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1.
BMJ Open ; 11(12): e050559, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34907050

RESUMO

BACKGROUND AND PURPOSE: COVID-19 pandemic, a global health crisis, is disrupting the present medical environment. This systematic review and meta-analysis aimed to evaluate the impact of the COVID-19 pandemic on stroke hospitalisations, especially haemorrhagic stroke. METHODS: The EMBASE, PubMed, Web of Science, Elsevier, Medline, Cochrane Library and Google Scholar electronic databases were searched for all relevant studies. Two researchers independently screened the studies, extracted data and assessed the quality of the included studies. Odds ratio (OR), total events, OR and 95% CI were considered as the effect size. A fixed-effects model was used to pool the study-specific estimate. The present study was performed by using Review Manager (V.5.3.0) software. We assessed the risk of bias using the Newcastle-Ottawa Scale. RESULTS: A total of 17 studies with 14 445 cases were included. Overall, the number of stroke admissions is lower in the pandemic period versus the control period (6252 vs 8193). The difference of haemorrhagic stroke is significant, with 1233 of 6252 cases in the pandemic group and 1621 of 8193 cases in the control group. Intracerebral haemorrhage is present in 461 of 1948 cases in the pandemic group and 618 of 2734 cases in the control group. As for subarachnoid haemorrhage, the difference between the two groups is significant, with 70 of 985 cases in the pandemic group and 202 of 1493 cases in the control group. CONCLUSIONS: The number of stroke admissions is lower in the pandemic period compared with the control period. There is a higher rate of haemorrhagic stroke in the pandemic period. Subgroup analysis identifies a significant increase in the occurrence of intracerebral haemorrhage in the pandemic period. Due to limited data and the impact of a single article, the impact of COVID-19 pandemic on subarachnoid haemorrhage is unclear.


Assuntos
COVID-19 , AVC Hemorrágico , Hospitalização , Humanos , Pandemias , SARS-CoV-2
2.
Artigo em Inglês | MEDLINE | ID: mdl-34781405

RESUMO

BACKGROUND: Microvascular decompression (MVD) has become accepted as an effective therapeutic option for hemifacial spasm (HFS); however, the curative rate of MVD for HFS varies widely (50-98%) in different medical centers. This study could contribute to the improvement of the MVD procedure. METHODS: We retrospectively analyzed 32 patients in whom initial MVD failed in other hospitals and who underwent a second MVD at our center. The clinical characteristics, operative findings, outcome of the second MVD, and complications were recorded. RESULTS: There were 18 women and 14 men (56.3 and 43.7%, respectively). The left-to-right ratio was 19:13. The mean age of the patients was 59.8 years. We found an undiscovered conflict site located in zone 4 in 10 patients and in the root entry zone in 8 patients. The initial MVD failed in nine patients because of ignorance of the arterioles that originate from the anterior inferior cerebellar artery. There were no special findings in four patients. No Teflon felts were found in the whole surgical field in one patient. CONCLUSION: Omission of the offending vessel is the most common cause of an unsuccessful MVD. Intraoperative abnormal muscle response associated with the Z-L response is a good measure to correctly identify the involved arterioles.

3.
Int J Gen Med ; 14: 6261-6275, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34629892

RESUMO

Introduction: The regulatory mechanisms of super enhancers (SEs) and ceRNA networks in LUAD progression are not well understood. We aimed to discover the prognostic-related ceRNA network regulated by SEs in metastatic LUAD. Methods: RNA-seq data were extracted from The Cancer Genome Atlas (TCGA) database. Differentially expressed (DE) RNAs were identified by edgeR. CeRNA network was predicted and visualized using starBase and Cytoscape. H3K27ac ChIP-seq data were derived from the Gene Expression Omnibus (GEO) database, and used for SE identification. Kaplan-Meier curve and multivariate Cox model were applied for prognostic analysis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network were performed for functional analysis. SEs of AC074117.1 were verified by ChIP-qPCR in A549 and H1299 cells. MTT assay was performed to analyze cell proliferation. Luciferase activity assay was carried out to validate the target targeting relationships of ceRNA network. Results: A total of 2355 DEmRNA, 483 DElncRNA and 155 DEmiRNA were identified between metastatic LUAD and adjacent normal tissues. CeRNA network consisting of 7 DElncRNAs, 18 DEmiRNAs and 15 DEmRNAs was constructed. Among the seven DElncRNAs in ceRNA network, only AC074117.1 was regulated by SEs. SE-regulated prognostic ceRNA sub-network consisting of FKBP3, E2F2, AC074117.1 and hsa-let-7c-5p was screened and verified. The overlapping co-expressed mRNAs of FKBP3, E2F2, AC074117.1 and hsa-let-7c-5p were mainly related to cell division and Fanconi anemia pathway. Genes in the ceRNA sub-network were correlated with DNA mismatch repair markers. Functional experiments proved that AC074117.1 was highly expressed in LUAD cells. AC074117.1 silencing notably inhibited proliferation of A549 and H1299 cells. Luciferase activity assay confirmed the direct relationship in AC074117.1-hsa-let-7c-5p-FKBP3/E2F2 network. Conclusion: A novel prognostic ceRNA sub-network regulated by SEs was identified in metastatic LUAD. This study provided potential therapeutic targets and prognostic markers for further study of metastatic LUAD.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34682557

RESUMO

Rapid urbanization of China has brought lifestyle changes resulting in a continuous decline in children's physical fitness (PF) and out-of-school physical activity (PA). To date, studies have been focused on correlates of PF and out-of-school PA, and patterns and trends based on geographic diversity and urban-rural contrasts. Western China, with a large rural population, has substantial urban-rural differences, but little work has been done to compare its children's physical fitness (PF) and out-of-school physical activity (PA) at a county level. A total of 715 primary school students (grades 3-6) were surveyed from one urban school (n = 438) and four rural schools (n = 277) in a county-level administrative unit, Yangling District, Shaanxi, in western China. Physical fitness index (PFI) was measured and calculated based on the revised Chinese Student Physical Fitness Standards. Out-of-school PA and other variables of demographics, behavior and perception were collected using questionnaires. Statistical analyses explored urban-rural differences and correlates of PFI and out-of-school PA. We found that the PFI (72.86 vs. 79.67) and weekly moderate-to-vigorous physical activity (MVPA) duration (167.57 vs. 220.08) of urban students were significantly lower than those of rural students. Weekly MVPA duration had the largest positive impact on PFI. Perceived availability of PA spaces was positively associated with both the urban and rural students' PF and PA, while screen time was negatively associated with PF and PA, especially for rural students. Facilitators of PA frequency include the perceived availability of PA time and parental educational level. Parents' PA habits had a positive impact on urban students' PA. No association between active school commuting and PF or PA was found. Our findings revealed that PF and out-of-school PA of urban students were clearly lower than among rural students. The health of rural children at the county level in western China should be paid much more attention during the process of rapid urbanization.


Assuntos
Aptidão Física , População Rural , Criança , China , Exercício Físico , Humanos , Instituições Acadêmicas , Estudantes
5.
J Control Release ; 338: 662-679, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34478751

RESUMO

Inflammatory feed-forward loops including the steps of "inflammatory cell recruitment", "inflammatory signaling pathway activation" and "inflammatory factor production" are essential in the development of breast cancer and its metastasis. Herein, a doxorubicin-loaded micellar low-molecular-weight-heparin-astaxanthin nanoparticle (LMWH-AST/DOX, LA/DOX NP) was developed. The hydrophilic LMWH could decrease the recruitment of neutrophils in liver and myeloid-derived suppressor cells (MDSCs) in lung and tumor through P-selectin blockage. The hydrophobic AST could inhibit nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Therefore, LA/DOX NPs could block these loops and suppress the liver metastasis by inhibiting the formation of neutrophil extracellular traps (NETs), inhibit the lung metastasis and alleviate the inflammatory and immunosuppressive microenvironment in tumor. This is the first functional nanoparticle reported to shut down inflammatory feed-forward loops and the formation of NETs, which provides a promising therapeutic strategy for breast cancer and its liver and lung metastasis.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina , Feminino , Heparina de Baixo Peso Molecular , Humanos , Fígado , Neoplasias Pulmonares/tratamento farmacológico , Metástase Neoplásica , Microambiente Tumoral
6.
J Am Chem Soc ; 143(39): 15924-15929, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34550688

RESUMO

Twisted carbon nanobelts could display persistent chirality, which is desirable for material applications, but their synthesis is very challenging. Herein, we report the successful synthesis and chiral resolution of such a kind of molecules (1-H and 1) with a figure-eight configuration. 1-H was synthesized first by macrocyclization through Suzuki coupling reaction followed by benzannulation via Bi(OTf)3-mediated cyclization reaction of vinyl ether. Oxidative dehydrogenation of 1-H gave the fully π-conjugated 1. Their twisted structures were confirmed by X-ray crystallographic analysis and calculations, and they can be resolved by chiral high-performance liquid chromatography. The isolated enantiomers showed persistent chiroptical properties according to the circular dichroism measurements, with moderate |gabs| values (0.0016 for 1-H and 0.005-0.007 for 1). Their photophysical properties were also briefly studied.

8.
Theranostics ; 11(18): 8692-8705, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522207

RESUMO

Background: Metastasis is one of the main reasons for the high mortality associated with pancreatic ductal adenocarcinoma (PDAC), and autophagy regulates the metastatic migration of tumor cells, their invasion of tissues, and their formation of focal adhesions. Inhibiting autophagy may suppress tumor growth and metastasis, but the abundant extracellular matrix hinders the deep penetration of therapeutic agents. Methods: To enhance the penetration of drugs that can inhibit metastasis of pancreatic cancer, a pH-responsive drug delivery system was formulated. Gemcitabine (GEM), a first-line chemotherapeutic drug against PDAC, was loaded in 6PA-modified DGL (PDGL) nanoparticles to afford PDGL-GEM. Then PDGL-GEM was co-precipitated with the autophagy inhibitor chloroquine phosphate (CQ) and calcium phosphate to formulate PDGL-GEM@CAP/CQ. The size and morphology of the resulting "nanobomb" PDGL-GEM@CAP/CQ were characterized, and their uptake into cells, cytotoxicity and ability to inhibit autophagy were analyzed at pH 6.5 and 7.4. The anti-tumor and anti-metastasis effects of the nanobomb were explored on mice carrying Pan 02 pancreatic tumor xenografts or orthotopic tumors. Results: The pH-induced dissolution of calcium phosphate facilitated the release of CQ from the nanobomb and deep penetration of PDGL-GEM. The internalization of PDGL-GEM and subsequent intracellular release of GEM inhibited tumor growth, while CQ downregulated autophagy in tumor cells and fibroblasts. In fact, inhibition of xenograft and orthotopic tumor growth was greater with the complete PDGL-GEM@CAP/CQ than with subassemblies lacking GEM or CQ. More importantly, mechanistic studies in vitro and in vivo suggested that the nanobomb inhibits metastasis by downregulating MMP-2 and paxillin, as well as reducing fibrosis. Conclusion: The pH-sensitive PDGL-GEM@CAP/CQ shows potential for inhibiting proliferation and metastasis of pancreatic cancer through an autophagy-dependent pathway.

9.
Biomed Res Int ; 2021: 6516202, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34458369

RESUMO

In sub-Saharan Africa, improving equitable access to healthcare remains a major challenge for public health systems. Health policymakers encourage the adoption of health insurance schemes to promote universal healthcare. Nonetheless, progress towards this goal remains suboptimal due to inequalities health insurance ownership especially among women. In this study, we aimed to explore the sociodemographic factors contributing to health insurance ownership among women in selected francophone countries in sub-Saharan Africa. Methods. This study is based on cross-sectional data obtained from Demographic and Health Surveys on five countries including Benin (n = 13,407), Madagascar (n = 12,448), Mali (n = 10,326), Niger (n = 12,558), and Togo (n = 6,979). The explanatory factors included participant age, marital status, type of residency, education, household wealth quantile, employment stats, and access to electronic media. Associations between health insurance ownership and the explanatory factors were analyzed using multivariate regression analysis, and effect sizes were reported in terms in average marginal effects (AMEs). Results. The highest percentage of insurance ownership was observed for Togo (3.31%), followed by Madagascar (2.23%) and Mali (2.2%). After stratifying by place of residency, the percentages were found to be significantly lower in the rural areas for all countries, with the most noticeable difference observed for Niger (7.73% in urban vs. 0.54% in rural women). Higher levels of education and wealth quantile were positively associated with insurance ownership in all five countries. In the pooled sample, women in the higher education category had higher likelihood of having an insurance: Benin (AME = 1.18; 95% CI = 1.10, 1.27), Madagascar (AME = 1.10; 95% CI = 1.05, 1.15), Mali (AME = 1.14; 95% CI = 1.04, 1.24), Niger (AME = 1.13; 95% CI = 1.07, 1.21), and Togo (AME = 1.17; 95% CI = 1.09, 1.26). Regarding wealth status, women from the households in the highest wealth quantile had 4% higher likelihood of having insurance in Benin and Mali and 6% higher likelihood in Madagascar and Togo. Conclusions. Percentage of women who reported having health insurance was noticeably low in all five countries. As indicated by the multivariate analyses, the actual situation is likely to be even worse due to significant socioeconomic inequalities in the distribution of women having an insurance plan. Increasing women's access to healthcare is an urgent priority for population health promotion in these countries, and therefore, addressing the entrenched sociodemographic disparities should be given urgent policy attention in an effort to strengthen universal healthcare-related goals.


Assuntos
Acesso aos Serviços de Saúde/estatística & dados numéricos , Seguro Saúde/estatística & dados numéricos , Propriedade/estatística & dados numéricos , Saúde da Mulher/estatística & dados numéricos , Adolescente , Adulto , África ao Sul do Saara , Estudos Transversais , Escolaridade , Feminino , Humanos , Estado Civil , Pessoa de Meia-Idade , População Rural , Fatores Sexuais , Fatores Socioeconômicos , Mulheres , Saúde da Mulher/economia , Adulto Jovem
10.
J Am Chem Soc ; 143(34): 13908-13916, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415756

RESUMO

The synthesis of kekulene and its higher homologues is a challenging task in organic chemistry. The first successful synthesis and characterization of the parent kekulene were reported by Diederich and Staab in 1978. Herein, we report the facile preparation of a series of edge-extended kekulenes by bismuth(III) triflate-catalyzed cyclization of vinyl ethers from the properly designed macrocyclic precursors. Their molecular structures were confirmed by X-ray crystallographic analysis and NMR spectroscopy. Their size- and symmetry-dependent electronic structures (frontier molecular orbitals, aromaticity) and physical properties (optical and electrochemical) were investigated by various spectroscopic measurements, assisted by theoretical calculations. Particularly, the acene-like units along each zigzag edge demonstrate a dominant local aromatic character. Our studies provide an easy synthetic strategy toward various fully fused carbon nanostructures and give some insights into the electronic properties of cycloarenes.

11.
Int J Pharm ; 607: 120975, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34363913

RESUMO

Surgery combined with postoperative treatment is a widely accepted therapeutic strategy against breast cancer. Macrophage-based carriers have been proved to be an effective postoperative drug delivery system due to their inflammatory tendency. However, the slow and incomplete release of the cargo and the postoperative inflammation remain to be solved. Here, we described a macrophage-mediated photothermal therapy combined with anti-inflammatory strategy to inhibit breast cancer postoperative relapse. The anti-inflammatory resveratrol and photothermal agent indocyanine green (ICG) were loaded in octaarginine (R8)-modified liposomes, then ingested by macrophages to form the macrophage-based drug delivery system (Res/ICG-R8-Lip@MP). Res/ICG-R8-Lip@MP showed effective tumor-targeting ability via inflammatory tropism of macrophages and excellent near-infrared (NIR) photothermal performance. In vitro experiments showed that the carrier could not only trigger drug release though inflammation, but also utilize the photothermal conversion property to destroy the macrophage-based carrier at the local tumor to maximize drug release. In vivo experiments indicated that Res/ICG-R8-Lip@MP ablated residual tumor tissues and reduced the postoperative inflammation, and at the same time achieved significant effect of inhibiting tumor postoperative relapse. This synergistic photothermal and anti-inflammatory strategy has great potential in postoperative treatment of breast cancer.


Assuntos
Hipertermia Induzida , Neoplasias de Mama Triplo Negativas , Anti-Inflamatórios , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Verde de Indocianina , Macrófagos , Recidiva Local de Neoplasia/prevenção & controle
12.
Cell Signal ; 87: 110093, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34302955

RESUMO

SOX17 has been shown to be involved in the transcriptional regulation of CXCR4, and CXCL12 functions by binding to its receptor CXCR4. Here, we explored the expression of SOX17 in neuroblastoma (NB), its mutual regulation with CXCL12, and its effects on cancer cell proliferation, migration and invasion. Five human NB cell lines and 15 pairs of NB and adjacent tissue specimens were used, to conduct RT-qPCR, immunohistochemistry, western blot, ELISA, CCK-8, colony formation, Edu, transwell, chromatin immunoprecipitation (ChIP), and dual-luciferase assays, to study the role of SOX17 in NB. SOX17 levels were reduced in both NB tissues and cell lines. SOX17 inhibited NB tumor growth, migration and invasion in vivo and suppressed NB cell proliferation, migration, and invasion in vitro. SOX17 knockdown or overexpression revealed a negative correlation between SOX17 and CXCL12/CXCR4 pathway activation. ChIP and dual-luciferase assays in NB cells demonstrated that SOX17 significantly inhibited CXCL12 gene and protein levels by binding to CXCL12 promoter regions. In vivo and in vitro experiments using the CXCR4 antagonist, AMD3100, demonstrated that cell proliferation, migration and invasion were significantly abrogated by AMD3100 in NB cells with SOX17 knocked down. Further, AMD3100 impaired growth of NB tumors with SOX17 knocked down in mice. Importantly, SOX17 bound to the CXCL12 promoter, which then activated downstream targets to regulate cell viability, proliferation, and migration. In conclusion, our data demonstrate that SOX17 expression is repressed in NB tissues and cells, and that SOX17 suppresses NB tumor formation and proliferation through inhibition of CXCL12/CXCR4 signaling.

13.
J Control Release ; 335: 38-48, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-33965503

RESUMO

Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel anti-inflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs). The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium. Synergistically, MMP-9, which is secreted by the recruited neutrophils and degrade the main component of articular cartilage, is reduced by the hydrophobic fragment d-α-tocopheryl succinate (TOS), functioning as a sword. In collagen-induced arthritis (CIA) mouse model, LT NPs show significant targeting effect, and exhibit prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. Our work proves that the multi-stage manipulation of neutrophils is feasible and effective, providing a new concept for RA treatment.


Assuntos
Artrite Experimental , Artrite Reumatoide , Militares , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Heparina de Baixo Peso Molecular , Humanos , Camundongos , Neutrófilos
14.
Glob Chang Biol ; 27(16): 3798-3809, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33934460

RESUMO

The 2015-2016 El Niño was one of the strongest on record, but its influence on the carbon balance is less clear. Using Northern Hemisphere atmospheric CO2 observations, we found both detrended atmospheric CO2 growth rate (CGR) and CO2 seasonal-cycle amplitude (SCA) of 2015-2016 were much higher than that of other El Niño events. The simultaneous high CGR and SCA were unusual, because our analysis of long-term CO2 observations at Mauna Loa revealed a significantly negative correlation between CGR and SCA. Atmospheric inversions and terrestrial ecosystem models indicate strong northern land carbon uptake during spring but substantially reduced carbon uptake (or high emissions) during early autumn, which amplified SCA but also resulted in a small anomaly in annual carbon uptake of northern ecosystems in 2015-2016. This negative ecosystem carbon uptake anomaly in early autumn was primarily due to soil water deficits and more litter decomposition caused by enhanced spring productivity. Our study demonstrates a decoupling between seasonality and annual carbon cycle balance in northern ecosystems over 2015-2016, which is unprecedented in the past five decades of El Niño events.


Assuntos
Ecossistema , El Niño Oscilação Sul , Atmosfera , Carbono , Ciclo do Carbono , Dióxido de Carbono
15.
Acta Biomater ; 133: 244-256, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34000465

RESUMO

Immune checkpoint blockade treatment is one of the most promising immunotherapies, which exhibits promising therapeutic effects on inhibition of metastasis. However, immunotherapy has little effect on pancreatic cancer, due to its extensive fibrotic matrix and immunosuppressive tumor microenvironment. Mild hyperthermia induced by photothermal therapy (PTT) has been proven to activate the immune responses in the tumor microenvironment. Herein, we designed a combine strategy of mild hyperthermia and immune checkpoint blockade (BMS-202) treatment with size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL), in which BMS-202 loaded small-sized albumin nanoparticle (HSA-BMS) was encapsulated. Mild hyperthermia reduced the tumor hypoxia, relieved the interstitial pressure and increased the recruitment of endogenous immune cells in tumors. In the meantime, small-sized HSA-BMS was released from large-sized HSA-BMS@CAP-ILTSL in response to fibroblast activation protein-α (FAP-α) and near-infrared (NIR) laser, and enhanced the immunological responses by recovering the activity of T lymphocytes, accompanied by secreting relevant cytokines (TNF-α and IFN-γ). The combined therapy (HSA-BMS@CAP-ILTSL) could not only significantly suppress the tumor growth in vivo, but also decrease the amounts of metastatic nodules in distant organs. These results suggested that size-adjustable nanoparticles had a great potential in the treatment of metastatic pancreatic cancer. STATEMENT OF SIGNIFICANCE: The desmoplastic stroma and hypoperfusion of pancreatic cancer imposed physical barriers to effective therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We constructed size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL) with size around 120 nm, where small sized albumin nanoparticle (10 nm) of immune checkpoint inhibitor (HSA-BMS) were encapsulated inside. Mild hyperthermia not only contributed to release HSA-BMS for penetration (blocking the immunosuppressive signals deep in the tumor), but enhanced tumor blood perfusion for infiltration of endogenous immune cells. In the two-pronged treatment, the pancreatic cancer immunotherapy significantly enhanced and the risk of cancer metastasis was reduced. Overall, the strategy provides a promising approach to increase drug accumulation and improve the anti-tumor immune activity in pancreatic cancer.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Humanos , Hipertermia , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Pancreáticas/terapia , Microambiente Tumoral
16.
Eur J Pharm Biopharm ; 165: 164-173, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34020022

RESUMO

Pancreatic ductal adenocarcinoma is one of the most lethal malignant tumors, its drug resistance, immunosuppression and metastasis makes the traditional chemotherapy and immunotherapy inefficient. Here we confirmed a 3-aminophenylboronic acid-modified low molecular weight heparin-D-α-tocopheryl succinate micellar nanoparticle (PBA-LMWH-TOS NP, PLT NP) could inhibit orthotopic pancreatic tumor and its spontaneous metastases. The small particle size and high affinity of PBA to sialic acid residue (SA) made PLT/PTX NPs significantly targeted and accumulated in both pancreatic tumor tissues and metastases. The immunosuppressive microenvironment of pancreatic tumor was most caused by the infiltration of immunosuppressive cells, mainly myeloid-derived suppressor cells (MDSCs). We first reported that P-selectin glycoprotein ligand-1 (PSGL-1) was expressed on the surfaces of MDSCs in pancreatic tumor tissues. Meanwhile, we found that LMWH could inhibit the early stage of adhesion cascade between vascular endothelial cells (VECs) and MDSCs by interfering with P-selectin/PSGL-1 binding, thus inhibiting MDSC recruitment to pancreatic tumor tissues. The therapeutic results indicated that PLT/PTX NPs could significantly improve the immune microenvironment of pancreatic tumor and inhibit spontaneous metastases. This nanosystem provides a new immune microenvironment regulation mechanism based on carrier materials in pancreatic tumor, and has high clinical application potential.

17.
J Control Release ; 335: 557-574, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34051289

RESUMO

Myeloid-derived suppressor cells (MDSCs) are the chief accomplices for assisting tumor's survival and suppressing anti-tumor immunity, which can be recruited by tumor-derived cytokines, such as granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF). The plentiful lactate dehydrogenase A (LDHA) in glycolysis is usually accompanied by abundant tumor-derived G-CSF and GM-CSF, further promoting MDSCs recruitment and immunosuppression. Herein, with the aim to achieve powerful anti-tumor immunity, an immunochemotherapy regimen basing on a redox-responsive nanoassembly (R-mPDV/PDV/DOX/siL) is developed, which integrates the combined strategy of restraining cytokines-mediated MDSCs recruitment through LDHA silencing and reinforcing tumor immunogenicity through anthracycline (DOX)-elicited immunogenic cell death (ICD) effects. This redox-responsive nanoassembly is self-assembled by three glutathione (GSH)-responsive polymers, which employ poly(δ-valerolactone) (PVL) as hydrophobic segment and 3, 3'-dithiodipropionic acid (DA) as linkage to connect hydrophilic segment. DOX is encapsulated in the core and LDHA siRNA (siL) is effectively compressed by cationic PAMAM. The cellular internalization and tumor-homing are strengthened by the specific recognition on integrin (αvß3) by c(RGDfk) (RGD) ligand. After escaping from endosomes/lysosomes, R-mPDV/PDV/DOX/siL is disintegrated through GSH-elicited cleavage of DA, realizing burst release of drugs and high-efficient LDHA silencing. The reduced expression of LDHA suppresses the generation of G-CSF and GM-CSF cytokines, restrains MDSCs recruitment and reinforces anti-tumor immunity. Eventually, this therapeutic regimen of DOX and siL on R-mPDV/PDV/DOX/siL nanoassembly achieved powerful anti-tumor efficiency on 4 T1 orthotopic tumor, opening the new horizons for immunochemotherapy.


Assuntos
Células Supressoras Mieloides , Neoplasias , Autofagia , Dendrímeros/administração & dosagem , Doxorrubicina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , L-Lactato Desidrogenase , Lactato Desidrogenase 5 , Oxirredução
19.
Nanomaterials (Basel) ; 11(3)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804795

RESUMO

In this study, phosphorus-modified alumina with large pore size was synthesized through a coprecipitation method. The carbon-covered, phosphorus-modified alumina with large pores was prepared by impregnating with glucose and carbonizing to further improve the adsorption of organic dyes. The morphology and structure of these composites were characterized by various analysis methods, and Rhodamine B (RhB) adsorption was also examined in aqueous media. The results showed that the specific surface area and pore size of the phosphorus-modified alumina sample AP7 (prepared with a P/Al molar ratio of 0.07) reached 496.2 m2·g-1 and 21.9 nm, while the specific surface area and pore size of the carbon-covered phosphorus-modified alumina sample CAP7-27 (prepared by using AP7 as a carrier for glucose at a glucose/Al molar ratio of 0.27) reached 435.3 m2·g-1 and 21.2 nm. The adsorption experiment of RhB revealed that CAP7-27 had not only an equilibrium adsorption capacity of 198 mg·g-1, but also an adsorption rate of 162.5 mg·g-1 in 5 min. These superior adsorption effects can be attributed to the similar pore structures of CAP7-27 with those of alumina and the specific properties with those of carbon materials. Finally, the kinetic properties of these composites were also studied, which were found to be consistent with a pseudo-second-order kinetic model and Langmuir model for isothermal adsorption analysis. This study indicates that the prepared nanomaterials are expected to be promising candidates for efficient adsorption of toxic dyes.

20.
Acta Biomater ; 134: 546-558, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33882357

RESUMO

The dilemma of tumor accumulation and deep penetration has always been a barrier in antitumor therapy. Stimuli-responsive size changeable drug delivery systems provide possible solutions. Nevertheless, the low size-shrinkage efficiency limited the antitumor effects. In this study, an instant pH-responsive size shrinkable nanoassemblies named self-aggregated DOX@HA-CD (SA-DOX@HA-CD) was formulated using small-sized hyaluronic acid modified carbon dots (HA-CD) as monomers, which could self-aggregate into raspberry-like structure via hydrophobicity force in neutral pH and rapidly disassemble into shotgun-like DOX-loaded CD monomer in simulated tumor microenvironment (pH 6.5), owing to the transformation in electrical charge and hydrophobicity/hydrophilicity of this system. The transmission electron microscopy showed that the clustered SA-DOX@HA-CD had a diameter of ~150 nm, and thoroughly disassembled into ~30 nm nanoparticles in response to acidic environment. The disassemble efficiency was approximately 100%. Attributed to this property, SA-DOX@HA-CD led to enhanced cellular internalization and accumulation in 4T1 cells in simulated tumor microenvironment, as well as deep tumor penetration in 3D tumor spheroid model. Besides, the imine bond between DOX and HA-CD endowed DOX with pH-responsive release profile in the acidic lysosome environment. Furthermore, in the orthotopic 4T1 tumor-bearing mouse model, SA-DOX@HA-CD demonstrated higher tumor accumulation than non-aggregated DOX-HA-CD. Meanwhile, in response to the acid tumor microenvironment, the dissociated DOX-HA achieved deep tumor penetration, which consequently resulted in 2.5-fold higher antitumor efficiency. The formulation of self-aggregated SA-DOX@HA-CD provides a simple and effective alternative to prepare pH-responsive size-shrinkable nanodrug delivery systems. STATEMENT OF SIGNIFICANCE: The heterogeneity of tumor vasculature and the high tumor interstitial pressure lead to the barriers in tumor accumulation and deep penetration, which calls for opposite properties (e.g. size) of drug delivery systems. To address this dilemma, various size changeable nanoparticles have been developed utilizing special features of tumor microenvironment, such as pH, enzyme and reactive oxygen species. Nevertheless, the current strategies face the problems of incomplete hydrolysis of chemical bonds or insufficient enzyme degradation, which result in only partial size shrinkage, hindering the tumor deep penetration effects. Here we developed a self-assembled nanocluster, which could respond to acidic pH rapidly and thoroughly disassemble into small nanodots due to the alteration of hydrophobicity/hydrophilicity/charge, leading to approximately 100% dissociation. This strategy provides a new concept for design of size changeable drug delivery systems.


Assuntos
Neoplasias da Mama , Nanopartículas , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Microambiente Tumoral
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