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1.
Artigo em Inglês | MEDLINE | ID: mdl-31713495

RESUMO

Peptides have acquired increasing interest as promising therapeutics, particularly as anti-cancer alternatives during the recent years. They have been reported to demonstrate incredible anti-cancer potentials due to its low manufacturing cost, ease of synthesis and great specificity and selectivity. Hepatocellular carcinoma (HCC) is among the leading cause of cancer death globally, and the effectiveness of current liver treatment has turned out to be a critical issue in treating the disease efficiently. Hence, new interventions are being explored for the treatment of hepatocellular carcinoma. Anticancer peptides (ACPs) were firstly identified as part of the innate immune system of living organisms, demonstrating promising activity against infectious diseases. Differentiated beyond the traditional effort on endogenous human peptides, the discovery of peptide drugs has evolved to rely more on isolation from other natural sources or through medicinal chemistry approach. Up to the present time, pharmaceutical industry intends to conduct more clinical trials for development of peptides as alternative therapy since peptides possess numerous advantages such as high selectivity and efficacy against cancers over normal tissues, as well as broad spectrum of anticancer activity. In this review, we present an overview of the literature concerning peptide's physicochemical properties and describe the contemporary status of several anticancer peptides currently engaged in clinical trials for the treatment of hepatocellular carcinoma.

2.
ACS Nano ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31714733

RESUMO

Tumorous vasculature plays key roles in sustaining tumor growth. Vascular disruption is accompanied by internal coagulation along with platelet recruitment and the resulting suppression of oxygen supply. We intend to artificially create this physiological process to establish the mutual feedback between vascular disruption and platelet-mimicking biotaxis for the cascade amplification of hypoxia-dependent therapy. To prove this concept, mesoporous silica nanoparticles are co-loaded with a hypoxia-activated prodrug (HAP) and a vessel-disruptive agent and then coated with platelet membranes. Upon entering into tumors, our nanotherapeutic can disrupt local vasculature for tumor inhibition. This platelet membrane-coated nanoplatform shares the hemorrhage-tropic function with parental platelets and can be persistently recruited by the vasculature-disrupted tumors. In this way, the intratumoral vascular disruption and tumor targeting are biologically interdependent and mutually reinforced. Relying on this mutual feedback, tumorous hypoxia was largely promoted by more than 20-fold, accounting for the effective recovery of the HAP's cytotoxicity. Consequently, our bioinspired nanodesign has demonstrated highly specific and effective antitumor potency via the biologically driven cooperation among intratumoral vascular disruption, platelet-mimicking biotaxis, cascade hypoxia amplification, and hypoxia-sensitive chemotherapy. This study offers a paradigm of correlating the therapeutic design with the physiologically occurring events to achieve better therapy performance.

3.
Biomaterials ; 223: 119472, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31499254

RESUMO

Inflammation during photothermal therapy (PTT) of tumor usually results in adverse consequences. Here, a biomembrane camouflaged nanomedicine (mPDAB) containing polydopamine and ammonia borane was designed to enhance PTT efficacy and mitigate inflammation. Polydopamine, a biocompatible photothermal agent, can effectively convert light into heat for PTT. Ammonia borane was linked to the surface of polydopamine through the interaction of hydrogen bonding, which could destroy redox homoeostasis in tumor cells and reduce inflammation by H2 release in tumor microenvironment. Owing to the same origin of outer biomembranes, mPDAB showed excellent tumor accumulation and low systemic toxicity in a breast tumor model. Excellent PTT efficacy and inflammation reduction made the mPDAB completely eliminate the primary tumors, while also restraining the outgrowth of distant dormant tumors. The biomimetic nanomedicine shows potentials as a universal inflammation-self-alleviated platform to ameliorate inflammation-related disease treatment, including but not limited to PTT for tumor.

4.
ACS Chem Neurosci ; 10(10): 4328-4336, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31411453

RESUMO

α-Conotoxin Vc1.1 inhibits the nicotinic acetylcholine receptor (nAChR) α9α10 subtype and has the potential to treat neuropathic chronic pain. To date, the crystal structure of Vc1.1-bound α9α10 nAChR remains unavailable; thus, understanding the structure-activity relationship of Vc1.1 with the α9α10 nAChR remains challenging. In this study, the Vc1.1 side chains were minimally modified to avoid introducing large local conformation perturbation to the interactions between Vc1.1 and α9α10 nAChR. The results suggest that the hydroxyl group of Vc1.1, Y10, forms a hydrogen bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required. However, Vc1.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue at this position increases the binding affinity of Vc1.1. Furthermore, the carboxyl group of Vc1.1, D11, forms two hydrogen bonds with α9 N154 and R81, respectively, whereas introducing an extra carboxyl group at this position significantly decreases the potency of Vc1.1. Second-generation mutants of Vc1.1 [S4 Dab, N9A] and [S4 Dab, N9W] increased potency at the α9α10 nAChR by 20-fold compared with that of Vc1.1. The [S4 Dab, N9W] mutational effects at positions 4 and 9 of Vc1.1 are not cumulative but are coupled with each other. Overall, our findings provide valuable insights into the structure-activity relationship of Vc1.1 with the α9α10 nAChR and will contribute to further development of more potent and specific Vc1.1 analogues.

5.
Biochem Pharmacol ; 169: 113613, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31445019

RESUMO

Previously, we reported that hepatic muscarinic receptors modulate both acute and chronic liver injury, however, the role of muscarinic receptors in fatty liver disease is unclear. We observed in patients who underwent weight loss surgery, a decrease in hepatic expression of M3 muscarinic receptors (M3R). We also observed that fat loading of hepatocytes, increased M3R expression. Based on these observations, we tested the hypothesis that M3R regulate hepatocyte lipid accumulation. Incubation of AML12 hepatocytes with 1 mM oleic acid resulted in lipid accumulation that was significantly reduced by co-treatment with a muscarinic agonist (pilocarpine or carbachol), an effect blocked by atropine (a muscarinic antagonist). Similar treatment of Hepa 1-6 cells, a mouse hepatoblastoma cell line, showed comparable results. In both, control and fat-loaded AML12 cells, pilocarpine induced time-dependent AMPKα phosphorylation and significantly up-regulated lipolytic genes (ACOX1, CPT1, and PPARα). Compound C, a selective and reversible AMPK inhibitor, significantly blunted pilocarpine-mediated reduction of lipid accumulation and pilocarpine-mediated up-regulation of lipolytic genes. BAPTA-AM, a calcium chelator, and STO-609, a calcium/calmodulin-dependent protein kinase kinase inhibitor, attenuated agonist-induced AMPKα phosphorylation. Finally, M3R siRNA attenuated agonist-induced AMPKα phosphorylation as well as agonist-mediated reduction of hepatocyte steatosis. In conclusion, this proof-of-concept study demonstrates that M3R has protective effects against hepatocyte lipid accumulation by activating AMPK pathway and is a potential therapeutic target for non-alcoholic fatty liver disease.

7.
Nat Commun ; 10(1): 3199, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324770

RESUMO

Most cancer vaccines are unsuccessful in eliciting clinically relevant effects. Without using exogenous antigens and adoptive cells, we show a concept of utilizing biologically reprogrammed cytomembranes of the fused cells (FCs) derived from dendritic cells (DCs) and cancer cells as tumor vaccines. The fusion of immunologically interrelated two types of cells results in strong expression of the whole tumor antigen complexes and the immunological co-stimulatory molecules on cytomembranes (FMs), allowing the nanoparticle-supported FM (NP@FM) to function like antigen presenting cells (APCs) for T cell immunoactivation. Moreover, tumor-antigen bearing NP@FM can be bio-recognized by DCs to induce DC-mediated T cell immunoactivation. The combination of these two immunoactivation pathways offers powerful antitumor immunoresponse. Through mimicking both APCs and cancer cells, this cytomembrane vaccine strategy can develop various vaccines toward multiple tumor types and provide chances for accommodating diverse functions originating from the supporters.

8.
PLoS One ; 14(7): e0219764, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31299062

RESUMO

Factors governing the development of liver fibrosis in nonalcoholic steatohepatitis (NASH) are only partially understood. We recently identified adipocyte enhancer binding protein 1 (AEBP1) as a member of a core set of dysregulated fibrosis-specific genes in human NASH. Here we sought to investigate the relationship between AEBP1 and hepatic fibrosis. We confirmed that hepatic AEBP1 expression is elevated in fibrosis compared to lobular inflammation, steatosis, and normal liver, and increases with worsening fibrosis in NASH patients. AEBP1 expression was upregulated 5.8-fold in activated hepatic stellate cells and downregulated during chemical and contact induction of biological quiescence. In LX-2 and HepG2 cells treated with high glucose (25 mM), AEBP1 expression increased over 7-fold compared to normal glucose conditions. In response to treatment with either fructose or palmitate, AEBP1 expression in primary human hepatocytes increased 2.4-fold or 9.6-fold, but was upregulated 55.8-fold in the presence of fructose and palmitate together. AEBP1 knockdown resulted in decreased expression of nine genes previously identified to be part of a predicted AEBP1-associated NASH co-regulatory network and confirmed to be upregulated in fibrotic tissue. We identified binding sites for two miRNAs known to be downregulated in NASH fibrosis, miR-372-3p and miR-373-3p in the AEBP1 3' untranslated region. Both miRNAs functionally interacted with AEBP1 to regulate its expression. These findings indicate a novel AEBP1-mediated pathway in the pathogenesis of hepatic fibrosis in NASH.

9.
Cytokine ; 123: 154789, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31352173

RESUMO

CCL20 (CC chemokine ligand 20) is emerging as an important regulatory molecule in a pathway common to virus infection, alcoholic hepatitis, and non-alcoholic fatty liver disease (NAFLD) leading to the development of hepatic fibrosis. We previously observed upregulation of CCL20 in patients with NAFLD fibrosis and human hepatic stellate cells (LX-2 cells) in response to lipid loading. To date, the mechanisms mediating the relationship between CCL20 and hepatic fibrogenesis remain unknown. In this study, we sought to characterize the molecular mechanisms by which CCL20 may contribute to fibrogenesis in NAFLD. We observed that CCL20 levels increased with worsening severity of liver histology in NAFLD patients (normal < steatosis < inflammation < fibrosis) and during LX-2 cell activation in a time-dependent manner. We found that treatment of LX-2 cells with CCL20 corresponded with increased levels of CCL20 and ACTA2, and decreased levels of PLAU and SERPINE1, effects mitigated by CCL20 knockdown. We identified a putative binding site for miR-590-5p, which we previously reported to be downregulated in NAFLD fibrosis, in the CCL20 3' untranslated region (3'UTR), and found that exogenous miR-590-5p functionally interacted with the CCL20 3'UTR to downregulate its expression. Transfection of LX-2 hepatic stellate cells with miR-590-5p mimic or silencing RNA resulted in decreased or increased CCL20 levels, respectively. Our results indicate an association between CCL20 and hepatic stellate cell activation that includes modulation of key ECM components and functional interactions with a miRNA previously implicated in NAFLD fibrosis. Together, these findings support a novel mechanism by which CCL20 may promote fibrogenesis in NAFLD.

10.
Sci Transl Med ; 11(491)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068442

RESUMO

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targets Wolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination of Wolbachia in the in vivo Litomosoides sigmodontis filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantify Wolbachia elimination in Brugia pahangi filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed in L. sigmodontis, Brugia malayi, and Onchocerca ochengi in vivo preclinical models of filarial disease and in vitro selectivity against Loa loa (a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.

11.
J Neurovirol ; 25(4): 525-539, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144288

RESUMO

Herpes simplex virus 1 (HSV-1) is a predominant cause of herpes simplex encephalitis (HSE), leading to a high mortality rate and severe neurological sequelae worldwide. HSE is typically accompanied by the blood-brain barrier (BBB) disruption, but the underlying mechanisms are unclear. To explore the disruption mechanisms of the BBB, quantitative analysis of the cellular proteome was carried out to investigate the proteomic changes that occur after infection. In this study, bEnd.3 cells were infected with HSV-1, followed by liquid chromatography-tandem mass spectrometry. A total of 6761 proteins were identified in three independent mass spectrometry analyses. Compared to the uninfected cells, 386 and 293 differentially expressed proteins were markedly upregulated or downregulated, respectively. Bioinformatic analysis showed that the activator protein-1 factor, including Fos, Jun, and ATF family proteins and cell adhesion molecules were significantly changed. Further validation of the changes observed for these proteins was carried out by western blotting and quantitative real-time PCR. Transendothelial electrical resistance (TEER) studies were performed to explore the effects of ATF3, Fra1, or JunB overexpression on the function of bEnd.3 cells. Characterization of the differential expression of these proteins in bEnd.3 cells will facilitate further exploration of BBB disruption upon HSV-1 infection.

12.
Chin J Integr Med ; 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31093879

RESUMO

OBJECTIVE: To investigate the neuromodulatory effect of pinellia total alkaloids (PTA) on the gamma-aminobutyric acidergic (GABAergic) system in epileptic rats, and preliminarily evaluate the anti-epileptic effect of PTA. METHODS: Ninety-one male Sprague-Dawley rats were randomized to a control group (n=17) or an epileptic group (n=74) using computer-generated random numbers. Status epilepticus (SE) was induced with pilocarpine in the epileptic group. Epileptic rats that survived SE were randomly divided into 4 groups, namely an epilepsy group (n=13), a topiramate (TPM, 60 mg/kg) group (n=12), a high-dose PTA (800 mg/kg) group (n=12), and a low-dose PTA (400 mg/kg) group (n=10). Treatments were given intragastrically once daily for 14 days. The control group and epilepsy group received normal saline. Spontaneous recurrent seizures (SRSs) were monitored 8-h daily for 7 days after treatment. Then, the hippocampal formation tissues were collected. GABA level was measured using enzyme-linked immunosorbent assay. Protein and mRNA expression levels of glutamate decarboxylase 65 (GAD65), GABA transporter-1 (GAT-1), GABA transaminase (GABA-T), and GABAA receptor (GABAAR) α4, α5, γ2 and δ subunits were measured using Western-blotting analysis and quantitative polymerase chain reaction. RESULTS: PTA lowered the incidence and frequency of SRS (both doses vs. the TPM group, P>0.05). Compared with the epilepsy group, PTA increased the levels of GABA (both doses P<0.01) and GAD65 (mRNA, 800 mg/kg, P<0.01), and suppressed the levels of GAT-1 (mRNA, 800 mg/kg, P<0.01; 400 mg/kg, P<0.05), GABA-T (mRNA, both doses P<0.01), and GABAAR δ subunit (protein, 800 mg/kg, P<0.05) and γ2 subunit (protein, both doses P<0.01). PTA upregulated the low-expressed mRNA levels of GABAAR α5 subunit (400 mg/kg, P<0.01), δ subunit (800 mg/kg, P<0.05), and γ2 subunit (400 mg/kg, P<0.05). CONCLUSIONS: PTA regulated the GABAergic system through modulating GABA levels and the expression levels of GAD65, GAT-1, GABA-T, and GABAAR α4, α5, γ2 and δ subunits. PTA may exert anti-epileptic effects on the pilocarpine-induced epilepsy model.

13.
FEBS Lett ; 593(10): 1040-1049, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31002393

RESUMO

Transcriptional regulation involves a series of sophisticated protein-protein and protein-DNA interactions (PPI and PDI). Some transcriptional complexes, such as c-Fos/c-Jun and their binding DNA fragments, have been conserved over the past one billion years. Considering the thermodynamic principle for transcriptional complex formation, we hypothesized that the c-Fos/c-Jun complex may represent a thermodynamic summit in the evolutionary space. To test this, we invented a new method, termed One-Pot-seq, which combines cDNA display and proximity ligation to analyse PPI/PDI complexes simultaneously. We found that the wild-type c-Fos/c-Jun complex is indeed the most thermodynamically stable relative to various mutants of c-Fos/c-Jun and binding DNA fragments. Our method also provides a universal approach to detect transcriptional complexes and explore transcriptional regulation mechanisms.

14.
Biomaterials ; 207: 76-88, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30959408

RESUMO

Various negative effects accompanying with the instability of bare liquid metal (LM) nanoparticles, including undesirable spontaneous coalescence, continuous photothermal performance deterioration and difficult multi-step functionalization, severely hinder its applications in biomedical area. In this study, we proposed a new concept of immobilized liquid metal nanoparticles based on a surface mesoporous silica coating strategy (LM@MSN). Strikingly, it was found that unsteady and vulnerable LM nanoparticles after immobilization exhibited enhanced stabilization and sustainable photothermal performance even with a long and repeated light irradiation in acidic environments. Moreover, integrating the properties of easy surface functionalization and high drug loading efficiency from silica shell, immobilized LM nanoparticle was further used for photothermal involved combinational therapy. The classical anticancer drug doxorubicin (DOX) was encapsulated in pores of silica shell and the hyaluronic acid (HA) was decorated on LM@MSN to construct LM@MSN/DOX@HA for tumor targeted combination therapy. Both in vitro and in vivo studies proved that LM@MSN/DOX@HA could significantly inhibit solid tumor growth under near infrared (NIR) irradiation by synergistic photothermal/chemotherapy.

15.
Adv Mater ; 31(18): e1900499, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30907473

RESUMO

Using the cytomembranes (FMs) of hybrid cells acquired from the fusion of cancer and dendritic cells (DCs), this study offers a biologically derived platform for the combination of immunotherapy and traditional oncotherapy approaches. Due to the immunoactivation implicated in the cellular fusion, FMs can effectively express whole cancer antigens and immunological co-stimulatory molecules for robust immunotherapy. FMs share the tumor's self-targeting character with the parent cancer cells. In bilateral tumor-bearing mouse models, the FM-coated nanophotosensitizer causes durable immunoresponse to inhibit the rebound of primary tumors post-nanophotosensitizer-induced photodynamic therapy (PDT). The FM-induced immunotherapy displays ultrahigh antitumor effects even comparable to that of PDT. On the other hand, PDT toward primary tumors enhances the immunotherapy-caused regression of the irradiation-free distant tumors. Consequently, both the primary and the distant tumors are almost completely eliminated. This tumor-specific immunotherapy-based nanoplatform is potentially expandable to multiple tumor types and readily equipped with diverse functions owing to the flexible nanoparticle options.


Assuntos
Membrana Celular/química , Células Dendríticas/citologia , Imunoterapia , Nanoestruturas/química , Animais , Anticorpos/química , Anticorpos/imunologia , Linhagem Celular Tumoral , Células Dendríticas/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Receptores de Hialuronatos/imunologia , Estruturas Metalorgânicas/química , Camundongos , Camundongos Nus , Nanoestruturas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Porfirinas/uso terapêutico , Transplante Heterólogo , Zircônio/química
16.
Anticancer Agents Med Chem ; 19(6): 740-749, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30836927

RESUMO

BACKGROUND: Multi Drug Resistance (MDR) is the phenomenon that cancers develop resistance to majority of chemotherapy drugs and is a serious obstacle to the treatment for Hepatocellular Carcinoma (HCC). Polo-Like Kinase 1 (PLK1) is a serine/threonine kinase associated with tumor growth and clinical prognosis in HCC and BI2536 is its potent inhibitor with IC50 of 0.83nM. AIMS: To test whether the down-regulation of PLK1 by its inhibitor BI2536 would have beneficial effects on the reversal of MDR in HCC cells. METHODS: The CCK-8 assay was used to determine the viability of HepG2/ADM and SMMC7721/ADM cells and their parental cells treated with BI2536. Then animal model studies were performed. Cell invasion assay and wound healing assay were used to determine the invasion ability and motility. Flow cytometric was used to test the apoptosis induced by BI2536. Western blot and quantitative real-time PCR were performed to test the change of expression of MDR and apoptosis-related gene. RESULTS: BI2536 down-regulated the expression of PLK1 protein and mRNA specifically. BI2536 can significantly reduce IC50 for ADM and other drugs in ADM-resistant HCC cells. Meanwhile, it inhibited cell viability, proliferation, and invasion, and induced cell cycle arrest and apoptosis in HCC cells with MDR. CONCLUSION: Our results suggest that PLK1 inhibitor BI2536 can re-sensitize HCC cancer cell with MDR through induction of apoptosis. Thus, PLK1 inhibitor BI2536 may act as an effective chemotherapeutic drug in the clinical treatment of HCC patients with MDR.

17.
Adv Mater ; 31(15): e1807211, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30803083

RESUMO

To engineer patient-derived cells into therapy-purposed biologics is a promising solution to realize personalized treatments. Without using gene-editing technology, a live cell-typed therapeutic is engineered for tumor treatment by artificially reprogramming macrophages with hyaluronic acid-decorated superparamagnetic iron oxide nanoparticles (HIONs). This nanoparticle-assisted cell-reprogramming strategy demonstrates profound advantages, due to the combined contributions from the biological regulation of HIONs and the intrinsic nature of macrophages. Firstly, the reprogrammed macrophages present a substantial improvement in their innate capabilities, such as more effective tumor targeting and more efficient generation of bioactive components (e.g., reactive oxygen species, bioactive cytokines) to suppress tumor growth. Furthermore, this cell therapeutic exhibits cytostatic/proapoptotic effects specific to cancer cells. Secondly, HIONs enable macrophages more resistant to the intratumoral immunosuppressive environment. Thirdly, the macrophages are endowed with a strong ability to prime in situ protumoral M2 macrophages into antitumor M1 phenotype in a paracrine-like manner. Consequently, a synergistic tumor-inhibition effect is achieved. This study shows that engineering nanomaterial-reprogrammed live cells as therapeutic biologics may be a more preferable option to the commonly used approaches where nanomaterials are administrated to induce bioresponse of certain cells in vivo.


Assuntos
Reprogramação Celular , Macrófagos/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Macrófagos/imunologia , Nanopartículas de Magnetita , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/imunologia
18.
Adv Mater ; 31(16): e1808278, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30803049

RESUMO

Synthetic biology based on bacteria has been displayed in antitumor therapy and shown good performance. In this study, an engineered bacterium Escherichia coli MG1655 is designed with NDH-2 enzyme (respiratory chain enzyme II) overexpression (Ec-pE), which can colonize in tumor regions and increase localized H2 O2 generation. Following from this, magnetic Fe3 O4 nanoparticles are covalently linked to bacteria to act as a catalyst for a Fenton-like reaction, which converts H2 O2 to toxic hydroxyl radicals (•OH) for tumor therapy. In this constructed bioreactor, the Fenton-like reaction occurs with sustainably synthesized H2 O2 produced by engineered bacteria, and severe tumor apoptosis is induced via the produced toxic •OH. These results show that this bioreactor can achieve effective tumor colonization, and realize a self-supplied therapeutic Fenton-like reaction without additional H2 O2 provision.


Assuntos
Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Neoplasias/terapia , Animais , Apoptose , Reatores Biológicos , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Nanopartículas de Magnetita/química , Camundongos Endogâmicos BALB C , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
19.
BMC Bioinformatics ; 20(1): 85, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777030

RESUMO

BACKGROUND: The identification of prognostic genes that can distinguish the prognostic risks of cancer patients remains a significant challenge. Previous works have proven that functional gene sets were more reliable for this task than the gene signature. However, few works have considered the cross-talk among functional gene sets, which may result in neglecting important prognostic gene sets for cancer. RESULTS: Here, we proposed a new method that considers both the interactions among modules and the prognostic correlation of the modules to identify prognostic modules in cancers. First, dense sub-networks in the gene co-expression network of cancer patients were detected. Second, cross-talk between every two modules was identified by a permutation test, thus generating the module network. Third, the prognostic correlation of each module was evaluated by the resampling method. Then, the GeneRank algorithm, which takes the module network and the prognostic correlations of all the modules as input, was applied to prioritize the prognostic modules. Finally, the selected modules were validated by survival analysis in various data sets. Our method was applied in three kinds of cancers, and the results show that our method succeeded in identifying prognostic modules in all the three cancers. In addition, our method outperformed state-of-the-art methods. Furthermore, the selected modules were significantly enriched with known cancer-related genes and drug targets of cancer, which may indicate that the genes involved in the modules may be drug targets for therapy. CONCLUSIONS: We proposed a useful method to identify key modules in cancer prognosis and our prognostic genes may be good candidates for drug targets.


Assuntos
Neoplasias/mortalidade , Algoritmos , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias/genética , Prognóstico , Análise de Sobrevida
20.
Microsc Microanal ; 25(1): 58-69, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30714545

RESUMO

The f-ratio quantitative X-ray microanalysis method has been recently developed for binary systems based on a scanning electron microscope/energy dispersive spectroscopy (SEM/EDS) system. This method incorporates traditional EDS experiments and Monte Carlo simulations, and calibration factors are calculated with standard samples to evaluate the differences between them. In this work, the f-ratio method was extended to Mg-Al-Zn multi-element systems using a cold field emission SEM and a tungsten emission SEM. Results show that the stability of the beam current does not influence the f-ratio quantification accuracy. Thus, the f-ratio method is suitable for quantitative X-ray mapping with a long-time acquisition or even an unstable beam current. Comparing with other quantitative techniques including the routine standardless analysis and the standard-based k-ratio method, the f-ratio method is a simple and accurate quantification method.

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