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1.
Front Immunol ; 11: 18, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082311

RESUMO

CD47 is an immunoglobulin that is overexpressed on the surface of many types of cancer cells. CD47 forms a signaling complex with signal-regulatory protein α (SIRPα), enabling the escape of these cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed by various types of solid tumors and to be associated with poor patient prognosis in various types of cancer. A growing number of studies have since demonstrated that inhibiting the CD47-SIRPα signaling pathway promotes the adaptive immune response and enhances the phagocytosis of tumor cells by macrophages. Improved understanding in this field of research could lead to the development of novel and effective anti-tumor treatments that act through the inhibition of CD47 signaling in cancer cells. In this review, we describe the structure and function of CD47, provide an overview of studies that have aimed to inhibit CD47-dependent avoidance of macrophage-mediated phagocytosis by tumor cells, and assess the potential and challenges for targeting the CD47-SIRPα signaling pathway in anti-cancer therapy.

2.
Angew Chem Int Ed Engl ; 59(8): 3226-3234, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31756258

RESUMO

Pathogenesis hallmarks for tuberculosis (TB) are the Mycobacterium tuberculosis (Mtb) escape from phagolysosomal destruction and limited drug delivery into infected cells. Several nanomaterials can be entrapped in lysosomes, but the development of functional nanomaterials to promote phagolysosomal Mtb clearance remains a big challenge. Here, we report on the bactericidal effects of selenium nanoparticles (Se NPs) against Mtb and further introduce a novel nanomaterial-assisted anti-TB strategy manipulating Ison@Man-Se NPs for synergistic drug-induced and phagolysosomal destruction of Mtb. Ison@Man-Se NPs preferentially entered macrophages and accumulated in lysosomes releasing Isoniazid. Surprisingly, Ison@Man-Se/Man-Se NPs further promoted the fusion of Mtb into lysosomes for synergistic lysosomal and Isoniazid destruction of Mtb. Concurrently, Ison@Man-Se/Man-Se NPs also induced autophagy sequestration of Mtb, evolving into lysosome-associated autophagosomal Mtb degradation linked to ROS-mitochondrial and PI3K/Akt/mTOR signaling pathways. This novel nanomaterial-assisted anti-TB strategy manipulating antimicrobial immunity and Mtb clearance may potentially serve in more effective therapeutics against TB and drug-resistant TB.

3.
Microbes Infect ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678658

RESUMO

CD4+/CD8+ T cells play a major role in conferring immune protection against tuberculosis (TB), but it remains unknown how the immune responses of CD4+/CD8+ T cells exactly correlate with the clinical variables and disease statuses during anti-TB chemotherapy. To address this, several major immune parameters of CD4+/CD8+ T cells in peripheral blood derived from pulmonary TB patients and healthy volunteers were evaluated. We observed that active TB infection induced lower CD3+ T cell and CD4+ T cell levels but higher CD8+T cell levels, while anti-TB chemotherapy reversed these effects. Also, anti-TB treatment induced enhanced production of IL-2 and IFN-γ but reduced expression of IL-10 and IL-6. Moreover, the dynamic changes of CD3, CD4, and CD8 levels did not show a significant association with sputum smear positivity. However, the frequencies of IL-2+CD4+ or IL-10 + CD4+ T effector subpopulation or IL-1ß production in peripheral blood showed significant difference between patients positive for sputum smear and patients negative for sputum smear after anti-TB treatment. These findings implicated that recovery of Th1/CD8+T cell effector levels might be critical immunological events in pulmonary TB patients after treatment and further suggested the importance of these immunological parameters as potential biomarkers for prediction of TB progress and prognosis.

4.
Int J Biol Macromol ; 141: 1287-1292, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31499107

RESUMO

ß-conglycinin is one of the most allergenic proteins, and its constituent subunits α', α, and ß are all potential allergens to humans. In the present study, we concentrated on the destructed antigenic sites of ß subunit of ß-conglycinin after high hydrostatic pressure (HHP) treatment. In this paper, the overlapping gene fragments of the ß subunit of ß-conglycinin were amplified by polymerase chain reaction (PCR) and cloned into T7 phage vectors. After being packaged in vitro, the recombinant T7 phage was constructed, and the overlapping fragments of the ß subunit were displayed on the phage surface. The recombinant phages that expressed the overlapping fragments of the ß subunit were used to react with specific antiserum by indirect ELISA to identify the HHP destructed antigenic sites. After three rounds of expression and identification, we used synthetic peptide technology to identify that the obtained fragment was a conformational epitope. We further confirmed that HHP treatment changed the conformational structure of ß-conglycinin, which reduced the antigenicity of the protein.

5.
Mater Sci Eng C Mater Biol Appl ; 103: 109777, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349400

RESUMO

Tuberculosis (TB), caused by M.tuberculosis (Mtb), has become a top killer among infectious diseases. Enhancing the ability of anti-TB drugs to kill intracellular Mtb in host cells remains a big challenge. Here, an innovative nano-system was developed to increase drug delivery and Mtb-killing efficacy in Mtb-infected macrophages. We employed mannose surface decoration to develop mannosylated and PEGylated graphene oxide (GO-PEG-MAN). Such nano-platform exhibited increased uptake by macrophages via mannose receptor-mediated endocytosis in vitro. Interestingly, drug-loaded GO-PEG-MAN was preferentially up-taken by mannose receptor-expressing mucosal CD14+ macrophages isolated from Mtb-infected rhesus macaques than drug-loaded GO-PEG. Consistently, the drug concentration was also significantly higher in macrophages than that in T and B cells expressing no or low mannose receptor, implicating a useful macrophage/mannose receptor-targeted drug-delivery system relevant to the in vivo settings. Concurrently, rifampicin-loaded GO-PEG-MAN (Rif@GO-PEG-MAN) significantly increased rifampicin uptake, inducing long-lasting higher concentration of rifampicin in macrophages. Such innovative Rif@GO-PEG-MAN could readily get into the lysosomes of the Mtb host cells, where rifampicin underwent an accelerated release in acidic lysosomic condition, leading to explosive rifampicin release after cell entry for more effective killing of intracellular Mtb. Most importantly, Rif@GO-PEG-MAN-enhanced intracellular rifampicin delivery and pharmacokinetics significantly increased the efficacy of rifampicin-driven killing of intracellular BCG and Mtb bacilli in infected macrophages both in vitro and ex vivo. Such innovative nanocarrier approach may potentially enhance anti-TB drug efficacy and reduce drug side effects.


Assuntos
Sistemas de Liberação de Medicamentos , Grafite , Macrófagos , Manose , Mycobacterium tuberculosis/metabolismo , Nanopartículas , Rifampina , Tuberculose , Animais , Grafite/química , Grafite/farmacocinética , Grafite/farmacologia , Humanos , Macaca mulatta , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Manose/química , Manose/farmacocinética , Manose/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Rifampina/química , Rifampina/farmacocinética , Rifampina/farmacologia , Células THP-1 , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Tuberculose/patologia
6.
Medicine (Baltimore) ; 98(15): e15037, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985652

RESUMO

RATIONALE: Herpes zoster infection typically involves the posterior root ganglia and most of the symptoms are sensory. Motor involvement can occur in the same distribution but is relatively uncommon. Segmental zoster paresis is a rare motor complication of Herpes zoster, mimicking an abdominal hernia, but it needs no surgery different from the real abdominal wall hernia. PATIENT CONCERNS: We present a case of a 58-year-old man with an abdominal protrusion and characteristical herpes zoster rash. DIAGNOSES: Initially, the surgeon regarded it as an abdominal hernia, while ultrasonography excluded the abdominal wall defect, and then the dermatologist diagnosed it as segmental herpes zoster abdominal paralysis. INTERVENTIONS: He received a treatment with oral acyclovir, mecobalamin, and vitamin B1. OUTCOMES: The abdominal wall bulge disappeared after 2 months, avoiding unnecessary surgery. LESSONS: Segmental zoster abdominal paresis, mimicking an abdominal hernia needs no surgery.


Assuntos
Gastroparesia/diagnóstico , Herpes Zoster/diagnóstico , Diagnóstico Diferencial , Gastroparesia/tratamento farmacológico , Gastroparesia/patologia , Hérnia Abdominal/diagnóstico , Herpes Zoster/tratamento farmacológico , Herpes Zoster/patologia , Humanos , Masculino , Pessoa de Meia-Idade
7.
Front Oncol ; 9: 133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906733

RESUMO

Aggressive angiomyxoma (AAM) is an uncommon mesenchymal myxoid tumor that almost solely involves the soft tissues of the perineum and pelvis. An AAM originating from the liver is extremely rare. Herein, we present a case of a 45-year-old female with a large mass in the left lateral lobe of the liver. She underwent a left lateral lobe hepatectomy. The histopathology of the resected specimen showed features that were characteristic of AAM. Immunohistochemical analysis of the neoplastic cells showed reactions to antibodies against CD34, smooth muscle actin (SMA), and Ki67 (2%) and showed no reactions to antibodies against Estrogen receptor (ER), C-keratin (CK), and Desmin. The patient was subsequently diagnosed with a primary AAM of the liver. This is the largest AAM of the liver that has been reported. We hereby report these findings and review the current literature.

8.
Methods Mol Biol ; 1886: 99-113, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30374864

RESUMO

As a high-resolution imaging technique, AFM has been found to be a novel tool for cell topography and its quantitative imaging. This chapter is focused on the introduction of AFM cell topography and its quantitative imaging, which includes the basic principle of AFM imaging, basic operation modes of AFM imaging, AFM imaging of biological sample, critical tips for AFM cell topography and its quantitative imaging, applications of AFM cell topography and its quantitative imaging, and perspective. We believe that this work will help to promote the technological and methodological developments of AFM cell topography and its quantitative imaging, promoting further application of AFM in cell biology, immunology, and medicine.


Assuntos
Técnicas Citológicas , Processamento de Imagem Assistida por Computador , Microscopia de Força Atômica/métodos , Animais , Biomarcadores , Humanos , Processamento de Imagem Assistida por Computador/métodos , Microscopia de Força Atômica/normas
9.
J Cell Biochem ; 120(3): 3736-3746, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30229997

RESUMO

Oridonin, an active diterpenoid isolated from Rabdosia rubescens, has been reported for its antitumor activity on several cancers. However, its effect on human esophageal cancer remains unclear. In this study, we demonstrated that oridonin could inhibit the growth of human esophageal cancer cells both in vitro and in vivo. Oridonin not only suppressed the proliferation, but also induced cell cycle arrest and mitochondrial-mediated apoptosis in KYSE-30, KYSE-150, and EC9706 cells with dose-dependent manner. Further mechanism studies revealed that oridonin led cell cycle arrest in esophageal cancer cells via downregulating cell cycle-related proteins, such as cyclin B1 and CDK2, while upregulating p53 and p21. Oridonin also increased proapoptotic protein Bax and reduced antiapoptotic protein Bcl-2, as well as the increased expression of cleaved caspase-3, -8, and -9. In addition, oridonin treatment could significantly inhibit the PI3K/Akt/mTOR and Ras/Raf signaling pathway. In vivo results further demonstrated that oridonin treatment markedly inhibited tumor growth in the esophageal cancer xenograft mice model. Taken together, these results suggest that oridonin may be a potential anticancer agent for the treatment of esophageal cancer.

10.
Onco Targets Ther ; 11: 8197-8200, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532559

RESUMO

Primary clear cell carcinoma of pancreas is extremely rare. We present a case of a 64-year-old male with a mass in the distal body and tail of the pancreas. He underwent a distal pancreatectomy. The histopathology of tumor cells showed features with abundant clear cytoplasm and prominent cell boundaries. Immunohistochemical analysis of neoplastic cells showed reactions to antibodies against cytokeratin-7 and showed no reactions to antibodies against hepatocyte nuclear factor-1ß, carbonic anhydrase 9, synaptophysin, and chromogranin A. The patient was subsequently diagnosed with a primary clear cell carcinoma of the pancreas. This is the first time we have encountered it. We report this rare case and update the current literature of this tumor.

11.
Medicine (Baltimore) ; 97(52): e13858, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593188

RESUMO

RATIONALE: Primary pancreatic tuberculosis is extremely rare, it presents with non-specific clinical symptoms and imaging features; it may be falsely identified as a malignancy of the pancreas. PATIENT CONCERNS: A 41-year-old male with no history of tuberculosis presented to our hospital with a 2-week history of jaundice. DIAGNOSES: Abdominal computed tomography (CT) showed a heterogeneous irregular hypodense mass in the head of the pancreas causing dilatation of the common bile duct (CBD), and it was enhanced after infusion of contrast material. Serum cancer antigen (CA) 19-9 was 124 U/mL (normal: 0-40 U/mL). He was preoperatively diagnosed as having a pancreatic carcinoma. INTERVENTIONS: A Whipple procedure (pancreaticoduodenectomy) was performed. The pancreatic tuberculosis was confirmed based on the postoperative histopathologic specimens and acid-fast stain of the drainage. Then isoniazid, rifampicin, and ethambutol were given for 6 months. OUTCOMES: The patient recovered very well. There was no evidence of tuberculosis recurrence, and the patient remained free of symptoms during the follow-up examination 1 year after surgery. LESSONS: Pancreatic tuberculosis should be considered when the mass is located on the head of the pancreas even with elevated serum CA19-9 levels.


Assuntos
Pancreatopatias/diagnóstico , Tuberculose Gastrointestinal/diagnóstico , Adulto , Antituberculosos/uso terapêutico , Antígeno CA-19-9/biossíntese , Diagnóstico Diferencial , Humanos , Masculino , Pancreatopatias/tratamento farmacológico , Pancreatopatias/cirurgia , Neoplasias Pancreáticas/diagnóstico , Pancreaticoduodenectomia/métodos , Tuberculose Gastrointestinal/tratamento farmacológico , Tuberculose Gastrointestinal/cirurgia
12.
Nanoscale Res Lett ; 13(1): 333, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30353236

RESUMO

Integrin ß1 is known to be involved in differentiation, migration, proliferation, wound repair, tissue development, and organogenesis. In order to analyze the binding probability between integrin ß1 ligand and cluster of differentiation 29 (CD29) receptors, atomic force microscopy (AFM) was used to detect native integrin ß1-coupled receptors on the surface of human adipose-derived stem cells (hADSc). The binding probability of integrin ß1 ligand-receptor interaction was probed by integrin ß1-functionalized tips on hADSc during early chondrogenic differentiation at the two-dimensional cell culture level. Cell morphology and ultrastructure of hADSc were measured by AFM, which demonstrated that long spindled cells became polygonal cells with decreased length/width ratios and increased roughness during chondrogenic induction. The binding of integrin ß1 ligand and CD29 receptors was detected by ß1-functionalized tips for living hADSc. A total of 1200 curves were recorded at 0, 6, and 12 days of chondrogenic induction. Average rupture forces were, respectively, 61.8 ± 22.2 pN, 60 ± 20.2 pN, and 67.2 ± 22.0 pN. Rupture events were 19.58 ± 1.74%, 28.03 ± 2.05%, and 33.4 ± 1.89%, respectively, which demonstrated that binding probability was increased between integrin ß1 ligand and receptors on the surface of hADSc during chondrogenic induction. Integrin ß1 and the ß-catenin/SOX signaling pathway were correlated during chondrogenic differentiation. The results of this investigation imply that AFM offers kinetic and visual insight into the changes in integrin ß1 ligand-CD29 receptor binding on hADSc during chondrogenesis. Changes in cellular morphology, membrane ultrastructure, and the probability of ligand-transmembrane receptor binding were demonstrated to be useful markers for evaluation of the chondrogenic differentiation process.

13.
Respir Res ; 19(1): 199, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305102

RESUMO

BACKGROUND: This study aimed at predicting the survival status on non-small cell lung cancer patients with the phenotypic radiomics features obtained from the CT images. METHODS: A total of 186 patients' CT images were used for feature extraction via Pyradiomics. The minority group was balanced via SMOTE method. The final dataset was randomized into training set (n = 223) and validation set (n = 75) with the ratio of 3:1. Multiple random forest models were trained applying hyperparameters grid search with 10-fold cross-validation using precision or recall as evaluation standard. Then a decision threshold was searched on the selected model. The final model was evaluated through ROC curve and prediction accuracy. RESULTS: From those segmented images of 186 patients, 1218 features were obtained via feature extraction. The preferred model was selected with recall as evaluation standard and the optimal decision threshold was set 0.56. The model had a prediction accuracy of 89.33% and the AUC score was 0.9296. CONCLUSION: A hyperparameters tuning random forest classifier had greater performance in predicting the survival status of non-small cell lung cancer patients, which could be taken for an automated classifier promising to stratify patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Tomografia Computadorizada por Raios X/tendências , Biomarcadores Tumorais , Bases de Dados Factuais/tendências , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Taxa de Sobrevida/tendências , Tomografia Computadorizada por Raios X/métodos
14.
Artif Cells Nanomed Biotechnol ; 46(sup3): S297-S307, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30183382

RESUMO

Graphene oxides (GO) is a promising building material to fabricate desired drug delivery system due to its excellent physicochemical properties. In this study, an innovative nano-drug (Ori@GE11-GO) was constructed based on GE11 peptide functionalized GO for targeted delivery of oridonin to realize the specific recognition of tumour cells and enhance anticancer efficiency. GE11 surface modification onto GO significantly increased the cellular uptake of GO in EGFR overexpressed oesophageal cancer cells (KYSE-30 and EC109 cells) than that of normal cells, indicating the EGFR targeting effects of Ori@GE11-GO. The internalized Ori@GE11-GO could accumulate into lysosomes and significantly inhibit the viability of cancer cells. Moreover, Ori@GE11-GO could effectively induce KYSE-30 and EC109 cells cycle arrest, apoptosis, mitochondrial membrane potential (△Ψm) disruption through the activation of apoptotic signalling pathways and the inhibition of EGFR/Ras/Raf/MEK/ERK signalling pathway, showing potential use of Ori@GE11-GO for cancer treatment. Taken together, this study demonstrates a good strategy for the construction of bio-functionalized GO drug delivery nanosystem to improve the cancer targeting efficiency of anticancer medicines.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Portadores de Fármacos , Neoplasias Esofágicas , Grafite , Nanopartículas , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Grafite/química , Grafite/farmacocinética , Grafite/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/uso terapêutico
15.
Bioinorg Chem Appl ; 2018: 1062562, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30073019

RESUMO

Zinc oxide nanoparticles (ZnO NPs) are used in an increasing number of industrial products such as rubber, paint, coating, and cosmetics. In the past two decades, ZnO NPs have become one of the most popular metal oxide nanoparticles in biological applications due to their excellent biocompatibility, economic, and low toxicity. ZnO NPs have emerged a promising potential in biomedicine, especially in the fields of anticancer and antibacterial fields, which are involved with their potent ability to trigger excess reactive oxygen species (ROS) production, release zinc ions, and induce cell apoptosis. In addition, zinc is well known to keep the structural integrity of insulin. So, ZnO NPs also have been effectively developed for antidiabetic treatment. Moreover, ZnO NPs show excellent luminescent properties and have turned them into one of the main candidates for bioimaging. Here, we summarize the synthesis and recent advances of ZnO NPs in the biomedical fields, which will be helpful for facilitating their future research progress and focusing on biomedical fields.

16.
Biomed Pharmacother ; 103: 1592-1601, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864947

RESUMO

Atomic force microscopy (AFM) is appropriately applied to the examination of hard surfaces and soft samples with extremely high resolution and ultrasensitive force, which cannot be obtained by other imaging techniques, including optical and electron microscopy. In the current study, AFM was employed to evaluate the anti-arthritic effect of licochalcone A (LCA), a flavonoid isolated from the root of Chinese medicinal herb Glycyrrhiza inflate, on rheumatoid arthritis synovial fibroblasts (RASFs) at the nanoscale for the first time. The morphology, ultrastructure and stiffness of RASFs was modified by LCA as determined by AFM, suggesting that LCA most likely exerts an anti-arthritic effect based on the key role of RASFs in the progression of RA. Further studies showed that the inhibitory effect of LCA on IκBα phosphorylation and degradation as well as on p65 nuclear translocation and phosphorylation contributed to altering the morphology, ultrastructure and stiffness of the RASF membrane. Interestingly, IKKß phosphorylation was not detectable in RASFs, indicating that LCA altered the morphology, ultrastructure and stiffness of the RASF membrane by inhibiting NF-κB activation independent of IKKß phosphorylation. Antigen-induced arthritis (AIA) was established in Sprague Dawley (SD) rats to validate the anti-arthritic effect of LCA, and LCA significantly decreased both the arthritis scores and paw swelling in the AIA rats, suggesting that LCA inhibits the progression and development of arthritis in vivo. Collectively, AFM provides evidence at the nanoscale to predict the anti-arthritic effect of drugs on RASFs, and LCA should be further investigated as a candidate agent for the treatment of arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Chalconas/uso terapêutico , Microscopia de Força Atômica , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Chalconas/química , Chalconas/farmacologia , Módulo de Elasticidade , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Masculino , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ratos Sprague-Dawley , Membrana Sinovial/patologia
17.
Pathol Res Pract ; 214(5): 691-699, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29567333

RESUMO

Matrine, as a natural alkaloid isolated from the traditional herb medicine sophora flavescens, has been proved to possess excellent biological activities, including anticancer effects. Now, this research aims to assess the anticancer activities and the mechanism of matrine against esophageal cancer cells, we investigated the proliferative inhibition, apoptosis induction, as well as the underlying mechanism of matrine on esophageal cancer KYSE-150 cells. It was found that matrine could suppress KYSE-150 cell proliferation and significantly mediate cell apoptosis in a dose-dependent relation by increasing intracellular reactive oxygen species level and triggering mitochondrial membrane potential disruption. More precise mechanism studies demonstrated that matrine could up-regulate the expression of Bax proteins and down-regulate the expression of Bcl-2 proteins, as well as the activation about caspase-3, 8 and 9 in KYSE-150 cells. The morphological analysis of KYSE-150 cells exhibited that matrine could destroy the F-actin and nuclei structures and induce morphological damage with increased surface height distribution and roughness of cell membrane. These results not only demonstrated the potential anticancer activity mechanism of matrine at nanoscale, but also provide preliminary guidance for the treatment of esophageal cancer using matrine.


Assuntos
Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Alcaloides , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Quinolizinas , Proteína X Associada a bcl-2/metabolismo
18.
Drug Deliv ; 24(1): 1549-1564, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29019267

RESUMO

Selenium nanoparticles (Se NPs) have attracted increasing interest in recent decades because of their anticancer, immunoregulation, and drug carrier functions. In this study, GE11 peptide-conjugated Se NPs (GE11-Se NPs), a nanosystem targeting EGFR over-expressed cancer cells, were synthesized for oridonin delivery to achieve enhanced anticancer efficacy. Oridonin loaded and GE11 peptide conjugated Se NPs (GE11-Ori-Se NPs) were found to show enhanced cellular uptake in cancer cells, which resulted in enhanced cancer inhibition against cancer cells and reduced toxicity against normal cells. After accumulation into the lysosomes of cancer cells and increase of oridonin release under acid condition, GE11-Ori-Se NPs were further transported into cytoplasm after the damage of lysosomal membrane integrity. GE11-Ori-Se NPs were found to induce cancer cell apoptosis by inducting reactive oxygen species (ROS) production, activating mitochondria-dependent pathway, inhibiting EGFR-mediated PI3K/AKT and inhibiting Ras/Raf/MEK/ERK pathways. GE11-Se NPs were also found to show active targeting effects against the tumor tissue in esophageal cancer bearing mice. And in nude mice xenograft model, GE11-Ori-Se NPs significantly inhibited the tumor growth via inhibition of tumor angiogenesis by reducing the angiogenesis-marker CD31 and activation of the immune system by enhancing IL-2 and TNF-α production. The selenium contents in mice were found to accumulate into liver, tumor, and kidney, but showed no significant toxicity against liver and kidney. This cancer-targeted design of Se NPs provides a new strategy for synergistic treating of cancer with higher efficacy and reduced side effects, introducing GE11-Ori-Se NPs as a candidate for further evaluation as a chemotherapeutic agent for EGFR over-expressed esophageal cancers.


Assuntos
Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Receptores ErbB/antagonistas & inibidores , Peptídeos/farmacologia , Selênio/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Diterpenos de Caurano/administração & dosagem , Diterpenos de Caurano/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Interleucina-2/biossíntese , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Nanopartículas/química , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Selênio/farmacocinética , Fator de Necrose Tumoral alfa/biossíntese
19.
Nanoscale ; 9(42): 16365-16374, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29052674

RESUMO

Poor bioavailability and non-specificity of chemotherapeutic agents are major challenges in breast cancer treatment. Antibodies and small molecules that block cell signaling pathways have shown promise in the clinic, but their application is also limited by the high costs and treatment dosages required. Novel therapies that aim to rapidly and specifically target malignant cells with long-lasting impact in the tumor microenvironment may ultimately improve clinical outcome in cancer patients. Here, we demonstrate that epidermal growth factor receptor (EGFR)-targeting GE11 peptides conjugated with PEGylated polylactic-co-glycolic acid (PLGA) nanoparticles can be used to effectively deliver an anti-cancer agent, curcumin, into EGFR-expressing MCF-7 cells in vitro and in vivo. Treatment of breast cancer cells and tumor-bearing mice with these curcumin-loaded nanoparticles gave rise to reduced phosphoinositide 3-kinase signaling, decreased cancer cell viability, attenuated drug clearance from the circulation, and suppressed tumor burden compared with free curcumin or non-EGFR targeting nanoparticles. The targeted nanoscale drug delivery system we describe here may provide a new strategy for the design of targeted cancer therapy vectors. Our study provides evidence that the efficacy of pharmacologic anti-cancer agents can be enhanced through their delivery in the form of modified nanoparticles that effectively target specific malignant cell types.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Curcumina/administração & dosagem , Portadores de Fármacos , Receptores ErbB/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas , Fosfatidilinositol 3-Quinases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Pharmacol Res ; 119: 479-489, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28411855

RESUMO

As the active anticancer component of Rabdosia Rubescens, oridonin has been proved to show strong anticancer activity in cancer cells, which is also found to be closely related to its specific inhibition effects on the EGFR tyrosine kinase activity. In this study, atomic force microscopy based single molecule force spectroscopy (AFM-SMFS) was used for real-time and in-situ detection of EGF-EGFR interactions in living esophageal cancer KYSE-150 cells to evaluate the anticancer activity of oridonin for the first time. Oridonin was found to induce apoptosis and also reduce EGFR expression in KYSE-150 cells. AFM-SMFS results demonstrated that oridonin could inhibit the binding between EGF and EGFR in KYSE-150 cells by decreasing the unbinding force and binding probability for EGF-EGFR complexes, which was further proved to be closely associated with the intracellular ROS level. More precise mechanism studies based on AFM-SMFS demonstrated that oridonin treatment could decrease the energy barrier width, increase the dissociation off rate constant and decrease the activation energy of EGF-EGFR complexes in ROS dependent way, suggesting oridonin as a strong anticancer agent targeting EGF-EGFR interactions in cancer cells through ROS dependent mechanism. Our results not only suggested oridonin as a strong anticancer agent targeting EGF-EGFR interactions in ROS dependent mechanism, but also highlighted AFM-SMFS as a powerful technique for pharmacodynamic studies by detecting ligand-receptor interactions, which was also expected to be developed into a promising tool for the screening and mechanism studies of drugs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos de Caurano/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Diterpenos de Caurano/química , Neoplasias Esofágicas/metabolismo , Esôfago/efeitos dos fármacos , Esôfago/metabolismo , Humanos , Isodon/química , Microscopia de Força Atômica
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