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Anti-tumor M1-like and pro-tumor M2-like tumor-associated macrophages (TAMs) coexist in tumor microenvironments (TME). The adverse effects of these M1/M2 subsets on tumors directly affect the current strategies to improve anti-tumor immune response. Therefore, it has attracted great attention to change the tumor immunosuppressive microenvironment by reprogramming TAMs. In this paper, we constructed biomimetic nanoparticles (HMMDN-Met@PM) targeting M2-like TAMs for macrophage re-polarization. In detail, the core of the biomimetic nanoparticles is metformin-loaded hollow mesoporous manganese dioxide nanoparticles (HMMDN-Met). Benefited from the hollow and porous structure of HMMDN, metformin, the regulator of M1/M2 adopted in this work, can be easily and widely loaded into HMMDN. Moreover, macrophage membranes were utilized for HMMDN-Met coating (HMMDN-Met@MM) to prevent the premature drug leakage and provide specific molecular recognition/TME targeting. In addition, M2 macrophage targeting peptide (M2pep) was modified on the surface of macrophage membrane to specifically deliver the drug to M2-like TAMs to promote the polarization of M2 to M1 macrophages. Through in vitro and in vivo studies, we found that the expression of surface markers and inflammatory factors CD206, Arg-1 and IL-10 of type M2 macrophages decreased, while the surface markers of type M1 macrophages and the expression of inflammatory factors CD80, TNF-α and iNOS increased, indicating the successful re-polarization of M2 macrophages and finally realizing the inhibition of tumor growth. At the same time, under the acidic and GSH conditions of tumor, HMMDN was decomposed into Mn2+, which is a contrast agent for magnetic resonance imaging, thus realizing the tracking of tumor. This work practices biomimetic nanosystem in targeted imaging and immunotherapy, paving the way for strategy designing for tumor inhibition.
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Metformina , Nanopartículas , Neoplasias , Humanos , Macrófagos Associados a Tumor , Biomimética , Neoplasias/tratamento farmacológico , Nanopartículas/química , Imunoterapia , Imageamento por Ressonância Magnética , Metformina/farmacologia , Microambiente TumoralRESUMO
Metastasis-induced high mortality of cancers urgently demands new approaches to simultaneously inhibit primary tumor metastasis and distant tumor growth. Herein, by rational design of a trident molecule Nap-Phe-Phe-Lys(SA-CPT)-Lys(SA-HCQ)-Tyr(H2PO3)-OH (Nap-CPT-HCQ-Yp) with three functional "spears" (i.e., a phosphotyrosine motif for enzymatic self-assembly, camptothecin (CPT) motif for chemotherapy, and hydroxychloroquine (HCQ) motif for autophagy inhibition) and nanobrush-nanoparticle-nanofiber transition property, we propose a novel strategy of intracellular enzymatic nanofiber formation and synergistic autophagy inhibition-enhanced chemotherapy and immunotherapy for spatial suppression of tumor metastasis. Under sequential alkaline phosphatase catalysis and carboxylesterase hydrolysis, Nap-CPT-HCQ-Yp undergoes nanobrush-nanoparticle-nanofiber transition, accompanied by the releases of CPT and HCQ. The formed intracellular nanofibers effectively inhibit the metastasis and invasion behaviors of cancer cells. Meanwhile, the released CPT and HCQ synergistically induce a prominent therapeutic effect through autophagy inhibition-enhanced chemotherapy. Furthermore, chemotherapy of Nap-CPT-HCQ-Yp enhances immunogenic cell death, resulting in the activation of toxic T-cells. Finally, a combination of checkpoint blockade therapy and Nap-CPT-HCQ-Yp-mediated chemotherapy elicits systemic antitumor immunity, thereby achieving efficient inhibitions of primary tumors as well as distant tumors in a breast tumor model. Our work offers a simple and feasible strategy for the design of "smart" multifunctional prodrugs to spatially suppress tumor metastasis.
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Neoplasias da Mama , Nanofibras , Nanopartículas , Pró-Fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Pró-Fármacos/uso terapêuticoRESUMO
The discrimination between dead and live cells is crucial for cell viability evaluation. Carbon dots (CDs), with advantages like simple and cost-effective synthesis, excellent biocompatibility, and high photostability, have shown potential for realizing selective live/dead cell staining. However, most of the developed CDs with the live/dead cell discrimination capacity usually have low photoluminescence quantum yields (PLQYs) and excitation wavelength-dependent fluorescence emission (which can cause fluorescence overlap with other fluorescent probes and make dual-color live/dead staining impossible), and hence, developing ultrabright CDs with excitation wavelength-independent fluorescence emission property for live/dead cell discrimination becomes an important task. Here, using a one-pot hydrothermal method, we prepared ultrasmall (â¼1.6 nm), ultrabright (PLQY: â¼78%), and excitation wavelength-independent sulfur-doped carbon dots (termed S-CDs) using rose bengal and 1,4-dimercaptobenzene as raw materials and demonstrated that the S-CDs could rapidly (â¼5 min) and accurately distinguish dead cells from live ones for almost all the cell types including bacterial, fungal, and animal cells in a wash-free manner. We confirmed that the S-CDs could rapidly pass through the dead cell surfaces to enter the interior of the dead cells, thus visualizing these dead cells. In contrast, the S-CDs could not enter the interior of live cells and thus could not stain these live cells. We further verified that the S-CDs presented better biocompatibility and higher photostability than the commercial live/dead staining dye propidium iodide, ensuring its bright application prospect in cell imaging and cell viability assessment. Overall, this work develops a type of CDs capable of realizing the live/dead cell discrimination of almost all the cell types (bacterial, fungal, and animal cells), which has seldom been achieved by other fluorescent nanoprobes.
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Carbono , Pontos Quânticos , Animais , Corantes Fluorescentes , Nitrogênio , Pontos Quânticos/toxicidade , Rosa Bengala , EnxofreRESUMO
Many noble metal-based nanoparticles have emerged for applications in cancer radiotherapy in recent years, but few investigations have been carried out for palladium nanoparticles. Herein, palladium nanosheets (Pd NSs), which possess a sheetlike morphology with a diameter of â¼14 nm and a thickness of â¼2 nm, were utilized as a sensitizer to improve the performance of radiotherapy. It was found that Pd NSs alone did not decrease the cell viability after treatment for as long as 130 h, suggesting the excellent cytocompatibility of the nanoagents. However, the viability of cancer cells treated with X-ray irradiation became lower, and the viability became even lower if the cells were co-treated with X-ray and Pd NSs, indicating the radiosensitization effect of Pd NSs. Additionally, compared with X-ray irradiation, the combined treatment of Pd NSs and X-ray irradiation induced the generation of more DNA double-stranded breaks and reactive oxygen species within cancer cells, which eventually caused elevated cell apoptosis. Moreover, in vivo experiments also verified the radiosensitization effect and the favorable biocompatibility of Pd NSs, indicating their potential for acquiring satisfactory in vivo radiotherapeutic effect at lower X-ray doses. It is believed that the present research will open new avenues for the application of noble metal-based nanoparticles in radiosensitization.
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Nanopartículas Metálicas , Radiossensibilizantes , Apoptose , Sobrevivência Celular , Nanopartículas Metálicas/toxicidade , Paládio , Radiossensibilizantes/toxicidadeRESUMO
Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin-based tumor microenvironment-responsive nanoagent is designed via the self-assembly of human serum albumin (HSA), dc-IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting-mediated mild-temperature PTT. The formed HSA/dc-IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near-infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia-induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc-IR825/GA NPs show pH-responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild-temperature PTT and chemotherapy. Taken together, the NIR-activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild-temperature PTT-based combination strategies.
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Albuminas/administração & dosagem , Hipertermia Induzida/métodos , Terapia de Alvo Molecular , Fototerapia/métodos , Células A549 , Albuminas/farmacocinética , Animais , Terapia Combinada , Endocitose , Humanos , Camundongos , Nanopartículas/uso terapêutico , Neoplasias/terapia , Temperatura , Distribuição TecidualRESUMO
The folding/unfolding behavior of proteins (enzymes) in confined space is important for their properties and functions, but such a behavior remains largely unexplored. In this article, we reported our finding that lysozyme and a double hydrophilic block copolymer, methoxypoly(ethylene glycol)5K-block-poly(l-aspartic acid sodium salt)10 (mPEG(5K)-b-PLD10), can form a polyelectrolyte complex micelle with a particle size of â¼30 nm, as verified by dynamic light scattering and transmission electron microscopy. The unfolding and refolding behaviors of lysozyme molecules in the presence of the copolymer were studied by microcalorimetry and circular dichroism spectroscopy. Upon complex formation with mPEG(5K)-b-PLD10, lysozyme changed from its initial native state to a new partially unfolded state. Compared with its native state, this copolymer-complexed new folding state of lysozyme has different secondary and tertiary structures, a decreased thermostability, and significantly altered unfolding/refolding behaviors. It was found that the native lysozyme exhibited reversible unfolding and refolding upon heating and subsequent cooling, while lysozyme in the new folding state (complexed with the oppositely charged PLD segments of the polymer) could unfold upon heating but could not refold upon subsequent cooling. By employing the heating-cooling-reheating procedure, the prevention of complex formation between lysozyme and polymer due to the salt screening effect was observed, and the resulting uncomplexed lysozyme regained its proper unfolding and refolding abilities upon heating and subsequent cooling. Besides, we also pointed out the important role the length of the PLD segment played during the formation of micelles and the monodispersity of the formed micelles. Furthermore, the lysozyme-mPEG(5K)-b-PLD10 mixtures prepared in this work were all transparent, without the formation of large aggregates or precipitates in solution as frequently observed in other protein-polyelectrolyte systems. Hence, the present protein-PEGylated poly(amino acid) mixture provides an ideal water-soluble model system to study the important role of electrostatic interaction in the complexation between proteins and polymers, leading to important new knowledge on the protein-polymer interactions. Moreover, the polyelectrolyte complex micelle formed between protein and PEGylated polymer may provide a good drug delivery vehicle for therapeutic proteins.
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Muramidase/química , Peptídeos/química , Polieletrólitos/química , Polietilenoglicóis/química , Animais , Varredura Diferencial de Calorimetria , Galinhas , Difusão Dinâmica da Luz , Micelas , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Ligação Proteica , Dobramento de ProteínaRESUMO
Lipid rafts are highly ordered small microdomains mainly composed of glycosphingolipids, cholesterol, and protein receptors. Optically distinguishing lipid raft domains in cell membranes would greatly facilitate the investigations on the structure and dynamics of raft-related cellular behaviors, such as signal transduction, membrane transport (endocytosis), adhesion, and motility. However, current strategies about the visualization of lipid raft domains usually suffer from the low biocompatibility of the probes, invasive detection, or ex situ observation. At the same time, naturally derived biomacromolecules have been extensively used in biomedical field and their interaction with cells remains a long-standing topic since it is closely related to various fundamental studies and potential applications. Herein, noninvasive visualization of lipid raft domains in model lipid bilayers (supported lipid bilayers and giant unilamellar vesicles) and live cells was successfully realized in situ using fluorescent biomacromolecules: the fluorescein isothiocyanate (FITC)-labeled glycol chitosan molecules. We found that the lipid raft domains in model or real membranes could be specifically stained by the FITC-labeled glycol chitosan molecules, which could be attributed to the electrostatic attractive interaction and/or hydrophobic interaction between the probes and the lipid raft domains. Since the FITC-labeled glycol chitosan molecules do not need to completely insert into the lipid bilayer and will not disturb the organization of lipids, they can more accurately visualize the raft domains as compared with other fluorescent dyes that need to be premixed with the various lipid molecules prior to the fabrication of model membranes. Furthermore, the FITC-labeled glycol chitosan molecules were found to be able to resist cellular internalization and could successfully visualize rafts in live cells. The present work provides a new way to achieve the imaging of lipid rafts and also sheds new light on the interaction between biomacromolecules and lipid membranes.
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OBJECTIVE: To clarify the factors associate with the length of stay (LOS) in Lushan Earthquake victims. METHODS: We retrospectively analyzed the medical information of 263 traumatic patients admitted to West China Hospital, Sichuan University after the Lushan Earthquake. Ten variables extracted for the analysis, including gender, age, injuried time, multiple injury, infection, comorbidities, Injury Severity Score (ISS), Revised Trauma Score (RTS) CRAMS score, and Prehospital Index (PHI). Univariable analysis using multiple stepwise regression analysis was performed to identify the factors associated with extended LOS. RESULTS: Infection, ISS score, and Pre-hospital Time were associated with extended LOS, and infection was the most weighted factor. The regression equation is: LOS (h) = 498.36 + 671.41 x Infection + 43.87 x ISS score - 5.12 x Pre-hospital Time. CONCLUSION: This study demonstrated that trauma patients with infections and high ISS scores were at increased risk for extended LOS and pre-hospital time decreased the risk.
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Terremotos , Tempo de Internação , China , Infecção Hospitalar , Desastres , Humanos , Escala de Gravidade do Ferimento , Traumatismo Múltiplo , Análise Multivariada , Análise de Regressão , Estudos RetrospectivosRESUMO
Small molecule-based photothermal agents (PTAs) hold promising future for photothermal therapy; however, unexpected inactivation exerts negative impacts on their application clinically. Herein, a self-regenerating PTA strategy is proposed by integrating 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTSâ¢+) with a thermodynamic agent (TDA) 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH). Under NIR laser, the photothermal effect of ABTSâ¢+ accelerates the production of alkyl radicals by AIPH, which activates the regeneration of ABTSâ¢+, thus creating a continuous positive feedback loop between photothermal and thermodynamic effects. The combination of ABTSâ¢+ regeneration and alkyl radical production leads to the tandem photothermal and thermodynamic tumor therapy. In vitro and in vivo experiments confirm that the synergistic action of thermal ablation, radical damage, and oxidative stress effectively realizes tumor suppression. This work offers a promising approach to address the unwanted inactivation of PTAs and provides valuable insights for optimizing combination therapy.
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The tumour-targeting efficiency of systemically delivered chemodrugs largely dictates the therapeutic outcome of anticancer treatment. Major challenges lie in the complexity of diverse biological barriers that drug delivery systems must hierarchically overcome to reach their cellular/subcellular targets. Herein, an "all-in-one" red blood cell (RBC)-derived microrobot that can hierarchically adapt to five critical stages during systemic drug delivery, that is, circulation, accumulation, release, extravasation, and penetration, is developed. The microrobots behave like natural RBCs in blood circulation, due to their almost identical surface properties, but can be magnetically manipulated to accumulate at regions of interest such as tumours. Next, the microrobots are "immolated" under laser irradiation to release their therapeutic cargoes and, by generating heat, to enhance drug extravasation through vascular barriers. As a coloaded agent, pirfenidone (PFD) can inhibit the formation of extracellular matrix and increase the penetration depth of chemodrugs in the solid tumour. It is demonstrated that this system effectively suppresses both primary and metastatic tumours in mouse models without evident side effects, and may represent a new class of intelligent biomimicking robots for biomedical applications.
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The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate antitumor immunity, herein a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) is rationally designed containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic Cip-OH and chemotherapeutic drug CPT are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment.
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Antineoplásicos , Neoplasias Colorretais , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Imunoterapia , Peptídeos/química , Peptídeos/farmacologia , Camptotecina/farmacologia , Camptotecina/química , Antibacterianos/farmacologia , Antibacterianos/química , Camundongos , Nanofibras/química , Ciprofloxacina/farmacologia , Ciprofloxacina/química , Liberação Controlada de Fármacos , Biotina/químicaRESUMO
This study aimed to investigate the feeding effect of wheat silage on growth performance, nutrient digestibility, rumen fermentation, and microbiota composition in feedlot lambs. Sixty-four male crossbred Chinese Han lambs (BW = 27.8 ± 0.67 kg, 3 months of age) were randomly assigned to four ration groups with wheat silage replacing 0% (WS0), 36% (WS36), 64% (WS64), and 100% (WS100) of oaten hay on forage dry matter basis. The concentrate-to-forage ratio was 80:20 and the feeding trial lasted 52 d. Increasing wheat silage inclusion linearly decreased dry matter intake by 4% to 27% (P < 0.01). However, increasing the wheat silage replacement of oaten hay by no more than 64% improved the feed efficiency by 14% as noted by the feed-to-gain ratio (P = 0.04). Apparent digestibility of organic matter (P < 0.01), neutral detergent fibre (P = 0.04) and acid detergent fibre (P < 0.01) quadratically increased. Ammonia nitrogen (P = 0.01) decreased while microbial protein production (P < 0.01) increased with the increase of wheat silage inclusion. Total volatile fatty acids concentration increased quadratically with the increase of wheat silage inclusion (P < 0.01), and the highest occurred in WS64. The molar proportion of acetate (P < 0.01) and acetate-to-propionate ratio (P = 0.04) decreased while butyrate (P < 0.01) and isovalerate (P = 0.04) increased. Increasing wheat silage inclusion increased the Firmicutes-to-Bacteroidota ratio by 226% to 357%, resulting in Firmicutes instead of Bacteroidota being the most abundant phylum. The relative abundance of cellulolytic Ruminococcus numerically increased but that of amylolytic Prevotella (P < 0.01) decreased as increasing wheat silage inclusion. Taken together, increasing wheat silage replacement of oaten hay by no more than 64% exhibited greater feed efficiency and fibre digestion despite low feed intake by feedlot lambs due to the change of Firmicutes-to-Bacteroidota ratio in the rumen.
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The aim of this study was to investigate whether guanidine acetic acid (GAA) yields a response in rapid-growing lambs depending on forage type. In this study, seventy-two small-tailed Han lambs (initial body weights = 12 ± 1.6 kg) were used in a 120-d feeding experiment after a 7-d adaptation period. A 2 × 3 factorial experimental feeding design was applied to the lambs, which were fed a total mixed ration with two forage types (OH: oaten hay; OHWS: oaten hay plus wheat silage) and three forms of additional GAA (GAA: 0 g/kg; UGAA: Uncoated GAA, 1 g/kg; CGAA: Coated GAA, 1 g/kg). The OH diet had a greater dry matter intake, average daily gain, and hot carcass weight than the OHWS diet. The GAA supplementation increased the final body weight, hot carcass weight, dressing percentage, and ribeye area in the longissimus lumborum. Meanwhile, it decreased backfat thickness and serum triglycerides. Dietary GAA decreased the acidity of the meat and elevated the water-holding capacity in mutton. In addition, the crude protein content in mutton increased with GAA addition. Dietary GAA (UGAA or CGAA) might be an effective additive in lamb fed by different forage types, as it has potential to improve growth performance and meat quality.
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Since atherosclerosis, a disease characterized by abnormal arterial lipid deposition, may lead to fatal cardiovascular diseases, imaging of atherosclerotic plaques is of great value for their pathological assessment. In this study, we propose a lipid droplet (LD)-hitchhiking strategy to in situ create Trojan foam cells for fluorescence/photoacoustic imaging of atherosclerotic plaques via homologous targeting effect. In our design, functional liposomes (DCP liposomes) composed of phospholipid dioleoylphosphatidylserine (DOPS), a novel LD inducer we found, and Cypate-PC, a synthesized lipid-like molecular probe, have demonstrated great capability of inducing LDs in monocytes/macrophages while being enveloped into the resulting Trojan foam cells. Taking advantage of homologous targeting effect, the imaging probe hitchhikes on the LDs in Trojan foam cells for targeted transport to the plaque sites. Moreover, the confinement in highly hydrophobic LDs endows the imaging probe with high efficiency in light absorption, enabling greatly intensified fluorescence/photoacoustic signals. The DCP liposomes have shown great potency in inducing the generation of Trojan foam cells, and eventually ex vivo fluorescence imaging and in vivo photoacoustic imaging of atherosclerotic plaques. The proposed strategy provides more insights into the design of targeted imaging methodologies, and also an effective avenue to facilitate the evaluation and subsequent treatment of atherosclerotic plaques.
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Aterosclerose , Técnicas Biossensoriais , Técnicas Fotoacústicas , Placa Aterosclerótica , Aterosclerose/patologia , Células Espumosas/patologia , Humanos , Gotículas Lipídicas/patologia , Lipossomos , Sondas Moleculares , Imagem Óptica , Fosfolipídeos , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologiaRESUMO
Cancer vaccine, which can promote tumor-specific immunostimulation, is one of the most important immunotherapeutic strategies and holds tremendous potential for cancer treatment/prevention. Here, we prepare a series of nanoparticles composed of doxorubicin- and tyrosine kinase inhibitor-loaded and hyaluronic acid-coated dendritic polymers (termed HDDT nanoparticles) and find that the HDDT nanoparticles can convert various cancer cells to micrometer-sized vesicles (1.6-3.2 µm; termed HMVs) with ~100% cell-to-HMV conversion efficiency. We confirm in two tumor-bearing mouse models that the nanoparticles can restrain tumor growth, induce robust immunogenic cell death, and convert the primary tumor into an antigen depot by producing HMVs in situ to serve as personalized vaccines for cancer immunotherapy. Furthermore, the HDDT-healed mice show a strong immune memory effect and the HDDT treatment can realize long-term protection against tumor rechallenge. Collectively, the present work provides a general strategy for the preparation of tumor-associated antigen-containing vesicles and the development of personalized cancer vaccines.
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Vacinas Anticâncer , Nanopartículas , Neoplasias , Camundongos , Animais , Células Dendríticas , Imunoterapia , Antígenos de Neoplasias , Neoplasias/tratamento farmacológico , ImunidadeRESUMO
Guanidine acetic acid (GAA) is increasingly considered as a nutritional growth promoter in monogastric animals. Whether or not such response would exist in rapid-growing lambs is unclear yet. The objective of this study was to investigate whether dietary supplementation with uncoated GAA (UGAA) and coated GAA (CGAA) could alter growth performance, nutrient digestion, serum metabolites, and antioxidant capacity in lambs. Seventy-two small-tailed Han lambs initially weighed 12 ± 1.6 kg were randomly allocated into six groups in a 2 × 3 factorial experimental design including two forage-type rations [Oaten hay (OH) vs. its combination with wheat silage (OHWS)] and three GAA treatment per ration: no GAA, 1 g UGAA, and 1 g CGAA per kg dry matter. The whole experiment was completed in two consecutive growing stages (stage 1, 13-30 kg; stage 2, 30-50 kg). Under high-concentrate feeding pattern (Stage 1, 25: 75; Stage 2, 20: 80), UGAA or CGAA supplementation in young lambs presented greater dry matter intake (DMI) in stage 1 and average daily gain (ADG) in the whole experimental period; lambs in OH group had higher ADG and DMI than that in OHWS group in stage 1 and whole experimental period, but this phenomenon was not observed in stage 2. Both UCGA and CGAA addition increased dietary DM, organic matter (OM), neutral detergent fiber (NDF), and acid detergent fiber (ADF) digestion in both stages. In blood metabolism, UCGA and CGAA addition resulted in a greater total protein (TP) and insulin-like growth factor 1(IGF-1) levels, as well as antioxidant capacity; at the same time, UCGA and CGAA addition increased GAA metabolism-creatine kinase and decreased guanidinoacetate N-methyltransferase (GAMT) and L-Arginine glycine amidine transferase catalyzes (AGAT) activity. In a brief, the results obtained in the present study suggested that GAA (UGAA and CGAA; 1 g/kg DM) could be applied to improve growth performance in younger (13-30 kg) instead of older (30-50 kg) lambs in high-concentrate feedlotting practice.
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Plasma membrane (PM), a fundamental building component of a cell, is responsible for a variety of cell functions and biological processes. However, it is still challenging to acquire its morphology and morphological variation information via an effective approach. Herein, we report a PM imaging study regarding an aggregation-induced emission luminogen (AIEgen) called tetraphenylethylene-naphthalimide+ (TPE-NIM+), which is derived from our previously reported tetraphenylethylene-naphthalimide (TPE-NIM). The designed AIEgen (TPE-NIM+) shows significant characteristics of ultrafast staining, high photostability, wash-free property, and long retention time at the PM, which can structurally be correlated with its positively charged quaternary amine and hydrophobic moiety. TPE-NIM+ is further applied for staining of different cell lines, proving its universal PM imaging capability. Most importantly, we demonstrate that TPE-NIM+ can clearly delineate the contours of densely packed living cells with high cytocompatibility. Therefore, TPE-NIM+ as a PM imaging reagent superior to currently available commercial PM dyes shall find a number of applications in the biological/biomedical fields and even beyond.
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Membrana Celular/química , Sondas Moleculares/química , Coloração e Rotulagem , Linhagem Celular , Humanos , Interações Hidrofóbicas e Hidrofílicas , Análise Espectral/métodos , Estilbenos/químicaRESUMO
The presence of drug efflux pumps and endo/lysosomal entrapment phenomena in multidrug-resistant cancer cells leads to insufficient and off-target accumulation of anticancer drugs in the cells, which severely reduces the drugs' therapeutic efficacies. Here, we prepare a novel type of photosensitizer (PS)-loaded supramolecular nanogel, which can utilize the endo/lysosomal entrapment for enhanced photodynamic therapy (PDT) of multidrug-resistant cancer. The PS-loaded nanogels can elude the drug efflux pumps, and be markedly internalized by drug-resistant cancer cells through the endocytic pathway. With their pH-sensitive properties, the internalized nanogels can aggregate in the acidic endosomes/lysosomes, thus retarding their exocytosis from the cells. Moreover, the lysosomes of the nanogel-treated cells are severely damaged after irradiation, which inhibits the protective autophagy and improves the photodynamic therapeutic performance of the nanogels. Besides, the in vivo experiments show that the nanogels significantly prolong the tumor retention of the PSs, thus enabling multiple PDT treatments after a single drug injection.
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Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fotoquimioterapia/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Endossomos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Nanogéis/uso terapêutico , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Bacterial infections, especially chronic infections caused by bacterial biofilms, have become a worldwide threat to public health. Encouragingly, the synergistic actions of two or more antibacterial drugs have been proven to be effective in treating refractory bacterial infections. Herein, we fabricated a robust antibacterial nanohybrid, the colistin-loaded polydopamine nanospheres (PDA NSs) decorated uniformly with small silver nanodots (u-CPSs), and the u-CPSs could realize synergistic bactericidal performance for combating bacterial infections. PDA NSs, as an adhesive nanocarrier, could bind to the bacterial surfaces, where the drugs (colistin and silver ions) on the PDA surfaces could be released persistently via a near-infrared laser-triggered manner. Interestingly, compared with colistin-loaded PDA NSs decorated sparsely with large silver nanoparticles (s-CPSs), the u-CPSs exhibited stronger antibacterial and antibiofilm effects. We have also demonstrated that the u-CPSs could disrupt the cell walls/membranes of Gram-negative Escherichia coli bacteria and induce the generation of toxic reactive oxygen species within the bacteria. Collectively, the present work exemplifies the exquisite design and synthesis of PDA-based nanohybrids for achieving synergistic antibacterial and antibiofilm activities, which may promote the development of more powerful nanoagents to fight against bacterial infections.
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Mitophagy is a specific self-protective autophagic process that degrades damaged or dysfunctional mitochondria, and is generally considered to reduce the effectiveness of mitochondria-targeted therapies. Here, we report an energy depletion-based anticancer strategy by selectively activating excessive mitophagy in cancer cells. We fabricate a type of mitochondria-targeting nanomicelles via the self-assembly of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and dc-IR825 (a near-infrared cyanine dye and a photothermal agent). The TPGS/dc-IR825 nanomicelles enable mitochondrial damage in cancer cells, which, for self-protection, activate two autophagic pathways, (1) mitophagy and (2) adenosine triphosphate (ATP) shortage-triggered autophagy. However, the excessive mitophagy/autophagy activities far surpass the degradative capacity of autolysosomes, leading to the formation of micrometer-sized vacuoles and degradation blockage. Immunofluorescence staining and Western blot analysis reveal that the nanomicelle-treated cancer cells are under severe ATP shortage, which eventually causes substantial cell death. Moreover, the nanomicelles intravenously injected into tumor-bearing mice show high tumor accumulation, long tumor retention, and inhibit the tumor growth by inducing excessive mitophagy/autophagy and energy depletion in tumor cells. Additional near-infrared laser irradiation treatment further enhances the in vitro and in vivo anticancer efficiencies of the nanomicelles, due to the excellent photothermal and photodynamic effects of dc-IR825. We believe that this work highlights the important role of mitophagy/autophagy in treating cancers.