Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 98
Filtrar
1.
Bioorg Chem ; 141: 106898, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37801783

RESUMO

Seven novel isocoumarins, prunolactones A-G (1-7), featuring an unusual 6/6/6/6/6 spiropentacyclic skeleton, together with two biosynthetic precursors phomopsilactone (8) and methyl 3-epi-shikimate (9), were isolated from the endophytic fungus Phomopsis prunorum guided by UPLC-QTOF-MS and 1H NMR spectroscopic analytical techniques. Their structures including absolute configurations of 1-7 were elucidated based on extensive spectroscopic data, X-ray diffraction analysis, and ECD calculations. Biogenetically, compounds 1-7 are proposed to be derived from polyketide and shikimate pathways via key intermolecular Diels - Alder reactions. Compounds 2, 3, and 7 showed significant in vivo proangiogenic activity in transgenic zebrafish.


Assuntos
Isocumarinas , Peixe-Zebra , Animais , Fungos/metabolismo , Isocumarinas/farmacologia , Isocumarinas/química , Estrutura Molecular , Esqueleto/metabolismo , Peixe-Zebra/metabolismo
2.
Adv Funct Mater ; 32(40): 2204462, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35942271

RESUMO

SARS-CoV-2 has led to a worldwide pandemic, catastrophically impacting public health and the global economy. Herein, a new class of lipid-modified polymer poly (ß-amino esters) (L-PBAEs) is developed via enzyme-catalyzed esterification and further formulation of the L-PBAEs with poly(d,l-lactide-coglycolide)-b-poly(ethylene glycol) (PLGA-PEG) leads to self-assembly into a "particle-in-particle" (PNP) nanostructure for gene delivery. Out of 24 PNP candidates, the top-performing PNP/C12-PBAE nanoparticles efficiently deliver both DNA and mRNA in vitro and in vivo, presenting enhanced transfection efficacy, sustained gene release behavior, and excellent stability for at least 12 months of storage at -20 °C after lyophilization without loss of transfection efficacy. Encapsulated with spike encoded plasmid DNA and mRNA, the lipid-modified polymeric PNP COVID-19 vaccines successfully elicit spike-specific antibodies and Th1-biased T cell immune responses in immunized mice even after 12 months of lyophilized storage at -20 °C. This newly developed lipid-polymer hybrid PNP nanoparticle system demonstrates a new strategy for both plasmid DNA and mRNA delivery with the capability of long-term lyophilized storage.

3.
Molecules ; 27(8)2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35458629

RESUMO

Nigrosporins B, an anthraquinone derivative obtained from the secondary metabolites of marine fungus Nigrospora oryzae. In this study, we characterized the distinctive anti-cancer potential of Nigrosporins B in vitro and underlying molecular mechanisms in human cervical cancer Ca Ski cells for the first time. The results of MTT assay showed that Nigrosporins B significantly inhibited the proliferation of multiple tumor cells in a dose-dependent manner, especially for the Ca Ski cells with an IC50 of 1.24 µM. Nigrosporins B exerted an apoptosis induction effect on Ca Ski cells as confirmed by flow cytometry, AO/EB dual fluorescence staining, mitochondrial membrane potential analysis and western blot assay. In addition, Nigrosporins B induced obvious autophagy accompanied with the increase of autophagic vacuoles and the acceleration of autophagic flux as indicated by Cyto-ID staining, mRFP-GFP-LC3 adenovirus transfection and western blot analysis. Interestingly, the combination of Nigrosporins B with the three autophagy inhibitors all significantly enhanced the cytotoxicity of Nigrosporins B on Ca Ski cells, indicating that the autophagy induced by Nigrosporins B might protect Ca Ski cells from death. Furthermore, we found that Nigrosporins B inhibited the phosphorylation of PI3K, AKT, mTOR molecules and increased the protein expression levels of PTEN and p-AMPKα in a dose-dependent manner, suggesting that Nigrosporins B induced apoptosis and protective autophagy through the suppression of the PI3K/AKT/mTOR signaling pathway. Together, these findings revealed the anti-cervical cancer effect of Nigrosporins B and the underlying mechanism of action in Ca Ski cells, it might be as a promising alternative therapeutic agent for human cervical cancer.


Assuntos
Antraquinonas , Fosfatidilinositol 3-Quinases , Neoplasias do Colo do Útero , Feminino , Humanos , Antraquinonas/farmacologia , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico
4.
BMC Med ; 19(1): 150, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34281550

RESUMO

BACKGROUND: Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach. METHODS: A total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset. RESULTS: Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10-8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10-7), Alzheimer's disease (0.80, [0.72, 0.89], P = 3.0 × 10-5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10-14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10-9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite. CONCLUSIONS: The present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations.


Assuntos
Diabetes Mellitus Tipo 2 , Expossoma , LDL-Colesterol , Estudo de Associação Genômica Ampla , Humanos , Longevidade , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
5.
J Nat Prod ; 84(5): 1434-1441, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33979168

RESUMO

In this study, eight natural isocoumarins (1-8) were isolated from a marine-derived Exserohilum sp. fungus. To explore their structure-activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a-1n, 2a, 3a-3c, 4a-4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC50 values of 1.1, 0.8, 0.4, and 2.6 µM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC50/IC50 = 675), high selectivity, and a notable drug-like profile.


Assuntos
Antimaláricos/farmacologia , Ascomicetos/química , Isocumarinas/farmacologia , Animais , Antozoários/microbiologia , Antimaláricos/síntese química , Organismos Aquáticos/química , China , Chlorocebus aethiops , DNA Girase , Hemeproteínas , Isocumarinas/síntese química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/farmacologia , Células Vero
6.
Int J Mol Sci ; 22(22)2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34830185

RESUMO

RCE-4, a steroidal saponin isolated from Reineckia carnea, has been studied previously and has exhibited promising anti-cervical cancer properties by inducing programmed cell death (PCD) of Ca Ski cells. Considering the cancer cells developed various pathways to evade chemotherapy-induced PCD, there is, therefore, an urgent need to further explore the potential mechanisms underlying its actions. The present study focused on targeting the Bcl-2-Beclin 1 complex, which is known as the key regulator of PCD, to deeply elucidate the molecular mechanism of RCE-4 against cervical cancer. The effects of RCE-4 on the Bcl-2-Beclin 1 complex were investigated by using the co-immunoprecipitation assay. In addition, autophagy-related genes (ATG) were also analyzed due to their special roles in PCD. The results demonstrated that RCE-4 inhibited the formation of the Bcl-2-Beclin 1 complex in Ca Ski cells via various pathways, and ATG 4B proteins involved in this process served as a key co-factor. Furthermore, based on the above, the sensitivity of RCE-4 to Ca Ski cells was significantly enhanced by inhibiting the expression of the ATG 4B by applying the ATG 4B siRNA plasmid.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Complexos Multiproteicos/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Saponinas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/genética , Asparagaceae/química , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Humanos , Estrutura Molecular , Complexos Multiproteicos/metabolismo , Fitosteróis/química , Ligação Proteica , Interferência de RNA , Saponinas/química , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
7.
Cancer Control ; 27(2): 1073274820936287, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614270

RESUMO

To evaluate whether high biologically effective dose (BED) radiotherapy improves local control and survival outcomes for patients with brain metastases (BMs) from small-cell lung cancer (SCLC) and to determine possible prognostic factors. From January 1998 to June 2018, 250 patients with BM from SCLC were retrospectively analyzed. The Cutoff Finder program was used to classify patients by BED. Overall survival (OS) and BM progression-free survival (BM-PFS) were analyzed using the Kaplan-Meier method and log-rank test. A Cox regression model was used to calculate the hazard ratio and 95% CI for prognostic factors for OS among the study population and propensity score (PS)-matched patients. A BED of 47.4 was taken as the optimal cutoff value. Both OS and BM-PFS were significantly improved in the high-BED (>47.4 Gy) than in the low-BED (≤47.4 Gy) group (median OS: 17.5 months vs 9.5 months, P < .001, median BM-PFS: 14.4 months vs 8.3 months, P < .001). Biologically effective dose (P < .001), Eastern Cooperative Oncology Group performance status (P = .047), smoking (P = .005), and pleural effusion (P = .004) were independent prognostic factors for OS. Propensity score matching with a ratio of 1:2 resulted in 57 patients in the high-BED group and 106 patients in the low-BED group. In the PS-matched cohort, OS and BM-PFS were significantly prolonged in the high-BED group compared with the low-BED group (P < .001). Biologically effective dose >47.4 Gy improves survival among patients with BM from SCLC. Eastern Cooperative Oncology Group score, smoking, and pleural effusion independently affect OS of SCLC patients with BM.


Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Pulmonares/mortalidade , Recidiva Local de Neoplasia/mortalidade , Radioterapia/mortalidade , Carcinoma de Pequenas Células do Pulmão/mortalidade , Adulto , Idoso , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Prognóstico , Pontuação de Propensão , Dosagem Radioterapêutica , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/radioterapia , Taxa de Sobrevida
8.
Proc Natl Acad Sci U S A ; 113(20): 5552-7, 2016 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-27140638

RESUMO

The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adipose tissue and angiogenesis, which facilitates the homing of targeted NPs to adipose angiogenic vessels, thereby amplifying their delivery. We show that i.v. administration of these NPs can target WAT vasculature, stimulate the angiogenesis that is required for the transformation of adipose tissue, and transform WAT into brown-like adipose tissue, by the up-regulation of angiogenesis and brown adipose tissue markers. In a diet-induced obese mouse model, these angiogenesis-targeted NPs have inhibited body weight gain and modulated several serological markers including cholesterol, triglyceride, and insulin, compared with the control group. These findings suggest that angiogenesis-targeting moieties with angiogenic stimulator-loaded NPs could be incorporated into effective therapeutic regimens for clinical treatment of obesity and other metabolic diseases.


Assuntos
16,16-Dimetilprostaglandina E2/administração & dosagem , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/irrigação sanguínea , Nanopartículas/administração & dosagem , Neovascularização Fisiológica , Obesidade/prevenção & controle , Tiazolidinedionas/administração & dosagem , Animais , Metabolismo dos Carboidratos , Dieta , Sistemas de Liberação de Medicamentos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanomedicina , Rosiglitazona
9.
Small ; 13(43)2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29045030

RESUMO

A major obstacle facing brain diseases such as Alzheimer's disease, multiple sclerosis, brain tumors, and strokes is the blood-brain barrier (BBB). The BBB prevents the passage of certain molecules and pathogens from the circulatory system into the brain. Therefore, it is nearly impossible for therapeutic drugs to target the diseased cells without the assistance of carriers. Nanotechnology is an area of growing public interest; nanocarriers, such as polymer-based, lipid-based, and inorganic-based nanoparticles can be engineered in different sizes, shapes, and surface charges, and they can be modified with functional groups to enhance their penetration and targeting capabilities. Hence, understanding the interaction between nanomaterials and the BBB is crucial. In this Review, the components and properties of the BBB are revisited and the types of nanocarriers that are most commonly used for brain drug delivery are discussed. The properties of the nanocarriers and the factors that affect drug delivery across the BBB are elaborated upon in this review. Additionally, the most recent developments of nanoformulations and nonconventional drug delivery strategies are highlighted. Finally, challenges and considerations for the development of brain targeting nanomedicines are discussed. The overall objective is to broaden the understanding of the design and to develop nanomedicines for the treatment of brain diseases.


Assuntos
Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos , Nanoestruturas/química , Animais , Portadores de Fármacos/química , Humanos , Ligantes , Ultrassom
10.
Proc Natl Acad Sci U S A ; 110(46): 18638-43, 2013 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-24167294

RESUMO

Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Quimioterapia Combinada/métodos , Nanopartículas/uso terapêutico , Interferência de RNA/fisiologia , RNA Interferente Pequeno/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Portadores de Fármacos/administração & dosagem , Inativação Gênica , Humanos , Luciferases , Platina/farmacocinética , RNA Interferente Pequeno/genética
11.
Phys Chem Chem Phys ; 17(34): 21810-8, 2015 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-26134464

RESUMO

The understanding of the formation of silicate oligomers in the initial stage of zeolite synthesis is of fundamental scientific and technological importance. The use of different organic structure directing agents is known to be a key factor in the formation of different silicate species, and the final zeolite structure. Tetramethylammonium (TMA(+)), for example, is indispensable for the formation of the LTA zeolite type. However, the role of a TMA(+) template has not yet been elucidated at the molecular level. In this study, ab initio molecular dynamic simulations were combined with thermodynamic integration to arrive at an understanding of the role of TMA(+) in the formation of various silicate species, ranging from dimer to 4-ring. Free energy profiles show that trimer and 3-ring silicate are less favourable than other oligomers such as linear tetramer, branched tetramer and 4-ring structures. TMA(+) exhibits an important role in controlling the predominant species in solution via its coordination with silicate structures during the reaction process. This can explain that formation of D4R·8TMA crystals, as observed in experiment, is controlled by the single 4-ring formation step.

12.
Medicine (Baltimore) ; 103(21): e38306, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38788014

RESUMO

We investigated the relationship among red cell distribution width (RDW), to total serum calcium (TSC) ratio (RCR), and in-hospital mortality in patients with acute ischemic stroke (AIS). This study was a retrospective analysis. The data of 2700 AIS patients was retrospectively analyzed from the Medical Information Mart for Intensive Care database (version IV). The main outcome of interest was in-hospital mortality. A Cox proportional hazards regression model was used to determine whether RCR was independently associated with in-hospital mortality. The Kaplan-Meier method was used to plot the survival curves for RCR. Subgroup analyses were performed to measure the mortality across various subgroups. The area under curve (AUC) of receiver operating characteristic curve (ROC) was calculated to ascertain the quality of RCR as a predictor of in-hospital mortality in patients with AIS. In the multivariate analysis, statistically significant differences were identified in age, ethnicity, length of ICU stay, mechanical ventilation, sequential organ failure assessment (SOFA) score, RDW, hemoglobin, RCR, whether taking anticoagulants, hyperlipidemia, and atrial fibrillation (P < .05). A threshold inflection point value of 1.83 was obtained through a two-piecewise regression model. There was a non-linear relationship between RCR and hospital mortality in patients with AIS. The hazard ratio (HR) and the 95% confidence intervals (CI) on the right and left of the inflection point were 0.93 (0.57-1.51; P = .7660) and 2.96 (1.37-6.42; P = .0060), respectively. The Kaplan-Meier curve indicated that survival rates were higher when RCR was ≤ 1.83 and lower when RDW was > 1.83 after adjustment for age, gender, BMI, ethnicity. The area under curve (AUC) of RCR was 0.715. A higher RCR was associated with an increased risk of in-hospital mortality in patients with AIS.


Assuntos
Cálcio , Índices de Eritrócitos , Mortalidade Hospitalar , AVC Isquêmico , Humanos , Feminino , Masculino , Estudos Retrospectivos , Idoso , AVC Isquêmico/sangue , AVC Isquêmico/mortalidade , Pessoa de Meia-Idade , Cálcio/sangue , Curva ROC , Idoso de 80 Anos ou mais , Modelos de Riscos Proporcionais , Fatores de Risco , Estimativa de Kaplan-Meier
13.
ACS Nano ; 18(24): 15499-15516, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38832815

RESUMO

T cell exhaustion has emerged as a major hurdle that impedes the clinical translation of stimulator of interferon genes (STING) agonists. It is crucial to explore innovative strategies to rejuvenate exhausted T cells and potentiate the antitumor efficacy. Here, we propose an approach utilizing MSA-2 as a STING agonist, along with nanoparticle-mediated delivery of mRNA encoding interleukin-12 (IL-12) to restore the function of T cells. We developed a lipid nanoparticle (DMT7-IL12 LNP) that encapsulated IL12 mRNA. Our findings convincingly demonstrated that the combination of MSA-2 and DMT7-IL12 LNP can effectively reverse the exhausted T cell phenotype, as evidenced by the enhanced secretion of cytokines, such as tumor necrosis factor alpha, interferon gamma, and Granzyme B, coupled with reduced levels of inhibitory molecules such as T cell immunoglobulin and mucin domain-3 and programmed cell death protein-1 on CD8+ T cells. Furthermore, this approach led to improved survival and tumor regression without causing any systemic toxicity in melanoma and lung metastasis models. These findings suggest that mRNA encoding IL-12 in conjunction with STING agonists has the potential to confer superior clinical outcomes, representing a promising advancement in cancer immunotherapy.


Assuntos
Interleucina-12 , Camundongos Endogâmicos C57BL , RNA Mensageiro , Interleucina-12/genética , Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Camundongos , Nanopartículas/química , Proteínas de Membrana/agonistas , Proteínas de Membrana/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Humanos , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linhagem Celular Tumoral , Exaustão das Células T
14.
ACS Nano ; 18(4): 3260-3275, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38227975

RESUMO

The ischemic stroke is a major global health concern, with high mortality and disability rates. Unfortunately, there is a dearth of effective clinical interventions for managing poststroke neuroinflammation and blood-brain barrier (BBB) disruption that are crucial for the brain injury evolving and neurological deficits. By leveraging the pathological progression of an ischemic stroke, we developed an M2 microglia-targeting lipid nanoparticle (termed MLNP) approach that can selectively deliver mRNA encoding phenotype-switching interleukin-10 (mIL-10) to the ischemic brain, creating a beneficial feedback loop that drives microglial polarization toward the protective M2 phenotypes and augments the homing of mIL-10-loaded MLNPs (mIL-10@MLNPs) to ischemic regions. In a transient middle cerebral artery occlusion (MCAO) mouse model of an ischemic stroke, our findings demonstrate that intravenously injected mIL-10@MLNPs induce IL-10 production and enhance the M2 polarization of microglia. The resulting positive loop reinforces the resolution of neuroinflammation, restores the impaired BBB, and prevents neuronal apoptosis after stroke. Using a permanent distal MCAO mouse model of an ischemic stroke, the neuroprotective effects of mIL-10@MLNPs have been further validated by the attenuation of the sensorimotor and cognitive neurological deficits. Furthermore, the developed mRNA-based targeted therapy has great potential to extend the therapeutic time window at least up to 72 h poststroke. This study depicts a simple and versatile LNP platform for selective delivery of mRNA therapeutics to cerebral lesions, showcasing a promising approach for addressing an ischemic stroke and associated brain conditions.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Microglia/patologia , Microglia/fisiologia , Barreira Hematoencefálica/patologia , Isquemia Encefálica/tratamento farmacológico , Doenças Neuroinflamatórias , Acidente Vascular Cerebral/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia
16.
Nat Commun ; 14(1): 4223, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37454146

RESUMO

Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated pyroptosis is a newly discovered mechanism in cancer immunotherapy; however, cleavage in the N terminus is required to activate pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA lipid nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced pyroptosis sensitizes tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold tumors.


Assuntos
Neoplasias , Piroptose , Animais , Camundongos , Feminino , Gasderminas , Imunoterapia , Microambiente Tumoral
17.
ACS Nano ; 17(15): 14852-14870, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37490628

RESUMO

Chronic liver injury and inflammation triggered by metabolic abnormalities initiate the activation of hepatic stellate cells (HSCs), driving fibrosis and parenchymal dysfunction, culminating in disorders such as nonalcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs capable of effectively treating NASH due to the challenges in addressing fibrosis and restoring extracellular matrix (ECM) homeostasis. We discovered a significant up-regulation of interleukin-11 (IL-11) in fibrotic livers using two well-established murine models of NASH. To leverage this signaling pathway, we developed a nanoparticle (NP)-assisted RNA interfering approach that specifically targets activated HSCs (aHSCs), blocking IL-11/ERK signaling to regulate HSC transdifferentiation along with fibrotic remodeling. The most potent NP, designated NP-AEAA, showed enhanced accumulation in fibrotic livers with NASH and was primarily enriched in aHSCs. We further investigated the therapeutic efficacy of aHSC-targeting NP-AEAA encapsulating small interfering RNA (siRNA) against IL11 or its cognate receptor IL11ra1 (termed siIL11@NP-AEAA or siIL11ra1@NP-AEAA, respectively) for resolving fibrosis and NASH. Our results demonstrate that both siIL11@NP-AEAA and siIL11ra1@NP-AEAA effectively inhibit HSC activation and resolve fibrosis and inflammation in two well-established murine models of NASH. Notably, siIL11ra1@NP-AEAA exhibits a superior therapeutic effect over siIL11@NP-AEAA, in terms of reducing liver steatosis and fibrosis as well as recovering liver function. These results constitute a targeted nanoparticulate siRNA therapeutic approach against the IL-11 signaling pathway of aHSCs in the fibrotic liver, offering a promising therapeutic intervention for NASH and other diseases.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Humanos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Células Estreladas do Fígado/metabolismo , Interleucina-11/metabolismo , Interleucina-11/farmacologia , Interleucina-11/uso terapêutico , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Fibrose , Inflamação/patologia , RNA Interferente Pequeno/metabolismo , Camundongos Endogâmicos C57BL
18.
ACS Nano ; 17(18): 17721-17739, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37669404

RESUMO

Atherosclerosis is a common pathology present in many cardiovascular diseases. Although the current therapies (including statins and inhibitors of the serine protease PCSK9) can effectively reduce low-density lipoprotein (LDL) cholesterol levels to guideline-recommended levels, major adverse cardiovascular events still occur frequently. Indeed, the subendothelial retention of lipoproteins in the artery wall triggers multiple events of inflammation in macrophages and is a major contributor to the pathological progression of atherosclerosis. It has been gradually recognized that modulating inflammation is, therefore, an attractive avenue to forestall and treat atherosclerosis and its complications. Unfortunately, challenges with specificity and efficacy in managing plaque inflammation have hindered progress in atherosclerosis treatment. Herein, we report an NP-mediated mRNA therapeutic approach to target atherosclerotic lesional macrophages, modulating inflammation in advanced atherosclerotic lesions for the treatment of atherosclerosis. We demonstrated that the targeted NPs containing IL-10 mRNA colocalized with M2-like macrophages and induced IL-10 production in atherosclerotic plaques following intravenous administration to Western diet (WD)-fed Ldlr-/- mice. Additionally, the lesions showed a significantly alleviated inflammatory response, as evidenced by reduced oxidative stress and macrophage apoptosis, resulting in decreased lipid deposition, diminished necrotic areas, and increased fiber cap thickness. These results demonstrate the successful delivery of mRNA therapeutics to macrophage-enriched plaques in a preclinical model of advanced atherosclerosis, showing that this targeted NP inflammation management approach has great potential for translation into a wide range of clinical applications.


Assuntos
Aterosclerose , Placa Aterosclerótica , Animais , Camundongos , Placa Aterosclerótica/tratamento farmacológico , Pró-Proteína Convertase 9 , Interleucina-10 , Aterosclerose/tratamento farmacológico , Inflamação
19.
ACS Appl Mater Interfaces ; 15(26): 31273-31284, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37354089

RESUMO

Kirsten rat sarcoma (KRAS) is the most commonly mutated oncogene in lung cancers. Gene therapy is emerging as a promising cancer treatment modality; however, the systemic administration of gene therapy has been limited by inefficient delivery to the lungs and systemic toxicity. Herein, we report a noninvasive aerosol inhalation nanoparticle (NP) system, termed "siKRAS@GCLPP NPs," to treat KRAS-mutant non-small-cell lung cancer (NSCLC). The self-assembled siKRAS@GCLPP NPs are capable of maintaining structural integrity during nebulization, with preferential distribution within the tumor-bearing lung. Inhalable siKRAS@GCLPP NPs show not only significant tumor-targeting capability but also enhanced antitumor activity in an orthotopic mouse model of human KRAS-mutant NSCLC. The nebulized delivery of siKRAS@GCLPP NPs demonstrates potent knockdown of mutated KRAS in tumor-bearing lungs without causing any observable adverse effects, exhibiting a better biosafety profile than the systemic delivery approach. The results present a promising inhaled gene therapy approach for the treatment of KRAS-mutant NSCLC and other respiratory diseases.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Camundongos , Animais , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , RNA Interferente Pequeno/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Nanopartículas/química , Mutação , Linhagem Celular Tumoral
20.
Psychol Res Behav Manag ; 16: 1165-1180, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37077763

RESUMO

Objective: Given the immense stress faced by medical staff during the COVID-19 pandemic, this study aimed to evaluate the relationship between mindful attention awareness, fatigue, and perceived symptoms among frontline nurses who performed nucleic acid sample collection during the COVID-19 pandemic, to reduce their fatigue and help them cope with perceived uncomfortable symptoms. Methods: A convenience sampling method was used to survey nurses who travelled to Hainan for nucleic acid sampling in August 2022 using an online (WeChat) questionnaire. A total of 514 frontline nurses who performed nucleic acid tests completed the questionnaire. The questionnaire covered basic demographic information, Mindful Attention Awareness Scale (MAAS) ratings, and Fatigue Severity Scale (FSS) ratings. Spearman correlation analysis was used to separate the relationship between MASS and FSS, and univariate and multivariate factor analyses were used to explore the relevant influences contributing to the occurrence of fatigue. Results: A total of 514 individuals completed the survey,93.97% (n=483) were female, mean age was 31.15 ± 5.7, MASS score was 69.01 ± 13.53, and 296 (57.59%) nurses experienced symptoms of fatigue during the auxiliary period. Spearman correlation analysis showed that FSS was associated with MASS. Multifactorial analysis showed that sex, age, marital status, fertility status, years of work, adaptation to dietary habits, hidrorrhea, and MAAS scores affected the presence of fatigue symptoms among the medical staff in Hainan (P<0.05). Conclusion: The psychological status of frontline nurses undergoing nucleic acid testing during the pandemic was poor, and the appearance of fatigue symptoms could be effectively reduced by increasing levels of positive thinking among medical staff to help them cope with public health emergencies.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA