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1.
Front Immunol ; 10: 1372, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258538

RESUMO

Over fifty percent of the people around the world is infected with Helicobacter pylori (H. pylori), which is the main cause of gastric diseases such as chronic gastritis and stomach cancer. H. pylori adhesin A (HpaA), which is a surface-located lipoprotein, is essential for bacterial colonization in the gastric mucosa. HpaA had been proposed to be a promising vaccine candidate against H. pylori infection. However, the effect of non-lipidated recombinant HpaA (rHpaA) to stimulate immune response was not very ideal, and the protective effect against H. pylori infection was also limited. Here, we hypothesized that low immunogenicity of rHpaA may attribute to lacking the immunostimulatory properties endowed by the lipid moiety. In this study, two novel lipopeptides, LP1 and LP2, which mimic the terminal structure of the native HpaA (nHpaA), were synthesized and TLR2 activation activity was confirmed in vitro. To investigate whether two novel lipopeptides could improve the protective effect of rHpaA against the infection of H. pylori, groups of mice were immunized either intramuscularly or intranasally with rHpaA together with LP1 or LP2. Compared with rHpaA alone, the bacterial colonization of the mice immunized with rHpaA plus LP2 via intranasal route was significantly decreased and the expression levels of serum IgG2a, IFN-γ, and IL-17 cytokines in spleen lymphocyte culture supernatant increased obviously, indicating that the enhanced protection of LP2 may be associated with elevated specific Th1 and Th17 responses. In conclusion, LP2 has been shown to improve the protective effect of rHpaA against H. pylori infection, which may be closely related to its ability in activating TLR2 by mimicking the terminal structure of nHpaA.

2.
Mol Biol Rep ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31342294

RESUMO

Acinetobacter baumannii (A. baumannii) is an opportunistic pathogen that causes serious infections in the lungs, blood, and brain in critically ill hospital patients, resulting in considerable mortality rates every year. Due to the rapid appearance of multi-drug resistance or even pan-drug resistance isolates, it is becoming more and more difficult to cure A. baumannii infection by traditional antibiotic treatment, alternative strategies are urgently required to combat A. baumannii infection. In this study, we developed a DNA vaccine encoding two antigens from A. baumannii, OmpA and Pal, and the immunogenicity and protective efficacy was further evaluated. The results showed that the DNA vaccine exhibited significant immune protective efficacy against acute A. baumannii infection in a mouse pneumonia model, and cross protective efficacy was observed when immunized mice were challenged with clinical strains of A. baumannii. DNA vaccine immunization induced high level of humoral response and a mixed Th1/Th2/Th17 cellular response, which protect against lethal bacterial challenges by decreased bacterial loads and pathology in the lungs, and reduced level of inflammatory cytokines expression and inflammatory cell infiltration in BALF. These results demonstrated that it is possible to prevent A. baumannii infection by DNA vaccine and both OmpA and Pal could be serve as promising candidate antigens.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31116632

RESUMO

Antibodies are effective alternative tools to combat infections caused by Pseudomonas aeruginosa (PA), especially multi-drug-resistant PA. Thus, to solve the urgent need for an anti-PA antibody drug, we hypothesized that anti-PA intravenous immunoglobulins could be a practical attempt. Exotoxin A (ETA) is one of the most important factors for PA infection and is also a critical target for the development of immune interventions. In this study, a total of 320 sera were collected from healthy volunteers. The concentration of ETA-specific antibodies was determined by a Luminex-based assay and then purified by affinity chromatography. The purified IgGs were able to neutralize the cytotoxicity of ETA in vitro. We showed they had a prophylactic and therapeutic protective effect in PA pneumonia and ETA toxemia models. In addition, administration of nonspecific IgGs also provided partial protection. Collectively, our results provide additional evidence for IVIG-based treatment of infections caused by multi-drug-resistant PA and suggest that patients at high risk of PA pneumonia could be prophylactically treated with anti-ETA IgGs or even with nonspecific IgGs.

4.
Emerg Microbes Infect ; 8(1): 734-748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31130074

RESUMO

Many pathogens infect hosts through various immune evasion strategies. However, the molecular mechanisms by which pathogen proteins modulate and evade the host immune response remain unclear. Enterohemorrhagic Escherichia coli (EHEC) is a pathological strain that can induce mitogen-activated protein (MAP) kinase (Erk, Jnk and p38 MAPK) and NF-κB pathway activation and proinflammatory cytokine production, which then causes diarrheal diseases such as hemorrhagic colitis and hemolytic uremic syndrome. Transforming growth factor ß-activated kinase-1 (TAK1) is a key regulator involved in distinct innate immune signalling pathways. Here we report that EHEC translocated intimin receptor (Tir) protein inhibits the expression of EHEC-induced proinflammatory cytokines by interacting with the host tyrosine phosphatase SHP-1, which is dependent on the phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction. Taken together, these results suggest that EHEC Tir negatively regulates proinflammatory responses by inhibiting the activation of TAK1, which is essential for immune evasion and could be a potential target for the treatment of bacterial infection.


Assuntos
Escherichia coli Êntero-Hemorrágica/patogenicidade , Infecções por Escherichia coli/fisiopatologia , Proteínas de Escherichia coli/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , MAP Quinase Quinase Quinases/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Fatores de Virulência/metabolismo , Animais , Infecções por Escherichia coli/microbiologia , Células HEK293 , Humanos , Macrófagos Peritoneais , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Células RAW 264.7
5.
Front Immunol ; 10: 781, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068928

RESUMO

Pseudomonas aeruginosa (PA) is a major cause of nosocomial infections, which remain an unsolved problem in the clinic despite conventional antibiotic treatment. A PA vaccine could be both an effective and economical strategy to address this issue. Many studies have shown that PcrV, a structural protein of the type 3 secretion system (T3SS) from PA, is an ideal target for immune prevention and therapy. However, difficulties in the production of high-quality PcrV likely hinder its further application in the vaccine industry. Thus, we hypothesized that an optimized PcrV derivative with a rational design could be produced. In this study, the full-length PcrV was divided into four domains with the guidance of its structure, and the Nter domain (Met1-Lys127) and H12 domain (Leu251-Ile294) were found to be immunodominant. Subsequently, Nter and H12 were combined with a flexible linker to generate an artificial PcrV derivative (PcrVNH). PcrVNH was successfully produced in E. coli and behaved as a homogenous monomer. Moreover, immunization with PcrVNH elicited a multifactorial immune response and conferred broad protection in an acute PA pneumonia model and was equally effective to full-length PcrV. In addition, passive immunization with anti-PcrVNH antibodies alone also showed significant protection, at least based on inhibition of the T3SS and mediation of opsonophagocytic killing activities. These results provide an additional example for the rational design of antigens and suggest that PcrVNH is a promising vaccine candidate for the control of PA infection.

6.
Sci Adv ; 5(4): eaau6547, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30949574

RESUMO

The interaction between gastric epithelium and immune response plays key roles in H. pylori-associated pathology. We demonstrated a procolonization and proinflammation role of MMP-10 in H. pylori infection. MMP-10 is elevated in gastric mucosa and is produced by gastric epithelial cells synergistically induced by H. pylori and IL-22 via the ERK pathway. Human gastric MMP-10 was correlated with H. pylori colonization and the severity of gastritis, and mouse MMP-10 from non-BM-derived cells promoted bacteria colonization and inflammation. H. pylori colonization and inflammation were attenuated in IL-22-/-, MMP-10-/-, and IL-22-/-MMP-10-/- mice. MMP-10-associated inflammation is characterized by the influx of CD8+ T cells, whose migration is induced via MMP-10-CXCL16 axis by gastric epithelial cells. Under the influence of MMP-10, Reg3a, E-cadherin, and zonula occludens-1 proteins decrease, resulting in impaired host defense and increased H. pylori colonization. Our results suggest that MMP-10 facilitates H. pylori persistence and promotes gastritis.

7.
J Cell Physiol ; 2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30710368

RESUMO

Heat shock proteins (HSPs) are crucial proteins in maintaining the homeostasis of human gastric epithelial cells. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the HSP90 family, has been shown to be involved in various crucial physiological processes, particularly against apoptosis. However, the regulation and function of TRAP1 in Helicobacter pylori infection is still unknown. Here, we found that TRAP1 expression was downregulated on human gastric epithelial cells during H. pylori infection by real-time polymerase chain reaction (PCR) and western blot analysis. Through virulence factors mutant H. pylori strains infection and inhibitors screening, we found that H. pylori vacuolating cytotoxin A ( vacA), but not cytotoxin-associated gene A ( cagA) protein, induced human gastric epithelial cells to downregulate TRAP1 via P38MAPK pathway by real-time PCR and western blot analysis. Furthermore, downregulation of TRAP1 with lentivirus carrying TRAP1 short hairpin RNA constructs impairs mitochondrial function, and increases apoptosis of gastric epithelial cells. The results indicate that H. pylori vacA downregulated TRAP1 is involved in the regulation of gastric epithelial cell apoptosis.

8.
J Immunother Cancer ; 7(1): 54, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808413

RESUMO

BACKGROUND: Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the nature, regulation, function, and clinical relevance of mast cells in human gastric cancer (GC) are presently unknown. METHODS: Flow cytometry analyses were performed to examine level and phenotype of mast cells in samples from 114 patients with GC. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Kaplan-Meier plots for patient survival were performed using the log-rank test. Mast cells, T cells and tumor cells were isolated or generated, stimulated and/or cultured for in vitro and in vivo function assays. RESULTS: Patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. These tumor-infiltrating mast cells accumulated in tumors by CXCL12-CXCR4 chemotaxis. Intratumoral mast cells expressed higher immunosuppressive molecule programmed death-ligand 1 (PD-L1), and mast cells induced by tumors strongly express PD-L1 proteins in both time-dependent and dose-dependent manners. Significant correlations were found between the levels of PD-L1+ mast cells and pro-inflammatory cytokine TNF-α in GC tumors, and tumor-derived TNF-α activated NF-κB signaling pathway to induce mast cell expression of PD-L1. The tumor-infiltrating and tumor-conditioned mast cells effectively suppressed normal T-cell immunity through PD-L1 in vitro, and tumor-conditioned mast cells contributed to the suppression of T-cell immunity and the growth of human GC tumors in vivo; the effect could be reversed by blocking PD-L1 on these mast cells. CONCLUSION: Thus, our results illuminate novel immunosuppressive and protumorigenic roles of mast cells in GC, and also present a novel mechanism in which PD-L1 expressing mast cells link the proinflammatory response to immune tolerance in the GC tumor milieu.

9.
Vaccine ; 37(8): 1053-1061, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30665774

RESUMO

Some plant polysaccharides (PPSs) had been used as the adjuvants for systemic vaccination. In this study, we investigated whether PPSs could exhibit adjuvant effect at the mucosa. Groups of mice were intranasally immunized with Epimedium Polysaccharide (EPS), Trollius chinensis polysaccharide (TCPS), Siberian solomonseal rhizome polysaccharide (SSRPS) and Astragalus polysaccharides (APS) together with ovalbumin (OVA). Significantly higher levels of OVA-specific IgG in serum and secretory IgA in saliva, vaginal wash and intestinal lavage fluid were induced after immunization with OVA plus one of the four PPSs compared to OVA alone. Antigen absorption and TLR2 (Toll-like receptor 2) activation may be related to their mucosal adjuvant effect. Of note, when APS used as an adjuvant, intranasally vaccination with recombination UreB (rUreB, Urease subunit B) conferred more robust protection against Helicobacter pylori (H. pylori). Immunized with rUreB in combination APS resulted in mixed specific Th1 and Th17 immune response, which may contribute to the inhibition of H. pylori colonization. Though specific Th2-dominant responses were elicited when the other three PPS intranasally immunized with rUreB, no significant difference in the protective effect were found between those groups and rUreb alone group. Taken together, the four PPSs may be promising candidates for mucosal adjuvant, and APS could enhance rUreB-specific protective immunity against H. pylori infection.

10.
Cell Death Dis ; 10(2): 79, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30692510

RESUMO

Interleukin-17 receptor B (IL-17RB), a member of the IL-17 receptor family activated by IL-17B/IL-17E, has been shown to be involved in inflammatory diseases. However, the regulation and function of IL-17RB in Helicobacter pylori (H. pylori) infection, especially in the early-phase is still unknown. Here, we found that gastric IL-17RB mRNA and protein were decreased in gastric mucosa of both patients and mice infected with H. pylori. In vitro experiments show that IL-17RB expression was down regulated via PI3K/AKT pathway on gastric epithelial cells (GECs) stimulated with H. pylori in a cagA-involved manner, while in vivo studies showed that the effect was partially dependent on cagA expression. IL-17E was also decreased during the early-phase of H. pylori infection, and provision of exogenous IL-17E resulted in increased CD11b+CD11c- myeloid cells accumulation and decreased bacteria colonization within the gastric mucosa. In the early-phase of H. pylori infection, IL-17E-IL-17RB promoted gastric epithelial cell-derived CXCL1/2/5/6 to attract CD11b+CD11c- myeloid cells, and also contributed to host defense by promoting the production of antibacterial protein Reg3a. This study defines a negative regulatory network involving IL-17E, GECs, IL-17RB, CD11b+CD11c- myeloid cells, and Reg3a in the early-phase of H. pylori infection, which results in an impaired host defense within the gastric microenvironment, suggesting IL-17RB as a potential early intervening target in H. pylori infection.

11.
Oncogene ; 38(17): 3134-3150, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30626935

RESUMO

Gastric cancer (GC) is the second leading cause of death among patients with cancer in China. The primary reason of GC treatment failure is metastasis. Therefore, identifying metastatic biomarkers and clarifying the regulatory mechanisms involved in the GC metastatic process are important. Here, we found that KIAA1199, a cell migration-inducing protein, was significantly overexpressed in GC and correlated with lymph node metastasis and poorer patient survival. Additionally, the introduction of KIAA1199 dramatically promoted GC cell proliferation and migration in vitro and in vivo, and the inhibition of KIAA1199 suppressed GC cell growth and migration and induced GC cell apoptosis. Cell migration is a functional consequence of the epithelial-mesenchymal transition (EMT). In this study, we found that KIAA1199 inhibition or overexpression regulated the expression of E-cadherin and N-cadherin through KIAA1199 binding to WW domain binding protein 11 (WBP11) and protein tyrosine phosphatase type IVA, member 3 (PTP4A3) and through the subsequent activation of the FGFR4/Wnt/ß-catenin and EGFR signaling pathways. More importantly, ectopic expression of WBP11 or PTP4A3 blocked the stimulatory effects of KIAA1199 on GC cell proliferation and migration. Meanwhile, we illustrated that KIAA1199 was a target gene of miR-29c-3p and that miR-29c-3p overexpression led to decreased migration of GC cells in vitro and in vivo by suppressing the expression of KIAA1199 and several key proteins in the Wnt/ß-catenin and EGFR signaling pathways (e.g., WBP11, FGFR4, and PTP4A3). Taken together, these data demonstrate that KIAA1199 promotes GC metastasis by activating EMT-related signaling pathways and that miR-29c-3p regulates GC cell migration in vitro and in vivo by regulating KIAA1199 expression and activating the FGFR4/Wnt/ß-catenin and EGFR signaling pathways. These findings provide a new understanding of GC development and progression and may provide novel therapeutic strategies for GC.


Assuntos
Proteínas de Ligação a DNA/metabolismo , MicroRNAs/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Proteínas/genética , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Regulação para Cima , Via de Sinalização Wnt
12.
J Nanobiotechnology ; 17(1): 6, 2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30660182

RESUMO

BACKGROUND: Helicobacter pylori (H. pylori) infection remains a global public health issue, especially in Asia. Due to the emergence of antibiotic-resistant strains and the complexity of H. pylori infection, conventional vaccination is the best way to control the disease. Our previous study found that the N-acetyl-neuroaminyllactose-binding hemagglutinin protein (HpaA) is an effective protective antigen for vaccination against H. pylori infection, and intranasal immunization with the immunodominant HpaA epitope peptide (HpaA 154-171, P22, MEGVLIPAGFIKVTILEP) in conjunction with a CpG adjuvant decreased bacterial colonization in H. pylori-infected mice. However, to confer more robust and effective protection against H. pylori infection, an optimized delivery system is needed to enhance the P22-specific memory T cell response. RESULTS: In this study, an intranasal nanoemulsion (NE) delivery system offering high vaccine efficacy without obvious cytotoxicity was designed and produced. We found that this highly stable system significantly prolonged the nasal residence time and enhanced the cellular uptake of the epitope peptide, which powerfully boosted the specific Th1 responses of the NE-P22 vaccine, thus reducing bacterial colonization without CpG. Furthermore, the protection efficacy was further enhanced by combining the NE-P22 vaccine with CpG. CONCLUSION: This epitope-loaded nanoemulsion delivery system was shown to extend antigen release and elicit potent Th1 response, it is an applicable delivery system for intranasal vaccine against H. pylori.


Assuntos
Portadores de Fármacos , Epitopos , Infecções por Helicobacter , Helicobacter pylori/imunologia , Fatores de Transcrição/imunologia , Administração Intranasal , Animais , Antígenos de Bactérias/imunologia , Sistemas de Liberação de Medicamentos , Emulsões , Epitopos/administração & dosagem , Epitopos/imunologia , Feminino , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas , Vacinas
13.
Cell Death Dis ; 9(10): 1034, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305610

RESUMO

Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, their precise mechanism of communication in gastric cancer remains largely unclear. Here, we found that patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. Tumor-derived adrenomedullin (ADM) induced mast cell degranulation via PI3K-AKT signaling pathway, which effectively promoted the proliferation and inhibited the apoptosis of GC cells in vitro and contributed to the growth and progression of GC tumors in vivo, and the effect could be reversed by blocking interleukin (IL)-17A production from these mast cells. Our results illuminate a novel protumorigenic role and associated mechanism of mast cells in GC, and also provide functional evidence for these mast cells to prevent, and to treat this immunopathogenesis feature of GC.

14.
Eur J Pharm Sci ; 125: 172-180, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296572

RESUMO

This study aimed to improve the solubility, reduce the side effects and enhance the efficacy of gambogic acid against acute myeloid leukemia in vitro and in vivo. This oil-in-water nanoemulsion (average size 17.20 ±â€¯0.11 nm, zeta potential 4.17 ±â€¯0.82 mV) containing Tween-80, glycol, squalene and gambogic acid with improving 4000 times solubility was prepared by pseudoternary phase diagrams. We found that this nanoemulsion successfully encapsulated gambogic acid; it was stable and showed an obvious delayed release effect for the drug in three different phosphate-buffered saline (pH = 2.0, 5.8 and 7.4). The half inhibiting concentration (IC50) of this nanoemulsion (480.7 µg/mL and 408 µg/mL) were 1.67 times and 1.98 times higher than those of its water solution (287 µg/mL and 206 µg/mL) after acting on the toxicity standard cell line (L929 line) for 24 h and 48 h, respectively. Importantly, acute injection toxicity indicated that the half lethal dose (LD50) of this nanoemulsion (23.25 mg/kg, 95% LD50, 21.7-25.16 mg/kg) was 1.26 times higher than that of its water solution (18.59 mg/kg, 95% LD50, 16.84-20.53 mg/kg). Compared with its suspension, the bioavailability of this nanoemulsion was 318.2%. Furthermore, this nanoemulsion had a better efficacy against the acute myeloid leukemia in vitro and in vivo by improving the time and percent of survival (MV4-11 engrafts mice) and reducing half inhibiting concentration values in acute myeloid leukemia such as Jurket, HL-60 and MV4-11 cells. Our studies suggested that this nanoemulsion may be a promising therapeutic medicine for acute myeloid leukemia.

15.
J Immunol Res ; 2018: 6248590, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30255106

RESUMO

Natural killer (NK) cell activity is influenced by a complex integration of signaling pathways activated downstream of both activating and inhibitory surface receptors. The tumor microenvironment can suppress NK cell activity, and there is a great clinical interest in understanding whether modulating tumor-mediated NK cell suppression and/or boosting preexisting NK cell numbers in cancer patients is therapeutically viable. To this light, we characterized the surface receptor phenotypes of peripheral blood NK cells and examined their clinical relevance to human gastric cancer (GC). We found that the proportion of peripheral blood NK cells which expressed the activating receptors NKp30, NKp46, NKG2D, and DNAM-1 was significantly decreased in GC patients compared to healthy donors, and that this decrease was positively associated with tumor progression. At the same time, plasma TGF-ß1 concentrations were significantly increased in GC patients and negatively correlated with the proportion of NKp30, NKp46, NKG2D, and DNAM-1 expressing NK cells. Furthermore, TGF-ß1 significantly downregulated the expression of NKp30, NKp46, NKG2D, and DNAM-1 on NK cells in vitro, and the addition of galunisertib, an inhibitor of the TGF-ß receptor subunit I, reversed this downregulation. Altogether, our data suggest that the decreased expression of activating receptors NKp30, NKp46, NKG2D, and DNAM-1 on peripheral blood NK cells is positively associated with GC progression, and that TGF-ß1-mediated NK cell suppression may be a therapeutically targetable characteristic of GC.

16.
Vaccine ; 36(42): 6301-6306, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30217524

RESUMO

HpaA is considered to be an effective protective antigen for vaccination against Helicobacter pylori (H. pylori) infection. Oral immunization with HpaA significantly decreases bacterial colonization in H. pylori infected mice. In this study, we investigated whether subcutaneous or intranasal immunization with HpaA could protect against H. pylori infection. Mice immunized subcutaneously with HpaA in Complete Freund's adjuvant, but not mice intranasally immunized with HpaA in CpG adjuvant acquired protection against H. pylori infection. However, intranasal immunization with immunodominant epitope peptides in CpG adjuvant protected mice against H. pylori infection, and immunodominant epitope peptides stimulated stronger Th1 responses and mediated more robust protection against H. pylori infection than subdominant ones. Our results suggest that the length of a candidate antigen is critical for particular vaccination routes, and that immunodominant epitope peptides are promising candidates for protection against H. pylori infection through nasal vaccination.

17.
Int J Nanomedicine ; 13: 4987-5002, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30214202

RESUMO

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most predominant and fatal pathogens at wound infection sites. MRSA is difficult to treat because of its antibiotic resistance and ability to form biofilms at the wound site. Methods: In this study, a novel nanoscale liquid film-forming system (LFFS) loaded with benzalkonium bromide was produced based on polyvinyl alcohol and chitosan. Results: This LFFS showed a faster and more potent effect against MRSA252 than benzalkonium bromide aqueous solution both in vitro and in vivo. Additionally, the LFFS had a stronger ability to destroy biofilms (5 mg/mL) and inhibit their formation (1.33 µg/mL). The LFFS inflicted obvious damage to the structure and integrity of MRSA cell membranes and caused increases in the release of alkaline phosphate and lactate dehydrogenase in the relative electrical conductivity and in K+ and Mg2+ concentrations due to changes in the MRSA cell membrane permeability. Conclusion: The novel LFFS is promising as an effective system for disinfectant delivery and for application in the treatment of MRSA wound infections.


Assuntos
Antibacterianos/farmacologia , Biofilmes , Quitosana/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Nanopartículas/química , Álcool de Polivinil/química , Cicatrização/efeitos dos fármacos , Animais , Biofilmes/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Liberação Controlada de Fármacos , Feminino , Humanos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nanopartículas/ultraestrutura
18.
Acta Biomater ; 77: 255-267, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30031164

RESUMO

As an ingredient of vaccines, adjuvants are indispensable for enhancing and directly inducing robust and extensive adaptive immune responses associated with vaccine antigens. In this study, we initially determined that a new molecular immunopotentiator, ophiopogonin D (OP-D), enhanced the antibody response to antigen. Because OP-D has certain disadvantages, including poor solubility, we next encapsulated OP-D in a nanoemulsion adjuvant (nanoemulsion-encapsulated OP-D, NOD) using low-energy emulsification methods. The NOD thus produced was small, with an average size of 76.45 nm, and exhibited good distribution (PdI value 0.16), significantly increasing the solubility of OP-D. Furthermore, NOD exhibited reduced cellular toxicity and acute toxicity. Our results showed that a fusion antigen of MRSA (HlaH35LIsdB348-465) formulated with NOD significantly improved humoral and cellular immune responses compared to those observed in the antigen/OP-D and antigen/AlPO4 groups. Compared with antigen/OP-D, the antigen formulated with NOD more effectively promoted antigen uptake by dendritic cells (DCs) and the activation of antigen-presenting cells (APCs). Moreover, the NOD-formulated antigen had ideal protective efficacy in a MRSA sepsis model by inducing more potent antibody responses and a Th1/Th17-biased CD4+ T cell immune response. Therefore, these results suggest that NOD is a promising and robust adjuvant platform for a MRSA vaccine. STATEMENT OF SIGNIFICANCE: We first identified a new powerful immunopotentiator, Ophiopogonin D, among dozens of natural products and then used nanotechnology to construct a highly efficient and low toxic adjuvant system (NOD). Our approach intersects natural medicinal chemistry, nanomaterials and immunology, revealing that a strong adjuvant activity of this adjuvant system was verified in vitro and in vivo, and the application of MRSA subunit vaccine model for survival experiments achieved a 100% protection rate. This research illustrate that NOD is a promising and robust adjuvant platform for subunit vaccines.

19.
Aging (Albany NY) ; 10(7): 1597-1608, 2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-30018181

RESUMO

Pneumonia caused by Acinetobacter baumannii has become a serious threat to the elderly. However, there are no experimental studies on the relevance between aging and A. baumannii infections. Here, we established an aged pneumonia mouse model by non-invasive intratracheal inoculation with A. baumannii. Higher mortality was observed in aged mice along with increased bacterial burdens and more severe lung injury. Increased inflammatory cell infiltration and enhanced pro-inflammatory cytokines at 24 hours post infection were detected in aged mice than those in young mice. Moreover, infected aged mice had lower myeloperoxidase levels in lungs and less reactive oxygen species-positive neutrophils in bronchoalveolar lavage fluid compared with infected young mice. Reduced efficacy of imipenem/cilastatin against A. baumannii was detected in aged mice. Vaccination of formalin-fixed A. baumannii provided 100% protection in young mice, whereas the efficacy of vaccine was completely diminished in aged mice. In conclusion, aging increased susceptibility to A. baumannii infection and impaired efficacies of antibiotics and vaccine. The aged mice model of A. baumannii pneumonia is a suitable model to study the effects of aging on A. baumannii infection and assess the efficacies of antibiotics and vaccines against A. baumannii for the elderly.

20.
Cell Death Dis ; 9(7): 763, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988030

RESUMO

Myeloid-derived suppressor cells (MDSCs) are a prominent component of the pro-tumoral response. The phenotype of and mechanisms used by MDSCs is heterogeneous and requires more precise characterization in gastric cancer (GC) patients. Here, we have identified a novel subset of CD45+CD33lowCD11bdim MDSCs in the peripheral blood of GC patients compared to healthy individuals. CD45+CD33lowCD11bdim MDSCs morphologically resembled neutrophils and expressed high levels of the neutrophil marker CD66b. Circulating CD45+CD33lowCD11bdim MDSCs effectively suppressed CD8+ T cells activity through the inhibition of CD8+ T cell proliferation and interferon-γ (IFN-γ) and granzyme B (GrB) production. The proportion of CD45+CD33lowCD11bdim MDSCs also negatively correlated with the proportion of IFN-γ+CD8+ T cell in the peripheral blood of GC patients. GC patient serum-derived IL-6 and IL-8 activated and induced CD45+CD33lowCD11bdim MDSCs to express arginase I via the PI3K-AKT signaling pathway. This pathway contributed to CD8+ T cell suppression as it was partially rescued by the blockade of the IL-6/IL-8-arginase I axis. Peripheral blood CD45+CD33lowCD11bdim MDSCs, as well as IL-6, IL-8, and arginase I serum levels, positively correlated with GC progression and negatively correlated with overall patient survival. Altogether, our results highlight that a subset of neutrophilic CD45+CD33lowCD11bdim MDSCs is functionally immunosuppressive and activated via the IL-6/IL-8-arginase I axis in GC patients.

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