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Oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanosine (CpG) motifs are readily recognized by Toll-like receptor 9 on immune cells, trigger an immunomodulatory cascade, induce a Th1 -biased immune milieu, and have great potential as an adjuvant in cancer vaccines. In this study, a green one-step synthesis process was adopted to prepare an amino-rich metal-organic nanoplatform (FN). The synthesized FN nanoplatform can simultaneously and effectively load model tumor antigens (OVA)/autologous tumor antigens (dLLC) and immunostimulatory CpG ODNs with an unmodified PD backbone and a guanine quadruplex structure to obtain various cancer vaccines. The FN nanoplatform and immunostimulatory CpG ODNs generate synergistic effects to enhance the immunogenicity of different antigens and inhibit the growth of established and distant tumors in both the murine E.G7-OVA lymphoma model and the murine Lewis lung carcinoma model. In the E.G7-OVA lymphoma model, vaccination efficiently increases the CD4+, CD8+, and tetramer+CD8+ T cell populations in the spleens. In the Lewis lung carcinoma model, vaccination efficiently increases the CD3+CD4+ and CD3+CD8+ T cell populations in the spleens and CD3+CD8+, CD3-CD8+, and CD11b+CD80+ cell populations in the tumors, suggesting the alteration of tumor microenvironments from cold to hot tumors.
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There is great interest in the incorporation of novel two-dimensional materials into Si-based technologies to realize multifunctional optoelectronic devices via heterogeneous integration. Here, we demonstrate a gate-tunable, self-driven, high-performance broadband phototransistor array based on a PdSe2/Si Schottky junction, which is fabricated by pre-depositing a semi-metallic PdSe2 film on a SOI substrate. In addition, thanks to the zero bandgap of the PdSe2 material and the PdSe2/Si vertical heterostructure, the prepared phototransistor exhibits pronounced photovoltaic properties in a wide spectral range from ultraviolet to near-infrared. The responsivity, specific detectivity and response time of the device at the incident light wavelength of 808 nm are 1.15 A W-1, 9.39 × 1010 Jones, and 27.1/40.3 µs, respectively, which are better than those of previously reported PdSe2-based photodetectors. The photoelectric performance can be further improved by applying an appropriate gate voltage to the phototransistor and the responsivity of the device increases to 1.61 A W-1 at VG = 5 V. We demonstrate the excellent imaging capabilities of a 4 × 4 array image sensor using PdSe2/SOI phototransistors under 375 nm, 532 nm, and 808 nm laser sources.
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The response of cells to environmental stimuli, under either physiological or pathological conditions, plays a key role in determining cell fate toward either adaptive survival or controlled death. The efficiency of such a feedback mechanism is closely related to the most challenging human diseases, including cancer. Since cellular responses are implemented through physical forces exerted on intracellular components, more detailed knowledge of force distribution through modern imaging techniques is needed to ensure a mechanistic understanding of these forces. In this work, we mapped these intracellular forces at a whole-cell scale and with submicron resolution to correlate intracellular force distribution to the cytoskeletal structures. Furthermore, we visualized dynamic mechanical responses of the cells adapting to environmental modulations in situ. Such task was achieved by using an informatics-assisted atomic force microscope (AFM) indentation technique where a key step was Markov-chain Monte Carlo optimization to search for both the models used to fit indentation force-displacement curves and probe geometry descriptors. We demonstrated force dynamics within cytoskeleton, as well as nucleoskeleton in living cells which were subjected to mechanical state modulation: myosin motor inhibition, micro-compression stimulation and geometrical confinement manipulation. Our results highlight the alteration in the intracellular prestress to attenuate environmental stimuli; to involve in cellular survival against mechanical signal-initiated death during cancer growth and metastasis; and to initiate cell migration.
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Two-dimensional (2D) PdSe2film has the characteristics of adjustable bandgap, high carrier mobility, and high stability. Photodetector (PD) based on 2D PdSe2exhibits wide spectral self-driving features, demonstrating enormous potential in the field of optical detection. Here, we design and fabricate PdSe2/Si heterojunction PDs with various thicknesses of the PdSe2films from 10 to 35 nm. Due to the enhancement of light absorption capacity and built-in electric field of heterojunction, the photodetector with thicker PdSe2film can generate more photo-generated carriers and effectively separate them to form a large photocurrent, thus showing more excellent photodetection performance. The responsivity and specific detectivity of the PdSe2/Si PDs with 10 nm, 20 nm, and 35 nm PdSe2films are 2.12 A W-1and 6.72 × 109Jones, 6.17 A W-1and 1.95 × 1010Jones, and 8.02 A W-1and 2.54 × 1010Jones, respectively (808 nm illumination). The PD with 35 nm PdSe2film exhibits better performance than the other two PDs, with the rise/fall times of 15.8µs/138.9µs atf= 1 kHz and the cut-off frequency of 8.6 kHz. Furthermore, we demonstrate that the properties of PdSe2/Si PD array have excellent uniformity and stability at room temperature and shows potential for image sensing in the UV-vis-NIR wavelength range.
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Background: Considering the diversity of tumors, it is of great significance to develop a simple, effective, and low-cost method to prepare personalized cancer vaccines. Methods: In this study, a facile one-pot synthetic route was developed to prepare cancer vaccines using model antigen or autologous tumor antigens based on the coordination interaction between Fe3+ ions and endogenous fumarate ligands. Results: Herein, Fe-based metal organic framework can effectively encapsulate tumor antigens with high loading efficiency more than 80%, and act as both delivery system and adjuvants for tumor antigens. By adjusting the synthesis parameters, the obtained cancer vaccines are easily tailored from microscale rod-like morphology with lengths of about 0.8 µm (OVA-ML) to nanoscale morphology with sizes of about 50~80 nm (OVA-MS). When cocultured with antigen-presenting cells, nanoscale cancer vaccines more effectively enhance antigen uptake and Th1 cytokine secretion than microscale ones. Nanoscale cancer vaccines (OVA-MS, dLLC-MS) more effectively enhance lymph node targeting and cross-presentation of tumor antigens, mount antitumor immunity, and inhibit the growth of established tumor in tumor-bearing mice, compared with microscale cancer vaccines (OVA-ML, dLLC-ML) and free tumor antigens. Conclusions: Our work paves the ways for a facile, rapid, and low-cost preparation approach for personalized cancer vaccines.
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Vacinas Anticâncer , Estruturas Metalorgânicas , Neoplasias , Animais , Camundongos , Autoantígenos , Ferro , Antígenos de Neoplasias , Neoplasias/terapiaRESUMO
The processing of type I procollagen is essential for fibril formation; however, the steps involved remain controversial. We constructed a live cell imaging system by inserting fluorescent proteins into type I pre-procollagen α1. Based on live imaging and immunostaining, the C-propeptide is intracellularly cleaved at the perinuclear region, including the endoplasmic reticulum, and subsequently accumulates at the upside of the cell. The N-propeptide is also intracellularly cleaved, but is transported with the repeating structure domain of collagen into the extracellular region. This system makes it possible to detect relative increases and decreases in collagen secretion in a high-throughput manner by assaying fluorescence in the culture medium, and revealed that the rate-limiting step for collagen secretion occurs after the synthesis of procollagen. In the present study, we identified a defect in procollagen processing in activated hepatic stellate cells, which secrete aberrant collagen fibrils. The results obtained demonstrated the intracellular processing of type I procollagen, and revealed a link between dysfunctional processing and diseases such as hepatic fibrosis.
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Colágeno , Pró-Colágeno , Colágeno/metabolismo , Retículo Endoplasmático/metabolismo , Pró-Colágeno/metabolismoRESUMO
We report carboxy-terminated silicon quantum dots (SiQDs) that exhibit high solubility in water due to the high molecular coverage of surface monolayers, bright light emission with high photoluminescence quantum yields (PLQYs), long-term stability in the PL property for monitoring cells, less toxicity to the cells, and a high photothermal response. We prepared water-soluble SiQDs by the thermal hydrosilylation of 10-undecenoic acid on their hydrogen-terminated surfaces, provided by the thermal disproportionation of triethoxysilane hydrolyzed at pH 3 and subsequent hydrofluoric etching. The 10-undecanoic acid-functionalized SiQDs (UA:SiQDs) showed long-term stability in hydrophilic solvents including ethanol and water (pH 7). We assess their interaction with live cells by means of cellular uptake, short-term toxicity, and, for the first time, long-term cytotoxicity. Results show that UA:SiQDs are potential candidates for theranostics, with their good optical properties enabling imaging for more than 18 days and a photothermal response having a 25.1% photothermal conversion efficiency together with the direct evidence of cell death by laser irradiation. UA:SiQDs have low cytotoxicity with full viability of up to 400 µg/mL for the short term and a 50% cell viability value after 14 days of incubation at a 50 µg/mL concentration.
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Pontos Quânticos , Silício , Fluorescência , Hidrogênio , Pontos Quânticos/química , Pontos Quânticos/toxicidade , Silício/química , ÁguaRESUMO
Warts are a common skin problem and are caused by infection with a virus. Warts are currently mainly treated by therapies involving ablating tissue or interrupting cellular division. However, all these existing treatments are either invasive or cause skin pain and tissue destruction. Imiquimod is a synthetic compound that belongs to the imidazoquinolinone family. It has been successfully used as a topical drug to treat external anogenital warts. However, topical imiquimod cream for warts is restricted by low skin permeability, and several side effects such as itching, pain, and erosions occur most frequently following topical treatment. Microneedle technology, a minimally invasive drug delivery system, has the potential to overcome the barrier of the stratum corneum. This technique would also offer a painless treatment choice and provide personalized therapies. In the study, we loaded imiquimod within dissolving microneedles using the molding method. Gelatin was used as a structural material for microneedle formation without adding a crosslinker. To our knowledge, this is the first study of using dissolving microneedles and exploring their utilization with imiquimod for the treatment of warts. First, we added fluorescent dye and trypan blue into the microneedles to evaluate the status of drugs in the microneedles and the degradation property of microneedles made of gelatin, respectively. Here we also prove the strength of the imiquimod microneedles and study their capability to penetrate the skin. The results show no apparent differences in mechanical failure after an additional imiquimod-loaded. Besides, we provide evidence that imiquimod microneedles induce secreted embryonic alkaline phosphatase (SEAP) in the RAW 264.7 macrophages. Gelatin does not affect the imiquimod in microneedles; a similar immune response was affected by the imiquimod alone or imiquimod complexed with gelatin. Our research demonstrates a proof of concept of using imiquimod microneedles for future warts treatment.
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Cellular mechanical properties are potential cancer biomarkers used for objective cytology to replace the current subjective method relying on cytomorphology. However, heterogeneity among intra/intercellular mechanics and the interplay between cytoskeletal prestress and elastic modulus obscured the difference detectable between malignant and benign cells. In this work, we collected high density nanoscale prestress and elastic modulus data from a single cell by AFM indentation to generate a cellular mechanome. Such high dimensional mechanome data was used to train a malignancy classifier through machine learning. The classifier was tested on 340 single cells of various origins, malignancy, and degrees of similarity in morphology and elastic modulus. The classifier showed instrument-independent robustness and classification accuracy of 89% with an AUC-ROC value of 93%. A signal-to-noise ratio 8 times that of the human-cytologist-based morphological method was also demonstrated, in differentiating precancerous hyperplasia cells from normal cells derived from the same lung cancer patient.
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Neoplasias , Biomarcadores , Módulo de Elasticidade , Humanos , Microscopia de Força AtômicaRESUMO
Osteogenesis imperfecta (OI) type V is an autosomal dominant disorder caused by the c.-14C > T mutation in the interferon-induced transmembrane protein 5 gene (IFITM5), however, its onset mechanism remains unclear. In this study, heterozygous c.-14C > T mutant mice were developed to investigate the effect of immunosuppressants (FK506 and rapamycin) on OI type V. Among the mosaic mice generated by Crispr/Cas9-based technology, mice with less than 40% mosaic ratio of c.-14C > T mutation survived, whereas those with more than 48% mosaic ratio exhibited lethal skeletal abnormalities with one exception. All heterozygous mutants obtained by mating mosaic mice with wild-type mice exhibited a perinatal lethal phenotype due to severe skeletal abnormalities. Administration of FK506, a calcineurin inhibitor, in the heterozygous fetuses improved bone mineral content (BMC) of the neonates, although it did not save the neonates from the lethal effects of the mutation, whereas rapamycin, an mTOR inhibitor, reduced BMC, suggesting that mTOR signaling is involved in the bone mineralization of heterozygous mutants. These findings could clarify certain aspects of the onset mechanism of OI type V and enable development of therapeutics for this condition.
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Heterozigoto , Imunossupressores/uso terapêutico , Proteínas de Membrana/genética , Mutação , Osteogênese Imperfeita/tratamento farmacológico , Sirolimo/farmacologia , Tacrolimo/farmacologia , Animais , Modelos Animais de Doenças , Genes Letais , Masculino , Camundongos , Camundongos Knockout , Mosaicismo , Osteogênese Imperfeita/genética , Sirolimo/uso terapêutico , Tacrolimo/uso terapêuticoRESUMO
A better understanding of the compatibility of water-soluble semiconductor quantum dots (QDs) upon contact with the bloodstream is important for biological applications, including biomarkers working in the first therapeutic spectral window for deep tissue imaging. Herein, we investigated the conformational changes of blood plasma proteins during the interaction with near-infrared light-emitting nanoparticles, consisting of Pluronic F127 shells and cores comprised of assembled silicon QDs terminated with decane monolayers. Albumin and transferrin have high quenching constants and form a hard protein corona on the nanoparticle. In contrast, fibrinogen has low quenching constants and forms a soft protein corona. A circular dichroism (CD) spectrometric study investigates changes in the protein's secondary and tertiary structures with incremental changes in the nanoparticle concentrations. As expected, the addition of nanoparticles causes the denaturation of the plasma proteins. However, it is noteworthy that the conformational recovery phenomena are observed for fibrinogen and transferrin, suggesting that the nanoparticle does not influence the ordered structure of proteins in the bloodstream. In addition, we observed enabled cellular uptake (NIH3T3 Fibroblasts) and minimal cytotoxicity using different cell lines (HeLa, A549, and NIH3T3). This study offers a basis to design QDs without altering the biomacromolecule's original conformation with enabled cellular uptake with minimal cytotoxicity.
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Synthetic oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanine (CpG) motifs trigger the immune response by stimulating endosomal Toll-like receptor (TLR) 9. Natural linear ODNs are susceptible to nuclease degradation, thereby limiting their clinical applications. Here, we designed monomeric G-quadruplex-based CpG ODNs (G4 CpG ODNs) containing CpG motifs in the central loop region of the G4 structure. The monomeric G4 CpG ODNs were more stable in serum than the linear ODNs. The monomeric G4 CpG ODNs containing two or three CpG motifs induced the production of immunostimulatory cytokines interleukin (IL)-6, IL-12, and interferon (IFN)-ß in mouse macrophage-like RAW264 cells. We also showed that the number of CpG motifs and the number of nucleotides between the CpG motif and G-tracts define the efficacy of the G4 CpG ODNs in activating TLR9. Incubating human peripheral blood mononuclear cells with G4 CpG ODNs promoted IL-6 and IFN-γ production, confirming their stimulatory effects on human immune cells. Mice given intraperitoneal injections of G4 CpG ODNs produced higher plasma IL-6 compared with injections of linear ODNs. These findings provide further understanding of the parameters governing the immunostimulatory activity of G4 CpG ODNs, thereby providing insights into the rational design of highly potent G4 CpG ODNs for vaccine adjuvants.
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Oligodesoxirribonucleotídeos , Receptor Toll-Like 9 , Adjuvantes Imunológicos/farmacologia , Animais , Ilhas de CpG , Citosina , Guanina , Leucócitos Mononucleares/metabolismo , Camundongos , Fosfatos , Receptor Toll-Like 9/metabolismoRESUMO
Transactivation response DNA-binding protein of 43 kDa (TDP-43) is a major constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We have previously shown neuronal cytoplasmic aggregate formation induced by recombinant adenoviruses expressing human wild-type and C-terminal fragment (CTF) TDP-43 under the condition of proteasome inhibition in vitro and in vivo. In the present study, we demonstrated that the formation of the adenoviral TDP-43 aggregates was markedly suppressed in rat neural stem cell-derived neuronal cells by co-infection of an adenovirus expressing heat shock transcription factor 1 (HSF1), a master regulator of heat shock response. We performed DNA microarray analysis and searched several candidate molecules, located downstream of HSF1, which counteract TDP-43 aggregate formation. Among these, we identified Praja 1 RING-finger E3 ubiquitin ligase (PJA1) as a suppressor of phosphorylation and aggregate formation of TDP-43. Co-immunoprecipitation assay revealed that PJA1 binds to CTF TDP-43 and the E2-conjugating enzyme UBE2E3. PJA1 also suppressed formation of cytoplasmic phosphorylated TDP-43 aggregates in mouse facial motor neurons in vivo. Furthermore, phosphorylated TDP-43 aggregates were detected in PJA1-immunoreactive human ALS motor neurons. These results indicate that PJA1 is one of the principal E3 ubiquitin ligases for TDP-43 to counteract its aggregation propensity and could be a potential therapeutic target for ALS and FTLD.
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Proteínas de Ligação a DNA/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Citoplasma/patologia , Fatores de Transcrição de Choque Térmico/metabolismo , Humanos , Camundongos , Ratos , Proteinopatias TDP-43/metabolismo , Proteinopatias TDP-43/patologiaRESUMO
Cancer cells, including malignant lymphoma cells, alter their metabolism, termed "metabolic reprograming," on initiation of malignant transformation as well as upon accumulation of genetic abnormalities. Here, to identify a novel therapeutic target involved in the metabolic changes during malignant lymphoma, we performed global analyses combined with shotgun proteomics, in silico database analysis, and clinic-pathologic analysis of nonneoplastic lymphoid tissue and malignant lymphoma tissue and verified the molecular functions in vitro. In total, 2002 proteins were detected from both samples and proteins related to fatty acid beta-oxidation (FAO) were detected more frequently in malignant lymphoma tissue. Consequently, the most frequently detected protein, the mitochondrial trifunctional enzyme subunit-alpha (HADHA), was identified as a potential target. Immunohistochemical analyses revealed that HADHA tended to be overexpressed in a high-grade subtype of malignant lymphoma tissue. Clinicopathologic study revealed that HADHA overexpression was correlated with significantly worse overall survival (P = 0.013) and was an independent prognostic predictor in diffuse large B-cell lymphoma (P = 0.027). In vitro, downregulation of HADHA negatively regulated cell growth by causing G0/G1 arrest (P = 0.0008) similar to treatment with etomoxir, an inhibitor of FAO (P = 0.032). Moreover, downregulation of HADHA increased the susceptibility to doxorubicin (P = 0.002) and etoposide (P = 0.004). Moreover, these phenotypes were confirmed in an HADHA knockout system. Thus, we provide a basis for a novel therapeutic strategy through the regulation of HADHA and FAO in patients with refractory malignant lymphoma.
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Linfoma , Subunidade alfa da Proteína Mitocondrial Trifuncional , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Descoberta de Drogas , Ácidos Graxos/metabolismo , Feminino , Humanos , Tecido Linfoide/química , Tecido Linfoide/metabolismo , Linfoma/metabolismo , Linfoma/mortalidade , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Subunidade alfa da Proteína Mitocondrial Trifuncional/antagonistas & inibidores , Subunidade alfa da Proteína Mitocondrial Trifuncional/genética , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Oxirredução , Proteoma/análise , Proteoma/metabolismoRESUMO
Liquid-phase exfoliated graphene sheets are promising candidates for printing electronics. Here, a high-performance printed 2.4 GHz graphene-based antenna is reported. Graphene conductive ink prepared by using liquid-phase exfoliation process is printed onto a water-transferable paper by using blade printing technique, which is then patterned as dipole antenna and transferred onto a target substrate. The fabricated dipole antenna (43 × 3 mm), exhibiting typical radiation patterns of an ideal dipole antenna, achieves -10 dB bandwidth of 8.9% and a maximum gain of 0.7 dBi. The printed graphene-antennas satisfy the application requirements of the Internet of Things and suggest its feasibility of replacing conventional metallic antennas in those applications.
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Phospholipid quantum dot micelles are useful for bio-applications because of their amphiphilicity and exceptional biocompatibilities. We investigated the uptake of phospholipid [polyethylene glycol (PEG), biotin, and folic acid terminated] modified CdSe/ZnS quantum dot micelles by cancer cells and its photostability under ultrviolet light in the C spectrum (UV-C) (254 nm) or UV-A (365 nm) light irradiation. The stability of micelles to the exposure of UV-C and UV-A light was assessed. Biotin-modified quantum dot micelles give photoluminescence enhancement under UV-C light irradiation. Folate modified micelle under UV-C and UV-A results show considerable photoluminescence enhancement. Photoluminescence lifetime measurements showed 7.04, 8.11 and 11.42 ns for PEG, folate, and biotin terminated phospholipid micelles, respectively. Folate and biotin-modified quantum dot micelles showed excellent uptake by HeLa cells under fluorescence confocal microscopy. Phospholipid CdSe/ZnS quantum dot micelles can be potentially used for diagnosis and treatment of cancer in the future.
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Pontos Quânticos/química , Transporte Biológico/efeitos da radiação , Células HeLa , Humanos , Micelas , Microscopia Confocal , Fosfolipídeos/metabolismo , Pontos Quânticos/metabolismo , Raios UltravioletaRESUMO
Transforming growth factor (TGF)-ß signaling in humans is stringently regulated to prevent excessive TGF-ß signaling. In tumors, TGF-ß signaling can both negatively and positively regulate tumorigenesis dependent on tumor type, but the reason for these opposite effects is unclear. TGF-ß signaling is mainly mediated via the Smad-dependent pathway, and herein we found that PDZK1-interacting protein 1 (PDZK1IP1) interacts with Smad4. PDZK1IP1 inhibited both the TGF-ß and the bone morphogenetic protein (BMP) pathways without affecting receptor-regulated Smad (R-Smad) phosphorylation. Rather than targeting R-Smad phosphorylation, PDZK1IP1 could interfere with TGF-ß- and BMP-induced R-Smad/Smad4 complex formation. Of note, PDZK1IP1 retained Smad4 in the cytoplasm of TGF-ß-stimulated cells. To pinpoint PDZK1IP1's functional domain, we created several PDZK1IP1 variants and found that its middle region, from Phe40 to Ala49, plays a key role in its Smad4-regulating activity. PDZK1IP1 knockdown enhanced the expression of the TGF-ß target genes Smad7 and prostate transmembrane protein androgen-induced (TMEPAI) upon TGF-ß stimulation. In contrast, PDZK1IP1 overexpression suppressed TGF-ß-induced reporter activities, cell migration, and cell growth inhibition. In a xenograft tumor model in which TGF-ß was previously shown to elicit tumor-promoting effects, PDZK1IP1 gain of function decreased tumor size and increased survival rates. Taken together, these findings indicate that PDZK1IP1 interacts with Smad4 and thereby suppresses the TGF-ß signaling pathway.
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Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Mapas de Interação de Proteínas , Transdução de Sinais , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Masculino , Camundongos Endogâmicos BALB C , FosforilaçãoRESUMO
Protein conformational changes are associated with potential cytotoxicity upon interaction with small molecules or nanomaterials. Protein misfolding leads to protein-mediated diseases; thus, it is important to study the conformational changes in proteins using nanoparticles as drug carriers. In this study, the conformational changes in hemoglobin and thrombin were observed using fluorescence spectroscopy, circular dichroism spectroscopy and molecular modelling studies after interaction with non-toxic, water-soluble near-infrared silicon quantum dot micelles. The molecular docking results indicated that the binding affinities of hemoglobin and thrombin with Si QD micelles are good. In addition, molecular dynamics simulations were performed to obtain more detailed information.
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A combination of chemotherapy and photothermal therapy (PTT) has emerged as a promising strategy for cancer therapy. To ensure that the chemotherapeutic drug and photothermal agent can be simultaneously delivered to the tumor site to exert their synergistic effects, a safe and efficient delivery system is needed. Herein, we fabricated doxorubicin hydrochloride (DOX)- and indocyanine green (ICG)-loaded microneedle (MN) patches (PVP@DOX/MSN@ICG) using a two-step casting process. Mesoporous silica nanoparticles (MSNs) were used to improve the ICG stability and avoid reducing its PTT efficiency in vivo. The MN patches exhibited a good skin penetration ability, and the tips of the MN patches were dissolved by the interstitial fluid to release DOX and ICG at the tumor sites. Under 808 nm laser irradiation within 2 min, the local temperature in the tumor quickly reached 48 °C at a low power of 0.34 W cm-2. A combination of chemotherapy and PTT for PVP@DOX/MSN@ICG MN patches may maximally induce human osteosarcoma MG-63 cells in vitro. Moreover, the in vivo results showed that PVP@DOX/MSN@ICG MN patches had the best antitumor effects because of synergistic chemotherapy and PTT. Therefore, the composite-dissolving MN patch is a promising strategy for enhancing the antitumor effect of chemotherapy alone and shows the potential for the synergistic therapy of superficial tumors.
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Antibióticos Antineoplásicos/administração & dosagem , Corantes/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Verde de Indocianina/administração & dosagem , Neoplasias/terapia , Animais , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Corantes/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Hipertermia Induzida/métodos , Verde de Indocianina/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Agulhas , Neoplasias/patologia , Fototerapia/métodosRESUMO
Conventional class B cytosine-guanine (CpG) (CpG-B) oligodeoxynucleotide (ODNs) consisting of a single-stranded (ss) phosphorothioate (PT) backbone (ss CpG-B-PT) is converted from a proinflammatory cytokine inducer to a type-I interferon (IFN) inducer when complexed with cationic materials. In this study, we designed ss CpG-B and double-stranded (ds) CpG-B ODNs with a phosphodiester (PD) backbone (ss CpG-B-PD and ds CpG-B-PD, respectively) that became type-I IFN inducers upon complexation with Lipofectamine 2000 (Lipo), a cationic liposome. The ds CpG-B-PD complex induced higher IFN-ß expression in mouse macrophage-like RAW264 cells than ss CpG-B-PD and ss CpG-B-PT complexes. The fold induction of IFN-ß increased with the number of CpG motifs in ds CpG-B-PD, and a complex of ds CpG-B-PD consisting of 72 base pairs with nine CpG motifs (ds CpG-B72-PD) and Lipo showed the highest capacity to induce IFN-ß. The materials and method used for complexation influenced the degree of IFN-ß induction: ds CpG-B72-PD entrapped by calcium phosphate (CaP) (ds CpG-B72-PD/CaP) showed a higher induction capacity than ds CpG-B72-PD adsorbed onto the CaP surface. Entrapment of ds CpG-B72-PD by CaP also enhanced the induction of the proinflammatory cytokine interleukin-12. Vaccinating mice with ds CpG-B72-PD/CaP in conjunction with ovalbumin (OVA) increased the ratios of OVA-specific CD8+ T cells to total CD8+ T cells in peripheral blood and of OVA-specific IgG2a associated with helper T (Th)1 cells to OVA-specific IgG1 associated with Th2 cells. These results indicate that ds CpG-B72-PD/CaP is an effective vaccine adjuvant that can activate both cellular and Th1-type humoral immune responses.