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1.
Francesca Avogadri Taha Merghoub Maureen F. Maughan Daniel Hirschhorn-Cymerman John Morris Erika Ritter Robert Olmsted Alan N. Houghton Jedd D. Wolchok 《PloS one》2010,5(9)
Background
Malignant melanoma is the deadliest form of skin cancer and is refractory to conventional chemotherapy and radiotherapy. Therefore alternative approaches to treat this disease, such as immunotherapy, are needed. Melanoma vaccine design has mainly focused on targeting CD8+ T cells. Activation of effector CD8+ T cells has been achieved in patients, but provided limited clinical benefit, due to immune-escape mechanisms established by advanced tumors. We have previously shown that alphavirus-based virus-like replicon particles (VRP) simultaneously activate strong cellular and humoral immunity against the weakly immunogenic melanoma differentiation antigen (MDA) tyrosinase. Here we further investigate the antitumor effect and the immune mechanisms of VRP encoding different MDAs.Methodology/Principal Findings
VRP encoding different MDAs were screened for their ability to prevent the growth of the B16 mouse transplantable melanoma. The immunologic mechanisms of efficacy were investigated for the most effective vaccine identified, focusing on CD8+ T cells and humoral responses. To this end, ex vivo immune assays and transgenic mice lacking specific immune effector functions were used. The studies identified a potent therapeutic VRP vaccine, encoding tyrosinase related protein 2 (TRP-2), which provided a durable anti-tumor effect. The efficacy of VRP-TRP2 relies on a novel immune mechanism of action requiring the activation of both IgG and CD8+ T cell effector responses, and depends on signaling through activating Fcγ receptors.Conclusions/Significance
This study identifies a VRP-based vaccine able to elicit humoral immunity against TRP-2, which plays a role in melanoma immunotherapy and synergizes with tumor-specific CD8+ T cell responses. These findings will aid in the rational design of future immunotherapy clinical trials. 相似文献2.
Background
Rift Valley fever (RVF) is an arthropod-borne viral zoonosis. Rift Valley fever virus (RVFV) is an important biological threat with the potential to spread to new susceptible areas. In addition, it is a potential biowarfare agent.Methodology/Principal Findings
We developed two potential vaccines, DNA plasmids and alphavirus replicons, expressing the Gn glycoprotein of RVFV alone or fused to three copies of complement protein, C3d. Each vaccine was administered to mice in an all DNA, all replicon, or a DNA prime/replicon boost strategy and both the humoral and cellular responses were assessed. DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited high titer neutralizing antibodies that were similar to titers elicited by the live-attenuated MP12 virus. Mice vaccinated with an inactivated form of MP12 did elicit high titer antibodies, but these antibodies were unable to neutralize RVFV infection. However, only vaccine strategies incorporating alphavirus replicons elicited cellular responses to Gn. Both vaccines strategies completely prevented weight loss and morbidity and protected against lethal RVFV challenge. Passive transfer of antisera from vaccinated mice into naïve mice showed that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited antibodies that protected mice as well as sera from mice immunized with MP12.Conclusion/Significance
These results show that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn administered alone or in a DNA prime/replicon boost strategy are effective RVFV vaccines. These vaccine strategies provide safer alternatives to using live-attenuated RVFV vaccines for human use. 相似文献3.
Comley LH Wishart TM Baxter B Murray LM Nimmo A Thomson D Parson SH Gillingwater TH 《PloS one》2011,6(3):e17639
Background
Mice expressing fluorescent proteins in neurons are one of the most powerful tools in modern neuroscience research and are increasingly being used for in vivo studies of neurodegeneration. However, these mice are often used under the assumption that the fluorescent proteins present are biologically inert.Methodology/Principal Findings
Here, we show that thy1-driven expression of yellow fluorescent protein (YFP) in neurons triggers multiple cell stress responses at both the mRNA and protein levels in vivo. The presence of YFP in neurons also subtly altered neuronal morphology and modified the time-course of dying-back neurodegeneration in experimental axonopathy, but not in Wallerian degeneration triggered by nerve injury.Conclusions/Significance
We conclude that fluorescent protein expressed in thy1-YFP mice is not biologically inert, modifies molecular and cellular characteristics of neurons in vivo, and has diverse and unpredictable effects on neurodegeneration pathways. 相似文献4.
Jennifer L. Konopka Joseph M. Thompson Alan C. Whitmore Drue L. Webb Robert E. Johnston 《Journal of virology》2009,83(23):12432-12442
The host innate immune response provides a critical first line of defense against invading pathogens, inducing an antiviral state to impede the spread of infection. While numerous studies have documented antiviral responses within actively infected tissues, few have described the earliest innate response induced systemically by infection. Here, utilizing Venezuelan equine encephalitis virus (VEE) replicon particles (VRP) to limit infection to the initially infected cells in vivo, a rapid activation of the antiviral response was demonstrated not only within the murine draining lymph node, where replication was confined, but also within distal tissues. In the liver and brain, expression of interferon-stimulated genes was detected by 1 to 3 h following VRP footpad inoculation, reaching peak expression of >100-fold over that in mock-infected animals. Moreover, mice receiving a VRP footpad inoculation 6, 12, or 24 h prior to an otherwise lethal VEE footpad challenge were completely protected from death, including a drastic reduction in challenge virus titers. VRP pretreatment also provided protection from intranasal VEE challenge and extended the average survival time following intracranial challenge. Signaling through the interferon receptor was necessary for antiviral gene induction and protection from VEE challenge. However, VRP pretreatment failed to protect mice from a heterologous, lethal challenge with vesicular stomatitis virus, yet conferred protection following challenge with influenza virus. Collectively, these results document a rapid modulation of the host innate response within hours of infection, capable of rapidly alerting the entire animal to pathogen invasion and leading to protection from viral disease.Venezuelan equine encephalitis virus (VEE) is an arthropod-borne, single-stranded, message-sense RNA virus belonging to the Alphavirus genus and Togaviridae family. Associated with periodic epidemics and equine epizootics in the Western Hemisphere, VEE also serves as a leading model for the study of alphavirus pathogenesis in vivo. In the murine model, which closely mimics infection of horses in nature, VEE causes a two-phase disease: an initial, acute lymphotropic phase characterized by a high serum viremia, followed by invasion of the central nervous system during a neurotropic phase that leads to fatal encephalitis (22, 27). Using the infectious molecular clone of VEE and an extensive panel of mutants blocked at various stages of infection, the course of infection and disease in the mouse model has been well characterized (3, 14, 15, 17, 27).Studies examining the molecular aspects of VEE pathogenesis have underscored the critical role of virus genetics and the subsequent host response in dictating the course and outcome of infection (6, 12, 23, 27, 35, 60, 64, 73). However, many details of the earliest host-pathogen interactions during VEE infection remain largely unknown. A tool paramount to studying early events in infection are VEE replicon particles (VRP). VRP are propagation-defective particles that undergo only one round of infection, as the structural genes which normally drive the assembly of progeny virions are deleted from the replicon genome (51). Infection of cells by VRP results in amplification of replicon viral RNA, but there is no packaging of new progeny and thus no further spread to other cells. As such, VRP infection is limited to the first round of targeted cells, allowing examination of the earliest interactions between virus and host.VRP infection of mice facilitated the identification of the draining lymph node (DLN) as the initial site of VEE viral amplification in vivo (44). Following footpad inoculation of mice with VRP, resident dendritic cells in the skin serve as the cellular target for infection. These infected dendritic cells then rapidly migrate from the site of inoculation in the skin to the local DLN (44). In the case of VRP infection, while no new viral progeny are packaged or released, the replicon genome continues to be replicated within these initially infected skin dendritic cells that have migrated and reside in the DLN. However, during infection with VEE virus, new viral progeny are eventually released into the DLN environment and infection spreads to adjacent cells.Based on these observations, we hypothesize that the earliest host-pathogen interactions within the DLN set the stage for the specific course of events that define VEE-induced pathogenesis. The innate immune response, including interferon (IFN) signaling, has been extensively documented as a critical component of controlling viral infection and spread (45, 47, 62, 66). In fact, utilizing a VRP-based mRNP-tagging system in vivo, we recently reported the robust activation of the host innate antiviral response directly within the infected cells of the DLN, as well as in surrounding uninfected bystander cells, at early times postinoculation (39). A consequence of this early, robust innate immune response at the initial site of replication is likely a contemporaneous induction of an antiviral state in tissues distal to the primary infection.We postulated that if early viral replication in the DLN induces the production of soluble immune mediators, such as IFN-α/β, then the induction of innate immune responses may be rapidly transmitted downstream from this primary site to distal tissues. Utilizing VRP to limit viral spread, we examined the host antiviral response within the DLN and tissues remote from the site of replication at early times following infection. In the liver and brain, the robust expression of a panel of IFN-stimulated genes, a hallmark of the antiviral state, was detected by 1 to 3 h following VRP footpad inoculation and peaked at expression levels >100-fold over mock animals. These results suggest that the early innate response to VRP infection is capable of rapidly inducing a systemically active antiviral state within the entire infected animal. Moreover, we found that mice pretreated by footpad inoculation with VRP for 6, 12, or 24 h were protected from an otherwise lethal VEE footpad or intranasal challenge, and the average survival time of mice challenged intracranially with VEE was significantly extended.Protection from VEE infection has typically been associated with the presence of neutralizing antibody (11, 24, 29, 49, 55). However, nonspecific protection against VEE has been suggested, including the involvement of the innate immune response (10, 26, 28, 33, 61, 73). In one instance, mice “vaccinated” with an attenuated clone of VEE were protected against lethal VEE challenge administered just 24 h after vaccination (26). In separate studies, the complete attenuation of a VEE mutant harboring a single noncoding nucleotide change was attributed to a heightened sensitivity of the virus to the host antiviral state (73). Additionally, mice with severe combined immunodeficiency survive longer than immunocompetent mice (9 days as opposed to 6 days) following infection with virulent VEE (12). These findings firmly indicate that the nonspecific host response to VEE is a critical component of controlling the earliest stages of infection.While IFN and the IFN-induced antiviral state are undoubtedly key mediators of the initial response to VRP infection in vivo, they may not solely be responsible for a rapidly induced protective state. In the challenge model presented here, VRP pretreatment was unable to protect mice from death following heterologous challenge with another IFN-sensitive virus, vesicular stomatitis virus (VSV). However, VRP pretreatment successfully protected mice from lethal challenge with influenza virus. Collectively, our results raise at least three important implications. First, the innate host response is rapidly mobilized following infection with VRP/VEE, at areas both proximal and distal to the site of active replication. Second, there exist components of the innate immune response to VEE that remain uncharacterized. Third, viruses are specifically and differentially sensitive to unique innate immune response profiles. These data provide new insight into the rapid mobilization of the host response to viral infection and present an effective pretreatment/challenge model to further investigate specific components of the innate response critical to protection against infectious pathogens. 相似文献
5.
Liu YH Cao JS Li GJ Wu XH Wang BG Xu P Hu TT Lu ZF Patrick JW Ruan YL 《Annals of botany》2012,109(7):1277-1284
Background and Aims
Coordination of sugar transport and metabolism between developing seeds and their enclosing fruit tissues is little understood. In this study the physiological mechanism is examined using two genotypes of asparagus bean (Vigna unguiculata ssp. sesquipedialis) differing in pod wall and seed growth rates. Pod growth dominates over seed growth in genotype ‘Zhijiang 121’ but not in ‘Zhijiang 282’ in which a ‘bulging pod’ phenotype is apparent from 8 d post-anthesis (dpa) onward.Methods
Seed and pod wall growth rates and degree of pod-bulging were measured in the two genotypes together with assays of activities of sucrose-degrading enzymes and sugar content in pod wall and seed and evaluation of cellular pathways of phloem unloading in seed coat using a symplasmic fluorescent dye, 5(6)-carboxyfluorescein (CF).Key Results
Activities of cell wall, cytoplasmic and vacuolar invertases (CWIN, CIN and VIN) were significantly smaller in pod walls of ‘282’ than in ‘121’ at 10 dpa onwards. Low INV activities were associated with weak pod wall growth of ‘282’. In seed coats, CF was confined within the vasculature in ‘282’ but moved beyond the vasculature in ‘121’, indicating apoplasmic and symplasmic phloem unloading, respectively. Higher CWIN activity in ‘282’ seed coats at 6–8 dpa correlated with high hexose concentration in embryos and enhanced early seed growth. However, CWIN activity in ‘282’ decreased significantly compared with ‘121’ from 10 dpa onwards, coinciding with earlier commencement of nuclei endoreduplication in their embryos.Conclusions
The study shows genotypic differences between ‘bulging pod’ and ‘non-bulging’ phenotypes of asparagus bean in sucrose metabolism in relation to the pathway of phloem unloading in developing seed coats, and to pod and seed growth. Low INV activity in pod wall corresponds to its shortened and weak growth period; by contrast, the apoplasmic path in the seed coat is associated with high CWIN activity and strong early seed growth. 相似文献6.
Martina Morowski Sebastian Brachs Dirk Mielenz Bernhard Nieswandt Sebastian Dütting 《PloS one》2014,9(9)
Background
Platelets are anuclear cell fragments derived from bone marrow megakaryocytes that safeguard vascular integrity, but may also cause pathological vessel occlusion. Reorganizations of the platelet cytoskeleton and agonist-induced intracellular Ca2+-mobilization are crucial for platelet hemostatic function. EF-hand domain containing 2 (EFhd2, Swiprosin-1) is a Ca2+-binding cytoskeletal adaptor protein involved in actin remodeling in different cell types, but its function in platelets is unknown.Objective
Based on the described functions of EFhd2 in immune cells, we tested the hypothesis that EFhd2 is a crucial adaptor protein for platelet function acting as a regulator of Ca2+-mobilization and cytoskeletal rearrangements.Methods and Results
We generated EFhd2-deficient mice and analyzed their platelets in vitro and in vivo. Efhd2-/- mice displayed normal platelet count and size, exhibited an unaltered in vivo life span and showed normal Ca2+-mobilization and activation/aggregation responses to classic agonists. Interestingly, upon stimulation of the immunoreceptor tyrosine-based activation motif-coupled receptor glycoprotein (GP) VI, Efhd2-/- platelets showed a slightly increased coagulant activity. Furthermore, absence of EFhd2 had no significant impact on integrin-mediated clot retraction, actomyosin rearrangements and spreading of activated platelets on fibrinogen. In vivo EFhd2-deficiency resulted in unaltered hemostatic function and unaffected arterial thrombus formation.Conclusion
These results show that EFhd2 is not essential for platelet function in mice indicating that other cytoskeletal adaptors may functionally compensate its loss. 相似文献7.
Background
Synapses exhibit strikingly different forms of plasticity over a wide range of time scales, from milliseconds to hours. Studies on synaptic plasticity typically use constant-frequency stimulation to activate synapses, whereas in vivo activity of neurons is irregular.Methodology/Principal Findings
Using extracellular and whole-cell electrophysiological recordings, we have here studied the synaptic responses at hippocampal mossy fiber synapses in vitro to stimulus patterns obtained from in vivo recordings of place cell firing of dentate gyrus granule cells in behaving rodents. We find that synaptic strength is strongly modulated on short- and long-lasting time scales during the presentation of the natural stimulus trains.Conclusions/Significance
We conclude that dynamic short- and long-term synaptic plasticity at the hippocampal mossy fiber synapse plays a prominent role in normal synaptic function. 相似文献8.
Sariol CA Martínez MI Rivera F Rodríguez IV Pantoja P Abel K Arana T Giavedoni L Hodara V White LJ Angleró YI Montaner LJ Kraiselburd EN 《PloS one》2011,6(4):e19323
Background
Pathogenic versus protective outcomes to Dengue virus (DENV) infection are associated with innate immune function. This study aimed to determine the role of increased TLR3- and TLR7/8-mediated innate signaling after Dengue infection of rhesus macaques in vivo to evaluate its impact on disease and anti-DENV immune responses.Methodology/Principal Findings
TLR3 and TLR7/8 agonists (emulsified in Montanide) were administered subcutaneously to rhesus macaques at 48 hours and 7 days after DENV infection. The Frequency and activation of myeloid dendritic cells, plasmacytoid dendritic cells, and B cells were measured by flow cytometry while the serum levels of 14 different cytokines and chemokines were quantified. Adaptive immune responses were measured by DENV-specific antibody subtype measurements. Results showed that the combined TLR agonists reduced viral replication and induced the development of a proinflammatory reaction, otherwise absent in Dengue infection alone, without any clear signs of exacerbated disease. Specifically, the TLR-induced response was characterized by activation changes in mDC subsets concurrent with higher serum levels of CXCL-10 and IL-1Ra. TLR stimulation also induced higher titers of anti-DENV antibodies and acted to increase the IgG2/IgG1 ratio of anti-DENV to favor the subtype associated with DENV control. We also observed an effect of DENV-mediated suppression of mDC activation consistent with prior in vitro studies.Conclusions/Significance
These data show that concurrent TLR3/7/8 activation of the innate immune response after DENV infection in vivo acts to increase antiviral mechanisms via increased inflammatory and humoral responses in rhesus macaques, resulting in decreased viremia and melioration of the infection. These findings underscore an in vivo protective rather than a pathogenic role for combined TLR3/7/8-mediated activation in Dengue infection of rhesus macaques. Our study provides definitive proof-of-concept into the mechanism by which DENV evades immune recognition and activation in vivo. 相似文献9.
Background
Insulin resistance (IR) is induced by chronic hepatitis C virus (HCV) genotypes 1 and 4 infections. It is not known whether drugs that affect IR such as Pioglitazone and Prednisone also affect serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The primary aim was to assess whether Pioglitazone by improving IR and/or inflammation decreases HCV viral load independently of standard of care HCV treatment. A secondary aim was to assess whether Prednisone, a drug that induces insulin resistance and stimulates HCV viral entry and replication in replicon culture systems, increases HCV viral load in this population.Methodology/Principal Findings
We designed a two-arm, parallel Pilot Study of overweight, treatment naïve genotype 4 HCV-infected patients at a public referral Liver Clinic in Giza, Egypt. The subjects received Pioglitazone (30 mg/day for 14 days) or Prednisone (40 mg/day for 4 days) in a randomized fashion, but the two arms can be considered independent pilot studies. Only changes from baseline within each arm were assessed and no contrasts of the interventions were made, as this was not an aim of the study. Among 105 consecutive HCV genotype 4 patients, 39 were enrolled based on the optimal sample size and power analysis according to the CONSORT statement; 20 to the Pioglitazone group and 19 to the Prednisone group. Pioglitazone was effective in decreasing serum HCV RNA at day-14 (n = 10; difference of means = 205,618 IU/ml; 95% CI 26,600 to 384,600; P<0.001). Although Prednisone did increase serum HCV RNA at day-4 (n = 10; change from baseline = −42,786 IU/ml; 95% CI −85,500 to −15,700; P = 0.049), the log10 HCV RNA titers were statistically not different from baseline day-0.Conclusion/Significance
This is the first documentation that Pioglitazone decreases the serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The novel findings of our Study provide the foundation for basic and clinical investigations on the molecular mechanisms responsible for the Pioglitazone-induced decrease in HCV genotype 4 RNA titers.Trial Registration
ClinicalTrials.gov NCT01157975相似文献10.
Background
Since free radical scavengers of parasite origin like glutathione-S-transferase and superoxide dismutase are being explored as prospective vaccine targets, availability of these molecules within the parasite infecting different hosts as well as different sites of infection is of considerable importance. Using Clinostomum complanatum, as a model helminth parasite, we analysed the effects of habitat of in vivo transformation on free radical scavengers of this trematode parasite.Methods
Using three different animal models for in vivo transformation and markedly different sites of infection, progenetic metacercaria of C. complanatum were transformed to adult ovigerous worms. Whole worm homogenates were used to estimate the levels of lipid peroxidation, a marker of oxidative stress and free radical scavengers.Results
Site of in vivo transformation was found to drastically affect the levels of free radical scavengers in this model trematode parasite. It was observed that oxygen availability at the site of infection probably influences levels of free radical scavengers in trematode parasites.Conclusion
This is the first report showing that habitat of in vivo transformation affects levels of free radical scavengers in trematode parasites. Since free radical scavengers are prospective vaccine targets and parasite infection at ectopic sites is common, we propose that infections at different sites, may respond differently to free radical scavenger based vaccines. 相似文献11.
Eller MA Slike BM Cox JH Lesho E Wang Z Currier JR Darden JM Polonis VR Vahey MT Peel S Robb ML Michael NL Marovich MA 《PloS one》2011,6(9):e24254
Background
We conducted a novel pilot study comparing different delivery routes of ALVAC-HIV (vCP205), a canarypox vaccine containing HIV gene inserts: env, gag and pol. We explored the concept that direct ex vivo targeting of human dendritic cells (DC) would enhance the immune response compared to either conventional intramuscular or intradermal injections of the vaccine alone.Methodology/Principal Findings
Healthy HIV-1 uninfected volunteers were administered ALVAC-HIV or placebo by intramuscular injection (IM), intradermal injection (ID) or subcutaneous injection (SQ) of autologous ex vivo transfected DC at months 0, 1, 3 and 6. All vaccine delivery routes were well tolerated. Binding antibodies were observed to both the ALVAC vector and HIV-1 gp160 proteins. Modest cellular responses were observed in 2/7 individuals in the DC arm and 1/8 in the IM arm as determined by IFN-γ ELISPOT. Proliferative responses were most frequent in the DC arm where 4/7 individuals had measurable responses to multiple HIV-1 antigens. Loading DC after maturation resulted in lower gene expression, but overall better responses to both HIV-1 and control antigens, and were associated with better IL-2, TNF-α and IFN-γ production.Conclusions/Significance
ALVAC-HIV delivered IM, ID or SQ with autologous ex vivo transfected DC proved to be safe. The DC arm was most immunogenic. Proliferative immune responses were readily detected with only modest cytotoxic CD8 T cell responses. Loading mature DC with the live viral vaccine induced stronger immune responses than loading immature DC, despite increased transgene expression with the latter approach. Volunteers who received the autologous vaccine loaded mature DC developed a broader and durable immune response compared to those vaccinated by conventional routes.Trial Registration
ClinicalTrials.gov NCT00013572相似文献12.
Mar Orzáez Mónica Sancho Sandra Marchán Laura Mondragón Rebeca Montava Juan García Valero Olatz Landeta Gorka Basa?ez Rodrigo J. Carbajo Antonio Pineda-Lucena Jordi Bujons Alejandra Moure Angel Messeguer Carmen Lagunas Carmen Herrero Enrique Pérez-Payá 《PloS one》2014,9(10)
Background
Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need.Methodology and Principal Findings
The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia.Conclusions
Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases. 相似文献13.
Background
Candida albicans is a low level commensal organism in normal human populations with the continuous potential to expand and cause a spectrum of clinical conditions.Methodology/Principal Findings
Using ex vivo human organ cultures and populations of primary human cells, we have developed several related experimental systems to examine early-stage interactions between C. albicans and mucosal surfaces. Experiments have been conducted both with exogenously added C. albicans and with overtly normal human mucosal surfaces supporting pre-existing infections with natural isolates of Candida. Under different culture conditions, we have demonstrated the formation of C. albicans colonies on human target cells and filament formation, equivalent to tissue invasion.Conclusions/Significance
These organ culture systems provide a valuable new resource to examine the molecular and cellular basis for Candida colonization of human mucosal surfaces. 相似文献14.
Li-Jen Su Chia-Chuan Chang Chih-Hsueh Yang Shur-Jong Hsieh Yi-Chin Wu Jin-Mei Lai Tzu-Ling Tseng Chi-Ying F. Huang Shih-Lan Hsu 《PloS one》2013,8(1)
Background
Graptopetalum paraguayense (GP) is a folk herbal medicine with hepatoprotective effects that is used in Taiwan. The aim of this study was to evaluate the hepatoprotective and antifibrotic effects of GP on experimental hepatic fibrosis in both dimethylnitrosamine (DMN)- and carbon tetrachloride (CCl4)-induced liver injury rats.Methods
Hepatic fibrosis-induced rats were fed with the methanolic extract of GP (MGP) by oral administration every day. Immunohistochemistry, biochemical assays, and Western blot analysis were performed. The effects of MGP on the expression of fibrotic markers and cytokines in the primary cultured hepatic stellate cells (HSCs) and Kupffer cells, respectively, were evaluated.Results
Oral administration of MGP significantly alleviated DMN- or CCl4-induced liver inflammation and fibrosis. High levels of alanine transaminase, aspartate transaminase, bilirubin, prothrombin activity and mortality rates also decreased in rats treated with MGP. There were significantly decreased hydroxyproline levels in therapeutic rats compared with those of the liver-damaged rats. Collagen I and alpha smooth muscle actin (α-SMA) expression were all reduced by incubation with MGP in primary cultured rat HSCs. Furthermore, MGP induced apoptotic cell death in activated HSCs. MGP also suppressed lipopolysaccharide-stimulated rat Kupffer cell activation by decreasing nitric oxide, tumor necrosis factor-α and interleukin-6 production, and increasing interleukin-10 expression.Conclusions
The results show that the administration of MGP attenuated toxin-induced hepatic damage and fibrosis in vivo and inhibited HSC and Kupffer cell activation in vitro, suggesting that MGP might be a promising complementary or alternative therapeutic agent for liver inflammation and fibrosis. 相似文献15.
16.
Jolice P. van den Berg Elisabeth A. M. Westerbeek Fiona R. M. van der Klis Guy A. M. Berbers Harrie N. Lafeber Ruurd M. van Elburg 《PloS one》2013,8(8)
Background
In preterm infants, a decreased immunological response and lower serological effectiveness are observed after immunizations due to ineffectiveness of both humoral and cellular immune mechanisms.Objective
To determine the effect of 80% neutral oligosaccharides [small-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS)] in combination with 20% pectin-derived acidic oligosaccharides (pAOS) on antibody concentrations after DTaP-IPV-Hib immunization in preterm infants.Design
In this randomized clinical trial, preterm infants with gestational age <32 weeks and/or birth weight <1500 g received enteral supplementation with scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Blood samples were collected at 5 and 12 months of age.Results
In total, 113 infants were included. Baseline and nutritional characteristics were not different in both groups. Geometric mean titers were not different after prebiotic supplementation at 5 months, Ptx (37/44 EU/ml), FHA (78/96 EU/ml), Prn (78/80 EU/ml), Diphtheria (0.40/0.57 IU/ml), Tetanus (0.74/0.99 IU/ml) and Hib (0.35/0.63 µg/ml), and at 12 months Ptx (55/66 EU/ml), FHA (122/119 EU/ml), Prn (116/106 Eu/ml), Diphtheria (0.88/1.11 IU/ml), Tetanus (1.64/1.79 IU/ml) and Hib (2.91/2.55 µg/ml).Conclusions
Enteral supplementation of neutral (scGOS/lcFOS) and acidic oligosaccharides (pAOS) does not improve the immunization response in preterm infants.Trial Registration
Controlled-Trials.com ISRCTN16211826 ISRCTN16211826 相似文献17.
18.
Antibody responses against xenotropic murine leukemia virus-related virus envelope in a murine model
Makarova N Zhao C Zhang Y Bhosle S Suppiah S Rhea JM Kozyr N Arnold RS Ly H Molinaro RJ Parslow TG Hunter E Liotta D Petros J Blackwell JL 《PloS one》2011,6(4):e18272
Background
Xenotropic murine leukemia virus-related virus (XMRV) was recently discovered to be the first human gammaretrovirus that is associated with chronic fatigue syndrome and prostate cancer (PC). Although a mechanism for XMRV carcinogenesis is yet to be established, this virus belongs to the family of gammaretroviruses well known for their ability to induce cancer in the infected hosts. Since its original identification XMRV has been detected in several independent investigations; however, at this time significant controversy remains regarding reports of XMRV detection/prevalence in other cohorts and cell type/tissue distribution. The potential risk of human infection, coupled with the lack of knowledge about the basic biology of XMRV, warrants further research, including investigation of adaptive immune responses. To study immunogenicity in vivo, we vaccinated mice with a combination of recombinant vectors expressing codon-optimized sequences of XMRV gag and env genes and virus-like particles (VLP) that had the size and morphology of live infectious XMRV.Results
Immunization elicited Env-specific binding and neutralizing antibodies (NAb) against XMRV in mice. The peak titers for ELISA-binding antibodies and NAb were 1∶1024 and 1∶464, respectively; however, high ELISA-binding and NAb titers were not sustained and persisted for less than three weeks after immunizations.Conclusions
Vaccine-induced XMRV Env antibody titers were transiently high, but their duration was short. The relatively rapid diminution in antibody levels may in part explain the differing prevalences reported for XMRV in various prostate cancer and chronic fatigue syndrome cohorts. The low level of immunogenicity observed in the present study may be characteristic of a natural XMRV infection in humans. 相似文献19.
Ann R. Hunt Shana Frederickson Toshiaki Maruyama John T. Roehrig Carol D. Blair 《PLoS neglected tropical diseases》2010,4(7)
Background
Venezuelan equine encephalitis virus (VEEV) is responsible for VEE epidemics that occur in South and Central America and the U.S. The VEEV envelope contains two glycoproteins E1 (mediates cell membrane fusion) and E2 (binds receptor and elicits virus neutralizing antibodies). Previously we constructed E1 and E2 epitope maps using murine monoclonal antibodies (mMAbs). Six E2 epitopes (E2c,d,e,f,g,h) bound VEEV-neutralizing antibody and mapped to amino acids (aa) 182–207. Nothing is known about the human antibody repertoire to VEEV or epitopes that engage human virus-neutralizing antibodies. There is no specific treatment for VEE; however virus-neutralizing mMAbs are potent protective and therapeutic agents for mice challenged with VEEV by either peripheral or aerosol routes. Therefore, fully human MAbs (hMAbs) with virus-neutralizing activity should be useful for prevention or clinical treatment of human VEE.Methods
We used phage-display to isolate VEEV-specific hFabs from human bone marrow donors. These hFabs were characterized by sequencing, specificity testing, VEEV subtype cross-reactivity using indirect ELISA, and in vitro virus neutralization capacity. One E2-specific neutralizing hFAb, F5n, was converted into IgG, and its binding site was identified using competitive ELISA with mMAbs and by preparing and sequencing antibody neutralization-escape variants.Findings
Using 11 VEEV-reactive hFabs we constructed the first human epitope map for the alphaviral surface proteins E1 and E2. We identified an important neutralization-associated epitope unique to the human immune response, E2 aa115–119. Using a 9 Å resolution cryo-electron microscopy map of the Sindbis virus E2 protein, we showed the probable surface location of this human VEEV epitope.Conclusions
The VEEV-neutralizing capacity of the hMAb F5 nIgG is similar to that exhibited by the humanized mMAb Hy4 IgG. The Hy4 IgG has been shown to limit VEEV infection in mice both prophylactically and therapeutically. Administration of a cocktail of F5n and Hy4 IgGs, which bind to different E2 epitopes, could provide enhanced prophylaxis or immunotherapy for VEEV, while reducing the possibility of generating possibly harmful virus neutralization-escape variants in vivo. 相似文献20.
Hong-Sheng Wang Zhuo-Jia Chen Ge Zhang Xue-Ling Ou Xiang-Ling Yang Chris K. C. Wong John P. Giesy Jun Du Shou-Yi Chen 《PloS one》2012,7(10)