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1.
J Immunol ; 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534212

RESUMO

The cannabinoid receptor 2 (CB2) is a receptor mainly expressed in immune cells and believed to be immunosuppressive in infective or inflammatory models. However, its role in sepsis has not been fully elucidated. In this study, we delineate the function and mechanism of CB2 in the cecal ligation and puncture-induced septic model in mice. The activation of CB2 signaling with HU308 led to decreased survival rates and more severe lung injury in septic mice, and lower IL-10 levels in peritoneal lavage fluid were observed in the CB2 agonist group. The mice with conditional knockout of CB2-encoding gene CNR2 in CD4+ T cells (CD4 Cre CNR2fl/fl) improved survival, enhanced IL-10 production, and ameliorated pulmonary damage in the sepsis model after CB2 activation. In addition, double-knockout of the CNR2 gene (Lyz2 Cre CD4 Cre CNR2fl/fl) decreased the susceptibility to sepsis compared with Lyz2 Cre CNR2fl/fl mice. Mechanistically, the blockade of IL-10 with the anti-IL-10 Ab abolished its protection in CD4 Cre CNR2fl/fl mice. In accordance with the animal study, in vitro results revealed that the lack of CNR2 in CD4+ cells elevated IL-10 production, and CB2 activation inhibited CD4+ T cell-derived IL-10 production. Furthermore, in the clinical environment, septic patients expressed enhanced CB2 mRNA levels compared with healthy donors in PBMCs, and their CB2 expression was inversely correlated with IL-10. These results suggested that the activation of CD4+ T cell-derived CB2 increased susceptibility to sepsis through inhibiting IL-10 production.

2.
Int Immunopharmacol ; 109: 108840, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35567856

RESUMO

Hypertensive renal injury (HRI) is a main cause of end-stage renal diseases, and CD4+ T cells and the secreted inflammatory cytokines contribute to the progress of HRI. However, the exact mechanisms remain unidentified in HRI, and there is still a shortage of effective treatments. Here, we aim to explore the role of interleukin-22 (IL-22) and its underlying mechanism in HRI. Serum IL-22 level and peripheral Th22 cells frequency in patients with HRI were detected by ELISA and flow cytometry respectively. Angiotension II (Ang II) was infused subcutaneously to C57BL/6 mice for 28 days. Hypertensive mice were treated with recombinant IL-22 (rIL-22), anti-IL-22 antibody, or JAK2/STAT3 pathway blocker AG-490 respectively. Blood pressure (BP), urinary albumin/creatinine ratio (UACR), serum creatinine (Scr) and renal histopathology were measured; renal Th22 cells proportion were evaluated; inflammatory factors were evaluated by ELISA; JAK2/STAT3 pathway and fibrosis related factors expression in kidney were detected by Western blot. Serum IL-22 and Th22 cells proportion in kidney of mice were elevated after Ang II infusion. Compared to Ang II-infused mice, treatment with rIL-22 resulted in further increased UACR, Scr, renal pathological damage, inflammation and renal fibrosis, accompanied by elevated BP and JAK2/STAT3 pathway activation. Conversely, anti-IL-22 antibody reduced inflammation, renal fibrosis and BP in Ang II treated mice. AG490 could compromised the above effects of rIL-22. Taken together, recombinant IL-22 may aggravate hypertensive renal damage mediated by Ang II in mice, which may be through promoting JAK2/STAT3 pathway activation. Anti-IL-22 antibody exerts the opposite effects. These data suggest the IL-22 signaling maybe a novel therapeutic target for the treatment of hypertensive renal injury.

3.
Zhongguo Yi Liao Qi Xie Za Zhi ; 46(2): 164-167, 2022 Mar 30.
Artigo em Chinês | MEDLINE | ID: mdl-35411743

RESUMO

Aiming at the current situation of performance testing of hemodialysis extracorporeal circulation tubing, which has slow efficiency, inaccurate measurement, and inconvenient testing, a portable detection system for testing the performance of hemodialysis extracorporeal circulation tubing is designed. The system mainly includes a hardware system and a software system. The hardware system uses STM32F407 single-chip microcomputer as the core to design the driving control of the roller pump; the software system uses the C++ real-time operating system, and the flow detection data is transmitted to the upper computer through RS485 communication and displayed. Experimental showed that the system detects the accuracy and the stability of the flow rate. It has the characteristics of stability and high precision. The relative error of the experimental measurement is within the range of ±10%. The weight of the whole machine is 2 kg, which improves the efficiency by 50% compared with the traditional detection method.


Assuntos
Circulação Extracorpórea , Diálise Renal , Computadores , Desenho de Equipamento , Microcomputadores , Software
4.
Explore (NY) ; 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35469747

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the landscape of advanced cancer treatment. However, immune checkpoint inhibitors can trigger effector T cells against self-antigens as well as tumor antigens, resulting in immune-related toxicities in normal organs, referred to as immune-related adverse events (irAEs). CASE SUMMARY: A 56-year-old man with undifferentiated gastric carcinoma received sintilimab plus paclitaxel and tegafur therapy. After five cycles of treatment, the patient was referred to the hospital for sudden onset urinary frequency, micturition pain, and urinary incontinence. Cystoscopy revealed the entire bladder mucosa was red and edematous but there was no evidence of tumor. Oral administration of Chai-Ling-Tang (Sairei-To) alleviated lower urinary tract symptoms (LUTS). Histological analysis revealed numerous infiltrates of CD3-positive and CD8-positive cells into the urothelium but no atypia, indicating a diagnosis of immune-related cystitis. Interestingly, the urothelial epithelium infiltrated by lymphocytes and subepithelial inflammatory cells strongly expressed cell boundary PD-L1. The dose of Chai-Ling-Tang was maintained and stopped 2 months later without recurrence of LUTS. Since recovering from cystitis, the patient remains alive with no disease progression. CONCLUSION: This report shows that Chai-Ling-Tang is safe and effective for treating immune-related cystitis. The detailed mechanism of action requires further investigation.

5.
Front Oncol ; 12: 863461, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35463328

RESUMO

Anaplastic lymphoma kinase (ALK) alterations in non-small cell lung cancer (NSCLC) can be effectively treated with a variety of ALK-targeted drugs. After the approval of the first-generation ALK inhibitor crizotinib which achieved better results in prolonging the progression-free survival (PFS) compared with chemotherapy, a number of next-generation ALK inhibitors have been developed including ceritinib, alectinib, brigatinib, and ensartinib. Recently, a potent, third-generation ALK inhibitor, lorlatinib, has been approved by the Food and Drug Administration (FDA) for the first-line treatment of ALK-positive (ALK+) NSCLC. These drugs have manageable toxicity profiles. Responses to ALK inhibitors are however often not durable, and acquired resistance can occur as on-target or off-target alterations. Studies are underway to explore the mechanisms of resistance and optimal treatment options beyond progression. Efforts have also been undertaken to develop further generations of ALK inhibitors. This review will summarize the current situation of targeting the ALK signaling pathway.

6.
Cancer Gene Ther ; 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35370291

RESUMO

Alternative splicing (AS) is a gene regulatory mechanism that drives protein diversity and dysregulation of AS plays a significant role in tumorigenesis. This study aimed to develop a prognostic signature based on AS and elucidate the role in tumor immune microenvironment (TIME) in clear cell renal cell carcinoma (ccRCC). The prognosis-related AS events were analyzed by univariate Cox regression analysis. Gene set enrichment analyses (GSEA) were performed for functional annotation. Prognostic signatures were identified and validated using univariate and multivariate Cox regression, LASSO regression, Kaplan-Meier survival analysis, and proportional hazards model. The context of TIME in ccRCC was also analyzed. Gene and protein expression data of C4orf19 were obtained from ONCOMINE website and Human Protein Altas. Splicing factors (SFs) regulatory networks were visualized. 4431 survival-related AS events in ccRCC were screened. Based on splicing subtypes, eight AS prognostic signatures were constructed. A nomogram with good prognostic prediction was generated. Furthermore, the prognostic signatures were significantly correlated with TIME diversity and immune checkpoint inhibitor (ICI)-related genes. C4orf19 was the only gene whose expression levels were downregulated among the prognostic AS-related genes, which is considered as a promising prognostic factor in ccRCC. Potential functions of SFs were determined by splicing regulatory networks. In our study, AS patterns of novel indicators for prognostic prediction of ccRCC were explored. The AS-SF networks provide information of regulatory mechanisms. Players of AS events related to TIME were investigated, which contribute to prognosis monitoring of ccRCC.

7.
Front Immunol ; 13: 834142, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35242138

RESUMO

BACKGROUND: To date, immunotherapy has improved the 5-year survival rate of patients with advanced non-small cell lung cancer (NSCLC) from 4% to 15%. However, only 30%-50% of the NSCLC patients respond to immune checkpoint inhibitors (ICIs) immunotherapy. Therefore, screening patients for potential benefit with precise biomarkers may be of great value. METHODS: First, an immunotherapy NSCLC cohort was analyzed to identify the gene mutations associated with the prognosis of ICI treatment. Further analyses were conducted using NSCLC cohort in The Cancer Genome Atlas (TCGA) project to validate the correlations between the specific gene mutations and tumor immunogenicity, antitumor immunity, and alterations in the tumor-related pathways using Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Gene set enrichment analysis (GSEA). RESULTS: In the immunotherapy NSCLC cohort (n = 266), significantly longer overall survival (OS) rates were observed in the PAK7-mutant type (PAK7-MT) group (n = 13) than the PAK7-wild type (PAK7-WT) group (n = 253) (P = 0.049, HR = 0.43, 95%CI = 0.23-0.79). In the TCGA cohort, PAK7 mutations were correlated with the higher tumor mutation burden (TMB) (14.18 vs. 7.13, P <0.001), increased neoantigen load (NAL) (7.52 vs. 4.30, P <0.001), lower copy number variation (CNV), and higher mutation rate in the DNA damage response (DDR)-related pathways. In addition, PAK7 mutations were also positively correlated with immune-related genes expressions and infiltrating CD8+ T cells (0.079 vs. 0.054, P = 0.005). GSEA results showed that several tumor-related pathways varied in the PAK7-MT group, suggesting the potential mechanisms that regulate the tumor immune-microenvironment. CONCLUSIONS: This study suggested that the PAK7 mutations might be a potential biomarker to predict the efficacy of immunotherapy for NSCLC patients. Considering the heterogeneity among the patients and other confounding factors, a prospective clinical trial is proposed to further validate the impact of PAK7 mutation on the immunotherapy outcomes in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Variações do Número de Cópias de DNA , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Estudos Prospectivos , Microambiente Tumoral/genética
8.
Pharm Biol ; 60(1): 394-403, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35271397

RESUMO

CONTEXT: Pterostilbene (PTE), a common polyphenol compound, exerts an anti-inflammatory effect in many diseases, including acute lung injury (ALI). OBJECTIVE: This study explores the potential mechanism of PTE pre-treatment against lipopolysaccharide (LPS)-induced ALI. MATERIALS AND METHODS: Sixty Sprague-Dawley rats were divided into control, ALI, 10 mg/kg PTE + LPS, 20 mg/kg PTE + LPS, and 40 mg/kg PTE + LPS groups. At 24 h before LPS instillation, PTE was administered orally. At 2 h before LPS instillation, PTE was again administered orally. After 24 h of LPS treatment, the rats were euthanized. The levels of inflammatory cells and inflammatory factors in the bronchoalveolar lavage fluid (BALF), the expression of nuclear receptor subfamily 4 group A member 1 (NR4A1), and the nuclear factor (NF)-κB pathway-related protein levels were detected. NR4A1 agonist was used to further investigate the mechanism of PTE pre-treatment. RESULTS: After PTE pre-treatment, the LPS induced inflammation was controlled and the survival rate was increased to 100% from 70% after LPS treatment 24 h. For lung injury score, it decreased to 1.5 from 3.5 after treating 40 mg/kg PTE. Compared with the control group, the expression of NR4A1 in the ALI group was decreased by 20-40%. However, the 40 mg/kg PTE pre-treatment increased the NR4A1 expression by 20-40% in the lung tissue. The results obtained with pre-treatment NR4A1 agonist were similar to those obtained by pre-treatment 40 mg/kg PTE. CONCLUSIONS: PTE pre-treatment might represent an appropriate therapeutic target and strategy for preventing ALI induced by LPS.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Estilbenos/farmacologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos , Masculino , Ratos , Ratos Sprague-Dawley , Estilbenos/administração & dosagem
9.
Curr Med Imaging ; 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35249499

RESUMO

BACKGROUND: Prognostic evaluation for hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) using drug-eluting beads (DEBs) is essential for guiding the personalized treatment and follow-up strategy. Apparent diffusion coefficient (ADC) has been reported as a biomarker in conventional TACE. OBJECTIVE: To evaluate the diagnostic value of ADCbaseline, ADC change, and ADCratio in predicting the early objective response for HCC after DEB-TACE. METHODS: This prospective single-center study included 32 consecutive patients undergoing dynamic contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging before and 1 month after DEB-TACE. After DEB-TACE, patients were grouped based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria into responders (complete response [CR], partial response [PR] ) and nonresponders (stable disease [SD], progressive disease [PD]). The Mann-Whitney U test and receiver operating characteristic (ROC) curves were performed to assess the statistical differences in ADCbaseline, ADC change, and ADCratio between responders and nonresponders. RESULTS: At post-DEB-TACE follow-up MRI, 62.5% (n = 20, 11 CRs, and 9 PRs) of patients showed objective response, and 37.5% (n = 12, 7 SDs, and 5 PDs) did not respond to chemoembolization. Nonresponders had a significantly higher ADCbaseline value than responders (p < 0.001). The ROC for identifying the response to chemoembolization demonstrated that the threshold ADCbaseline value of 0.920 × 10-3 mm2/s had 100% sensitivity and 70% specificity. The ADC change and ADCratio of responders were higher than that of nonresponders (p < 0.001). CONCLUSION: ADCbaseline, ADC change, and ADCratio may be utilized as a noninvasive biomarker for predicting the early response of HCC to DEB-TACE.

10.
J Inflamm Res ; 15: 987-1004, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35210807

RESUMO

BACKGROUND: Streptococcus pneumoniae (SP) is the most common cause of bacterial pneumonia, especially for people with immature or compromised immune systems. In addition to vaccination and antibiotics, immune regulation through microbial intervention has emerged in recent anti-SP infection research. This study investigated the therapeutic effect of a combination of live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus (CBLEB), a widely used probiotic drug, on SP infection in rats. METHODS: An immunocompromised SP-infection rat model was established by intraperitoneal injection of cyclophosphamide and nasal administration of SP strain ATCC49619. Samples from SP-infected, SP-infected and CBLEB-treated, and healthy rats were collected to determine blood indicators, serum cytokines, gut microbiota, faecal and serum metabolomes, lung- and colon-gene transcriptions, and histopathological features. RESULTS: CBLEB treatment alleviated weight loss, inflammation, organ damage, increase in basophil percentage, red cell distribution width, and RANTES levels and decrease in total protein and albumin levels of immunocompromised SP-infection rats. Furthermore, CBLEB treatment alleviated dysbiosis in gut microbiota, including altered microbial composition and the aberrant abundance of opportunistic pathogenic bacterial taxa such as Eggerthellaceae, and disorders in gut and serum metabolism, including altered metabolomic profiles and differentially enriched metabolites such as 2,4-di-tert-butylphenol in faeces and L-tyrosine in serum. The transcriptome analysis results indicated that the underlying mechanism by which CBLEB fights SP infection is mainly attributed to its regulation of immune-related pathways such as TLR and NLR signalling in the lungs and infection-, inflammation- or metabolism-related pathways such as TCR signalling in the colon. CONCLUSION: The present study shows a potential value of CBLEB in the treatment of SP infection.

11.
Cancer Gene Ther ; 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35169299

RESUMO

A deeper understanding of the interaction between tumor cell and the immune microenvironment in bladder cancer may help select predictive and prognostic biomarkers. The current study aims to construct a prognostic signature for bladder cancer by analysis of molecular characteristics, as well as tumor-immune interactions. RNA-sequencing and clinical information from bladder cancer patients were downloaded from the TCGA database. The single sample Gene Sets Enrichment Analysis (ssGSEA) and Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) were employed to separate the samples into two clusters. Lasso Cox regression was performed to construct an immune gene signature for bladder cancer. The correlation between key target genes of immune checkpoint blockade and the prognostic signature was also analyzed. Dataset from Gene Expression Omnibus (GEO) was retrieved for validation. Two immunophenotypes and immunological characteristics were identified, and a 17-immune gene signature was constructed to provide an independent prognostic signature for bladder cancer. The signature was verified through external validation and correlated with genomic characteristics and clinicopathologic features. Finally, a nomogram was generated from the clinical characteristics and immune signature. Our study reveals a tumor-immune microenvironment signature useful for prognosis in bladder cancer. The results provide information on the potential development of treatment strategies for bladder cancer patients. Prospective studies are warranted to validate the prognostic capability of this model, but these data highlight the role of the microenvironment in the clinical outcome of patients.

12.
Oncol Res Treat ; 45(5): 281-290, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35114663

RESUMO

BACKGROUND: A previous meta-analysis suggested that use of bevacizumab is associated with an increased risk of infection in cancer patients. With the continuous accumulation of evidence in non-small-cell lung cancer (NSCLC), we performed a new, focused meta-analysis of randomized controlled trials (RCTs) to quantify the relative risk (RR) and incidence of infectious complications in those individuals treated with bevacizumab. METHODS: Electronic databases were searched, including PubMed, Embase, and Cochrane databases. Eligible studies were prospective randomized clinical trials of NSCLC patients treated with bevacizumab with toxicity data on infectious complications. RR, overall incidence rates, and 95% confidence intervals (CI) were calculated using fixed- or random-effects models, depending on the heterogeneity of the included studies. RESULTS: A total of 4,545 patients from 14 prospective RCTs were included in the meta-analysis. Treatment with bevacizumab was not associated with an increased risk of all-grade (RR 1.12, 95% CI: 0.84-1.49) or high-grade (RR 1.11, 95% CI: 0.86-1.41) infections, respectively. The summary incidences of all-grade and high-grade infections in patients receiving bevacizumab in the treatment group were 16.4% (95% CI: 15.7-17.2%) and 4.3% (95% CI: 3.0-6.1%), respectively. CONCLUSIONS: The use of bevacizumab is not associated with a significantly higher risk of infections in NSCLC patients. These data provide reassurance regarding the risk of infection in patients with NSCLC receiving bevacizumab.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Incidência , Neoplasias Pulmonares/tratamento farmacológico
13.
BMC Pulm Med ; 22(1): 54, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-35123465

RESUMO

BACKGROUND: Radiation recall pneumonitis (RRP) is unpredictable but associated with severe radiation damage in previously irradiated fields. Chemotherapy and targeted drugs have been reported to contribute to RRP. Here we report a case of a patient with non-small cell lung cancer (NSCLC) who developed RRP following administration of immune checkpoint inhibitor (ICI) 18 months after the end of re-irradiation. CASE PRESENTATION: A 69-year-old man received adjuvant chemoradiotherapy post-operatively. He underwent thoracic re-irradiation for oligometastatic NSCLC. On second recurrence, pembrolizumab combined with nab-paclitaxel were administered. After six months, he developed symptoms of persistent cough and dyspnea, with consistent pneumonitis on CT images. The clinical time frame and significant radiographic evidence raised suspicion for RRP. Symptoms resolved after steroids. CONCLUSIONS: RRP is a rare occurrence. Patients undergoing immunotherapy after prior irradiation may be at increased risk of this rare radiation pneumonitis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/terapia , Pneumonite por Radiação/induzido quimicamente , Reirradiação/efeitos adversos , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , China , Terapia Combinada , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Metástase Linfática/tratamento farmacológico , Metástase Linfática/radioterapia , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Reirradiação/métodos , Resultado do Tratamento
14.
J Phys Chem Lett ; 13(8): 1985-1990, 2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35188776

RESUMO

The modulation of the properties of emission from multiple emission states in a single-component organic luminescent material is highly desirable in data anticounterfeiting, information storage, and bioapplications. Here, a single-component luminescent organic crystal of difluoroboron diphenyl ß-diketonate with controllable multiple emission colors is successfully reported. The temperature-dependent luminescence experiments supported by high-level theoretical calculations demonstrate that the ratio of the fluorescence between the monomer and excimer and the phosphorescence maxima of the excimer can be effectively regulated. In addition, the temperature-dependent fluorescence and afterglow dual-emission color changes provide a new strategy for the design of highly accurate double-checked temperature sensors.

15.
Sci Adv ; 8(7): eabm1418, 2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35171673

RESUMO

Small interfering RNA (siRNA) therapeutic is considered to be a promising modality for the treatment of hyperlipidemia. Establishment of a thermostable clinically applicable delivery system remains a most challenging issue for siRNA drug development. Here, a series of ionizable lipid-like materials were rationally designed; 4 panels of lipid formulations were fabricated and evaluated on the basis of four representative structures. The lead lipid (A1-D1-5) was stable at 40°C, and the optimized formulation (iLAND) showed dose and time dual-dependent gene silencing pattern with median effective dose of 0.18 mg/kg. In addition, potent and durable reduction of serum cholesterol and triglyceride were achieved by administering siRNAs targeting angiopoietin-like 3 or apolipoprotein C3 (APOC3) in high-fat diet-fed mice, db/db mice, and human APOC3 transgenic mice, respectively, accompanied by displaying ideal safety profiles. Therefore, siRNA@iLAND prepared with thermostable A1-D1-5 demonstrates substantial value for siRNA delivery, hyperlipidemia therapy, and prevention of subsequent metabolic diseases.

16.
Kaohsiung J Med Sci ; 38(4): 347-356, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35005835

RESUMO

Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa. M2 macrophage polarization can reduce inflammation and repair tissue injury during AR development. Studies have substantiated the involvement of miRNAs in AR pathogenesis. Herein, the molecular mechanism of miR-214-3p in AR development was explored. To mimic the AR environment, ovalbumin (OVA) was used to treat macrophages. MiR-214-3p and glycogen synthase kinase 3 beta (GSK3B) expression in nasal mucus tissues and macrophages was assessed by RT-qPCR. The M2 phenotypic signature of CD206 in macrophages was assessed by flow cytometry. The protein expression of GSK3B and M2 macrophage markers (ARG-1 and IL-10) was evaluated by western blotting. The correlation between miR-214-3p and GSK3B was validated by a luciferase reporter assay. We found that miR-214-3p was overexpressed in macrophages and nasal mucus tissues from AR patients. MiR-214-3p facilitated M2 polarization of macrophages upon OVA stimulation. Mechanistically, miR-214-3p targeted the GSK3B 3' untranslated region in macrophages. In addition, GSK3B was downregulated in macrophages and nasal mucus tissues from AR patients. In rescue assays, GSK3B downregulation reversed the inhibitory effects of miR-214-3p silencing on M2 polarization of macrophages treated with OVA. Overall, miR-214-3p facilitates M2 macrophage polarization by targeting GSK3B.


Assuntos
MicroRNAs , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Ativação de Macrófagos/genética , Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo
17.
Oncogene ; 41(10): 1434-1444, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35034094

RESUMO

The role of B cells in the anti-tumor immune response remains controversial. An increase in the number of B cells in the peripheral blood of some tumor patients has been associated with poor immunotherapy efficacy. However, the mechanism leading to the generation of these cells is not well-described. Using a fibrosarcoma model, we show that intraperitoneal administration of a xenogeneic antigen in tumor-bearing mice evokes large increases in antigen-specific serum immunoglobulin formation compared to tumor-naïve mice. An inability of tumor-bearing mice to induce enhanced antibody production after myeloid cell depletion suggests the antibody responses are CD11b+ myeloid cell-dependent. In vitro, CD11b+ myeloid cells promoted B cell proliferation, activation, and survival. High levels of tumor necrosis factor (TNF)-α were produced by CD11b+ cells, and TNF-α blockade inhibited B cell responses. CD11b+ cells appear to be important promoters of B cell responses and targeting B cells may increase the efficacy of immunotherapy in tumor-bearing hosts.


Assuntos
Fibrossarcoma , Fator de Necrose Tumoral alfa , Animais , Antígeno CD11b , Fibrossarcoma/patologia , Humanos , Imunoterapia , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/patologia , Fator de Necrose Tumoral alfa/fisiologia
18.
Chem Commun (Camb) ; 58(26): 4168-4171, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35094034

RESUMO

Small interfering RNA (siRNA)-based therapeutics represent a novel and compelling drug modality, provided that safe and competent vectors are available for their delivery. Here, we report a biodegradable amphiphilic poly(aminoester) dendrimer for effective siRNA delivery. This dendrimer is readily biodegradable upon enzyme action, and harnesses the delivery features of both lipid and polymer vectors thanks to its lipid/dendrimer hybrid structure. This study opens new perspectives for developing biodegradable and biocompatible vectors for siRNA therapeutics.


Assuntos
Dendrímeros , Dendrímeros/química , Poli A , RNA Interferente Pequeno/química
19.
Curr Opin Oncol ; 34(1): 89-94, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34636350

RESUMO

PURPOSE OF REVIEW: Cancer cells evade immune surveillance partly due to the immunosuppressive features of the tumor microenvironment (TME). Currently approved immuno-oncology drugs for the treatment of lung cancer are aimed to inhibit immune checkpoints, such as programmed death protein-1 (PD-1), PD ligand-1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4. Despite these, researchers are currently racing to create the optimal cancer immunotherapy treatments. RECENT FINDINGS: Novel immunotherapeutic drugs mainly act on activated immune cells and exert their therapeutic effects by enhancing antitumor responses. In this article, we review new therapies for the treatment of lung cancer that enhance T cell priming, remove coinhibitory signals, supply costimulatory signals and condition the TME. SUMMARY: As more immunotherapeutic targets are in studies, designing multimodal strategies to provide greater efficacy with lower toxicity will be necessary.


Assuntos
Imunoterapia , Neoplasias Pulmonares , Antígeno B7-H1 , Humanos , Vigilância Imunológica , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos T , Microambiente Tumoral
20.
Annu Int Conf IEEE Eng Med Biol Soc ; 2021: 3734-3737, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34892048

RESUMO

Brain imaging using conventional head coils presents several problems in routine magnetic resonance (MR) examination, such as anxiety and claustrophobic reactions during scanning with a head coil, photon attenuation caused by the MRI head coil in positron emission tomography (PET)/MRI, and coil constraints in intraoperative MRI or MRI-guided radiotherapy. In this paper, we propose a super resolution generative adversarial (SRGAN-VGG) network-based approach to enhance low-quality brain images scanned with body coils. Two types of T1 fluid-attenuated inversion recovery (FLAIR) images scanned with different coils were obtained in this study: joint images of the head-neck coil and digital surround technology body coil (H+B images) and body coil images (B images). The deep learning (DL) model was trained using images acquired from 36 subjects and tested in 4 subjects. Both quantitative and qualitative image quality assessment methods were performed during evaluation. Wilcoxon signed-rank tests were used for statistical analysis. Quantitative image quality assessment showed an improved structural similarity index (SSIM) and peak signal-to-noise ratio (PSNR) in gray matter and cerebrospinal fluid (CSF) tissues for DL images compared with B images (P <.01), while the mean square error (MSE) was significantly decreased (P <.05). The analysis also showed that the natural image quality evaluator (NIQE) and blind image quality index (BIQI) were significantly lower for DL images than for B images (P <.0001). Qualitative scoring results indicated that DL images showed an improved SNR, image contrast and sharpness (P<.0001). The outcomes of this study preliminarily indicate that body coils can be used in brain imaging, making it possible to expand the application of MR-based brain imaging.


Assuntos
Encéfalo , Processamento de Imagem Assistida por Computador , Encéfalo/diagnóstico por imagem , Estudos de Viabilidade , Humanos , Redes Neurais de Computação , Neuroimagem , Tecnologia
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