Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 174
Filtrar
1.
Nat Commun ; 12(1): 5393, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518553

RESUMO

Dynamin belongs to the large GTPase superfamily, and mediates the fission of vesicles during endocytosis. Dynamin molecules are recruited to the neck of budding vesicles to assemble into a helical collar and to constrict the underlying membrane. Two helical forms were observed: the one-start helix in the constricted state and the two-start helix in the super-constricted state. Here we report the cryoEM structure of a super-constricted two-start dynamin 1 filament at 3.74 Å resolution. The two strands are joined by the conserved GTPase dimeric interface. In comparison with the one-start structure, a rotation around Hinge 1 is observed, essential for communicating the chemical power of the GTPase domain and the mechanical force of the Stalk and PH domain onto the underlying membrane. The Stalk interfaces are well conserved and serve as fulcrums for adapting to changing curvatures. Relative to one-start, small rotations per interface accumulate to bring a drastic change in the helical pitch. Elasticity theory rationalizes the diversity of dynamin helical symmetries and suggests corresponding functional significance.

2.
J Immunol Res ; 2021: 9321196, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34568500

RESUMO

Probiotic-based therapies have been shown to be beneficial for chemotherapy-induced mucositis. Previous research has demonstrated that a probiotic mixture (Bifidobacterium brevis, Lactobacillus acidophilus, Lactobacillus casei, and Streptococcus thermophilus) can ameliorate chemotherapy-induced mucositis and dysbiosis in rats, but the underlying mechanism has not been completely elucidated. We aimed to determine the inhibitory effects of the probiotic mixture on cisplatin-induced mucositis and pica and the underlying mechanism, focusing on the levels of 5-hydroxytryptamine (5-HT, serotonin) regulated by the gut microbiota. A rat model of mucositis and pica was established by daily intraperitoneal injection of cisplatin (6 mg/kg) for 3 days. In the probiotic+cisplatin group, predaily intragastric injection of the probiotic mixture (1 × 109 CFU/kg BW) was administrated for 1 week before cisplatin injection. This was then followed by further daily probiotic injections for 6 days. Histopathology, pro-/anti-inflammatory cytokines, oxidative status, and 5-HT levels were assessed on days 3 and 6. The structure of the gut microbiota was analyzed by 16S rRNA gene sequencing and quantitative PCR. Additionally, 5-HT levels in enterochromaffin (EC) cells (RIN-14B cell line) treated with cisplatin and/or various probiotic bacteria were also determined. The probiotic mixture significantly attenuated kaolin consumption, inflammation, oxidative stress, and the increase in 5-HT concentrations in rats with cisplatin-induced intestinal mucositis and pica. Cisplatin markedly increased the relative abundances of Enterobacteriaceae_other, Blautia, Clostridiaceae_other, and members of Clostridium clusters IV and XIVa. These levels were significantly restored by the probiotic mixture. Importantly, most of the genera increased by cisplatin were significantly positively correlated with colonic 5-HT. Furthermore, in vitro, the probiotic mixture had direct inhibitory effects on the 5-HT secretion by EC cells. The probiotic mixture protects against cisplatin-induced intestine injury, exhibiting both anti-inflammatory and antiemetic properties. These results were closely related to the reestablishment of intestinal microbiota ecology and normalization of the dysbiosis-driven 5-HT overproduction.

3.
Cancer Med ; 10(17): 5739-5747, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34374226

RESUMO

BACKGROUND: The occurrence of cardiovascular events is a major cause of death in patients with cancer. Small studies have documented a connection between specific brain alterations and autonomic cardiac dysfunctions, possibly resulting in a worse prognosis. We aimed to refine the knowledge of fatal cardiac events in patients with brain metastasis (BM). METHODS: We performed a Surveillance, Epidemiology, and End Results SEER registry-based investigation (timeline: 2010-2016) and extracted all the advanced patients who had experienced fatal cardiac outcomes. Populations were compared according to the presence or not BM. Kaplan-Meier (KM) methodology was used for survival analysis and a multivariate model was developed by adjusting for multiple possible confounders. RESULTS: Most related BM and cardiac death were observed at the site of lung cancer (81.4%). We extracted 3187 patients with lung cancer site, including 417 patients who had experienced fatal heart-specific with a history of BM, which is considered a BM group. The second group of heart-specific death included 2770 patients was stated as a non-BM group. Patients who had experienced heart-specific death in the BM group were predominately male, right side, upper site, and non-small type (62.11%, 54.92%, 51.56%, 69.78%), respectively. The survival outcomes between BM and the non- BM was significantly prominent (p = 0.003; median: 2 months vs. 3 months).The negative prognostic independent significance of heart-fatal events was confirmed after adjusting for multiple variables (HR = 0.76, CI = 0.68-84, p < 0.0001). The metastatic liver site was significantly associated with poorer survival rates (HR = 0.68; CI = 0.52-0.88, p = 0.005). We revealed a possible connection between the brain and heart functions. CONCLUSIONS: The prognosis of heart-specific death patients in BM is unfavorable compared to non-BM settings in lung cancer. We may be at the gates of a new field of neurocardiooncology.

4.
J Exp Med ; 218(9)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34342641

RESUMO

Activation of NLRP3 inflammasome is precisely controlled to avoid excessive activation. Although multiple molecules regulating NLRP3 inflammasome activation have been revealed, the checkpoints governing NLRP3 inflammasome activation remain elusive. Here, we show that activation of NLRP3 inflammasome is governed by GSTO1-promoted ASC deglutathionylation in macrophages. Glutathionylation of ASC inhibits ASC oligomerization and thus represses activation of NLRP3 inflammasome in macrophages, unless GSTO1 binds ASC and deglutathionylates ASC at ER, under control of mitochondrial ROS and triacylglyceride synthesis. In macrophages expressing ASCC171A, a mutant ASC without glutathionylation site, activation of NLRP3 inflammasome is GSTO1 independent, ROS independent, and signal 2 less dependent. Moreover, AscC171A mice exhibit NLRP3-dependent hyperinflammation in vivo. Our results demonstrate that glutathionylation of ASC represses NLRP3 inflammasome activation, and GSTO1-promoted ASC deglutathionylation at ER, under metabolic control, is a checkpoint for activating NLRP3 inflammasome.

5.
Cardiovasc Toxicol ; 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34410632

RESUMO

To investigate the efficacy of Slit2 in the rats with coronary heart disease (CHD). CHD model were constructed by feeding high-fat food and injecting with pituitrin in rat, followed by recombinant Slit2 treatment, and then the cardiac function was evaluated by echocardiography, and the indicators concerning the cardiomyocyte injury markers and lipoprotein status and oxidative stress were measured. The Slit2 expression in the heart tissues was identified by immunofluorescence. Enzyme-linked immunosorbent assay (ELISA) was carried out to detect inflammatory cytokines, H2DCFDA staining to determine the ROS generation in heart tissues, Masson trichrome staining to observe myocardial fibrosis, and qRT-PCR and Western blotting to detect gene and protein expressions. Slit2 decreased the levels of LDH, CK-MB, cTnI, TG, TC and LDL-C and increased HDL-C level in CHD rats. In the normal heart tissues, Slit2 expression was significantly lower in cardiomyocytes than cardiac fibroblasts. Furthermore, the expressions of VCAM-1, ICAM-1, fibronectin and TGF-ß1 were increased in the heart tissues of CHD rats with the obvious myocardial fibrosis, which were dose-dependently reversed by recombinant Slit2. In addition, recombinant Slit2 also dose-dependently increased the activity of NO, SOD, CAT and GSH-Px, and decreased TNF-α, IL-6, MCP-1, MDA and ROS in CHD rats. Slit2 was downregulated in myocardial tissue and plasma of CHD rats. Recombinant Slit2, by regulating the level of blood lipid, can relieve the myocardial fibrosis, inflammation and oxidative stress in CHD.

6.
Bioengineered ; 12(1): 4331-4348, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34338158

RESUMO

Lung adenocarcinoma (LUAD) is one of the main causes of cancer deaths globally. Redox is emerging as a crucial contributor to the pathophysiology of LUAD, which can be regulated by long non-coding RNAs (lncRNAs). The aim of our research is to identify a novel redox-related lncRNA prognostic signature (redox-LPS) for better prediction of LUAD prognosis. 535 LUAD samples from The Cancer Genome Atlas (TCGA) database and 226 LUAD samples from the Gene Expression Omnibus (GEO) database were included in our study. 67 redox genes and 313 redox-related lncRNAs were identified. After performing LASSO-Cox regression analysis, a redox-LPS consisting of four lncRNAs (i.e., CRNDE, CASC15, LINC01137, and CYP1B1-AS1) was developed and validated. Our redox-LPS was superior to another three established models in predicting survival probability of LUAD patients. Univariate and multivariate Cox regression analysis revealed that risk score and stage were independent prognostic indicators. A nomogram plot including risk score and stage was constructed to predict survival probability of LUAD patients; this was further verified by calibration curves. Functional enrichment analysis and gene set enrichment analysis, were performed to determine the differences in cellular processes and signaling pathways between the high - and low-risk subgroups. A variety of algorithms (such as single-sample gene set enrichment analysis and CIBERSOFT) were conducted to uncover the landscape of tumor immune microenvironment in the high- and low-risk subgroups. In conclusion, a novel independent redox-LPS was constructed and validated for LUAD patients, which might provide new insights for clinical decision-making and precision medicine.

7.
Nano Lett ; 21(14): 6304-6313, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34264088

RESUMO

Adoptively transferred natural killer T (NKT) cells confer distinct cancer surveillance without causing obvious side effects, making them a promising candidate for cancer immunotherapy. However, their therapeutic efficacy is limited by inefficient tumor infiltration and inadequate activation in an immunosuppressive tumor microenvironment. To overcome these obstacles, we develop a strategy of using photothermal therapy (PTT) to promote the antitumor ability of adoptively transferred NKT cells. The transferred NKT cells are efficiently recruited to PTT-treated tumors in response to PTT-created inflammation. Moreover, PTT treatment promotes the activation of NKT cells and enhances the NKT cell-initiated immune cascade. As a consequence, the combined therapy of PTT plus NKT cell transfer exhibits excellent growth inhibition of local tumors. Moreover, it efficiently rejects distant tumors and elicits long-term immunological memory to prevent tumor recurrence. Overall, the current study opens new paths to the clinical translation of NKT cells for cancer immunotherapy.


Assuntos
Células T Matadoras Naturais , Neoplasias , Linhagem Celular Tumoral , Humanos , Imunoterapia , Neoplasias/terapia , Fototerapia , Microambiente Tumoral
8.
Nat Commun ; 12(1): 4349, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272394

RESUMO

Bacterial extracellular polysaccharides (EPSs) play critical roles in virulence. Many bacteria assemble EPSs via a multi-protein "Wzx-Wzy" system, involving glycan polymerization at the outer face of the cytoplasmic/inner membrane. Gram-negative species couple polymerization with translocation across the periplasm and outer membrane and the master regulator of the system is the tyrosine autokinase, Wzc. This near atomic cryo-EM structure of dephosphorylated Wzc from E. coli shows an octameric assembly with a large central cavity formed by transmembrane helices. The tyrosine autokinase domain forms the cytoplasm region, while the periplasmic region contains small folded motifs and helical bundles. The helical bundles are essential for function, most likely through interaction with the outer membrane translocon, Wza. Autophosphorylation of the tyrosine-rich C-terminus of Wzc results in disassembly of the octamer into multiply phosphorylated monomers. We propose that the cycling between phosphorylated monomer and dephosphorylated octamer regulates glycan polymerization and translocation.


Assuntos
Cápsulas Bacterianas/química , Cápsulas Bacterianas/metabolismo , Proteínas de Escherichia coli/química , Escherichia coli/metabolismo , Proteínas de Membrana/química , Periplasma/metabolismo , Polissacarídeos Bacterianos/metabolismo , Proteínas Tirosina Quinases/química , Motivos de Aminoácidos , Domínio Catalítico , Microscopia Crioeletrônica , Citoplasma/metabolismo , Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Espectrometria de Massas , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Moleculares , Periplasma/química , Fosforilação , Conformação Proteica em alfa-Hélice , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Tirosina/química , Tirosina/metabolismo
9.
Cell ; 184(14): 3660-3673.e18, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34166615

RESUMO

Membrane remodeling and repair are essential for all cells. Proteins that perform these functions include Vipp1/IM30 in photosynthetic plastids, PspA in bacteria, and ESCRT-III in eukaryotes. Here, using a combination of evolutionary and structural analyses, we show that these protein families are homologous and share a common ancient evolutionary origin that likely predates the last universal common ancestor. This homology is evident in cryo-electron microscopy structures of Vipp1 rings from the cyanobacterium Nostoc punctiforme presented over a range of symmetries. Each ring is assembled from rungs that stack and progressively tilt to form dome-shaped curvature. Assembly is facilitated by hinges in the Vipp1 monomer, similar to those in ESCRT-III proteins, which allow the formation of flexible polymers. Rings have an inner lumen that is able to bind and deform membranes. Collectively, these data suggest conserved mechanistic principles that underlie Vipp1, PspA, and ESCRT-III-dependent membrane remodeling across all domains of life.

10.
Small ; : e2100510, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34081390

RESUMO

The design and fabrication of transition metal dichalcogenides (TMDs) are of paramount significance for water-splitting process. However, the limited active sites and restricted conductivity prevent their further application. Herein, a polarization boosted strategy is put forward for the modification of TMDs to promote the absorption of the intermediates, leading to the improved catalytic performance. By the forced assembly of TMDs (WS2 as the example) and carbon nanotubes (CNTs) via spray-drying method, such frameworks can remarkably achieve low overpotentials and superior durability in alkaline media, which is superior to most of the TMDs-based catalysts. The two-electrode cell for water-splitting also exhibits perfect activity and stability. The enhanced catalytic performance of WS2 /CNTs composite is mainly owing to the strong polarized coupling between CNTs and WS2 nanosheets, which significantly promotes the charge redistribution on the interface of CNTs and WS2 . Density functional theory (DFT) calculations show that the CNTs enrich the electron content of WS2 , which favors electron transportation and accelerates the catalysis. Moreover, the size of WS2 is restricted caused by the confinement of CNTs, leading to the increased numbers of active sites, further improving the catalysis. This work opens a feasible route to achieve the optimized assembling of TMDs and CNTs for efficient water-splitting process.

11.
J Thorac Oncol ; 16(9): 1533-1546, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34033974

RESUMO

INTRODUCTION: Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. METHODS: Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. RESULTS: A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation. CONCLUSIONS: Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL. TRIAL REGISTRATION: NCT02824458.


Assuntos
Neoplasias Pulmonares , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica , Intervalo Livre de Doença , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , Quinazolinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular
12.
J Adv Res ; 29: 45-54, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33842004

RESUMO

Background: The US Food and Drug Administration (FDA) has approved several immunotherapeutic drugs for cancer since 2010, and many more are still being evaluated in other clinical studies. These inhibitors significantly increase response rates and result in the treatment of patients with advanced cancer. However, cancer immunotherapy leads to essential cardiac toxicity properties that have become distinct from other cancer patients' care and are mostly related to their etiology. Aim of review: As potential implications, the occurrence of cardiovascular adverse events is particularly challenging and needs a comprehensive understanding of overall cancer-related etiology, clinical outcomes with different variable severity, and management. Key scientific concepts of review: In terms of improving the overall survival of patients with cancer, clinicians should be careful in selecting either programmed cell death-1 (PD-1) or its programmed cell death ligand (PDL-1) inhibitors by evaluating their risk and clinical benefit for early intervention and decrease the level of morbidity and mortality of their patients. This review focuses on the effectiveness of PD-1/PL-1 antibodies and associated cardiotoxicity adverse events, including etiological mechanisms, diagnosis, and treatment.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Cardiopatias/induzido quimicamente , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Cardiotoxicidade/terapia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Bloqueio Cardíaco/induzido quimicamente , Cardiopatias/diagnóstico , Cardiopatias/terapia , Humanos , Imunoterapia/métodos , Miocardite/induzido quimicamente , Neoplasias/imunologia , Estados Unidos
13.
Commun Biol ; 4(1): 481, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863979

RESUMO

Gag is the HIV structural precursor protein which is cleaved by viral protease to produce mature infectious viruses. Gag is a polyprotein composed of MA (matrix), CA (capsid), SP1, NC (nucleocapsid), SP2 and p6 domains. SP1, together with the last eight residues of CA, have been hypothesized to form a six-helix bundle responsible for the higher-order multimerization of Gag necessary for HIV particle assembly. However, the structure of the complete six-helix bundle has been elusive. Here, we determined the structures of both Gag in vitro assemblies and Gag viral-like particles (VLPs) to 4.2 Å and 4.5 Å resolutions using cryo-electron tomography and subtomogram averaging by emClarity. A single amino acid mutation (T8I) in SP1 stabilizes the six-helix bundle, allowing to discern the entire CA-SP1 helix connecting to the NC domain. These structures provide a blueprint for future development of small molecule inhibitors that can lock SP1 in a stable helical conformation, interfere with virus maturation, and thus block HIV-1 infection.


Assuntos
Tomografia com Microscopia Eletrônica , HIV-1/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Microscopia Crioeletrônica , HIV-1/genética
14.
Oncogene ; 40(20): 3548-3563, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33927350

RESUMO

Mitochondrial oxidative phosphorylation (OXPHOS) is a vital regulator of tumor metastasis. However, the mechanisms governing OXPHOS to facilitate tumor metastasis remain unclear. In this study, we discovered that arginine 21(R21) and lysine 108 (K108) of mitochondrial ribosomal protein S23 (MRPS23) was methylated by the protein arginine methyltransferase 7 (PRMT7) and SET-domain-containing protein 6 (SETD6), respectively. R21 methylation accelerated the poly-ubiquitin-dependent degradation of MRPS23 to a low level. The MRPS23 degradation inhibited OXPHOS with elevated mtROS level, which consequently increased breast cancer cell invasion and metastasis. In contrast, K108 methylation increased MRPS23 stability, and K108 methylation coordinated with R21 methylation to maintain a low level of MRPS23, which was in favor of supporting breast cancer cell survival through regulating OXPHOS. Consistently, R21 and K108 methylation was correlated with malignant breast carcinoma. Significantly, our findings unveil a unique mechanism of controlling OXPHOS by arginine and lysine methylation and point to the impact of the PRMT7-SETD6-MRPS23 axis during breast cancer metastasis.

15.
Ann Palliat Med ; 10(3): 3277-3285, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33849112

RESUMO

BACKGROUND: Small-cell lung cancer (SCLC) is a type of lung cancer with high invasiveness and poor prognosis. Although SCLC is effective for initial treatment, the vast majority of patients will relapse, the efficacy of posterior line therapy is limited, and there is a lack of effective treatment. At the same time, in the past 30 years, there has been little progress in first-line treatment. With the progress of antiangiogenic therapy, whether it can be used in the treatment of SCLC is worth exploring. Therefore, a single-arm multicenter clinical study was conducted on the efficacy, optimization, and safety of endostatin combined chemotherapy in SCLC. METHODS: This study is a prospective non-blind single-arm multicenter study. From January 2016 to July 2019, a total of 22 patients with histologically diagnosed SCLC were enrolled in three centers. The treatment regimen was as follows: continuous intravenous pump infusion of endostatin (90 mg) for 72 hours, 3 days before chemotherapy, and continuous pump infusion of endostatin (120 mg) for 96 hours the next day following the infusion of chemotherapeutic drugs; the chemotherapy regimen was administered with standard platinum combined with etoposide once every 21 days. After six cycles, endostatin maintenance therapy was used until the disease progressed or intolerable adverse reactions occurred. The therapeutic effect was evaluated by imaging and oncology markers every two cycles, and the adverse reactions, tumor progression time, and patient survival time were recorded. RESULTS: Among the 21 patients analyzed, the median progression-free survival (PFS) was 8.0 months, the median overall survival (OS) was 13.6 months, the objective effective rate (ORR) was 61.9%, and the disease control rate (DCR) was 95.2%. All patients tolerated the treatment. The main adverse reactions were myelosuppression, albuminuria, nausea, and vomiting. The incidence of grade 3 or 4 adverse reactions was 7.2%, which could be relieved by symptomatic support treatment. There were no treatment-related deaths. CONCLUSIONS: Endostatin combined with platinum-etoposide is safe and effective in the treatment of SCLC.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Endostatinas/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Resultado do Tratamento
16.
J Transl Med ; 19(1): 150, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858440

RESUMO

BACKGROUND: Sidedness (right/left) of colorectal cancer (CRC) is essential for treatment. Whether carcinogenesis of tobacco varies by sidedness remains unclear. The present study aims to evaluate the sidedness tendency of cigarette smoking and to explore its impact on prognosis. METHODS: In the multi-center retrospective study, data on 46 166 Chinese CRC patients were extracted from a big-data platform. Logistic regression analyses were performed to evaluate qualitative and quantitative associations between smoking and tumor sidedness. Survival analyses were conducted in metastatic CRC. RESULTS: History of smoking was associated with left-sided CRC (LSCRC; Adjusted odds ratio, 1.25; 95% CI, 1.16 - 1.34; P < .001). The sidedness tendency towards LSCRC increased from non-smokers, to ex-smokers, and to current smokers (P for trend < .001). Longer duration (P for trend < .001) and larger total amount of cigarette smoking (P for trend < .001) were more associated with LSCRC, respectively. The association was confirmed in both left-sided colon cancer and rectal cancer, but was stronger for rectal cancer (P = .016). Alcoholism significantly enhanced the association by 7% (P = .027). Furthermore, prognostic advantage of metastatic LSCRC diminished among ever-smokers, with contrary survival impacts of smoking on either side of CRC. CONCLUSIONS: History of smoking was associated with LSCRC in a positive dose-response relationship, and presented opposite prognostic impacts on right- and left-sided tumors. Smoking potentially plays an instrumental role in the mechanism for sidedness heterogeneity in CRC.


Assuntos
Fumar Cigarros , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Estudos Retrospectivos , Tabaco
17.
Int J Nanomedicine ; 16: 2597-2613, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833514

RESUMO

Introduction: Limited by tumor vascular barriers, restricted intratumoural T cell infiltration and nanoparticles accumulation remain major bottlenecks for anticancer therapy. Platelets are now known to maintain tumor vascular integrity. Therefore, inhibition of tumor-associated platelets may be an effective method to increase T cell infiltration and drug accumulation at tumor sites. Herein, we designed an ultrasound-responsive nitric oxide (NO) release nanosystem, SNO-HSA-PTX, which can release NO in response to ultrasound (US) irradiation, thereby inhibiting platelet function and opening the tumor vascular barrier, promoting drug accumulation and T cell infiltration. Methods: We evaluated the ability of SNO-HSA-PTX to release NO in response to US irradiation. We also tested the effect of SNO-HSA-PTX on platelet function. Plenty of studies including cytotoxicity, pharmacokinetics study, biodistribution, blood perfusion, T cell infiltration, in vivo antitumor efficacy and safety assessment were conducted to investigate the antitumor effect of SNO-HSA-PTX. Results: SNO-HSA-PTX with US irradiation inhibited tumor-associated platelets activation and induced openings in the tumor vascular barriers, which promoted the accumulation of SNO-HSA-PTX nanoparticles to the tumor sites. Meanwhile, the damaged vascular barriers allowed oxygen-carrying hemoglobin to infiltrate tumor regions, alleviating hypoxia of the tumor microenvironment. In addition, the intratumoral T cell infiltration was augmented, together with chemotherapy and NO therapy, which greatly inhibited tumor growth. Discussion: Our research designed a simple strategy to open the vascular barrier by inhibiting the tumor-associated platelets, which provide new ideas for anti-tumor treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Linfócitos do Interstício Tumoral/imunologia , Nanopartículas/administração & dosagem , Óxido Nítrico/metabolismo , Compostos Nitrosos/química , Paclitaxel/farmacologia , Albumina Sérica Humana/química , Ondas Ultrassônicas , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Food Chem ; 352: 129402, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33690074

RESUMO

A non-thermal processing method was developed to promote preservation of brown rice using dielectric barrier discharge cold plasma (DBD-CP). Physicochemical properties including free fatty acid (FFA) content, surface color change, volatile organic components (VOCs) and flavor fingerprints were evaluated in brown rice submitted to DBD-CP. FFA levels were 25.2% lower in treated samples compared to the control, and a more stable surface color was obtained at the end of the storage period. A total of 35 major VOCs could be detected in treated samples, and reduced levels of hexanal can be used as an indicator of DBD-CP treatment in brown rice during storage. Moreover, the flavor fingerprints in DBD-CP treated groups can be successfully distinguished through headspace gas chromatography ion mobility spectrometry. Collectively, application of DBD-CP treatment could be utilized as a feasible approach to promote stabilization of brown rice and preserve flavor during storage.


Assuntos
Temperatura Baixa , Oryza/química , Gases em Plasma/química , Paladar , Impedância Elétrica , Compostos Orgânicos Voláteis/análise
19.
Hum Genomics ; 15(1): 15, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637127

RESUMO

BACKGROUND: Myocardial infarction (MI), a common type of coronary heart disease, is the major cause of morbidity and mortality around the world. Chemokine-mediated inflammatory cell infiltration and local inflammatory damage response are recent research hotspots. Hence, we attempted to examine the role of C-X-C motif chemokine 16 (CXCL16) as a potential candidate in MI. METHODS: Human cardiomyocytes were treated with hypoxia/reoxygenation (H/R) to establish an in vitro cell model. GEO database provided the clinical data of MI patients and GSEA verified the relationship of chemokine and MI. CCK-8 and flow cytometry analyses were used to measure cell viability and apoptosis. Bioinformatics analysis and luciferase reporter assay were conducted to determine the correlation between CXCL16 and miR-545. qRT-PCR and western blot assays were performed to investigate the expression level of the indicated genes. The activity of lactate dehydrogenase (LDH) and the levels of TNF-α, IL-6, IL-1ß, and IL-10 were explored using ELISA assay. RESULTS: CXCL16 was increased in MI. CXCL16 knockdown can reverse the inhibitory effect of H/R treatment on cell viability, while overexpression of CXCL16 showed the opposite trend. MiR-545 directly targeted CXCL16 and negatively regulated CXCL16 levels. MiR-545 promoted cell proliferation and inhibited apoptosis in the MI cell model, which attenuated the CXCL16-induced injury on cardiomyocytes. CONCLUSION: These findings demonstrated that CXCL16 aggravated MI damage through being directly targeted by miR-545 and mediating inflammatory responses, thereby providing potential therapeutic targets for MI therapy.

20.
Biochem Biophys Res Commun ; 547: 9-14, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33588236

RESUMO

Lactic acid in tumor microenvironment inhibits iNKT cell functions and thus dampens their anti-tumor efficacy. The underlying mechanisms remain unclear. Here, we show that phosphodiesterase-5 inhibitors, sildenafil and tadalafil, promote IFN-γ and IL-4 production in iNKT cells in a cGMP-PKG pathway dependent manner. To favor their cytokine production, iNKT cells reduce Pde5a mRNA lever after activation. In line with the reduction of cytokines caused by lactic acid, lactic acid elevates Pde5a mRNA lever in activated iNKT cells. As a result, phosphodiesterase-5 inhibitor partially restores the cytokine production in lactic acid-treated cells. Our results demonstrate that phosphodiesterase-5 inhibits cytokine production in iNKT cells, and that contributes to the lactic acid-caused dysfunction of iNKT cells.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Ácido Láctico/farmacologia , Células T Matadoras Naturais/efeitos dos fármacos , Neoplasias/imunologia , Inibidores da Fosfodiesterase 5/farmacologia , Animais , Proliferação de Células , Citocinas/imunologia , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Citrato de Sildenafila/farmacologia , Tadalafila/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...