. At the global level, the parameters normalized clustering coefficients and small-worldness were significantly decreased in hemodialysis patients compared with those noted in healthy controls. At the regional level, abnormal nodal metrics (increased or decreased nodal degree, betweenness centrality and efficiency) were widely found in hemodialysis patients compared with those of healthy controls. The network-based statistical method was employed and two disrupted neural circuits with 18 nodes and 19 edges (P = 0.0139, corrected) and 10 nodes and 11 edges (P = 0.0399, corrected) were detected. Of note, the edge-increased functional connectivity was associated with the salience network and the frontal-temporal-basal ganglia connection, whereas the edge-decreased functional connectivity was associated with the frontoparietal network. The graph-theory method may be one of the potential tools to detect disruptions of cerebral functional connectivity and provide important evidence for understanding the neuropathology of hemodialysis patients from the disrupted network organization perspective.

3.
Chin J Integr Med ; 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32144561

RESUMO

OBJECTIVE: To study the effect and mechanism of Huayu Wan (, HYW) in combination of chemotherapy of tumor treatment. METHODS: HYW serum was added in Lewis cells to assess its impact on fluorescent doxorubicin delivery in vitro. Then, Lewis tumor cells was implanted in C57BL/6 mice via xenograft transplantation. Tumor growth was measured and signal intensity corresponding to blood flow was assessed by laser doppler perfusion imaging (LDPI). Finally, the effect of HYW on the effificacy of doxorubicin was studied. RESULTS: HYW can improve the transfer of fluorescent doxorubicin into cells. The blood flow signal in the tumor tissues of the HYW group was higher than that of the control group (P<0.01). Furthermore, HYW improved drug delivery of doxorubicin to tumor tissues, and this activity was associated with HYW-induced microvascular proliferation (P<0.01). CONCLUSIONS: HYW can promote microangiogenesis and increase blood supply in tumor tissues, which in turn may increase the risk of metastasis. At the same time, HYW increases drug delivery and improves the effificacy of chemotherapy drugs through vascular proliferation. Therefore, rational judgment must be exercised when considering applying HYW to an antitumor regimen.

4.
Front Hum Neurosci ; 14: 80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218727

RESUMO

Structural and functional brain alterations have been always observed in end-stage renal disease (ESRD) patients undergoing hemodialysis. The present study aimed to investigate the gray matter volume (GMV) changes in hemodialysis patients compared with those noted in healthy subjects, as well as explore the associated functional connectivity alterations based on the abnormal GMV regions. The experiments revealed the effects of regional morphometry aberrance on the brain functional integrity. A total of 46 hemodialysis patients (53.11 ± 1.58 years, 28 males) and 47 healthy subjects (55.57 ± 0.86 years, 22 males) were enrolled in the present study. All subjects underwent high-resolution T1-weighted imaging, resting-state functional MR imaging, and laboratory examinations were performed in hemodialysis patients. The GMV deficits were analyzed using voxel-based morphometry (VBM) and regions with GMV alteration were defined as seeds for functional connectivity analysis. Correlation analyses between significantly different regions and the results of the blood examination were further performed. We found that bilateral thalamus exhibited significantly increased volumes in the hemodialysis patients compared with those of the healthy subjects. However, the bilateral rectus, bilateral caudate, and bilateral temporal gyrus demonstrated significantly decreased volumes. When the regions with GMV alterations were defined as seeds, the hemodialysis patients exhibited decreased integrations in the thalamo-cortical network and within the basal-ganglia connection. The present study revealed the presence of different types of structural and functional brain impairments in hemodialysis patients.

5.
Sleep Med ; 69: 34-40, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045852

RESUMO

OBJECTIVE: Brain iron deposition in hemodialysis (HD) patients increases over time. Iron deficiency in gray matter nuclei has been reported to lead to idiopathic restless legs syndrome (RLS) symptoms. Regardless of unpleasant RLS sensations, the patterns of iron deposition between hemodialysis patients with RLS (HD-RLS) and hemodialysis patients without RLS (HD-nRLS) are still unclear. To evaluate the differences in iron deposition patterns between HD-RLS and HD-nRLS patients, we utilized quantitative susceptibility mapping (QSM). METHODS: In sum, 24 HD-RLS patients, 25 HD-nRLS patients and 30 age- and sex-matched healthy controls (HCs) were enrolled. The QSM was used to assess susceptibility values of the regions of interest (ROIs), including the caudate nucleus (CN), putamen (PUT), globus pallidus (GP), thalamus (THA), substantia nigra (SN), red nucleus (RN) and dentate nucleus (DN). RESULTS: HD duration was significantly longer in HD-RLS patients than in HD-nRLS patients (P < 0.05). The susceptibility of HD-RLS and HD-nRLS patients in PUT was higher than that in HCs (P < 0.05), illustrating elevated iron content in the nucleus. Compared with HD-nRLS patients, HD-RLS patients demonstrated reduced susceptibility in CN and PUT (both P < 0.05). Compared with HCs, HD-RLS patients displayed decreased susceptibility in DN (P < 0.05). CONCLUSIONS: Different iron deposition patterns between HD-RLS and HD-nRLS patients in PUT and DN, which further support disturbed sensory processing in RLS, may be involved in RLS pathogenesis in HD patients.

6.
Cancer Med ; 9(1): 179-193, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31724326

RESUMO

The current criteria for defining the recurrence risks of stage II colorectal cancer (CRC) are not robust; therefore, we aimed to explore novel gene signatures to predict recurrence risks and to reveal the underlying mechanisms of stage II CRC. First, the gene expression profiles of 124 patients with stage II CRC from The Cancer Genome Atlas (TCGA) database were obtained to screen differentially expressed genes (DEGs). A total of 202 DEGs, including 128 upregulated and 74 downregulated, were identified in the recurrence group (n = 24) compared to the nonrecurrence group (n = 100). Furthermore, the top 5 DEGs (ZNF561, WFS1, SLC2A1, MFI2, and PTGR1) were identified by random forest variable hunting, and four (ZNF561, WFS1, SLC2A1, and PTGR1) were selected to create a four-gene recurrent model (GRM), with an area under the curve (AUC) of 0.882 according to the receiver operating characteristic curve, and the robust diagnostic effectiveness of the GRM was further validated with another gene expression profiling dataset (GSE12032), with an AUC of 0.943. The diagnostic effectiveness of the GRM regarding recurrence was associated with poor disease-free survival in all stages of CRC. In addition, gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed 18 enriched functions and 6 enriched pathways. Four genes, ABCG2, CACNA1F, CYP19A1, and TF, were identified as hub genes by the protein-protein interaction network, which further validated that these genes were correlated with a poor pathologic stage and overall survival in all stages of CRC. In conclusion, the GRM can effectively classify stage II CRC into groups of high and low risks of recurrence, thereby making up for the prognostic value of the traditional clinicopathological risk factors defined by the National Comprehensive Cancer Network guidelines. The hub genes may be useful therapeutic targets for recurrence. Thus, the GRM and hub genes could offer clinical value in directing individualized and precision therapeutic regimens for stage II CRC patients.

7.
Lancet Oncol ; 21(2): 306-316, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31879220

RESUMO

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.

8.
Biomacromolecules ; 21(2): 444-453, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31851512

RESUMO

Self-assembled peptide nanofibers have been widely studied in cancer nanotherapeutics with their excellent biocompatibility and low toxicity of degradation products, showing the significant potential in inhibiting tumor progression. However, poor solubility prevents direct intravenous administration of nanofibers. Although water-soluble peptide precursors have been formed via the method of phosphorylation for intravenous administration, their opportunities for broad in vivo application are limited by the weak capacity of encapsulating drugs. Herein, we designed a novel restructured reduced glutathione (GSH)-responsive drug delivery system encapsulating doxorubicin for systemic administration, which achieved the intracellular restructuration from three-dimensional micelles into one-dimensional nanofibers. After a long blood circulation, micelles endocytosed by tumor cells could degrade in response to high GSH levels, achieving more release and accumulation of doxorubicin at desired sites. Further, the synergistic chemotherapy effects of self-assembled nanofibers were confirmed in both in vitro and in vivo experiments.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31814841

RESUMO

The purpose of this study was to prepare a dioscin nanosuspension (Dio-NS) that has a better distance and high solubility for oral administration and to evaluate its hepatoprotective effects. Optimal primary manufacture parameters, including shear time, shear speed, emulation temperature, pressure, and cycles of homogenization, were determined by single-factor experiments. The concentrations of dioscin, SDS, and soybean lecithin were optimized using the central composite design-response surface method, and their effects on the mean particle size (MPS) and particle size distribution of Dio-NS were investigated. Characterization of the Dio-NS formulations included examinations of the surface morphology and physical status of dioscin in Dio-NS, the stability of Dio-NS at different temperatures, in vitro solubility, and liver protective effect in vivo. Under optimal conditions, Dio-NS had an MPS of 106.72 nm, polydispersity index of 0.221, and zeta potential of -34.27 mV. Furthermore, the proportion of dioscin in Dio-NS was approximately 21.26%. The observation of particles with a spherical shape and the disappearance of crystalline peaks indicated that the physical and chemical properties of Dio-NS were altered. Furthermore, we observed that the dissolution of Dio-NS was superior to that of a physical mixture and Dio-GZF. Moreover, Dio-NS was demonstrated to have a protective effect against CCl4-induced acute liver damage in mice that was equivalent to that of silymarin (a positive control drug) at the same dose. The good hepatoprotective effect of our Dio-NS preparation can provide a theoretical basis for investigating its absorption mechanisms in the body.

11.
Chem Commun (Camb) ; 55(89): 13406-13409, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31637391

RESUMO

A new small molecular hole-transporting material, 1,3,6,8-tetrakis[N-(p-methoxyphenyl)-N'-(9,9'-dimethyl-9H-fluoren-2-yl)-amino]pyrene (TFAP) was synthesized and applied in CH3NH3PbI3-perovskite solar cells. A best power conversion efficiency of 19.7% with a photovoltage of 1.11 V has been achieved.

12.
Lipids Health Dis ; 18(1): 179, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639005

RESUMO

BACKGROUND: Ceramide plays pathogenic roles in nonalcoholic fatty liver disease (NAFLD) via multiple mechanisms, and as such inhibition of ceramide de novo synthesis in the liver may be of therapeutically beneficial in patients with NAFLD. In this study, we aimed to explore whether inhibition of ceramide signaling by myriocin is beneficial in animal model of NAFLD via regulating autophagy. METHODS: Sprague Dawley rats were randomly divided into three groups: standard chow (n = 10), high-fat diet (HFD) (n = 10) or HFD combined with oral administration of myriocin (0.3 mg/kg on alternate days for 8 weeks) (n = 10). Liver histology and autophagy function were measured. HepG2 cells were incubated with fatty acid with or without myriocin treatment. Lipid accumulation and autophagy markers in the HepG2 cells were analyzed. Serum ceramide changes were studied in 104 subjects consisting healthy adults, liver biopsy-proven patients with NAFLD and liver biopsy-proven patients with chronic hepatitis B (CHB). RESULTS: Myriocin reversed the elevated body weight and serum transaminases and alleviated dyslipidemia in HFD fed rats. Myriocin treatment significantly attenuated liver pathology including steatosis, lobular inflammation and ballooning. By qPCR analysis, it was revealed that myriocin corrected the expression pattern of fatty acid metabolism associated genes including Fabp1, Pparα, Cpt-1α and Acox-2. Further, myriocin also restored the impaired hepatic autophagy function in rats with HFD-induced NASH, and this has been verified in HepG2 cells. Among the sphingolipid species that we screened in lipidomic profiles, significantly increased ceramide was observed in NASH patients as compared to the controls and non-NASH patients, regardless of whether or not they have active CHB. CONCLUSIONS: Ceramide may play an important regulatory role in the autophagy function in the pathogenesis of NASH. Hence, blockade of ceramide signaling by myriocin may be of therapeutically beneficial in NASH. TRIAL REGISTRATION: Registration ID: ChiCTR-DDT-13003983 . Data of registration: 13 May, 2013, retrospectively registered.

13.
ACS Omega ; 4(2): 3392-3397, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-31459554

RESUMO

Heterojunction catalysts are attracting attention in the field of photocatalytic hydrogen generation for their effective light utilization and charge separation personalities. In this work, we report a simple and low-cost two-step solvothermal method for synthesizing Cu2O/TiO2 heterojunction catalysts with an octahedral morphology and a mean particle size of about 30 nm. It is found that the introduction of Cu2O astonishingly enhances the photocatalytic performance of TiO2. Under the condition of methanol acting as a sacrificial agent, the heterojunction with 0.19% Cu species shows an optimal hydrogen generation rate of 24.83 mmol g-1 h-1, which is nearly 3 orders of magnitude higher than that of the pristine TiO2 catalyst.

14.
Front Mol Neurosci ; 12: 159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316347

RESUMO

Spinocerebellar ataxia 3, also known as Machado-Joseph disease (SCA3/MJD), is a rare autosomal-dominant neurodegenerative disease caused by an abnormal expansion of CAG repeats in the ATXN3 gene. In the present study, we performed a global metabolomic analysis to identify pathogenic biochemical pathways and novel biomarkers implicated in SCA3 patients. Metabolic profiling of serum samples from 13 preclinical SCA3 patients, 13 symptomatic SCA3 patients, and 15 healthy controls were mapped using ultra-high-performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry techniques. The symptomatic SCA3 patients showed a metabolic profile significantly distinct from those of the preclinical SCA3 patients and healthy controls. The principal differential metabolites were involved in the amino acid (AA) metabolism and fatty acid metabolism pathways. In addition, four candidate serum biomarkers, FFA 16:1 (palmitoleic acid), FFA 18:3 (linolenic acid), L-Proline and L-Tryptophan, were selected to discriminate between symptomatic SCA3 patients and healthy controls by receiver operator curve analysis with an area under the curve of 0.979. Our study demonstrates that symptomatic SCA3 patients present distinct metabolic profiles with perturbed AA metabolism and fatty acid metabolism, and FFA 16:1, FFA 18:3, L-Proline and L-Tryptophan are identified as potential disease biomarkers.

15.
Drug Dev Ind Pharm ; 45(9): 1556-1564, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271317

RESUMO

Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor. Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR. Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo. Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs. Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Nanoconjugados/química , Compostos Organofosforados/administração & dosagem , Acetais/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Composição de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Micelas , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Compostos Organofosforados/química , Compostos Organofosforados/farmacocinética , Poliésteres/química , Polietilenoglicóis/química , Distribuição Tecidual
16.
Mol Pharm ; 16(7): 2966-2979, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095914

RESUMO

Doxorubicin (DOX) is a first-line chemo drug for cancer therapy, yet it fails to treat multi-drug-resistant tumors. Hypoxia is a major causative factor leading to chemotherapy failure. Particularly, hypoxia up-regulates its responsive transcription factor-hypoxia-inducible factors (HIF)-to induce the overexpression of drug resistant genes. Metformin (MET) is recently found to cooperate with DOX against multiple tumors. As a mitochondrial inhibitor, MET could suppress tumor oxygen consumption, and thereby modulate the hypoxic tumor microenvironment. In this study, we used cationic liposomes to codeliver both DOX and MET for treating multi-drug-resistant breast cancer cells-MCF7/ADR. Faster release of MET enhanced the cytotoxicity of DOX through attenuating hypoxic stress both in vivo and in vitro. MET diminished the cellular oxygen consumption and inhibited HIF1α and P-glycoprotein (Pgp) expression in vitro. In addition, the dual-drug-loaded liposomes increased tumor targeting and intratumoral blood oxygen saturation, which suggested that the tumor reoxygenation effect of MET facilitated the exertion of its synergistic activity with DOX against MCF7/ADR xenografts. In general, our study represents a feasible strategy to boost the therapeutic effect in treating multi-drug-resistant cancer by improving the hypoxic tumor microenvironment.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30998478

RESUMO

Chronic Kidney Disease (CKD) is a menace that is affecting 10% of the world population and 15% of the South African population. The early and cheap diagnosis of this disease with accuracy and reliability will save 20,000 lives in South Africa per year. Scientists are developing smart solutions with Artificial Intelligence (AI). In this paper, several typical and recent AI algorithms are studied in the context of CKD and the extreme gradient boosting (XGBoost) is chosen as our base model for its high performance. Then, the model is optimized and the optimal full model trained on all the features achieves a testing accuracy, sensitivity and specificity of 1.000, 1.000 and 1.000, respectively. Note that, to cover the widest range of people, the time and monetary costs of CKD diagnosis have to be minimized with fewest patient tests. Thus the reduced model using fewer features is desirable while it should still maintain high performance. To this end, the set-theory based rule is presented which combines a few feature selection methods with their collective strengths. The reduced model using about a half of the original full features performs better than the models based on individual feature selection methods and achieves accuracy, sensitivity and specificity of 1.000, 1.000 and 1.000, respectively.

18.
Oncol Lett ; 17(4): 3709-3718, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30930982

RESUMO

Pancreatic cancer has an overall 5-year survival rate of only 9%, due to its rapid metastasis and poor prognosis. To combat this disease, novel therapeutic targets and biomarkers are required. In this study, immunohistochemistry was used to detect the expression of P21 activated kinase 2 (PAK2) protein in the tissues of cancer and the paired adjacent normal tissues. The association between PAK2 and the clinicopathologic features of patients with pancreatic cancer was subsequently analyzed. The results indicated that PAK2 was overexpressed in the cancer tissues, which indicated high pTNM stage, poor tumor grade, lymph node metastasis and vascular invasion. In addition, the results demonstrated evidence of a close association between PAK2 expression and poor prognosis of patients with pancreatic cancer. The results also suggested that PAK2 may promote pancreatic cancer cell proliferation and migration in vitro through clone formation, MTT, wound healing and Transwell assays. The present study further identified that PAK2 could stimulate pancreatic cancer growth and metastasis in mice. Decreased expression of proliferation marker protein Ki-67 and proliferating cell nuclear antigen in response to PAK2 knockdown further verified the role of PAK2 in promoting cell proliferation by western blot analysis. In addition, the expression levels of matrix metallopeptidase (MMP) 2 and MMP9 were decreased in PANC1 and BxPC3 cell lines transfected with PAK2-short hairpin RNA as indicated in western blot analysis, suggesting a function of PAK2 in promoting cell invasion. Collectively, these findings revealed a critical role for PAK2 in the development of pancreatic cancer and may have important implications for the management of this disease.

19.
Medicine (Baltimore) ; 98(17): e15393, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027136

RESUMO

RATIONALE: Combination of polyserositis and elevated serum CA 125 is common in tumor or infectious disease, but this clinical combination is also found in other diseases. It could be the initial manifestation of pseudo-pseudo Meigs' syndrome (PPMS), which is characterized by the presence of polyserositis and raised CA-125 level in systemic lupus erythematosus (SLE). PATIENT'S CONCERNS: A 44-year-old Chinese female was admitted with three months history of painless abdominal distension accompanied by watery diarrhea 5-6 times daily, shortness of breath, fatigue, lower limb swelling, and 10 kg weight loss. The test results showed peripheral cytopenias, hypoproteinemia, renal dysfunction and elevated CA 125, antidouble-stranded DNA antibodies, and anti-Sjogren's syndrome A antigen antibody was positive. There is no evidence for the diagnosis of solid tumor according to the results of imaging modality and pathological examination. DIAGNOSIS: The patient was diagnosed as pseudo-pseudo Meigs syndrome. INTERVENTION: The patient received hormone, leflunomide, and Plaquenil therapy. OUTCOMES: The patient's symptoms were relieved and the laboratory index was improved after the treatment of hormone and immunosuppressant. LESSONS SUBSECTIONS AS PER STYLE: PPMS is characterized by the combination of serous effusion and elevated serum CA 125 with no evidence of tumor among SLE patients. Clinicians should be aware of the diagnosis of PPMS avoiding unnecessary anxiety or surgical interventions.


Assuntos
Ascite/diagnóstico , Antígeno Ca-125/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Derrame Pleural/diagnóstico , Adulto , Ascite/terapia , Diagnóstico Diferencial , Feminino , Humanos , Lúpus Eritematoso Sistêmico/terapia , Derrame Pleural/terapia , Síndrome
20.
Funct Integr Genomics ; 19(4): 633-643, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30850904

RESUMO

Vascular calcification is a common complication in patients with chronic kidney disease (CKD). It is an important predictor of cardiovascular disease and all-cause mortality. Previous studies have confirmed that bone marrow mesenchymal stem cell (BMSC) therapy can reduce vascular calcification, but the specific mechanism is still controversial. In this study, we aimed to investigate the mechanisms of BMSC-derived exosomes (EXO) in improving vascular calcification. BMSCs were cultured and EXO were isolated using the Total Exosome Isolation Reagent. Human aortic vascular smooth muscle cells (HA-VSMCs) were cultured into three groups: control group, high phosphorus group, and high phosphorus plus EXO group. Then, indicators related to smooth muscle cell calcification and microRNA profiles were analyzed. BMSC-derived exosomes inhibited high phosphorus-induced calcification in HA-VSMCs. Besides, EXO treatment reduced calcium content and decreased the alkaline phosphatase (AKP) activity in high phosphorus co-incubated HA-VSMCs. MicroRNA (miRNA) and mRNA expression profiles analyses revealed that 63 miRNAs were significantly upregulated and 1424 genes were significantly downregulated in HA-VSMCs after EXO treatment. Functional miRNA-gene regulatory network revealed that mTOR, MAPK, and Wnt signaling pathway were involved in vascular calcification. BMSC-derived exosomes alleviated high phosphorus-induced calcification in HA-VSMC through modifying miRNA profiles.


Assuntos
Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Calcificação Vascular/metabolismo , Fosfatase Alcalina/metabolismo , Cálcio/metabolismo , Células Cultivadas , Exossomos/genética , Redes Reguladoras de Genes , Humanos , MicroRNAs/metabolismo , Fósforo/toxicidade , Transcriptoma , Regulação para Cima , Calcificação Vascular/etiologia , Calcificação Vascular/genética
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