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1.
Cancer Lett ; 525: 55-66, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-34562520

RESUMO

The members of the solute carrier (SLC) superfamily are vital membrane transporters in human cells. In the present study, we determine the expression and function of SLC5 family members in colorectal cancer (CRC). Expression analysis based on The Cancer Genome Atlas database and potential clinical relation analysis based on the Oncomine database indicate that SLC5A7 is downregulated and is predicted to correlate with the staging, and prognosis response of CRC. Additional results demonstrate that SLC5A7 is downregulated and correlates with good prognosis in patients with CRC. Ectopic expression of SLC5A7 either by overexpression, or uptake of choline efficiently inhibits CRC growth. Examination of the molecular mechanism reveals that SLC5A7 promotes p53 protein expression by directly interacting with and modifying p53 and disrupting the interaction between p53 and MDM2 in wild type p53 CRC cells. Our findings establish the clear correlation between SLC5A7 and tumour growth, providing a novel potential therapeutic target for CRC.

2.
Immunol Res ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34860323

RESUMO

Reliable noninvasive biomarkers are needed to accurately assess disease activity and prognosis in patients with systemic lupus erythematosus (SLE). The purpose of this study was to investigate the clinical relevance of Wnt5A with disease activity and severity with cutaneous involvement in particular in SLE patients; its concentrations in plasma and urine were examined and analyzed. In the cross-sectional study, the clinical relevance of Wnt5A protein was evaluated in both plasma and urine of SLE patients and healthy cohorts using commercial enzyme-linked immunosorbent assays (ELISA). Significantly, more abundances of Wnt5A protein were determined in both of plasmas and urines of SLE patients compared to healthy cohorts (p < 0.0001), which were even higher in active disease (AD) SLE patients relative to low disease activity (LDA) SLE patients (p < 0.0001). Meanwhile, the ROC curve analysis demonstrated that the plasma and urine Wnt5A were potential candidate biomarkers for identifying the disease activity and severity in SLE patients. The discriminant function analysis further revealed that the plasma and urine Wnt5A were separated and distinct for AD SLE patients and healthy controls. In consistence, the disease severity was correlated with the plasma and urine Wnt5A as ascertained by CLASI activity score and the prevalence of serositis in SLE patients. These results suggest that Wnt5A, as a summary measure for different inflammatory processes, could be a potential biomarker for accessing the disease activity, and a noninvasive biomarker for evaluating the disease severity in terms of cutaneous involvement in SLE patients.

3.
J Clin Lab Anal ; : e24049, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34708888

RESUMO

BACKGROUND: There is evidence that a high level of serum lactate dehydrogenase (LDH) is associated with poorer overall survival in acute myeloid leukemia (AML), but its link to 60-day mortality of AML remains unclear. METHODS: All patients newly diagnosed with AML were included in this cohort study. LDH was measured for the first time after admission. Multivariable logistic regression was used to explore the association between serum LDH and 60-day mortality. Interaction and stratified analyses were conducted including age, sex, albumin, glucose, myoglobin, and standard chemotherapy. RESULTS: Three hundred and seventy-one patients ≥15 years of age, who were newly diagnosed with AML, were consecutively selected. The total prevalence of 60-day mortality was 27.2% (101/371), while it was 32.1% (42/131) and higher than in the LDH ≥570U/L compared with the LDH<570U/L, with the prevalence of 24.6% (59/240); however, the difference was not statistically significant. In multivariate regression models, odd ratios and corresponding 95% confidence intervals (CIs) for Log2 and twice limit of normal (ULN) of LDH were 1.46 (1.0, 2.14) and 2.76 (1.24, 6.16), respectively. Interaction analysis revealed no interactive role in the association between LDH concentration and 60-day mortality. CONCLUSIONS: Serum LDH level was associated with 60-day mortality, especially for the patients with LDH ≥570U/L.

4.
Appl Opt ; 60(27): 8472-8479, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34612948

RESUMO

Due to the sensitivity of wave plates to the angle of incidence (AOI) of light, the accuracy of a dual rotating retarder Mueller matrix polarimeter is also influenced by the AOI. Unlike other conventional systematic errors, the phase retardance error of wave plates caused by AOI is a periodic perturbation rather than a constant. We propose a new method to eliminate the influence of AOI based on a numerical calibration method. To verify the reliability of the proposed calibration method, we measured various types of samples in a transmission Mueller matrix measuring system, such as air, dichroic samples, and birefringent samples, with different AOI conditions. It is demonstrated that the new calibration method can effectively eliminate the influence of AOI. After calibration, the maximum measurement error can be reduced to less than 0.02.

5.
Int J Oncol ; 59(5)2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34698360

RESUMO

Diffuse large B­cell lymphoma (DLBCL) is a common and fatal malignant tumor caused by B­lymphocytes. Long non­coding RNA (lncRNA) GAS5 (growth arrest specific 5) has been reported to function as a tumor suppressor gene, and is differentially expressed in DLBCL. The present study aimed to explore the potential mechanisms of action of lncRNA GAS5 in the proliferation of DLBCL cells. The expression levels of GAS5, miR­18a­5p and Runt­related transcription factor 1 (RUNX1) in DLBCL cell lines were detected using reverse transcription­quantitative polymerase chain reaction, and their effects on cell proliferation, the cell cycle and apoptosis were determined using 5­ethynyl­2'­deoxyuridine assay and flow cytometry. Dual­luciferase reporter and RNA pull-down assays were used to evaluate the interaction between GAS5 and miR­18a­5p, or between miR­18a­5p and RUNX1. Chromatin immunoprecipitation assay was used to identify the interaction between RUNX1 and BAX. The expression levels of GAS5 and RUNX1 were downregulated; however, miR­18a­5p expression was upregulated in the DLBCL cell lines compared with the normal controls. GAS5 directly interacted with miR­18a­5p by acting as a competing endogenous RNA (ceRNA) and reversed the low expression of RUNX1 induced by miR­18a­5p. Additionally, the knockdown of RUNX1 reversed the inhibitory effects of GAS5 on the proliferation and cell cycle G1 arrest, and its promoting effects on the apoptosis of OCI­Ly3 and TMD8 cells. Moreover, RUNX1 enhanced BAX expression by directly binding to the BAX promoter. On the whole, the present study demonstrates that GAS5 functions as a ceRNA, inhibiting DLBCL cell proliferation by sponging miR­18a­5p to upregulate RUNX1 expression. These findings may provide a potential therapeutic strategy for DLBCL.

6.
Front Genet ; 12: 636392, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659329

RESUMO

Background: Hypoxia is a crucial factor in the progression of various tumors, including gastric cancer (GC). Circular RNAs (circRNAs) are important regulators in GC, and this study focused on researching circC6orf132 in GC progression under hypoxia. Methods: In vitro experiments were performed in GC cells under hypoxia (1% O2). CircC6orf132, microRNA-873-5p (miR-873-5p), and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) levels were examined by real-time polymerase chain reaction (qRT-PCR). Colony formation assay and transwell assay were used for detecting cell proliferation and migration or invasion. Glycolytic metabolism was evaluated using lactate production, glucose uptake, and adenosine triphosphate (ATP) level and extracellular acidification rate (ECAR). Western blotting was performed for determining protein expression. The target interaction was analyzed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. In vivo assay was conducted via mouse xenograft model. Results: The expression of circC6orf132 was significantly high in GC cells under hypoxia. Hypoxia-induced GC proliferation, migration, invasion, and glycolysis were reversed by silencing circC6orf132. CircC6orf132 targeted miR-873-5p; and the inhibition of circC6orf132 knockdown for the effects of hypoxia on GC cells was abrogated by miR-873-5p inhibitor. PRKAA1 was validated as a downstream gene of miR-873-5p, and miR-873-5p functioned as an anticancer molecule in GC cells under hypoxia by downregulating PRKAA1 level. CircC6orf132 could regulate PRKAA1 by sponging miR-873-5p. CircC6orf132/miR-873-5p/PRKAA1 axis could regulate GC progression under the hypoxic condition. CircC6orf132 downregulation reduced tumorigenesis in vivo through affecting the miR-873-5p/PRKAA1 axis. Conclusion: CircC6orf132 has been affirmed to promote proliferation, migration, invasion, and glycolysis in GC under hypoxia, partly by depending on the regulation of miR-873-5p/PRKAA1 axis.

7.
Photodiagnosis Photodyn Ther ; 36: 102516, 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34469794

RESUMO

BACKGROUND AND AIM: It is generally believed that bacteria can not develop resistance to antimicrobial photodynamic therapy (aPDT). This work employed a polymyxin-resistant Escherichia coli clinical isolate (E15017) to study whether it could become resistant to aPDT mediated by haematoporphyrin monomethyl ether (HMME) via consecutive photodynamic treatments at sub-lethal condition. METHODS: The sub-lethal and lethal photodynamic treatment conditions for E15017 were determined by colony forming units (CFU) assay. Bacterial cells of E15017 were treated with 20 cycles of repeated sub-lethal HMME-mediated aPDT, and subsequently subjected to aPDT at lethal condition. The antibiotic susceptibility, zeta-potential and membrane integrity of sub-lethal aPDT treated E15017 cells were also investigated. RESULTS: After 20 cycles of repeated HMME-mediated aPDT treatments at sub-lethal condition, E15017 cells didn't become more resistant to aPDT. Sub-lethal HMME-mediated aPDT decreased the MIC values of E15017 to ceftazidime and polymyxin E by 4 and 2-fold, respectively, and increased the electronegativity of bacterial surface and affected the bacterial membrane integrity. CONCLUSIONS: The results obtained in this study confirmed that antibiotic-resistant bacteria could not develop resistance to aPDT, and HMME-mediated aPDT is an attractive potential treatment for MDR E. coli caused infections.

8.
Biomed Opt Express ; 12(8): 5128-5138, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34513246

RESUMO

Diabetes is an important public health problem and finding quick testing methods with high accuracy, reliability, and convenience are important to control the blood glucose of diabetic patients. In this study, a sensor based on a weak measurement scheme was developed for the specific detection of glucose for the first time. The detection of glucose using the proposed method was completed by the high sensitivity and resolution of the weak measurement based on optical rotation detection, as well as the change in the optical rotation before and after the specific oxidation of glucose. The resolution of the as-obtained glucose sensor was around 2.71×10-3 g/L (1.50×10-2 mmol/L), and the detection range was 0-11 g/L (0-61 mmol/L).

9.
Anal Chem ; 93(38): 12914-12920, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34523343

RESUMO

Flow battery electrodes are vital for performing redox reactions, and an in-depth understanding of reaction kinetics and spatial distribution differences in electrodes is very important for improving the efficiency of electrochemical reactions. In this study, a reflection-type phase-sensitive weak measurement imaging system was developed for the detection of flow batteries. The phase difference between two polarization components in total internal reflection caused by electrode redox processes was measured by weak value amplification. The resulting refractive index resolution of the imaging system was estimated to be 2.8-4.2 × 10-6 RIU. The real-time monitoring ability of the system was demonstrated by linear sweep voltammetry tests of vanadium redox batteries. Compared to traditional optical methods, the proposed weak measurement imaging sensor did not require coating, as it can be used in acid electrolytes of vanadium flow batteries. Meanwhile, the weak value amplification effect led to a higher resolution than the total internal reflection system shown in our previous work, thereby resulting in more accurate detection of electrochemical reactions. In sum, the proposed sensor looks very promising for the detection of electrochemical reactions in flow batteries, water splitting, electrochemical corrosion, and electrocatalysis.


Assuntos
Fontes de Energia Elétrica , Eletrólitos , Eletrodos , Oxirredução , Vanádio
10.
J Microbiol Biotechnol ; 31(9): 1200-1209, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34319262

RESUMO

Sepsis is an acute inflammatory response that leads to life-threatening complications if not quickly and adequately treated. Cytolysin, hemolysin, and pneumolysin are toxins produced by gram-positive bacteria and are responsible for resistance to antimicrobial drugs, cause virulence and lead to sepsis. This work assessed the effects of aloe-emodin (AE) and photodynamic therapy (PDT) on sepsis-associated gram-positive bacterial toxins. Standard and antibiotic-resistant Enterococcus faecalis, Staphylococcus aureus, and Streptococcus pneumonia bacterial strains were cultured in the dark with varying AE concentrations and later irradiated with 72 J/cm-2 light. Colony and biofilm formation was determined. CCK-8, Griess reagent reaction, and ELISA assays were done on bacteria-infected RAW264.7 cells to determine the cell viability, NO, and IL-1ß and IL-6 pro-inflammatory cytokines responses, respectively. Hemolysis and western blot assays were done to determine the effect of treatment on hemolysis activity and sepsis-associated toxins expressions. AE-mediated PDT reduced bacterial survival in a dose-dependent manner with 32 µg/ml of AE almost eliminating their survival. Cell proliferation, NO, IL-1ß, and IL-6 cytokines production were also significantly downregulated. Further, the hemolytic activities and expressions of cytolysin, hemolysin, and pneumolysin were significantly reduced following AE-mediated PDT. In conclusion, combined use of AE and light (435 ± 10 nm) inactivates MRSA, S. aureus (ATCC 29213), S. pneumoniae (ATCC 49619), MDR-S. pneumoniae, E. faecalis (ATCC 29212), and VRE (ATCC 51299) in an AE-dose dependent manner. AE and light are also effective in reducing biofilm formations, suppressing pro-inflammatory cytokines, hemolytic activities, and inhibiting the expressions of toxins that cause sepsis.

11.
Cancer Sci ; 112(7): 2679-2691, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33949040

RESUMO

BCR-ABL1 gene fusion associated with additional DNA lesions involves the pathogenesis of chronic myelogenous leukemia (CML) from a chronic phase (CP) to a blast crisis of B lymphoid (CML-LBC) lineage and BCR-ABL1+ acute lymphoblastic leukemia (BCR-ABL1+ ALL). The recombination-activating gene RAG1 and RAG2 (collectively, RAG) proteins that assemble a diverse set of antigen receptor genes during lymphocyte development are abnormally expressed in CML-LBC and BCR-ABL1+ ALL. However, the direct involvement of dysregulated RAG in disease progression remains unclear. Here, we generate human wild-type (WT) RAG and catalytically inactive RAG-expressing BCR-ABL1+ and BCR-ABL1- cell lines, respectively, and demonstrate that BCR-ABL1 specifically collaborates with RAG recombinase to promote cell survival in vitro and in xenograft mice models. WT RAG-expressing BCR-ABL1+ cell lines and primary CD34+ bone marrow cells from CML-LBC samples maintain more double-strand breaks (DSB) compared to catalytically inactive RAG-expressing BCR-ABL1+ cell lines and RAG-deficient CML-CP samples, which are measured by γ-H2AX. WT RAG-expressing BCR-ABL1+ cells are biased to repair RAG-mediated DSB by the alternative non-homologous end joining pathway (a-NHEJ), which could contribute genomic instability through increasing the expression of a-NHEJ-related MRE11 and RAD50 proteins. As a result, RAG-expressing BCR-ABL1+ cells decrease sensitivity to tyrosine kinase inhibitors (TKI) by activating BCR-ABL1 signaling but independent of the levels of BCR-ABL1 expression and mutations in the BCR-ABL1 tyrosine kinase domain. These findings identify a surprising and novel role of RAG in the functional specialization of disease progression in BCR-ABL1+ leukemia through its endonuclease activity.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Proteínas de Fusão bcr-abl/metabolismo , Proteínas de Homeodomínio/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Nucleares/metabolismo , Hidrolases Anidrido Ácido/metabolismo , Animais , Crise Blástica/genética , Crise Blástica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Progressão da Doença , Proteínas de Fusão bcr-abl/genética , Instabilidade Genômica , Xenoenxertos , Histonas/análise , Proteínas de Homeodomínio/genética , Humanos , Técnicas In Vitro , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteína Homóloga a MRE11/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico
12.
Photodiagnosis Photodyn Ther ; 34: 102311, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33930578

RESUMO

BACKGROUND AND AIM: Antimicrobial photodynamic therapy (aPDT) has shown great potential for treatment of superficial or localized multidrug-resistant (MDR) Acinetobacter baumannii infections. The purpose of this study was to investigate the cytotoxicity and in vivo safety of aloe-emodin (AE), and its photodynamic treatment efficacy against MDR A. baumannii infections. METHODS: The cytotoxicity (dark toxicity) and phototoxicity of AE to human immortalized keratinocytes and mice fibroblasts were detected by CCK-8 kit. Low and high doses of AE were intravenously injected into mice to evaluate the safety of AE in vivo. Bioluminescent MDR A. baumannii strain was employed to establish the infection model on BALB/c mice after skin scald, and infection status and therapeutic effect of AE-mediated aPDT were assessed by animal imaging system. The peripheral blood of mice was analyzed by flow cytometer. RESULTS: AE had low cytotoxicity to human immortalized keratinocytes and mice fibroblasts, and had certain phototoxicity to these cells under light irradiation. The in vivo experiments demonstrated that AE caused no obvious effects on the weight and pathological changes of mice. AE-mediated aPDT was effective in the treatment of MDR A. baumannii caused infections in mice after skin scald. CONCLUSIONS: AE has potential to be used in the photodynamic treatment of MDR A. baumannii caused superficial infections after scald.


Assuntos
Acinetobacter baumannii , Aloe , Anti-Infecciosos , Emodina , Fotoquimioterapia , Animais , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Farmacorresistência Bacteriana Múltipla , Emodina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico
13.
Cell Biol Int ; 45(7): 1423-1435, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33675276

RESUMO

Regulatory functions of circRNAs by targeting the micro RNA (miRNA)/mRNA axis have been increasingly found in oral squamous cell carcinoma (OSCC). CircRNA keratin 1 (CircKRT1) and miR-495-3p were dysregulated in OSCC. Programmed death ligand 1 (PDL1) was an important immunotherapeutic molecule in OSCC. Our objective was to explore whether circKRT1 could regulate cancer progression and immune evasion in OSCC by affecting the miR-495-3p/PDL1 axis. RNA expression was examined by quantitative real-time polymerase chain reaction. All protein levels were detected by western blot. OSCC cell growth was assessed by CCK-8 and colony formation assays. Cell migratory and invasive abilities were evaluated by transwell assay. CD8+ T-cell cytotoxicity was determined via lactate dehydrogenase assay. CD8+ T-cell percentage and apoptosis were analyzed by flow cytometry. Target screening was performed by Veen Diagram and RNA pull-down assay. Target binding was verified using dual-luciferase reporter and RNA immunoprecipitation assays. A xenograft in mice was conducted for in vivo experiment. CircKRT1 and PDL1 were highly expressed in OSCC tissues and cells. CircKRT1 knockdown repressed OSCC cell growth, migration, invasion, epithelial-mesenchymal transition, and CD8+ T-cell apoptosis, but enhanced CD8+ T cytotoxicity and percentage. The inhibitory effects of circKRT1 downregulation on OSCC progression and immune evasion were related to PDL1 expression inhibition. CircKRT1 sponged miR-495-3p and miR-495-3p targeted PDL1. OSCC progression and immune evasion were regulated by circKRT1 via the miR-495-3p/PDL1 axis. CircKRT1 also facilitated OSCC progression in vivo by regulating miR-495-3p and PDL1. This study clarified that circKRT1 worked as a miR-495-3p sponge to regulate PDL1, consequently affecting cancer progression and immune evasion in OSCC.

14.
Oncol Rep ; 45(2): 693-705, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33416167

RESUMO

Oncogenic Bcr­Abl kinase mimics pre­B cell receptor (pre­BCR) survival signals in BCR­ABL1­positive B­cell acute lymphoblastic leukemia (BCR­ABL1+ B­ALL), driving B­cell progenitor malignant transformation; thus, defining a particularly unfavorable prognosis for patients. During B­cell development, pre­BCR differentiation signaling components terminate proliferative expansion and promote B­cell maturation. To study whether pre­BCR differentiation signaling components regulate the initiation and development of BCR­ABL1+ B­ALL, the tumor suppression mechanism of differentiation­related signaling molecules in BCR­ABL1­transformed pro­B cells were analyzed. The results demonstrated that Bcr­Abl kinase activated the PI3K/Akt pathway, promoting cell growth, and upregulated Aid expression, increasing genomic instability in pro­B cells. These findings suggest that Bcr­Abl kinase mediates pro­B cell malignant transformation. Furthermore, the present data revealed that BCR­ABL1 oncogenic stress triggered enhanced expression of B­cell differentiation components B­cell linker (Blnk) and forkhead box protein O1 (Foxo1) in BCR­ABL1 transformed pro­B cells. Using the CRISPR/Cas9­mediated Blnk or Foxo1 knockout BCR­ABL1­transformed pro­B cells, it was identified that, in BCR­ABL1­transformed pro­B cells, Blnk and Foxo1 reduced Bcr­Abl kinase activity to induce cell cycle arrest and decrease genomic instability. In addition, Blnk suppressed the PI3K/Akt pathway to reduce Foxo1 phosphorylation and heighten the Foxo1 activity, indicating that, in BCR­ABL1­transformed pro­B cells, Foxo1 participated in the regulation of Bcr­Abl kinase by Blnk. The present data highlighted the antitumor mechanisms of Blnk and Foxo1 in the regulation of Bcr­Abl kinase, and thus, may offer an alternative therapeutic strategy to Bcr­Abl kinase regulation in BCR­ABL1+ B­ALL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Forkhead Box O1/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular , Transformação Celular Neoplásica/patologia , Proteína Forkhead Box O1/genética , Proteínas de Fusão bcr-abl/genética , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética
15.
Oncoimmunology ; 9(1): 1747688, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32363119

RESUMO

In our previous studies, using a B cell vaccine (scFv-Her2), the targeting of tumor-associated antigen Her2 (human epidermal growth factor receptor-2) to B cells via the anti-CD19 single chain variable fragment (scFv) was shown to augment tumor-specific immunity, which enhanced tumor control in the prophylactic and therapeutic setting. However, the fusion protein displayed limited activity against established tumors, and local relapses often occurred following scFv-Her2 treatment, indicating that scFv-Her2-induced responses are inadequate to maintain anti-tumor immunity. In this study, targeting the IV region (D4) of the extracellular region of Her2 to B cells via CD19 molecules (scFv-Her2D4) was found to enhance IFN-γ-producing-CD8+ T cell infiltration in tumor tissues and reduced the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). However, negative co-stimulatory molecules such as programmed cell death protein-1 (PD-1), CD160, and LAG-3 on T cells and programmed death protein ligand-1 (PD-L1) on tumor cells were upregulated in the tumor microenvironment after scFv-Her2D4 treatment. Further, anti-PD1 administration enhanced the efficacy of scFv-Her2D4 and anti-tumor immunity, as evidenced by the reversal of tumor-infiltrating CD8+ T cell exhaustion and the reduction of MDSCs and Treg cells, which suppress T cells and alter the tumor immune microenvironment. Moreover, combining this with anti-PD1 antibodies promoted complete tumor rejection. Our data provide evidence of a close interaction among tumor vaccines, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and tumor vaccine therapy.


Assuntos
Antígenos CD19 , Linfócitos B , Vacinas Anticâncer , Receptor ErbB-2 , Proteínas Recombinantes de Fusão , Animais , Linfócitos B/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Feminino , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/farmacologia
16.
Photochem Photobiol Sci ; 19(4): 485-494, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32232258

RESUMO

The extensive and repetitive use of antifungal drugs has led to the development of drug-resistant Candida albicans. Antimicrobial photodynamic therapy (aPDT) has received considerable attention as an emerging and promising approach to combat drug-resistant microbes. This study evaluated the photodynamic effects mediated by aloe emodin (AE), a natural compound isolated from Aloe vera and Rheum palmatum, on azole-sensitive and azole-resistant C. albicans in vitro. AE exhibited no significant dark toxicity, but in the presence of light, effectively inactivated C. albicans cells in a concentration-dependent manner. The uptake of AE by fungal cells was investigated by confocal laser scanning microscopy (CLSM), and the results showed that AE possessed stronger ability to enter into C. albicans cells following light irradiation. Transmission electron microscopy analysis suggested that AE-mediated aPDT could induce damage to the cell wall, cytoplasm, and nucleus. Damage to the surface of C. albicans was observed by scanning electron microscopy. These results suggest that AE is a potential PS for use in aPDT of drug-resistant C. albicans strains, and AE-mediated aPDT shows promise as an antifungal treatment.


Assuntos
Antraquinonas/farmacologia , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Antraquinonas/química , Antifúngicos/química , Candida albicans/citologia , Luz , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fármacos Fotossensibilizantes/química , Fototerapia
17.
Sci Rep ; 10(1): 4126, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139788

RESUMO

The recombination activating gene (RAG or RAG1/RAG2 complex)-mediated adaptive immune system is a hallmark of jawed vertebrates. It has been reported that RAG originated in invertebrates. However, whether RAG further evolved once it arose in jawed vertebrates remains largely unknown. Here, we found that zebrafish RAG (zRAG) had a lower activity than mouse RAG (mRAG). Intriguingly, the attenuated stability of zebrafish RAG2 (zRAG2), but not zebrafish RAG1, caused the reduced V(D)J recombination efficiency compared to mRAG at 37 °C which are the body temperature of most endotherms except birds. Importantly, the lower temperature 28 °C, which is the best temperature for zebrafish growth, made the recombination efficiency of zRAG similar to that of mRAG by improving the stability of zRAG2. Consistent with the prementioned observation, the V(D)J recombination of Rag2KI/KI mice, which zRAG2 was substituted for mRAG2, was also severely impaired. Unexpectedly, Rag2KI/KI mice developed cachexia syndromes accompanied by premature death. Taken together, our findings illustrate that the evolution of zebrafish RAG2 protein is required for adapting to the elevated body temperature of the higher endothermic vertebrates.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Temperatura Corporal , Linhagem Celular , Proliferação de Células/genética , Proliferação de Células/fisiologia , Proteínas de Ligação a DNA/genética , Evolução Molecular , Feminino , Células HEK293 , Humanos , Immunoblotting , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Estabilidade Proteica , Reação em Cadeia da Polimerase em Tempo Real , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
18.
Anal Bioanal Chem ; 412(12): 2731-2741, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32157359

RESUMO

A one-step synthesis using the reversed-phase suspension polymerization method and ultraviolet light curing is proposed for preparing the Raman-encoded suspension array (SA). The encoded microcarriers are prepared by doping the Raman reporter molecules into an aqueous phase, and then dispersing the aqueous phase in an oil phase and curing by ultraviolet light irradiation. The multiplexed biomolecule detection and various concentration experiments confirm the qualitative and quantitative analysis capabilities of the Raman-encoded SA with a limit of detection of 52.68 pM. The narrow bandwidth of the Raman spectrum can achieve a large number of codes in the available spectral range and the independence between the encoding channel and the fluorescent label channel provides the encoding method with high accuracy. This preparation method is simple and easy to operate, low in cost, and high in efficiency. A large number of hydrogel-based encoding microbeads could be quickly obtained with good biocompatibility. Most importantly, concentrating plenty of Raman reporter molecules inside the microbeads increases the signal intensity and means the molecular assembly is not limited by the functional groups; thus, the types of materials available for Raman encoding method are expanded. Furthermore, the signal intensity-related encoding method is verified by doping different proportions of Raman reporter molecules with our proposed synthesis method, which further increases the detection throughput of Raman-encoded SA. Graphical Abstract.

20.
Neoplasia ; 22(3): 142-153, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32062068

RESUMO

The BCL6 proto-oncogene encodes a transcriptional repressor, which is required for germinal centers (GCs) formation and lymphomagenesis. Previous studies have been reported that the constitutive expression of BCL6 leads to diffuse large B cell lymphoma (DLBCL) through activation-induced cytidine deaminase (AID) mediated chromosomal translocations and mutations. However, other DLBCLs (45%) without structural variants were characterized by abnormally high level of BCL6 expression through an unknown mechanism. Herein, we report that deficiency in AID or methyltransferase 1 (DNMT1) triggers high level of BCL6 expression. AID-DNMT1 complex binds to -0.4 kb -0 kb region of BCL6 promoter and contributes to generate BCL6 methylation which results in inhibition of BCL6 expression. The proteasome pathway inhibitor MG132 induces accumulation of AID and DNMT1, causes decreased BCL6 expression, and leads to cell apoptosis and tumor growth inhibition in DLBCL cell xenograft mice. These findings propose mechanistic insight into an alternative cofactor role of AID in assisting DNMT1 to maintain BCL6 methylation, thus suppress BCL6 transcription in DLBCL. This novel mechanism will provide a new drug selection in the therapeutic approach to DLBCL in the future.


Assuntos
Citidina Desaminase/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Genes Reporter , Humanos , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Ligação Proteica
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