Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 71
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
FASEB J ; 37(8): e23047, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37392373

RESUMO

Diabetic cardiomyopathy (DCM) is one of the main complications in type I diabetic patients. Activated macrophage is critical for directing the process of inflammation during the development of DCM. The present study focused on the roles of CD226 on macrophage function during the DCM progression. It has been found that the number of cardiac macrophages in the hearts of streptozocin (STZ)-induced diabetes mice was significantly increased compared with that in non-diabetes mice, and the expression level of CD226 on cardiac macrophages in STZ-induced diabetes mice was higher than that in non-diabetes mice. CD226 deficiency attenuated the diabetes-induced cardiac dysfunction and decreased the proportion of CD86+ F4/80+ macrophages in the diabetic hearts. Notably, adoptive transfer of Cd226-/- - bone marrow derived macrophages (BMDMs) alleviated diabetes-induced cardiac dysfunction, which may be due to the attenuated migration capacity of Cd226-/- -BMDM under high glucose stimulation. Furthermore, CD226 deficiency decreased the macrophage glycolysis accompanying by the downregulated hexokinase 2 (HK2) and lactate dehydrogenase A (LDH-A) expression. Taken together, these findings revealed the pathogenic roles of CD226 played in the process of DCM and provided a basis for the treatment of DCM.


Assuntos
Antígenos de Diferenciação de Linfócitos T , Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Glicólise , Coração , Macrófagos , Antígenos de Diferenciação de Linfócitos T/genética
2.
Langmuir ; 40(21): 11056-11066, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38739782

RESUMO

The anti-aging agent TiO2-polyacrylonitrile (PAN) and the mechanical strengthening agent CSW-PAN were prepared by radical polymerization using rutile nano-titanium dioxide (TiO2) and anhydrous calcium sulfate whisker (CSW) as raw materials. The structures of TiO2-PAN and CSW-PAN were characterized using Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Simultaneously, the mechanical properties, aging properties, and thermal stability of TiO2-PAN/CSW-PAN/polypropylene (PP) composites were studied, and the results showed that the surfaces of nano-titanium dioxide and calcium sulfate whiskers were successfully grafted with acrylonitrile. Owing to the introduction of new elements, such as acrylonitrile, nano-titanium dioxide and calcium sulfate whiskers have anti-aging properties. In comparison of the impact strength and tensile strength of TiO2-PAN/PP and TiO2-PAN/CSW-PAN/PP before aging, it can be proven that adding CSW-PAN can significantly enhance the mechanical properties of TiO2-PAN/CSW-PAN/PP. After 1000 h of aging, the tensile strength of the ternary composite TiO2-PAN/CSW-PAN/PP was 19.88 MPa when the addition amount of TiO2-PAN and CSW-PAN was 3%. Moreover, the impact strength of the ternary composite material TiO2-PAN/CSW-PAN/PP after 1000 h of aging is even better than that of non-aging pure PP materials, proving that the service life of improved PP products is extended, unnecessary waste and environmental pollution can be relieved, and the needs of specific engineering fields can be met.

3.
Mikrochim Acta ; 191(8): 443, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38955844

RESUMO

CoFe@C was first prepared by calcining the precursor of CoFe-metal-organic framework-74 (CoFe-MOF-74), then an electrochemical sensor for the determination of neohesperidin dihydrochalcone (NHDC) was constructed, which was stemmed from the novel CoFe@C/Nafion composite film modified glassy carbon electrode (GCE). The CoFe@C/Nafion composite was verified by field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM). Electrochemical impedance spectroscopy (EIS) was used to evaluate its electrical properties as a modified material for an electrochemical sensor. Compared with CoFe-MOF-74 precursor modified electrode, CoFe@C/Nafion electrode exhibited a great synergic catalytic effect and extremely increased the oxidation peak signal of NHDC. The effects of various experimental conditions on the oxidation of NHDC were investigated and the calibration plot was tested. The results bespoken that CoFe@C/Nafion GCE has good reproducibility and anti-interference under the optimal experimental conditions. In addition, the differential pulse current response of NHDC was linear with its concentration within the range 0.08 ~ 20 µmol/L, and the linear regression coefficient was 0.9957. The detection limit was as low as 14.2 nmol/L (S/N = 3). In order to further verify the feasibility of the method, it was successfully used to determine the content of NHDC in Chinese medicine, with a satisfactory result, good in accordance with that of high performance liquid chromatography (HPLC).


Assuntos
Chalconas , Cobalto , Técnicas Eletroquímicas , Eletrodos , Limite de Detecção , Estruturas Metalorgânicas , Cobalto/química , Estruturas Metalorgânicas/química , Chalconas/química , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Hesperidina/análogos & derivados , Hesperidina/análise , Hesperidina/química , Polímeros de Fluorcarboneto/química , Oxirredução , Carbono/química , Reprodutibilidade dos Testes , Ferro/química
4.
Small ; 19(23): e2300594, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36755191

RESUMO

A primary concern about photodynamic therapy (PDT) is its inability to regulate the generation levels of reactive oxidative species (ROS) based on the complex microenvironment, resulting in the impairment toward normal tissues and immunosuppression. Besides, tumor metastasis also compromises PDT's efficacy and drives mortality. However, it is very challenging to achieve such two goals within one nanosystem. Here, the nanoassembly (CPR) with self-regulated photodynamic and antimetastasis properties comprises three parts: chlorin e6-conjugated ß-cyclodextrin (CD-Ce6) acts as the main PDT agent and ferrocene (Fc)-terminated phenylboronic acid-containing conjugates entering into the cavity of CD-Ce6, as well as rosmarinic acid (RA)-boronic acid crosslinked shell. Compared with non-crosslinked counterpart, CPR displays better stability and enhanced tumor accumulation. Under laser irradiation, CPR generates plenty of ROS to damage tumor cells and induce immunogenic cell death. Mildly acidic TME partly cleaves the crosslinkers to dissociate antioxidant RAs from micelles, which together with Fc in CPR scavenge PDT-induced ROS in the TME. By contrast, under acidic lysosomal conditions, Fc catalyzes abundant H2 O2 in tumor cells to produce highly cytotoxic •OH, while RA continuously reduces ferroptosis-generated Fc+ into Fc, both to augment the PDT efficacy in tumor cells. CPR also remarkably hinders the epithelial-mesenchymal transition to prevent the lung metastasis.


Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Fototerapia , Cinamatos/farmacologia , Porfirinas/farmacologia , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Ácido Rosmarínico
5.
Immunol Invest ; 51(6): 1833-1842, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35468025

RESUMO

Ulcerative colitis (UC) is a refractory and recurring inflammatory bowel disease (IBD). Monocytes and macrophages are major components of the mononuclear phagocyte system (MPS), and the balance between inflammatory monocytes and small peritoneal macrophages plays important roles in UC. However, the mechanisms governing the balance between inflammatory monocytes and small peritoneal macrophages in UC need to be clarified further. Here, we found that the expression levels of CD226 on different subsets of monocytes/macrophages are varied in UC mice. The expression levels of CD226 on patrolling monocytes (pMos) and small peritoneal macrophages (SPMs) were markedly increased, while the expression levels of CD226 on inflammatory monocytes (iMos) were decreased in UC mice. Significantly, the percentage of iMos was enhanced while the percentage of SPMs were decreased in CD226 knockout UC mice compared with that in wildtype UC mice. Moreover, CD226 deficiency suppressed the migration capacity of macrophages. Therefore, our data suggest that CD226 plays critical roles in regulating the function and balance of monocytes/macrophages in mouse UC and targeting CD226 in MPS may be developed as a potent therapy for UC.


Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Animais , Colite Ulcerativa/metabolismo , Macrófagos/metabolismo , Macrófagos Peritoneais/metabolismo , Camundongos , Monócitos/metabolismo
6.
IEEE Trans Inf Theory ; 68(6): 3991-4019, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36274655

RESUMO

This paper studies a general framework for high-order tensor SVD. We propose a new computationally efficient algorithm, tensor-train orthogonal iteration (TTOI), that aims to estimate the low tensor-train rank structure from the noisy high-order tensor observation. The proposed TTOI consists of initialization via TT-SVD [1] and new iterative backward/forward updates. We develop the general upper bound on estimation error for TTOI with the support of several new representation lemmas on tensor matricizations. By developing a matching information-theoretic lower bound, we also prove that TTOI achieves the minimax optimality under the spiked tensor model. The merits of the proposed TTOI are illustrated through applications to estimation and dimension reduction of high-order Markov processes, numerical studies, and a real data example on New York City taxi travel records. The software of the proposed algorithm is available online (https://github.com/Lili-Zheng-stat/TTOI).

7.
Mol Pharm ; 18(12): 4341-4353, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34779630

RESUMO

The formation of protein corona (PC) around nanoparticles (NPs) has been reported inside biological conditions. This effect can alter delivery capacity toward the targeted tissues. Here, we synthesized folic acid-modified chitosan NPs (FA-CS NPs) using different concentrations of folic acid (5, 10, and 20%). FA-CS NPs were exposed to plasmas of breast cancer patients and healthy donors to evaluate the possibility of PC formation. We also monitored uptake efficiency in in vitro conditions after incubation with human breast cancer cell line MDA-MB-231 and monocyte/macrophage-like Raw264.7 cells. Data showed that the formation of PC around FA-CS NPs can change physicochemical properties coincided with the rise in NP size and negative surface charge. SDS-PAGE electrophoresis revealed differences in the type and content rate of plasma proteins attached to NP surface in a personalized manner. Based on MTT data, the formation of PC around NPs did not exert cytotoxic effects on MDA-MB-231 cells while this phenomenon reduced uptake rate. Fluorescence imaging and flow cytometry analyses revealed reduced cellular internalization rate in NPs exposed to patients' plasma compared to the control group. In contrast to breast MDA-MB-231 cells, Raw264.7 cells efficiently adsorbed the bare and PC-coated NPs from both sources, indicating the involvement of ligand-receptor-dependent and independent cellular engulfment. These data showed that the PC formed on the FA-CS NPs is entirely different in breast cancer patients and healthy counterparts. PC derived from patients' plasma almost abolishes the targeting efficiency of FA-CS NPs even in different mechanisms, while this behavior was not shown in the control group. Surprisingly, Raw264.7 cells strongly adsorbed the PC-coated NPs, especially when these particles were in the presence of patients' sera. It is strongly suggested that the formation of PC around can affect delivering capacity of FA-CS NPs to cancer cells. It seems that the PC-coated FA-CS NPs can be used as an efficient delivery strategy for the transfer of specific biomolecules in immune system disorders.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Quitosana/química , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Nanopartículas/química , Linhagem Celular Tumoral , Feminino , Humanos , Macrófagos/fisiologia
8.
J Stat Plan Inference ; 213: 50-71, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33364672

RESUMO

Quantum state tomography, which aims to estimate quantum states that are described by density matrices, plays an important role in quantum science and quantum technology. This paper examines the eigenspace estimation and the reconstruction of large low-rank density matrix based on Pauli measurements. Both ordinary principal component analysis (PCA) and iterative thresholding sparse PCA (ITSPCA) estimators of the eigenspace are studied, and their respective convergence rates are established. In particular, we show that the ITSPCA estimator is rate-optimal. We present the reconstruction of the large low-rank density matrix and obtain its optimal convergence rate by using the ITSPCA estimator. A numerical study is carried out to investigate the finite sample performance of the proposed estimators.

9.
Planta ; 252(6): 95, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33130990

RESUMO

MAIN CONCLUSION: The Arabidopsis transcription factor NAC103 is up-regulated and its encoding protein is stabilized by ABA treatment, which positively regulates several ABA-responsive downstream genes during seed germination and seedlings growth. The Arabidopsis transcription factor NAC103 was previously found to be involved in endoplasmic reticulum (ER) stress and DNA damage responses. In this study, we report the new biological function of NAC103 in abscisic acid (ABA) response during seed germination and seedling growth in Arabidopsis. The expression of NAC103 was up-regulated and the NAC103 protein was stabilized by ABA treatment. Both the loss-of-function mutants of NAC103, created by targeted gene-editing, and the over-expression plants of NAC103 have no obvious germination-related phenotype under normal growth conditions. However, under exogenous ABA treatment conditions, the NAC103 mutants were less sensitive to ABA during seed germination; in contrast, the NAC103 over-expression plants were more sensitive to ABA during seed germination and young seedling growth. Further, NAC103 regulated several ABA-responsive downstream genes including MYB78, MYB3, PLP3, AMY1, and RGL2. These results demonstrate that NAC103 positively regulates ABA response in Arabidopsis.


Assuntos
Ácido Abscísico , Proteínas de Arabidopsis , Arabidopsis , Germinação , Plântula , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Germinação/efeitos dos fármacos , Germinação/genética , Plântula/efeitos dos fármacos , Plântula/genética , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Sementes/efeitos dos fármacos , Sementes/genética , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Inorg Chem ; 56(10): 5953-5958, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28448126

RESUMO

In this work, we first found a surprising solvothermal reaction for direct dinitration of quinoline derivative. To explore the application in direct nitroquinoline synthesis, this reaction was subsequently modified as an equivalent reaction in a Schlenk tube. More significantly, after a constant attempt, nitrated derivative was obtained in optimized condition with a zinc(II) sulfate catalyst, where some substrates with strong electron-withdrawing group were first nitrated by a directly catalyzed condition. This new zinc(II)-catalyzed aromatic C-H activation reaction is the first example of direct dinitration by a single catalyst, which will be a new facile and environmentally friendly strategy to access synthetically useful nitroquinoline derivative.

11.
J Nat Prod ; 80(9): 2547-2550, 2017 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-28829608

RESUMO

Two tetranortriterpenoids with new skeletons, xylomexicanins I and J (1 and 2), were isolated during the investigation of chemical constituents from seeds of the Chinese mangrove, Xylocarpus granatum. Xylomexicanin I (1) is an unprecedented limonoid with bridged B- and C-rings. A biosynthesis pathway for 1 from xylomexicanin F is proposed.


Assuntos
Limoninas/isolamento & purificação , Meliaceae/química , Sementes/química , Limoninas/química , Estrutura Molecular
12.
Des Monomers Polym ; 20(1): 468-475, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29491818

RESUMO

(3-(tert-butylperoxy)propyl) trimethoxysilane (TBPT), is a tailor-made new style silane coupling agent with peroxide group, which have ability of initiating polymerization. This study used TBPT to generate free radical, and initiated the polymerization of acrylonitrile (AN), thereby forming polyacrylonitrile (PAN) in two approaches, thermal initiation system and redox initiation system. Meanwhile this study bonded TBPT onto nano-TiO2 to get modified nano-TiO2 by means of the coupling function of TBPT, and then made the peroxide group of the modified nano-TiO2 decompose and initiate the polymerization of AN in thermal initiation system and redox initiation system respectively. The products were investigated and analyzed by FTIR, XPS and TG. The result showed that on one hand, in the products of the thermal initiation there was PAN, which both attached and unattached to the modified nano-TiO2; on the other hand, in the products of the redox initiation system the PAN unattached to the modified nano-TiO2 was produced, while the PAN attached to the modified nano-TiO2 was not.

13.
Analyst ; 141(12): 3821-31, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27010726

RESUMO

Digital PCR (dPCR) is an emerging technology for genetic analysis and clinical diagnostics. To facilitate the widespread application of dPCR, here we developed a new micropatterned superporous absorbent array chip (µSAAC) which consists of an array of microwells packed with highly porous agarose microbeads. The packed beads construct a hierarchically porous microgel which confers superior water adsorption capacity to enable spontaneous filling of PDMS microwells for fluid compartmentalization without the need of sophisticated microfluidic equipment and operation expertise. Using large λ-DNA as the model template, we validated the µSAAC for stochastic partitioning and quantitative digital detection of DNA molecules. Furthermore, as a proof-of-concept, we conducted dPCR detection and single-molecule sequencing of a mutation prevalent in blood cancer, the chromosomal translocation t(14;18), demonstrating the feasibility of the µSAAC for analysis of disease-associated mutations. These experiments were carried out using the standard molecular biology techniques and instruments. Because of its low cost, ease of fabrication, and equipment-free liquid partitioning, the µSAAC is readily adaptable to general lab settings, which could significantly facilitate the widespread application of dPCR technology in basic research and clinical practice.


Assuntos
DNA/análise , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase/métodos
14.
RSC Adv ; 14(9): 6041-6047, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38362080

RESUMO

By employing the radical polymerization method, acrylonitrile (AN) was grafted on the surface of nano titanium dioxide (TiO2), and the calcium sulfate whisker (CSW) was modified using the coupling agent KH570 to provide ultraviolet (UV)-absorption capacity. The prepared TiO2-PAN and CSW-PAN materials can improve the anti-aging performance and mechanical properties of polypropylene (PP) and meet the application requirements of high-performance polypropylene. Further, the obtained PP composites show prolonged service life and application scope, which can effectively reduce white waste and avoid both resource waste and environmental pollution.

15.
Adv Sci (Weinh) ; 11(1): e2303175, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37934012

RESUMO

Cancer immunotherapy using anti-programmed death-ligand 1 (PD-L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, and overall low patient response rate impede its further clinical application. Mounting evidence has revealed that PD-L1 is not only present in tumor cell membrane but also in cytoplasm, exosome, or even nucleus. Among these, the dynamic and spatial heterogeneous expression of PD-L1 in tumors is mainly responsible for the unsatisfactory efficacy of PD-L1 antibodies. Hence, numerous studies focus on inhibiting or degrading PD-L1 to improve immune response, while a comprehensive understanding of the molecular mechanisms underlying spatial heterogeneity of PD-L1 can fundamentally transform the current status of PD-L1 antibodies in clinical development. Herein, the concept of spatial heterogeneous expression of PD-L1 is creatively introduced, encompassing the structure and biological functions of various kinds of PD-L1 (including mPD-L1, cPD-L1, nPD-L1, and exoPD-L1). Then an in-depth analysis of the regulatory mechanisms and potential therapeutic targets of PD-L1 is provided, seeking to offer a solid basis for future investigation. Moreover, the current status of agents is summarized, especially small molecular modulators development directed at these new targets, offering a novel perspective on potential PD-L1 therapeutics strategies.


Assuntos
Antígeno B7-H1 , Neoplasias , Humanos , Antígeno B7-H1/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Imunoterapia/métodos , Anticorpos , Receptor de Morte Celular Programada 1
16.
Int J Biol Macromol ; 279(Pt 3): 135304, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39242009

RESUMO

Gellan gum has been widely used in many industries due to its excellent physical properties. In this study, the effects of different fermentation conditions on molecular weight and production of gellan gum were analyzed, and the optimized fermentation conditions for a high molecular weight gellan gum (H-GG: 6.42 × 105 Da) were obtained, which increased the molecular weight and yield of gellan gum by 201.4 % and 44.9 % respectively. Fourier transform infrared spectroscopy (FT-IR) and x-ray diffraction (XRD) analysis indicated that H-GG has similar characteristic absorption and semi-crystalline structures with the initial gellan gum (I-GG), and it was composed of glucose, rhamnose, and glucuronic acid showing no obvious changes in the molecular structure. Scanning electron microscope (SEM) observation revealed that the filaments of H-GG were slender, longer, and looser with larger pores. Importantly, gel properties analysis showed that the gel strength, viscoelasticity, and water-holding capacity of H-GG were better than those of I-GG, and the rheological results revealed that the H-GG is a pseudoplastic fluid with higher apparent viscosity and stable viscoelasticity at 20-70 °C. Therefore, the molecular weight and yield of gellan gum are significantly affected by fermentation conditions, and the obtained H-GG demonstrates improved gel and rheological properties.


Assuntos
Fermentação , Peso Molecular , Polissacarídeos Bacterianos , Polissacarídeos Bacterianos/química , Reologia , Viscosidade , Fenômenos Químicos , Difração de Raios X , Espectroscopia de Infravermelho com Transformada de Fourier
17.
Sci Adv ; 10(25): eadn8079, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38905336

RESUMO

Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered by AUTAC molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] and nucleoside analog methotrexate (MTX) through supramolecular interactions for tumor-specific protein degradation. Their nanostructures allow for precise localization and delivery into cancer cells, where the intracellular acidic environment can disrupt the supramolecular interactions to release MTX for eradicating tumor cells, modulating tumor-associated macrophages, activating dendritic cells, and inducing autophagy. Specifically, the induced autophagy facilitates the released GN for degrading immunosuppressive IDO to further enhance effector T cell activity and inhibit tumor growth and metastasis. This study offers a unique strategy for building a nanoplatform to advance the field of AUTAC in tumor immunotherapy.


Assuntos
Autofagia , Imunoterapia , Imunoterapia/métodos , Animais , Camundongos , Humanos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proteólise , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nanopartículas/química , Metotrexato/farmacologia , Metotrexato/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/imunologia
18.
J Control Release ; 370: 354-366, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38685387

RESUMO

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an effective way to initiate an immune response against tumors, and the research on agonists targeting STING has become a new hotspot in the development of antitumor drugs. However, as a novel STING agonist, the limited bioavailability and activation routes of manganese ions (Mn2+) significantly hinder its antitumor effects. To address these challenges, we have designed a metal-coordinated nucleoside metabolic inhibitor (gemcitabine, Gem)-induced metal nanotheranostic (MGP) with PEGylation. This formulation synergistically enhanced the immune response against cancer cells by sensitizing the cGAS-STING pathway and promoting immunogenic cell death (ICD). Modified with PEG derivatives, MGP was efficiently delivered to the tumor site and was internalized by cancer cells. Upon internalization, the release of Mn2+ triggered the activation of the cGAS-STING pathway, while the release of Gem induced DNA damage. On the one hand, the damaged DNA caused by Gem leaked into the cytoplasm, synergistically amplified Mn2+-induced activation of the cGAS-STING pathway, and induced the production of the tumor cytotoxic factor IFN-ß. On the other hand, Mn2+-mediated chemodynamic therapy (CDT) exhibited an ICD effect, which further synergized with the activation of the cGAS-STING pathway to promote dendritic cells (DCs) maturation and antigen-specific T cells infiltration. Both in vitro and in vivo studies have demonstrated that MGP nanotheranostics could elicit a robust antitumor effect, especially when combined with anti-PD-1. This study provided a new paradigm for intensifying immune activation by constructing metal coordination nanotheranostics.


Assuntos
Antineoplásicos , Imunoterapia , Manganês , Proteínas de Membrana , Neoplasias , Animais , Humanos , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/química , Manganês/química , Nucleotidiltransferases/metabolismo , Camundongos , Feminino , Camundongos Endogâmicos C57BL , Nanomedicina Teranóstica/métodos , Transdução de Sinais/efeitos dos fármacos , Polietilenoglicóis/química , Camundongos Endogâmicos BALB C , Nanopartículas Metálicas/administração & dosagem , Morte Celular Imunogênica/efeitos dos fármacos
19.
J Leukoc Biol ; 116(1): 103-117, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38660893

RESUMO

It has been found that CD226 plays an important role in regulating macrophage function, but its expression and function in macrophages during renal fibrogenesis have not been studied. Our data demonstrated that CD226 expression in macrophages was obviously upregulated in the unilateral ureteral obstruction model, while CD226 deficiency attenuated collagen deposition in renal interstitium along with fewer M1 within renal cortex and renal medulla and a lower level of proinflammatory factors compared to that of control littermates. Further studies demonstrated that Cd226-/- bone marrow-derived macrophages transferring could significantly reduce the tubular injury, collagen deposition, and proinflammatory cytokine secretion compared with that of Cd226+/+ bone marrow-derived macrophages transferring in the unilateral ureteral obstruction model. Mechanistic investigations revealed that CD226 promoted proinflammatory M1 macrophage accumulation in the kidney via suppressing KLF4 expression in macrophages. Therefore, our results uncovered a pathogenic role of CD226 during the development of chronic kidney disease by promoting monocyte infiltration from peripheral blood into the kidney and enhancing macrophage activation toward the inflammatory phenotype by suppressing KLF4 expression.


Assuntos
Antígenos de Diferenciação de Linfócitos T , Movimento Celular , Fibrose , Fator 4 Semelhante a Kruppel , Ativação de Macrófagos , Macrófagos , Animais , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Antígenos de Diferenciação de Linfócitos T/metabolismo , Camundongos Endogâmicos C57BL , Rim/patologia , Rim/metabolismo , Rim/imunologia , Masculino , Obstrução Ureteral/patologia , Camundongos Knockout , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo
20.
ACS Nano ; 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39415568

RESUMO

The unsatisfactory treatment outcome of Alzheimer's disease (AD) can be attributed to two primary factors, the intricate pathogenic mechanisms leading to restricted treatment effectiveness against single targets and the hindered drug accumulation in brain due to blood-brain barrier obstruction. Therefore, we developed a carrier-free nanomodulator (NanoDS) through the self-assembly of donepezil and simvastatin for direct nose-to-brain delivery. This approach facilitated a rapid and efficient traversal through the nasal epithelial barrier, enabling subsequent drug release and achieving multiple therapeutic effects. Among them, donepezil effectively ameliorated the symptoms of AD and restored synaptic plasticity. Simvastatin exerted a neurotrophic effect and facilitated the clearance of amyloid-ß aggregation. At the same time, NanoDS demonstrated effective anti-inflammatory and antioxidative stress effects. This therapy for AD is approached from both symptomatic and etiological perspectives. In the treatment of FAD4T transgenic mice, it highly improved spatial memory impairment and cognitive deficits while restoring the homeostasis of brain microenvironment. Collectively, our study presented a paradigm for both achieving efficient brain delivery and offering pleiotropic therapies for AD.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA