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1.
J Nat Prod ; 82(10): 2707-2712, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31593459

RESUMO

Tetraena mongolica Maxim, a relict originating from the Tertiary Period, is an endemic species of Zygophyllaceae in China. Three new monoterpenoids (1-3), two new phenols (4, 5) with unusual O-sulfoglucosyl groups, a new flavonoid (6), and nine known compounds were isolated from the leaves of T. mongolica. The structures of these compounds were determined by interpretation of NMR, MS, and ECD data. Some of the isolated compounds showed protective effects on HEK 293t cells damaged by CdCl2, with IC50 values being 55.7 and 80.3 µM for compounds 7 and 8, respectively, at the time point of 48 h after treatment.

2.
Life Sci ; 238: 116979, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31647947

RESUMO

AIMS: Alzheimer's disease (AD) is closely related to abnormal glucose metabolism in the central nervous system. Progesterone has been shown to have obvious neuroprotective effects in the pathogenesis of AD, but the specific mechanism has not been fully elucidated. Therefore, the purpose of this study was to investigate the effect of progesterone on the glucose metabolism of neurons in amyloid precursor protein (APP)/presenilin 1 (PS1) mice and Aß-induced AD cell model. MATERIALS AND METHODS: APP/PS1 mice were treated with 40 mg/kg progesterone for 40 days and primary cultured cortical neurons were treated with 1 µM progesterone for 48 h.Then behavior tests,2-NBDG glucose uptake tests and the protein levels of glucose transporter 3 (GLUT3), GLUT4, cAMP-response element binding protein (CREB) and proliferator-activated receptor γ (PPARγ) were examined. KEY FINDINGS: Progesterone increased the expression levels of GLUT3 and GLUT4 in the cortex of APP/PS1 mice, accompanied by an improvement in learning and memory. Progesterone increased the levels of CREB and PPARγ in the cerebral cortex of APP/PS1 mice. In vitro, progesterone increased glucose uptake in primary cultured cortical neurons, this effect was blocked by the progesterone receptor membrane component 1 (PGRMC1)-specific blocker AG205 but not by the progesterone receptor (PR)-specific blocker RU486. Meanwhile, progesterone increased the expression of GLUT3, GLUT4, CREB and PPARγ, and AG205 blocked this effect. SIGNIFICANCE: These results confirm that progesterone significantly improves the glucose metabolism of neurons.One of the mechanisms of this effect is that progesterone upregulates protein expression of GLUT3 and GLUT4 through pathways PGRMC1/CREB/GLUT3 and PGRMC1/PPARγ/GLUT4.

3.
Chem Commun (Camb) ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31661086

RESUMO

A highly transparent and stretchable electrode based on a Au nanomesh, electrodeposited with a thin layer of MnO2 with a transparency of 84.7% is introduced. The as-prepared transparent, stretchable, and imperceptible supercapacitor (TSPS) exhibits a specific capacitance of 0.53 mF cm-2 and excellent bending stability, together with high stretchability (up to 160% strain).

4.
J Immunother Cancer ; 7(1): 250, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519211

RESUMO

BACKGROUND: Antibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer therapy. Here we describe a humanized antibody recognizing the RON plexin-semaphorin-integrin (PSI) domain with increased drug delivery capability for potential clinical application. METHOD: Monoclonal antibody PCM5B14 specific to the human and monkey RON PSI domain was generated and characterized by various immunological methods. Humanized antibody H5B14 was created by grafting PCM5B14 complementarity-determining regions into human IgG1/κ acceptor frameworks and conjugated with monomethyl auristatin E and duocarmycin to form two H5B14-based ADCs. Stability of H5B14-based ADCs in human plasma was measured using hydrophobic interaction chromatography. Various biochemical and biological assays were used to determine ADC- regulated RON internalization, cell viability, spheroid formation, and death of cancer stem-like cells. Efficacies of H5B14-based ADCs in vivo were validated using tumor xenograft models. Maximal tolerated doses of H5B14-based ADCs were established in mice. RESULTS: H5B14 was highly specific to the human RON PSI domain and superior over other anti-RON ADCs in induction of RON internalization in various cancer cell lines tested. H5B14-based ADCS had a drug to antibody ratio of ~ 3.70:1 and were stable in human plasma with a minimal dissociation within a 10-day period. Functionally, H5B14-mediated drug delivery decreased cell viability at early stages with an average IC50 at ~ 20 nM in multiple cancer cell lines examined. H5B14-based ADCs also inhibited spheroid formation and caused death of cancer stem-like cells with RON+/CD44+/ESA+ phenotypes. In vivo, H5B14-based ADCs in a single injection inhibited tumor xenograft growth mediated by multiple cancer cell lines. Tumoristatic concentrations calculated from xenograft tumor models were in the range of 0.63 to 2.0 mg/kg bodyweight. Significantly, H5B14-based ADCs were capable of eradicating tumors at variable levels across multiple xenograft models regardless their malignant statuses. Toxicologically, H5B14-based ADCs were well tolerated in mice up to 60 mg/kg. CONCLUSION: H5B14-based ADCs targeting the RON PSI domain are superior in inducing RON internalization, leading to robust drug delivery and overall inhibition and eradication of tumors in multiple xenograft models. These findings warrant H5B14-based ADCs for clinical trials in the future.

5.
J Plant Physiol ; 239: 38-51, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181407

RESUMO

Reaumuria trigyna (Reaumuria Linn genus, family Tamaricaceae), an endangered dicotyledonous shrub with the features of a recretohalophyte, is endemic to the Eastern Alxa-Western Ordos area of China. Based on R. trigyna transcriptome data and expression pattern analysis of RtWRKYs, RtWRKY23, a Group II WRKY transcription factor, was isolated from R. trigyna cDNA. RtWRKY23 was mainly expressed in the stem and was induced by salt, drought, cold, ultraviolet radiation, and ABA treatments, but suppressed by heat treatment. Overexpression of RtWRKY23 in Arabidopsis increased chlorophyll content, root length, and fresh weight of the transgenic lines under salt stress. Real-time quantitative PCR (qPCR) analysis and yeast one-hybrid analysis demonstrated that RtWRKY23 protein directly or indirectly modulated the expression levels of downstream genes, including stress-related genes AtPOD, AtPOD22, AtPOD23, AtP5CS1, AtP5CS2, and AtPRODH2, and reproductive development-related genes AtMAF5, AtHAT1, and AtANT. RtWRKY23 transgenic Arabidopsis had higher proline content, peroxidase activity, and superoxide anion clearance rate, and lower H2O2 and malondialdehyde content than WT plants under salt stress conditions. Moreover, RtWRKY23 transgenic Arabidopsis exhibited later flowering and shorter pods, but little change in seed yield, compared with WT plants under salt stress. Our study demonstrated that RtWRKY23 not only enhanced salt stress tolerance through maintaining the ROS and osmotic balances in plants, but also participated in the regulation of flowering under salt stress.


Assuntos
Flores/crescimento & desenvolvimento , Proteínas de Plantas/genética , Tolerância ao Sal/genética , Tamaricaceae/fisiologia , Fatores de Transcrição/genética , Sequência de Aminoácidos , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Alinhamento de Sequência , Tamaricaceae/genética , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
6.
Small ; 15(33): e1901966, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31225719

RESUMO

Nanoparticle (NP) superlattices have attracted increasing attention due to their unique physicochemical properties. However, key questions persist regarding the correlation between short- and long-range driving forces for nanoparticle assembly and resultant capability to predict the transient and final superlattice structure. Here the self-assembly of Ag NPs in aqueous solutions is investigated by employing in situ liquid cell transmission electron microscopy, combined with atomic force microscopy-based force measurements, and theoretical calculations. Despite the NPs exhibiting instantaneous Brownian motion, it is found that the dynamic behavior of NPs is correlated with the van der Waals force, sometimes unexpectedly over relatively large particle separations. After the NPs assemble into clusters, a delicate balance between the hydration and van der Waals forces results in a distinct distribution of particle separation, which is ascribed to layers of hydrated ions adsorbed on the NP surface. The study demonstrates pivotal roles of the complicated correlation between interparticle forces; potentially enabling the control of particle separation, which is critical for tailoring the properties of NP superlattices.

7.
Plant Cell Environ ; 42(9): 2584-2596, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31083779

RESUMO

It is well known that xylem embolism can be repaired by bark water uptake and that the sugar required for embolism refilling can be provided by corticular photosynthesis. However, the relationship between corticular photosynthesis and embolism repair by bark water uptake is still poorly understood. In this study, the role of corticular photosynthesis in embolism repair was assessed using Salix matsudana branch segments dehydrated to -1.9 MPa (P50 , water potential at 50% loss of conductivity). The results indicated that corticular photosynthesis significantly promoted water uptake and nonstructural carbohydrate (NSC) accumulation in the bark and xylem during soaking, thereby effectively enhancing the refilling of the embolized vessels and the recovery of hydraulic conductivity. Furthermore, the influence of the extent of dehydration on the embolism refilling enhanced by corticular photosynthesis was investigated. The enhanced refilling effects were much higher in the mildly dehydrated (-1.5 MPa) and moderately dehydrated (-1.9 MPa) branch segments than in the severely dehydrated (-2.2 MPa) branch segments. This study provides evidence that corticular photosynthesis plays a crucial role in xylem embolism repair by bark water uptake for mildly and moderately dehydrated branches.

8.
Carbohydr Res ; 480: 1-6, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132553

RESUMO

Fucosylated human milk oligosaccharides (HMOs) have important biological functions. Enzymatic synthesis of such compounds requires robust fucosyltransferases. A C-terminal 66-amino acid truncated version of Helicobacter pylori α1-3-fucosyltransferase (Hp3FT) is a good candidate. Hp3FT was biochemically characterized to identify optimal conditions for enzymatic synthesis of fucosides. While N-acetyllactosamine (LacNAc) and lactose were both suitable acceptors, the former is preferred. At a low guanosine 5'-diphospho-ß-L-fucose (GDP-Fuc) to acceptor ratio, Hp3FT selectively fucosylated LacNAc. Based on these enzymatic characteristics, diverse fucosylated HMOs, including 3-fucosyllactose (3-FL), lacto-N-fucopentaose (LNFP) III, lacto-N-neofucopentaose (LNnFP) V, lacto-N-neodifucohexaose (LNnDFH) II, difuco- and trifuco-para-lacto-N-neohexaose (DF-paraLNnH and TF-para-LNnH), were synthesized enzymatically by varying the ratio of the donor and acceptor as well as controlling the order of multiple glycosyltransferase-catalyzed reactions.

10.
Soft Robot ; 6(3): 414-421, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30917090

RESUMO

Nowadays, stretchable/epidermal electronics based on liquid alloys has attracted more and more attention, and various processing techniques have subsequently been developed to demonstrate diverse applications never seen before. However, to fully exploit its potential advantages, epidermal electronics is still searching for a technique meeting all demands on resolution, pattern complexity, and operational flexibility. In this study, we propose a technique that allows for complex and high-density patterns on thin stretchable substrates by combining ultraviolet laser patterning of a modified water-soluble mask, atomized spray deposition of liquid alloys on a flexible temporary substrate, lift-off by water dissolving, and finally, component integration and encapsulation. With this new technique, it was possible to make epidermal precision strain sensors with liquid alloy patterns of high density, which were capable of monitoring fine local skin movements such as the detailed process of wrinkle formation as well as the overall motion of the body part. In addition, this process is highly efficient and well controllable, with high potential for possible industrial automation and massive production.

11.
J Immunother Cancer ; 7(1): 75, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30871619

RESUMO

BACKGROUND: Aberrant expression of the RON receptor tyrosine kinase is a pathogenic feature and a validated drug target in various types of cancers. Currently, therapeutic antibodies targeting RON for cancer therapy are under intensive evaluation. Here we report the development and validation of a novel humanized anti-RON antibody-drug conjugate for cancer therapy. METHODS: Antibody humanization was achieved by grafting sequences of complementarity-determining regions from mouse monoclonal antibody Zt/g4 into human IgG1/κ acceptor frameworks. The selected humanized Zt/g4 subclone H1L3 was conjugated with monomethyl auristatin E using a dipeptide linker to form H-Zt/g4-MMAE. Pharmacokinetic analysis of H-Zt/g4-MMAE was determined using hydrophobic interaction chromatography and a MMAE ADC ELISA kit. Biochemical and biological assays were used for measuring RON expression, internalization, cell viability and death. Therapeutic efficacies of H-Zt/g4-MMAE were validated in vivo using three pancreatic cancer xenograft models. Toxicological activities of H-Zt/g4-MMAE were determined in mouse and cynomolgus monkey. RESULTS: H-Zt/g4-MMAE had a drug to antibody ratio of 3.77:1 and was highly stable in human plasma with a dissociation rate less than 5% within a 20 day period. H-Zt/g4-MMAE displayed a favorable pharmacokinetic profile in both mouse and cynomolgus monkey. In vitro, H-Zt/g4-MMAE induced RON internalization, which results in killing of pancreatic cancer cells with IC50 values at 10-20 nM. In vivo, H-Zt/g4-MMAE inhibited pancreatic cancer xenograft growth with tumoristatic concentrations at 1~3 mg/kg bodyweight. Significantly, H-Zt/g4-MMAE eradicated tumors across multiple xenograft models regardless their chemoresistant and metastatic statuses. Moreover, H-Zt/g4-MMAE inhibited and eradicated xenografts mediated by pancreatic cancer stem-like cells and by primary cells from patient-derived tumors. Toxicologically, H-Zt/g4-MMAE is well tolerated in mice up to 60 mg/kg. In cynomolgus monkey, H-Zt/g4-MMAE up to 30 mg/kg had a manageable and reversible toxicity profile. CONCLUSIONS: H-Zt/g4-MMAE is superior in eradication of pancreatic cancer xenografts with favorable pharmacokinetic profiles and manageable toxicological activities. These findings warrant the transition of H-Zt/g4-MMAE into clinical trials in the future.

12.
J Coll Physicians Surg Pak ; 29(2): 189-190, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30700365

RESUMO

The aim of this study was to investigate the clinical diagnostic value of combined detection of serum C-reactive protein (CRP) and procalcitonin (PCT) for bacterial infectious diseases in children. It was a case control study carried out from October 2016 to March 2018. A total of 150 children with bacterial infectious disease were assigned to the observation group, and 150 healthy children without infectious diseases were assigned to the control group. The research showed that CRP and PCT levels, positive rates of CRP and PCT detection in observation group were higher than those in control group (p<0.001); sensitivity and diagnostic coincidence rate, detection specificity of CRP combined with PCT were higher than those in single PCT or CRP (p<0.001, <0.001 and 0.013, respectively). CRP combined with PCT detection enjoys good clinical application value in diagnosis of bacterial infectious diseases in children.


Assuntos
Infecções Bacterianas/diagnóstico , Proteína C-Reativa/análise , Pró-Calcitonina/sangue , Infecções Bacterianas/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença
13.
ACS Appl Mater Interfaces ; 11(10): 10373-10379, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781948

RESUMO

Skin-like electronics require materials that are conducting, soft, intrinsically stretchable, and highly robust. However, electronic devices often consist of multilayers, and the failure of the electronic devices mostly starts from the debonding of the layers because of poor interfacial adhesion and large mechanical mismatch. Herein, we introduce a fully organic and intrinsically stretchable electrode that achieves high robustness by grafting the substrate to improve the interfacial adhesion and by introducing deep folds and wrinkles to improve the stretchability. The electrode exhibits a sheet resistance of 90 Ω/□ and negligible change in resistance at strains of up to 100% and shows no fatigue over 10 000 cyclic stretches to 100% strain. An iontronic skin with the electrodes is capable of detecting tiny objects exemplified by walking ants or fruit flies weighing less than 1 mg, and the device can be cyclically stretched to 30% for 1000 times without fatigue. The high robustness and stretchability of the fully organic iontronic skin lie in the wrinkle structures, small mechanical mismatch, and high interfacial strength among different layers. This work offers a general way to fabricate highly stretchable and robust devices.

14.
Oncogene ; 38(21): 4028-4046, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30692632

RESUMO

The nuclear factor E2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) signaling cascades is a key transcriptional pathway governing cellular oxidative stress and tumor development. Mammalian hepatitis B X-interacting protein (HBXIP) has critical roles in modulating cancer malignance and tumor progression. However, whether HBXIP interacts with KEAP1 and NRF2 is unclear. Here, we found that HBXIP can effectually compete with NRF2 for binding with KEAP1 protein via its highly conserved GLNLG motif. The HBXIP-mediated reduction in NRF2-KEAP1 complexes promotes NRF2 accumulation and nuclear entry, which facilities the activation of antioxidant response element (ARE)-dependent signaling cascades, thereby reducing the accumulation of endogenous cellular reactive oxygen species (ROS). We also found a strong positive correlation between HBXIP expression and NRF2 expression in breast cancer cells, tissue microarrays and clinical breast cancer tissues. Furthermore, this positive correlation was further confirmed via analysis of 1905 clinical cases of breast carcinoma provided by the cancer genomics database cBioPortal. Strikingly, disrupting the HBXIP-KEAP1 axis via mutating the GLNLG motif of HBXIP leads to potent inhibition of the malignancy of breast carcinoma both in vivo and in vitro. Our findings broaden our understanding of HBXIP as a modulation factor of cellular oxidative stress and address a novel regulatory mechanism governing redox homeostasis and the progression of breast carcinoma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/fisiologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Metástase Neoplásica/patologia , Animais , Elementos de Resposta Antioxidante/fisiologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Feminino , Células HEK293 , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Proteínas Oncogênicas/metabolismo , Estresse Oxidativo/fisiologia , Ligação Proteica/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
15.
ACS Appl Mater Interfaces ; 11(7): 7148-7156, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30675789

RESUMO

Owing to the great deformability from fluid, liquid alloy-based soft electronics has inherent advantages over rigid-based ones for applications such as stretchable intelligence or soft robotics, where high fidelity of three-dimensional (3D) conformability or dynamic morphology is required. However, current fabrications heavily rely on planar techniques, which severely limit their great potential in such attracting applications. By tuning the wettability of liquid alloy on a soft substrate through a selective surface morphology modification, we present a flexography printing technique of liquid alloy circuits on both planar (from diverse materials) and 3D complex surfaces and investigate the tuning mechanism and the relation between liquid alloy wettability and surface morphology modification. In a demonstration, high-fidelity printing of liquid alloy circuits can be deployed not only on the outline but also on small pits of strawberry surface, and the circuits work well in a dynamic deformation. Furthermore, being compatible with current industry process, our technique can be highly potential for future mass manufacturing of liquid alloy-based soft electronics.

16.
Plant Genome ; 11(3)2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30512031

RESUMO

Nees & Arn. ex Watt, a perennial wild rice species with a GG genome, preserves many important genes for cultivated rice ( L.) improvement. At present, however, no genetic resource is available for studying . Here, we report 91,562 high-quality transcripts of assembled de novo. Moreover, comparative transcriptome analysis revealed that 1311 single-copy orthologous pairs shared by and (Zoll. & Moritzi) Baill. that may have undergone adaptive evolution. We performed an analysis of the genes potentially involved in plant-pathogen interactions to explore the molecular basis of disease resistance, and isolated the full-length cDNAs of () and () orthologs from . The overexpression of in Nipponbare and functional characterization showed enhanced the resistance of transgenic Nipponbare to rice blast resulting from the presence of the gene. , an alternatively spliced transcript of the blast resistance gene in encodes a 1024-amino acid polypeptide with a C-terminal thioredoxin domain. This study provides an important resource for functional and evolutionary studies of the genus .

17.
Front Microbiol ; 9: 2724, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30483236

RESUMO

Ebolavirus (EBOV) life cycle involves interactions with numerous host factors, but it remains poorly understood, as does pathogenesis. Herein, we synthesized 65 siRNAs targeting host genes mostly connected with aspects of the negative-sense RNA virus life cycle (including viral entry, uncoating, fusion, replication, assembly, and budding). We produced EBOV transcription- and replication-competent virus-like particles (trVLPs) to mimic the EBOV life cycle. After screening host factors associated with the trVLP life cycle, we assessed interactions of host proteins with trVLP glycoprotein (GP), VP40, and RNA by co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP). The results demonstrate that RNAi silencing with 11 siRNAs (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) decreased the replication efficiency of trVLPs. Co-IP revealed nine candidate host proteins (FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) potentially interacting with trVLP GP, and four (ANXA5, GRP78, HSPA1A, and HSP90AB1) potentially interacting with trVLP VP40. Ch-IP identified nine candidate host proteins (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, MAPK11, MEK2, and NTRK1) interacting with trVLP RNA. This study was based on trVLP and could not replace live ebolavirus entirely; in particular, the interaction between trVLP RNA and host proteins cannot be assumed to be identical in live virus. However, the results provide valuable information for further studies and deepen our understanding of essential host factors involved in the EBOV life cycle.

18.
Micromachines (Basel) ; 9(10)2018 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-30424452

RESUMO

Great diversity of process technologies and materials have been developed around stretchable electronics. A subset of them, which are made up of zigzag metal foil and soft silicon polymers, show advantages of being easy to manufacture and low cost. However, most of the circuits lack durability due to stress concentration of interconnects entirely embedded in elastic polymer silicone such as polydimethylsiloxane (PDMS). In our demonstration, tunnel encapsulation technology was introduced to relieve stress of these conductors when they were stretched to deform in and out of plane. It was realized by dissolving the medium of Polyvinyl Alcohol (PVA), previous cured together with circuits in polymer, to form the micro-tunnel which not only guarantee the stretchability of interconnect, but also help to improve the durability. With the protection of tunnel, the serpentine could stably maintain the designed shape and electrical performance after 50% strain cycling over 20,000 times. Finally, different materials for encapsulation were employed to provide promising options for applications in portable biomedical devices which demand duplicate distortion.

19.
Cell Physiol Biochem ; 50(3): 1055-1067, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30355918

RESUMO

BACKGROUND/AIMS: Monoclonal antibodies (mAbs) are presently the most promising treatment against Ebola virus disease (EVD), and cocktail of two or more antibodies likely confers protection through complementary mechanisms. Zaire Ebolavirus (EBOV) glycoprotein (GP) and viral protein 40 (VP40) are targets for designing neutralizing antibodies. Currently, the antiviral therapeutics of mAb-cocktails are still limited solely to anti-GP antibodies,there is no Abs cocktail against Zaire EBOV GP and VP40, which both have important interactions with host cellular membrane. METHODS: We used hybridoma technology to produce anti-Zaire EBOV GP mAb against GP receptor binding domain, and anti-Zaire EBOV VP40 mAbs against the N-terminal domain, the C-terminal domain, respectively; synthesized Zaire EBOV transcription and replication competent virus like particles (trVLPs), which model even all aspects of the EBOV life cycles in order to evaluate the anti-viral effect of mAbs. Then, we characterized the anti- Zaire EBOV trVLPs effect of anti-GP and VP40 mAbs in vitro by real time-PCR, immunofluorescence assay and western blot analysis. RESULTS: Our results demonstrate that anti-GP or anti-VP40 mAbs effectively inhibit trVLPs replication. The cocktails of anti-GP and anti-VP40 mAbs, or between anti-VP40 mAbs, had synergistic anti-trVLPs effect. Meanwhile, the detailed DNA and amino acid sequences of the mAbs were checked. CONCLUSION: The study verifies neutralizing efficacy of anti-GP or anti-VP40 mAb, report promising cocktail of anti-GP and anti-VP40 mAb, or cocktail of two anti-VP40 mAbs. To our knowledge, this is the first account to report the important anti-viral effect of cocktails of anti-GP and anti-VP40 mAbs in vitro.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Ebolavirus/metabolismo , Glicoproteínas/imunologia , Proteínas Virais/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , Reações Antígeno-Anticorpo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Virais/genética , Proteínas Virais/metabolismo
20.
Mol Cancer Ther ; 17(12): 2654-2664, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30275241

RESUMO

Triple-negative breast cancer (TNBC) is a highly diverse group of malignant neoplasia with poor outcome. Currently, the lack of effective therapy has fostered a major effort to discover new targets to treat this malignant cancer. Here we identified the RON receptor tyrosine kinase as a therapeutic target for potential TNBC treatment. We analyzed RON expression in 168 primary TNBC samples via tissue microarray using anti-RON IHC staining and demonstrated that RON was widely expressed in 76.8% TNBC samples with overexpression in 76 cases (45.2%). These results provide the molecular basis to target RON for TNBC therapy. To this end, anti-RON monoclonal antibody Zt/g4-drug monomethyl auristatin E conjugate (Zt/g4-MMAE) was developed with a drug to antibody ratio of 3.29 and tested in a panel of TNBC cell lines with different phenotypes. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulted in cell-cycle arrest followed by massive cell death. The calculated IC50 values ranged from 0.06 to 3.46 µg/mL dependent on individual TNBC cell lines tested. Zt/g4-MMAE also effectively killed TNBC stem-like cells with RON+/CD44+/CD24- phenotypes and RON-negative TNBC cells through the bystander effect. In vivo, Zt/g4-MMAE at 10 mg/kg in a Q12 × 2 regimen completely eradicated TNBC xenografts without the regrowth of xenograft tumors. In conclusion, increased RON expression is a pathogenic feature in primary TNBC samples. Zt/g4-MMAE is highly effective in eradicating TNBC xenografts in preclinical models. These findings lay the foundation for using anti-RON Zt/g4-MMAE in clinical trials as a novel strategy for TNBC treatment.

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