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1.
J Clin Lab Anal ; : e23949, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34498315

RESUMO

BACKGROUND: This study was designed to evaluate the impact of polymorphisms in the urate transporter 1 (URAT1) gene on the uricosuric action of losartan therapy in hypertensive patients suffering from hyperuricemia. METHODS: A MassARRAY approach was used to detect single nucleotide polymorphism (SNP) loci in the URAT1 and CYP2C9 genes (16 and 2 loci, respectively) in 111 patients with hypertension and hyperuricemia taking losartan and in 121 healthy controls. In addition, we compared serum urate (SUA) levels and other key clinical biochemistry indices between these two patient groups. RESULTS: We detected significant differences between the two patient groups with respect to age, SUA, urea, creatine, triglycerides, high-density lipoprotein, low-density lipoprotein, and fasting plasma glucose (all p < 0.05). In addition, we found that hypertensive patients with hyperuricemia were more likely to exhibit the rs3825016(C/T) (36.9% vs 21.5%, p = 0.03), and we determined that a 2-week treatment course with losartan was associated with significant decreases in SUA values (p < 0.001). CONCLUSION: Our findings indicate that the URAT1 rs3825016 polymorphism may influence the uricosuric action of losartan.

2.
Mol Ther ; 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34547464

RESUMO

N6-methyladenosine (m6A) mRNA modification plays critical roles in various biological events and involves in multiple complex diseases. However, the role of m6A modification in autophagy in nonalcoholic fatty liver disease (NAFLD) remains largely unknown. Here, we report that m6A modification was increased in livers of NAFLD mouse models and in free fatty acids (FFAs)-treated hepatocytes, and the abnormal m6A modification was attributed to the upregulation of methyltransferase like 3 (METTL3) induced by lipotoxicity. Knockdown of METTL3 promoted hepatic autophagic flux and lipid drops (LDs) clearance, while overexpression METTL3 inhibited these process. Mechanistically, METTL3 directly bound to Rubicon mRNA and mediated the m6A modification. While YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), as a partner of METTL3, interacted with the m6A-marked Rubicon mRNA and promoted its stability. Subsequently, RUBICON inhibited autophagosome-lysosome fusion and further blocked LDs clearance. Together, our results showed a critical role of METTL3 and YTHDF1 in regulating lipid metabolism via autophagy pathway and provided a novel insight into m6A mRNA methylation in NAFLD.

3.
Fish Shellfish Immunol ; 118: 111-118, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34481087

RESUMO

The need for accurate assessments of in vitro generated antibody prompted examination of the effect of antigen on secreted antibody concentrations and affinities. It was found that the antigen concentrations commonly employed for in vitro stimulation were able to significantly compromise IgM titer and affinity estimates in rainbow trout. Specifically, IgM titers were underestimated with the high affinity antibodies being specifically blocked. To remedy this, pulsed antigen cultures were employed, and it was found to reveal more accurate IgM antibody titers and affinity estimates. Additionally, pulsed dose responses provided evidence that high antigen concentrations specifically suppressed high affinity B cell induction. Optimal expression of high affinity antibodies required exposure to lower concentrations of antigen. Each affinity subpopulation appeared to possess a graded sensitivity to each dose of antigen, revealing the complex dynamic for differential IgM-bearing B cell induction that is possible during a response. These results reveal not only the need for antigen removal prior to in vitro antibody secretion, but also the possible role of high zone immunological tolerance on IgM affinity maturation in rainbow trout.

4.
Biomed Res Int ; 2021: 5521058, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337018

RESUMO

Background: Gastric cancer (GC) is the most common type of cancer. It is highly malignant and is characterized by rapid and uncontrolled growth. The antitumour activity of Baicalin was studied in multiple cancers. However, its mechanism of action has not been fully elucidated. We provided a systematic understanding of the mechanism of action of baicalin against GC using a transcriptome analysis of RNA-seq. Methods: Human GC cells (SGC-7901) were exposed to 200 µg/ml baicalin for 24 h. RNA-seq with a transcriptome, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to identify the antitumour effects of baicalin on SGC-7901 cells in vitro. A protein-protein interaction (PPI) network of differentially expressed genes (DEGs) was constructed. A competitive endogenous RNA (ceRNA) network was constructed and further analysed after validation using qRT-PCR. Results: A total of 68 lncRNAs, 20 miRNAs, and 1648 mRNAs were differentially expressed in baicalin-treated SGC-7901 GC cells. Three lncRNAs, 6 miRNAs, and 7 mRNAs were included in the ceRNA regulatory network. GO analysis revealed that the main DEGs were involved in the biological processes of the cell cycle and cell death. KEGG pathway analysis further suggested that the p53 signalling pathway was involved in the baicalin-induced antitumour effect on SGC-7901 cells. Further confirmation using qPCR indicated that baicalin induced an antitumour effect on SGC-7901 cells, which is consistent with the results of the sequencing data. Conclusions: In summary, the mechanism of baicalin against GC involves multiple targets and signalling pathways. These results provide new insight into the antitumour mechanism of baicalin and help the development of new strategies to cure GC.


Assuntos
Flavonoides/uso terapêutico , Perfilação da Expressão Gênica , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mapas de Interação de Proteínas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
5.
Drug Des Devel Ther ; 15: 1509-1519, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33888977

RESUMO

Background: Increasing evidences have revealed that solasodine, isolated from Solanum sisymbriifolium fruits, has multiple functions such as anti-oxidant, anti-tumor and anti-infection. However, its role in pancreatic cancer has not been well studied. Methods: To explore the role of solasodine in pancreatic cancer, human pancreatic cell lines including SW1990 and PANC1 were treated with different concentrations of solasodine for 48 h, and cell viability was evaluated by MTT assay, cell invasion and migration were evaluated by Transwell assay. The effect of solasodine on the apoptosis of SW1990 and PANC1 cells was detected by flow cytometry. To further explore the antitumor effect of solasodine in vivo, an SW1990 tumor-bearing mouse model was constructed. The effects of solasodine on cytokines in the serum of SW1990 tumor-bearing mice were also evaluated by ELISA assay. Results: Specifically, in vitro, solasodine could significantly inhibit the proliferation of pancreatic cancer cell lines SW1990 and PANC1 cells. Flow cytometric analysis indicated that solasodine could induce apoptosis of SW1990 and PANC1 cells. Western blot assay indicated that solasodine could significantly inhibit the activation of Cox-2/Akt/GSK3ß signal pathway. Meanwhile, the release of Cytochrome c from mitochondria to cytoplasm which can raise the caspases cascade (C-caspase 3 and C-caspase 9) was significantly enhanced by solasodine. In vivo, the results showed that solasodine had potent anti-tumor activities with a lower cytotoxicity. In addition, the serum TNF-α, IL-2 and IFN-γ levels in SW1990 tumor-bearing mice after the treatment of solasodine was significantly increased. Conclusion: Taken together, our results suggested that the solasodine could prevent the progression of pancreatic cancer by inhibiting proliferation and promoting apoptosis, as well as stimulating immunity, suggesting that solasodine might be a potential therapeutic strategy for pancreatic cancer.

6.
Dev Comp Immunol ; 114: 103836, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32835835

RESUMO

CXC chemokine receptor 4 (CXCR4), a member of seven-transmembrane (7-TM) G-protein-coupled receptor superfamily, is the receptor of the CXC chemokine ligand 12 (CXCL12), and plays important roles in host defense and inflammation. In the current study, we cloned and identified a homolog of CXCR4 from Nile tilapia (Oreochromis niloticus), designated as OnCXCR4. The open reading frame of OnCXCR4 is 1149 bp encoding a peptide of 382 amino acids, and the predicted molecular weight is 42.65 kDa OnCXCR4 shares common features of CXCR4 family, including a 7-TM domain and a characteristic CXC motif (containing CYC). Expression analysis showed that OnCXCR4 constitutively expresses in various tested tissues of Nile tilapia, with the highest level in the anterior kidney. When stimulated with Streptococcus agalactiae, Aeromonas hydrophila, Poly(I:C), or LPS in vivo and in vitro, the expression of OnCXCR4 was significantly regulated. AMD3100, a CXCR4 antagonist, could not only inhibit the chemotactic activity of the recombinant OnCXCL12 protein on the leukocytes from anterior kidney, but also reduce the expression of OnCXCR4 significantly. Taken together, these results of our study above indicate that OnCXCR4 may play important roles in host defense against bacterial infectionin in Nile tilapia, and being a receptor of OnCXCL12 to exert functions.

7.
Carbohydr Polym ; 254: 117410, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33357896

RESUMO

Active and intelligent packaging films with multiple functions including antioxidant, antibacterial and colorimetric pH indicator properties were developed by incorporating Clitoria ternatea (CT) extract into gellan gum (G) film. G enhanced the stability of CT anthocyanins and allowed the anthocyanins to release from G film in a pH-responsive behavior. Heat-treated soy protein isolate (HSPI) was able to interact with G and CT anthocyanins through the formation of electrostatic forces and covalent bonds. G film blended with HSPI greatly reduced the swelling capacity of G/HSPI composite film and controlled the anthocyanins release at pH greater than 6.0. The physical and mechanical properties of G films such as hydrophobicity, water vapor permeability, swelling capacity and tensile strength were also significantly modified by addition of HSPI to G films. The smart films changed their color with the increase of total volatile basic nitrogen (TVBN) values during progressive spoilage of shrimp, revealing their potential application for monitoring seafood freshness.


Assuntos
Antocianinas/química , Clitoria/química , Embalagem de Alimentos/métodos , Qualidade dos Alimentos , Extratos Vegetais/química , Polissacarídeos Bacterianos/química , Materiais Inteligentes/química , Cor , Colorimetria/métodos , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Permeabilidade , Alimentos Marinhos , Proteínas de Soja/química , Eletricidade Estática , Vapor , Resistência à Tração
8.
J Diabetes Investig ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33289308

RESUMO

AIMS: Type 2 diabetes mellitus (T2DM) is correlated with systemic atherosclerosis. Statin therapies have been proved to reduce low-density lipoprotein cholesterol (LDL-C) level, protecting T2DM patients from cardiovascular events. Recently, more interest has been focused on the regression of lower extremity atherosclerotic disease (LEAD) for the potential prevention of amputation. However, the effects of pitavastatin and atorvastatin on LEAD in T2DM patients have not been directly compared. METHODS: This study compared the effects of pitavastatin and atorvastatin on femoral total plaque areas (FTPA), and lipids and glucose metabolism in T2DM patients with elevated LDL-C level and LEAD. T2DM patients with LDL-C level > 2.6mmol/L and LEAD were randomly assigned to receive either pitavastatin 2mg/d or atorvastatin 10mg/d for 48 weeks. FTPA were measured at baseline and the end of the study. Levels of glucose and lipids profile were measured periodically. The efficacy was evaluated in 63 patients. RESULTS: The percent change in FTPA measurements were similar between pitavastatin group and atorvastatin group (-17.79±21.27% vs -14.34±16.33%), as were the changes in LDL-C (-44.0±18.0% vs -40.3±18.2%) and triglyceride (17.6±20.0% vs 16.2±17.0%). But the level of high-density lipoprotein cholesterol (HDL-C) was significantly higher in the pitavastatin group compared with the atorvastatin group after 48 weeks of treatment (12.9±10.3% vs 7.2±11.7%, P<0.05). There were no significant differences between groups for the measurements of glucose metabolism. CONCLUSION: In T2DM patients with elevated LDL-C level and LEAD, 48 weeks of treatment with either pitavastatin or atorvastatin was associated with significant regression of FTPA. Pitavastatin treatment resulted in a significantly higher HDL-C level compared with atorvastatin treatment.

9.
J Asthma Allergy ; 13: 615-623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33235472

RESUMO

Objective: Bermuda grass pollen is a common inhaled allergen. The aim of this study was to investigate the molecular sensitization patterns to major pollen allergens (Bermuda grass, Mugwort and Timothy grass) and cross-reactive carbohydrate determinants (CCD) in Bermuda grass sensitized patients in southern China. Methods: Serum specific IgE (sIgE) levels of Bermuda grass allergen components (Cyn d 1 and Cyn d 12), Timothy grass allergen components (Phl p 1, Phl p 4, Phl p 5, Phl p 7 and Phl p 12), Mugwort allergen components (Art v 1, Art v 3 and Art v 4) and CCD were detected in 78 patients sensitized to Bermuda grass via EUROBlotMaster system. Results: Compared with CCD-positive patients, those with negative CCD results had significant higher positive rates of Cyn d 1 (47.8% vs 14.5%), Phl p 1 (26.1% vs 7.3%), Phl p 12 (21.7% vs 3.6%) and Art v 4 (26.1% vs 3.6%) (all p < 0.05). Patients <18 years old had the highest positive rate of Cyn d 1 (40.7%). Additionally, rhinitis patients had the highest positive rate of Cyn d 1 (60.0%), and all patients with Cyn d 12 sensitization (17.2%) were asthmatic patients. Optimal scale analysis showed that Phl p 1 and Cyn d 1 were closely related (Cronbach's alpha = 85.1%). Conclusion: The highest positive rate of pollen allergen components was Cyn d 1 in Bermuda grass sensitized patients in southern China. Most patients were sensitized to CCD alone, and CCD may have less interference in the detection of Cyn d 1, Art v 4, Phl p 1 and Phl p 12. The sensitization patterns of pollen allergen components varied in different ages and diseases, and the diagnostic strategy of pollen allergen needs to be considered in the future.

10.
J Mol Endocrinol ; 65(4): 149-161, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33064661

RESUMO

This study aimed to identify circular RNAs differentially expressed in the islets of type 2 diabetes (T2DM) models and clarify their roles in the control of ß-cell functions. Circular RNAs dysregulated in the islets of diabetic db/db mice were identified by high-throughput RNA sequencing. Then, the expression level of the selected circular RNA circ-Tulp4 was confirmed by real-time PCR in the islets of diabetic models and Min6 cells. MTS, EdU, western blot, flow cytometric analysis, and luciferase assay were performed to investigate the impact of circ-Tulp4 on ß-cell functions. This study identified thousands of circular RNAs in mouse pancreatic islets. The circ-Tulp4 level significantly decreased in the diabetic models and altered in the Min6 cells under lipotoxic condition. The modulation of circ-Tulp4 level in Min6 cells regulated cell proliferation. Furthermore, an interaction was demonstrated between circ-Tulp4 and miR-7222-3p, which suppressed the expression of cholesterol esterification-related gene, sterol O-acyltransferase 1 (SOAT1). The accumulation of soat1 activated cyclin D1 expression, thus promoting cell cycle progression. These findings showed that circ-Tulp4 regulated ß-cell proliferation via miR-7222-3p/soat1/cyclin D1 signaling. Our research suggested that circ-Tulp4 might be a potential therapeutic intervention for T2DM. Besides, soat1 might be important for ß-cell adaptation to lipotoxicity.

11.
Talanta ; 219: 121346, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32887075

RESUMO

N-glycan modification is reported to be important in regulating the structure and function of immunoglobulins in mammals. While, the study on teleost immunoglobulin glycosylation is still limitted. In this study, we constructed a TNP-antigen driven model, and detected the site-specific N-glycans of PBS-immunized and TNP-specific Oreochromis niloticus serum IgM through 18O-labeling and nanoLC-MS/MS. These methods are widely used for peptide enrichment and protein modification identification, but rarely used in detecting the level of N-glycosylation in teleost Igs that driven by specific antigen. The results revealed that there are four N-glycosylation sites in O.niloticus IgM heavy chain, namely, the Asn-315 site in the CH2 domain, the Asn-338 site in the CH3 domain, and the Asn-509 and Asn-551 sites in the CH4 domain, All of the four residues were efficiently N-glycosylated. After immunized with TNP-antigen, the signal strength of oligomannose in the TNP-specific IgM in primary mass spectrometry was significantly higher than that in the PBS-immunized IgM. Notably, the TNP-specific IgM had an Asn-509 site fully occupied with oligomannose, while only a small amount of oligomannose was found in the PBS-immunized IgM of this site. N-glycans in other sites were mainly complex-type with a low content of fucosylation and sialylated. The oligomannose in TNP-specific IgM was further verified to be essential for the binding of IgM and MBL. These results demonstrated that the TNP-antigen induced the site-specific oligomannose modification of O.niloticus IgM heavy chain, and played an important role in the interaction of IgM and MBL, which provided insights into the evolutionary understanding of the IgM oligomannose modification and function.


Assuntos
Polissacarídeos , Espectrometria de Massas em Tandem , Animais , Glicosilação , Imunoglobulina M , Vertebrados
12.
Theranostics ; 10(22): 10001-10015, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929330

RESUMO

Angiogenesis enhances cancer metastasis and progression, however, the roles of transcription regulation in angiogenesis are not fully defined. ZNF322A is an oncogenic zinc-finger transcription factor. Here, we demonstrate a new mechanism of Kras mutation-driven ZNF322A transcriptional activation and elucidate the interplay between ZNF322A and its upstream transcriptional regulators and downstream transcriptional targets in promoting neo-angiogenesis. Methods: Luciferase activity, RT-qPCR and ChIP-qPCR assays were used to examine transcription regulation in cell models. In vitro and in vivo angiogenesis assays were conducted. Immunohistochemistry, Kaplan-Meier method and multivariate Cox regression assays were performed to examine the clinical correlation in tumor specimens from lung cancer patients. Results: We validated that Yin Yang 1 (YY1) upregulated ZNF322A expression through targeting its promoter in the context of Kras mutation. Reconstitution experiments by knocking down YY1 under KrasG13V activation decreased KrasG13V-promoted cancer cell migration, proliferation and ZNF322A promoter activity. Knockdown of YY1 or ZNF322A attenuated angiogenesis in vitro and in vivo. Notably, we validated that ZNF322A upregulated the expression of sonic hedgehog (Shh) gene which encodes a secreted factor that activates pro-angiogenic responses in endothelial cells. Clinically, ZNF322A protein expression positively correlated with Shh and CD31, an endothelial cell marker, in 133 lung cancer patient samples determined using immunohistochemistry analysis. Notably, patients with concordantly high expression of ZNF322A, Shh and CD31 correlated with poor prognosis. Conclusions: These findings highlight the mechanism by which dysregulation of Kras/YY1/ZNF322/Shh transcriptional axis enhances neo-angiogenesis and cancer progression in lung cancer. Therapeutic strategies that target Kras/YY1/ZNF322A/Shh signaling axis may provide new insight on targeted therapy for lung cancer patients.


Assuntos
Proteínas Hedgehog/genética , Neoplasias Pulmonares/genética , Neovascularização Patológica/genética , Proteínas Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/genética , Transcrição Genética/genética , Fator de Transcrição YY1/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Células Endoteliais/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Patológica/patologia , Oncogenes/genética , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética
13.
J Clin Lab Anal ; 34(9): e23400, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32578294

RESUMO

BACKGROUND: This study aimed to investigate the correlation of long non-coding RNA T-cell factor 7 (lnc-TCF7) with clinical features and prognosis in patients with multiple myeloma (MM). METHODS: Totally, 216 newly diagnosed symptomatic MM patients and 60 healthy controls (HCs) were enrolled. Bone marrow samples were collected from patients before treatment and from HCs on donation to detect lnc-TCF7 expression in plasma cells by reverse transcription quantitative polymerase chain reaction. Besides, clinical response, progression-free survival (PFS), and overall survival (OS) of patients were assessed. RESULTS: Lnc-TCF7 expression was increased in patients with MM compared with HCs. Lnc-TCF7 expression was highest in international staging system (ISS) stage III patients, followed by ISS stage II patients, and then ISS stage I patients, while lnc-TCF7 expression was similar in patients with different immunoglobulin subtypes and Durie-Salmon stages. Regarding chromosomal abnormalities, lnc-TCF7 expression positively correlated with t(4; 14) and Del(17p), whereas no correlation of lnc-TCF7 expression with t(14; 16), 1q21 amplification, Del(13q), or hyperdiploid was observed in patients with MM. Furthermore, lnc-TCF7 expression positively correlated with serum creatinine, beta-2-microglobulin, and lactate dehydrogenase in patients. Besides, lnc-TCF7 was negatively associated with complete response but not overall response rate in patients. Additionally, patients with lnc-TCF7 high expression exhibited shorter PFS and OS compared to patients with lnc-TCF7 low expression. CONCLUSION: Lnc-TCF7 might have clinical value in aiding disease management and prognosis prediction of MM.

14.
Fish Shellfish Immunol ; 104: 314-323, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32540504

RESUMO

Chemokines are a class of small molecular weight cytokines of 6-14 kDa, exerting important roles in the regulation of various inflammatory diseases and immune cell migration. In this study, we have identified the CXCL12 gene from Nile tilapia (Oreochromis niloticus), including CXCL12a (OnCXCL12a) and CXCL12b (OnCXCL12b). The open reading frames of OnCXCL12a and OnCXCL12b are 309 and 297 bp, encoding 102 and 98 amino acids, respectively. Multiple alignment showed that OnCXCL12a and OnCXCL12b have characteristics of CXC chemokines and share high identity with CXCL12 amino acid sequences from the known species. Tissue distribution in the healthy fish indicated that OnCXCL12a and OnCXCL12b expressed in all examined tissues, with the highest expression in muscle and anterior kidney, respectively. After challenged by Streptococcus agalactiae, Poly(I:C) and LPS in vivo and in vitro, OnCXCL12 is transcriptionally up-regulated in immune tissues and cells significantly. The recombinant OnCXCL12 proteins, (r)OnCXCL12a and (r)OnCXCL12b, enhance the release of nitric oxide and increase the expression of inflammatory cytokines (TNF-α, IL-6, and IL-10) in anterior kidney leukocytes, as well as exhibit chemotactic activity for leukocytes from anterior kidney. Summarizing, these results indicate that OnCXCL12 is involved in the immune response of Nile tilapia against pathogen infection and may play an important role in mediating inflammatory response.


Assuntos
Quimiocina CXCL12/genética , Quimiocina CXCL12/imunologia , Ciclídeos/genética , Ciclídeos/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Animais , Citocinas/imunologia , Doenças dos Peixes/imunologia , Rim/citologia , Rim/imunologia , Leucócitos/imunologia , Lipopolissacarídeos/farmacologia , Poli I-C/farmacologia , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae
15.
Front Immunol ; 11: 824, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32536909

RESUMO

The momentous discovery of phagocytic activity in teleost B cells has caused a dramatic paradigm shift from the belief that phagocytosis is performed mainly by professional phagocytes derived from common myeloid progenitor cells, such as macrophages/monocytes, neutrophils, and dendritic cells. Recent advances on phagocytic B cells and their microbicidal ability in teleost fish position B cells at the crossroads, bridging innate with adaptive immunity. Most importantly, an increasing body of experimental evidence demonstrates that, in both teleosts and mammals, phagocytic B cells can recognize, take up, and destroy particulate antigens and then present those processed antigens to CD4+ T cells to elicit adaptive immune responses and that the phagocytosis is mediated by pattern recognition receptors and involves multiple cytokines. Thus, current findings collectively indicate that teleost phagocytic B cells, as well as their counterpart mammalian B1-B cells, can be considered one kind of professional phagocyte. The aim of this review is to summarize recent advances regarding teleost phagocytic B cells, with a particular focus on the recognizing receptors and modulating mechanisms of phagocytic B cells and the process of antigen presentation for T-cell activation. We also attempt to provide new insights into the adaptive evolution of the teleost fish phagocytic B cell on the basis of its innate and adaptive roles.


Assuntos
Linfócitos B/imunologia , Peixes/imunologia , Fagócitos/imunologia , Fagocitose/imunologia , Animais , Apresentação do Antígeno , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Citocinas/metabolismo , Ativação Linfocitária
16.
Fish Shellfish Immunol ; 102: 203-210, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32330627

RESUMO

Siglec-1, one of the sialic acid-binding immunoglobulin-type lectins, is closely related to the recognition of host-pathogen and cell-cell interactions in the adaptive and innate immune systems. In this communication, a Siglec-1-like gene (OnSiglec-1-like) from Nile tilapia (Oreochromis niloticus) was analyzed. Relative expression revealed that the OnSiglec-1-like was expressed in all tested tissues, and the highest expression was found in the anterior kidney. Upon Streptococcus agalactiae (S. agalactiae) infection, the expression of OnSiglec-1-like was up-regulated in anterior kidney and spleen significantly in vivo. Additionally, the same phenomenon was observed in anterior kidney leukocytes upon LPS and S. agalactiae challenges as well in vitro. Western-blotting and ELISA analyses revealed that recombinant OnSiglec-1-like protein possessed high binding activity to LTA, LPS and S. agalactiae. Further, the recombinant OnSiglec-1-like was able to agglutinate S. agalactiae. Moreover, with the digestion of specific sialidase, the phagocytic ability of macrophages to S. agalactiae was greatly enhanced. Taken together, these results indicated that the Siglec-1-like possesses conserved functions of agglutination and promotion of macrophage phagocytic activity in Nile tilapia.


Assuntos
Ciclídeos/genética , Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Imunidade Adaptativa/genética , Aglutinação/imunologia , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Imunidade Inata/genética , Macrófagos/imunologia , Fagocitose/imunologia , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae/fisiologia
17.
Endocrinology ; 161(7)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32324218

RESUMO

Increasing evidence indicates that long noncoding RNAs (lncRNAs) have crucial roles in various biological processes. However, the contribution of lncRNAs to ß-cell dysfunction and their roles in diabetes therapeutics remain poorly understood. The aim of this study was to identify the lncRNAs dysregulated in diabetic islets and to explore the lncRNAs involved in ß-cell function as potential therapeutic targets. By using RNA sequencing and real-time PCR, we identified thousands of lncRNAs in the islets of db/db mice and db/m littermate mice. Among the differentially expressed lncRNAs, lncRNA-Malat1 (metastasis-associated lung adenocarcinoma transcript 1) was reduced in the islets of db/db mice and palmitate-treated MIN6 cells. The results of TUNEL, Western blot and flow cytometric analyses, and GSIS assays revealed that Malat1 knockdown significantly induced ß-cell apoptosis and inhibited insulin secretion. Mechanistically, RNA immunoprecipitation showed that Malat1 enhanced polypyrimidine tract-binding protein 1 (Ptbp1) protein stability by direct interaction, thereby adjusting the ratio of pyruvate kinase muscle (PKM) isoforms 1 and 2 (PKM1/PKM2). Moreover, luciferase assay and chromatin immunoprecipitation indicated that Malat1 was transcriptionally activated by pancreatic and duodenal homeobox 1 (Pdx1), through which exendin-4 alleviated lipotoxicity-induced ß-cell damage. In summary, our findings suggested the involvement of Malat1 in ß-cell dysfunction under diabetic conditions via the Malat1/Ptbp1/PKM2 pathway. In addition, exendin-4 ameliorated ß-cell impairment by Pdx1-mediated Malat1 upregulation. Hence, Malat1 may serve as a therapeutic target for the treatment of type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Exenatida/uso terapêutico , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ilhotas Pancreáticas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Avaliação Pré-Clínica de Medicamentos , Exenatida/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Camundongos , Piruvato Quinase/metabolismo
18.
ACS Appl Mater Interfaces ; 12(16): 18823-18832, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32182415

RESUMO

Dendritic large-pore mesoporous silica nanoparticles (DLMSN) is an important biodegradable drug carrier due to its high porosity, which can be prepared by coassembly of a major template and an auxiliary template in aqueous solution, followed by hydrolysis of tetraethyl orthosilicate (TEOS). The auxiliary template is key to obtaining dendritic large-pore structures; however, how to choose the auxiliary template to obtain the desired pore structure is largely unknown. This is because the formation mechanism of DLMSN is still not clear. In this study, a series of therapeutic agent molecules were used as the auxiliary templates to study the control of the pore morphology of DLMSN. Transmission electron microscopy observation and theoretical modeling were used to study the micelle formation, and early stage silica formation was also observed. It is proposed that the silica branches and sheets formed by hydrolysis of TEOS on single micelle and micelle bundles, which formed the initial nanoparticles with spherical structures and new silica species growing on the early formed particles to form DLMSN. The fine control of pore morphology was demonstrated by using auxiliary templates with different structural characteristics, which were used for selective drug loading. This work provides a design strategy of how to choose suitable auxiliary templates for preparing DLMSN with desired pore structure for biomedical applications.


Assuntos
Nanopartículas/química , Dióxido de Silício/química , Cetrimônio/química , Etanolaminas/química , Hidrólise , Micelas , Tamanho da Partícula , Porosidade
19.
Fish Shellfish Immunol ; 99: 562-571, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109611

RESUMO

Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), a kind of protein tyrosine phosphatases (PTPs), is a critical regulator of antigen receptor signal transduction. Signal transduction of BCR is regulated by phosphatases in teleost as in mammals. In this study, SHP1 from Nile tilapia (Oreochromis niloticus) (OnSHP1) was identified and characterized, including the expression pattern against bacterial infection and regulation function in BCR signaling pathway. The open reading frame of OnSHP1 contains 1749 bp of nucleotide sequence, encoding a protein of 582 amino acids. The OnSHP1 protein was highly conversed compared to that of other species, including two amino-terminal SH2 domains at the N terminus and a PTP catalytic domain. Transcriptional expression analysis revealed that OnSHP1 was detected in all examined tissues and highly expressed in spleen. The up-regulated OnSHP1 expression was observed in peripheral blood, spleen and anterior kidney following challenge with Streptococcus agalactiae or lipopolysaccharide (LPS) in vivo, as well as that displayed in leukocytes stimulated with S. agalactiae or LPS in vitro. Further, after induction with mouse anti-tilapia IgM monoclonal antibody in vitro, OnSHP1 was significantly up-regulated in leukocytes. When spleen leukocytes treated with PTP Inhibitor II in vitro, the phosphorylation level of OnSHP1 at the phosphorylation sites (Y535 and Y557) and the cytoplasmic free Ca2+ concentration were up-regulated significantly. Overall, the findings of this study indicate that SHP1 gets involved in host defense against bacterial infection and BCR signaling pathway in Nile tilapia.


Assuntos
Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia , Transdução de Sinais/imunologia , Infecções Estreptocócicas/veterinária , Animais , Doenças dos Peixes/microbiologia , Proteínas de Peixes/genética , Imunidade Inata , Leucócitos/imunologia , Filogenia , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae
20.
Dev Comp Immunol ; 106: 103629, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31987875

RESUMO

Interleukin 6 (IL-6) is a pleiotropic cytokine that exerts its biological functions through interaction with its receptor system consisting of a ligand-specific IL-6 receptor (IL-6R) and a common signal-transducing receptor (gp130). In this study, OnIL-6R and Ongp130 genes from Nile tilapia (Oreochromis niloticus) were identified, and their roles in bacterial or viral infection and in regulation of inflammatory response involved in IL-6 were investigated. The open reading frames (ORFs) of OnIL-6R and Ongp130 are 2019 bp and 2679 bp, encoding 672 and 892 amino acids, respectively. Domain analysis of the deduced amino acid sequences of OnIL-6R and Ongp130 showed that both of them contained a conserved Ig-like domain, FNIII domains, and a WSXWS motif. The transcripts of OnIL-6R and Ongp130 were widely expressed in all examined tissues. Following in vivo challenges with Streptococcus agalactia, Poly I: C and lipopolysaccharide (LPS), the mRNAs of OnIL-6R and Ongp130 were notably induced in liver, head kidney and spleen. The transcriptional up-regulations of OnIL-6R and Ongp130 were also detected in Nile tilapia monocytes/macrophages and lymphocytes after in vitro stimulations with S. agalactiae, Poly I: C and LPS. Besides, increasing mRNA levels of the inflammation-related cytokines (IL-1ß, TNF-α, IL-6, IL-10, and MIF) induced by recombinant OnIL-6 could be further enhanced by co-treatment with recombinant soluble OnIL-6R in lymphocytes. Furthermore, recombinant soluble Ongp130 suppressed the induction of expression of these cytokines in lymphocytes when co-stimulated with (r)OnIL-6 and (r)sOnIL-6R. Taken together, these results indicated that OnIL-6R and Ongp130 were likely involved in the resistance to bacterial or viral infection in Nile tilapia. Moreover, soluble OnIL-6R and soluble Ongp130 have an agonistic effect or antagonistic effect in the inflammation response involved in OnIL-6.


Assuntos
Ciclídeos/imunologia , Receptor gp130 de Citocina/genética , Proteínas de Peixes/genética , Receptores de Interleucina-6/genética , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/fisiologia , Viroses/imunologia , Animais , Clonagem Molecular , Receptor gp130 de Citocina/metabolismo , Citocinas/metabolismo , Resistência à Doença , Proteínas de Peixes/metabolismo , Imunidade Inata , Mediadores da Inflamação/metabolismo , Poli I-C/imunologia , Receptores de Interleucina-6/metabolismo , Regulação para Cima
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