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PubMed2004

Apoptosis signaling triggered by the marine alkaloid ascididemin is routed via caspase-2 and JNK to mitochondria.

The marine alkaloid ascididemin (ASC) was shown to exert cytotoxicity even against multidrug-resistant cancer cells. Here, we address the signaling pathways utilized by ASC to trigger apoptosis in Jurkat leukemia T cells. We show that ASC (0.5-20 microM) induces a mitochondrial pathway that requires the activation of the initiator caspase-2 upstream of mitochondria. ASC-triggered apoptosis occurred independent of CD95, but required mitochondrial dysfunction. The activation of caspase-2 was shown to precede the processing of caspase-8, -9 and -3. The specific caspase-2 inhibitor zVDVADfmk abrogated ASC-induced DNA fragmentation almost completely. Overexpression of Bcl-x(L) blocked caspase-8 but not caspase-2 processing. Conversely, caspase-2 inhibition strongly reduced caspase-9 activation. As a possible link between caspase-2 and mitochondrial dysfunction, Bid was found to be cleaved by ASC. In addition, JNK was activated by ASC upstream of mitochondria via reactive oxygen species. The specific JNK inhibitor SP600125 partially inhibited caspase-2 and -9 processing as well as cytochrome c release and DNA fragmentation indicating that JNK contributes to, but is not necessary for ASC-mediated apoptosis. Thus, ASC triggers a pathway in which early activation of caspase-2 provides a possible link between its DNA-damaging activity and the induction of mitochondrial dysfunction. The activation of JNK contributes to this signaling upstream of mitochondria.

Alkaloids↗

PubMed1998

Immunomodulation induced by Ascaris suum extract in mice: effect of anti-interleukin-4 and anti-interleukin-10 antibodies.

Simultaneous immunization of mice with an Ascaris suum extract (Asc) and ovalbumin (OA) markedly affects the immune response to OA. The role of interleukin (IL)-4 and IL-10 induced by Asc immunization on the modulation of antigen-specific and mitogen-induced responses was investigated following single or combined cytokine-specific monoclonal antibody (MoAb) treatment of mice before immunization with OA + Asc. Immediate hypersensitivity reactions to aggregated OA and OA-specific immunoglobulin (Ig)G2a antibody production were completely restored only when both IL-4 and IL-10 were neutralized. These findings were associated with enhanced interferon (IFN)-gamma secretion by OA-stimulated lymph node (LN) cells. In addition, the Asc-specific cytokine response in anti-IL-4 plus anti-IL-10 MoAb treated mice was shifted towards a Th1 phenotype, with an increase in IFN-gamma and IL-2 levels and a decrease in IL-4, but not in IL-10, levels. Consequently, Asc-specific IgG2a antibody production increased, whereas IgE titres diminished in these animals. These results indicate that IL-4 and IL-10 act together in the Asc-induced mechanism of antigen-specific pansuppression. In contrast, modulation of Concanavalin A (Con A)-induced cytokine responses in Asc-immunized mice appears to be essentially mediated by an IL-4-dependent mechanism, since the neutralization of just IL-4 (and not of IL-10), either in vivo or in vitro, changed the cytokine profile from a Th2 towards a Th1 type. However, OA and Asc-specific cell responses were not modified by either anti-IL-4 or by anti-IL-4 + anti-IL-10 MoAbs in vitro treatments, suggesting that the induction of a Th2 response to Asc components concomitant to OA immunization has a strong suppressive effect on the priming stage of OA-specific Th1 type response.

Adjuvants, Immunologic↗

PubMed1999

Protection against UV-induced systemic immunosuppression in mice by a single topical application of the antioxidant vitamins C and E.

PURPOSE: Reactive oxygen species are involved in UV-induced suppression of the immune system. Topical treatment with the antioxidant vitamins C (L-ascorbic acid, ASC) and E (D-alpha-tocopherol, TOC) can support the endogenous antioxidant defence system and prevent immunosuppression. MATERIALS AND METHODS: Mice were topically treated with a single dose of ASC, TOC or a combination and irradiated with UVB. Then systemic immunosuppression was measured using a model based on the induction of a contact hypersensitivity response to dinitrofluorobenzene. To investigate the mechanism of protection, cis-urocanic acid-induced immunosuppression was investigated in a different contact hypersensitivity model measuring local immunosuppression. The levels of ASC and TOC in the epidermis were determined by HPLC. RESULTS: Both ASC and TOC prevented UV-induced suppression of the contact hypersensitivity response. TOC was effective at doses of 2.5 to 10 nmol/cm2 and ASC at 0.5 to 5 micromol/cm2. At the highest dose, the response in the ASC-treated mice was no longer significantly different from that in the positive control group. Contrary to expectations, combinations of the two compounds did not provide additional protection. The experiments with ASC or TOC against immunosuppression by cis-urocanic acid also yielded protection, but this was less efficient than against UV. The concentrations of ASC and TOC in the epidermis were so low that UVB absorption could be excluded as the cause of the protection. CONCLUSIONS: ASC and TOC can be used to prevent systemic UV-induced immunosuppression. They are effective at relatively low doses after a single topical application prior to the irradiation.

Animals↗

PubMed1980

Meiosis in Neurospora crassa. I. The isolation of recessive mutants defective in the production of viable ascospores.

A scheme has been devised for efficient isolation of recessive meiotic mutants of Neurospora crassa. These mutants were detected by their reduced fertility or by the abortion of ascospores. Their isolation involved the selection and screening of the strains arising from ascospores disomic (n + 1) for linkage group I (LG I), which bears the mating-type locus. These strains are self-fertile heterokaryons that contain two types of haploid nuclei of opposite mating types (A + a). Selfings of these strains are homozygous for genes on all linkage groups except LGI and therefore allow the expression of recessive mutants with an altered sexual cycle. Using this selection procedure, three classes of mutants were detected. In one class, mutants had an early block in perithecial development (class I), and in another mutants had altered perithecia, but apparently unaltered fertility (class III). No recessive mutants were observed and all mutants tested (eight of class I and two of class III) were expressed only when used as the maternal parent. A third mutant class displayed normal production of perithecia, but defective formation of asci (class IIA), or black ascospores (class IIB). Four of 13 class IIA mutants were analyzed, and two of them [asc(DL131) and asc (DL400)] were definitely recessive analysis of 10 of 13 class IIB mutants disclosed six recessive, mutually complementing mutants: ase(DL95), asc(DL243), asc(DL711), asc(DL879), asc(DL917m) and asc(DL961). Mutants asc(DL95), asc(DL243) and the previously studied mei-1 mutant (Smith 1975) complemented one another in crosses, but did not recombine. These may be alleles of the same gene, or they may comprise a gene cluster.

Crosses, Genetic↗

PubMed1995

Uteroferrin induces lipid peroxidation in endometrial and conceptus microsomal membranes and is inhibited by apotransferrin, retinol binding protein, and the uteroferrin-associated proteins.

Iron-containing proteins catalyze lipid peroxidation when combined with either H2O2 or ascorbic acid (ASC). Microsomal membranes were prepared from Day 13 endometrial and conceptus tissues (5 pigs) and from Day 30 endometrial, placental, fetal liver, and fetus minus fetal liver tissues (5 pigs). Microsomal membranes were subjected to the following in vitro treatments: 1) no treatment, 2) 50 microM ASC, 3) 100 microM uteroferrin (UF), 4) 50 microM ASC + 100 microM UF, 5) 50 microM ASC + 100 microM UF + 10 microM apotransferrin (transferrin with no iron bound; ATF), and 6) 50 microM ASC + 100 microM UF + 10 microM holotransferrin (transferrin saturated with iron; HTF). For treatments 7 through 10, membranes were preincubated (0 degrees C, 3 h) with either 7) no treatment, 8) 50 microM fetuin, 9) 50 microM holoretinol binding protein (holoRBP: retinol binding protein [HoloRBP] with retinol bound), or 10) 50 microM apoRBP (RBP with no retinol bound) followed by incubation with 50 microM ASC + 100 microM UF. Lipid peroxidation was measured in the samples as thiobarbituric acid reactive substances (TBARS). Endogenous TBARS were greater (p < 0.05) in Day 13 conceptus than in Day 13 endometrium and were highest (p < 0.05) on Day 30 in fetal liver. Combined ASC and UF caused a large increase (p < 0.05) in TBARS in all membranes except Day 30 placental membranes. Addition of ATF, but not HTF, decreased TBARS production in all membrane preparations. HoloRBP, but not fetuin or apoRBP, decreased (p < 0.05) TBARS production in all but Day 30 endometrial membranes. In other experiments, when combined with ASC, UF/UF-associated protein complex induced less (p < 0.01) lipid peroxidation in fetal liver microsomal membranes than did free UF. Catalase and superoxide dismutase had no effect on UF-induced lipid peroxidation in fetal liver membranes. These results indicate that 1) UF combined with ASC induces lipid peroxidation in Day 13 endometrial and conceptus and Day 30 endometrial, fetal liver, and fetus minus liver microsomal membranes, and 2) ATF, holoRBP, and the UF-associated proteins, but not catalase or superoxide dismutase, inhibit this reaction.

Acid Phosphatase↗

PubMed1999

Pneumococcal conjugate vaccination in toddlers: mucosal antibody response measured as circulating antibody-secreting cells and as salivary antibodies.

BACKGROUND: Our previous studies have shown an antibody-secreting cell (ASC) response to pneumococcal vaccines in adults and suggested that a high IgA ASC response is an indicator of a secretory IgA response in saliva. We believe that the mucosal immune response is potentially an important characteristic of the pneumococcal vaccines and should thus be measured when the new pneumococcal conjugate vaccines are evaluated. OBJECTIVES: To study mucosal and serum antibody responses to pneumococcal conjugate vaccines in toddlers. METHODS: Each investigational vaccine, containing either 3 or 10 microg of pneumococcal PS serotypes 6B, 14, 19F and 23F conjugated to either diphtheria toxoid (PncD) or tetanus protein (PncT), was administered to 10 children (a total of 40 children). The ASC response was measured on Day 7 after immunization by enzyme-linked immunospot assay, and the salivary and serum antibodies were measured before and 7 and 28 days after the immunization by enzyme immunoassay. RESULTS: The vaccines studied induced ASC responses to the pneumococcal polysaccharides (PS) in all children vaccinated. The ASC responses to the PS components of the vaccine (the geometric mean number of ASCs varying from 120 to 160 ASC/10(6) cells) were lower than those seen earlier in adults after conjugate vaccine (240 to 2015 ASC/10(6) cells), but comparable with those seen earlier in adults after pneumococcal PS vaccine (113 to 136 ASC/10(6) cells). The ASC response was clearly dominated by IgA-secreting cells. Salivary IgA responses were detected in 35% of the children, but IgG was rarely detected in saliva. A positive correlation was demonstrated between the number of IgA ASCs and salivary IgA concentration (r = 0.70, P = 0.01), suggesting that a high number of IgA ASCs after parenteral immunization is an indicator of a secretory IgA response in saliva. On Day 28 after immunization increased serum concentrations of IgG were detected in most vaccinees (75 to 95%, depending on the serotype). CONCLUSIONS: Both mucosal and systemic antibody responses were induced by PncD and PncT vaccines in toddlers.

Antibodies, Bacterial↗

PubMed1994

Intestinal and circulating antibody-forming cells in IgA-deficient individuals after oral cholera vaccination.

In search for a possible explanation for the different susceptibility to mucosal infections in IgA-deficient (IgAd) individuals, the frequency of total immunoglobulin-secreting cells (ISC) and vaccine-specific antibody-secreting cells (ASC) in intestinal mucosa and peripheral blood was determined by the enzyme-linked immunospot (ELISPOT) assay before and after peroral vaccination with a B subunit-whole cell cholera vaccine. Two groups of IgAd individuals, frequently infected and non-infected respectively, and normal controls were studied. Before cholera vaccination there were significantly higher frequencies of total IgM and IgG ISC in the gut, but not in the blood, in the IgAd individuals than in the controls. However, there were no significant differences between healthy and infection-prone IgAd individuals in this respect. In response to oral cholera vaccination, intestinal cholera toxin (CT)-specific IgG and IgM ASC were significantly more abundant among the IgAd individuals with a history of frequent infections than among the healthy IgAd individuals and controls. A similar difference in IgG and IgM ASC, although not significant, was also noted in blood. In IgAd individuals with frequent infections the vaccine induced variable anti-CT IgM ASC responses in the gut, ranging from no increase to a few strikingly high responses. In the controls, the CT-specific responses were dominated by IgA ASC. The data show that oral cholera vaccination evoked strong CT-specific IgG ASC responses, and in some cases also strong IgM ASC responses in the intestinal mucosa of IgAd patients with a history of frequent infections. The healthy IgAd individuals unexpectedly responded with lower numbers of CT-specific IgG ASC and did not show any increase of CT-specific IgM ASC in the intestinal mucosa. Thus, inability to mount a mucosal immune response to an oral antigen cannot in itself explain recurrent infections among many IgAd individuals.

Administration, Oral↗

PubMed1997

The comparative effect of acidified sodium chlorite and chlorhexidine mouthrinses on plaque regrowth and salivary bacterial counts.

Acidified sodium chlorite (ASC) is recognised as a highly potent, broad spectrum antimicrobial system that has been successfully developed for uses in veterinary, food processing and medical device fields. The current studies aimed to investigate the persistence of antimicrobial action and plaque inhibitory properties of 3 ASC mouthrinses by comparison with positive control, chlorhexidine 0.12%, and placebo control, water, rinses. Both studies were randomised, double-blind, cross-over 5-cell designs balanced for carryover. The 1st study involved 15 healthy subjects who immediately before and at 30, 60, 180, 300 and 420 min after rinsing provided 2 ml saliva samples. The samples were immediately processed for total anaerobic bacterial counts recorded after 96 h incubation. Washout periods were a minimum of 3 days. The second study involved 20 healthy subjects who on day 1 of each study were rendered plaque free, suspended normal oral hygiene methods and commenced rinsing twice daily with the allocated rinse. On day 5, plaque was scored by index and area after disclosing with erythrosin. Washout periods were 2 1/2 days. The 3 ASC and chlorhexidine rinses produced similar reductions in salivary bacterial counts which remained significantly below the placebo control to 7 h. There were no significant differences between ASC and chlorhexidine rinses except at 30 and 60 min when significantly greater reductions were produced by 2 ASC rinses compared to the chlorhexidine rinse. Plaque indices and areas were considerably and significantly lower with the ASC and chlorhexidine rinses compared to the placebo rinse. There were no significant differences between plaque scores for the 3 ASC rinses and the chlorhexidine rinse, although for 2 ASC rinses plaque scores were lower than for the chlorhexidine rinse. The results indicate that the 3 ASC rinses have equivalent plaque inhibitory action to chlorhexidine as a rinse. Similar to chlorhexidine, the plaque inhibitory action of the rinses appears to be derived from a persistence of antimicrobial action in the mouth.

Anti-Infective Agents, Local↗

PubMed1998

Specific-antibody-secreting cells in the rectums and genital tracts of nonhuman primates following vaccination.

To determine optimal strategies to induce specific-antibody-secreting cells (specific ASC) in the rectal and vaginal mucosae, we immunized monkeys with a prototype mucosal immunogen, cholera toxin (CT), given locally or via gastric or parenteral administration. Repeated rectal or vaginal CT immunizations induced strong mucosal and systemic ASC responses. The mucosal responses were, however, confined to the immunization sites and comprised high levels of both specific antitoxin immunoglobulin A (IgA) and IgG. Large numbers of specific IgA and IgG ASC were detected in cell suspensions from dissociated genital and rectal tissues, demonstrating local accumulation of effector B cells at these sites. Intragastric immunization with CT did not per se give rise to cervicovaginal or rectal ASC responses but did prime for a rectal IgA ASC response to local booster immunization. Both rectal and vaginal immunizations also induced circulating blood IgG ASC and IgA ASC. In conclusion, these results show that local administration of antigen to the rectal or vaginal mucosa results in higher ASC responses than systemic or distant mucosal delivery. Furthermore, both the vaginal and the rectal mucosae can serve as inductive sites for systemic ASC responses. These observations should be relevant to the development of vaccines against sexually transmitted diseases such as that caused by human immunodeficiency virus.

Administration, Intranasal↗

PubMed2004

BTS randomised feasibility study of active symptom control with or without chemotherapy in malignant pleural mesothelioma: ISRCTN 54469112.

BACKGROUND: The incidence of mesothelioma is rising rapidly in the UK. There is no generally accepted standard treatment. The BTS recommends active symptom control (ASC). It is not known whether chemotherapy in addition prolongs survival or provides worthwhile palliation with acceptable toxicity. Palliation as recorded by patients has been fully reported for only two regimens: mitomycin, vinblastine, and cisplatin (MVP), and vinorelbine (N). The BTS and collaborators planned to conduct a phase III randomised trial comparing ASC only, ASC+MVP, and ASC+N in 840 patients with survival as the primary outcome measure. The aim of the present study was to assess the acceptability of the trial design to patients and the suitability of two standard quality of life (QL) questionnaires for mesothelioma. METHODS: Collaborating centres registered all new patients with mesothelioma. Those eligible and giving informed consent completed EORTC QLQ-C30+LC13 and FACT-L QL questionnaires and were randomised between all three or any two of (1) ASC only, (2) ASC+4 cycles of MVP, and (3) ASC+12 weekly doses of N. RESULTS: During 1 year, 242 patients were registered of whom 109 (45%) were randomised (55% of the 197 eligible patients). Fifty two patients from 20 centres were randomised to an option including ASC only. This translates into a rate of 312 per year from 60 centres interested in collaborating in the phase III trial. The EORTC QL questionnaire was superior to FACT-L in terms of completeness of data and patient preference. Clinically relevant palliation was achieved with ASC. CONCLUSION: The planned phase III trial is feasible.

Adult↗

PubMed1974

A serum component related to nonimmunoglobulin amyloid protein AS, a possible precursor of the fibrils.

A nonimmunoglobulin protein with the molecular weight of 9,145 (protein AS) has been shown to be a principal component of the amyloid fibrils in different clinical types of amyloidosis. A protein component, antigenically closely related to protein AS, was detected in human sera. The protein AS-related component (protein ASC) was found in the sera of many groups of patients, including 48 out of 55 patients with various clinical types of amyloidosis. No structural relationship of protein ASC to the plasma component of amyloid was found. Protein ASC was also present with high frequency in the serum of diseases known to be frequently complicated by amyloidosis. In some cases, ASC was found in the sera of patients 2-3 yr before the diagnosis of amyloidosis was established. Protein ASC was also frequently found in hypogammaglobulinemia. Among normal individuals, protein ASC was seldom detected in the serum by our techniques, but there was a noticeable increase with age and during pregnancy. Moreover, a more sensitive technique, immunoelectro-osmophoresis, revealed protein ASC in a higher number of sera from both patients and normal controls. Thus protein ASC was suggested to be a normal serum constituent, usually present only in minor quantities. Under certain conditions, protein ASC increases considerably in serum, and may in such instances act as a precursor for the deposition of amyloid fibrils in the tissues.

Adult↗

PubMed2001

Expression of apoptosis-associated speck-like protein containing a caspase recruitment domain, a pyrin N-terminal homology domain-containing protein, in normal human tissues.

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a pyrin N-terminal homology domain (PYD)- and caspase recruitment domain (CARD)-containing a proapoptotic molecule. This molecule has also been identified as a target of methylation-induced silencing (TMS)-1. We cloned the ASC cDNA by immunoscreening using an anti-ASC monoclonal antibody. In this study, we determined the binding site of the anti-ASC monoclonal antibody on ASC and analyzed the expression of ASC in normal human tissues. ASC expression was observed in anterior horn cells of the spinal cord, trophoblasts of the placental villi, tubule epithelium of the kidney, seminiferous tubules and Leydig cells of the testis, hepatocytes and interlobular bile ducts of the liver, squamous epithelial cells of the tonsil and skin, hair follicle, sebaceous and eccrine glands of the skin, and peripheral blood leukocytes. In the colon, ASC was detected in mature epithelial cells facing the luminal side rather than immature cells located deeper in the crypts. These observations indicate that high levels of ASC are abundantly expressed in epithelial cells and leukocytes, which are involved in host defense against external pathogens and in well-differentiated cells, the proliferation of which is regulated.

Animals↗

PubMed2002

A switch in dehydrogenase to reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells.

As exemplified in patients with Cushing's syndrome, glucocorticoids play an important role in regulating adipose tissue distribution and function, but circulating cortisol concentrations are normal in most patients with obesity. However, human omental adipose stromal cells (ASCs) can generate glucocorticoid locally through the expression of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 1 (11 beta-HSD1), which, in intact cells, has been considered to be an oxoreductase, converting inactive cortisone (E) to cortisol (F). Locally produced F can induce ASC differentiation, but the relationship between 11 beta-HSD1 expression and adipocyte differentiation is unknown. Primary cultures of paired omental (om) and sc ASC and adipocytes were prepared from 17 patients undergoing elective abdominal surgery and cultured for up to 14 d. Expression and activity of 11 beta-HSD isozymes were analyzed together with early (lipoprotein lipase) and terminal (glycerol 3 phosphate dehydrogenase) markers of adipocyte differentiation. On d 1 of culture, 11 beta-HSD1 activity in intact om ASCs exceeded oxoreductase activity in every patient (78.9 +/- 24.9 vs. 15.8 +/- 3.7 [mean +/- SE] pmol/mg per hour, P < 0.001), and in sc ASCs, relative activities were similar (40.6 +/- 12.2 vs. 36.9 +/- 8.8). Conversely, in freshly isolated om adipocytes, reductase activity exceeded dehydrogenase activity (23.6 +/- 1.5 vs. 6.2 +/- 0.8 pmol/mg per hour, P < 0.01). Following 14 d of culture in serum-free conditions with addition of 10 nM insulin (Ctr) or insulin with 100 nM F (+F), lipoprotein lipase/18S RNA levels increased in both the Ctr- and +F-treated ASCs, but glycerol 3 phosphate dehydrogenase increased only in the +F cultures. In both cases, however, 11 beta-HSD1 oxoreductase activity exceeded dehydrogenase activity (Ctr: 53.3 +/- 9.0 vs. 32.4 +/- 10.5, P < 0.05; +F: 65.6 +/- 15.6 vs. 37.1 +/- 11.5 pmol/mg per hour, P < 0.05), despite no significant changes in 11 beta-HSD1 mRNA levels. In sc ASCs, dehydrogenase activity was similar to reductase activity in both Ctr- and +F-treated cells. Type 2 11 beta-HSD expression was undetectable in each case. These data show that in intact, undifferentiated om ASCs, 11 beta-HSD1 acts primarily as a dehydrogenase, but in mature adipocytes oxoreductase activity predominates. Because glucocorticoids inhibit cell proliferation, we postulate that 11 beta-HSD1 activity in uncommitted ASCs may facilitate proliferation rather than differentiation. Once early differentiation is initiated, a "switch" to 11 beta-HSD1 oxoreductase activity generates F, thus promoting adipogenesis. Site-specific regulation of the set-point of 11 beta-HSD1 activity may be an important mechanism underpinning visceral obesity.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed2002

PELA microspheres loaded H. pylori lysates and their mucosal immune response.

AIM: To prepare poly (D,L-lactide)-polyethylene glycol copolymer (PELA) microspheres loaded H.pylori lysates or Cystografin and observe their targeting in gastrointestinal mucous membrane or analyze the mucosal immune responses by oral administration. METHODS: PELA microspheres loaded H.pylori lysates or Cystografin were prepared by double emulsion evaporation method. Their distribution in gastrointestinal mucous membrane was observed by CT. Balb/c mice orally immunized in mucosal immune responses, whose antibody production in salivary and gut washing and antibody secreting cells in Peyer's patches (PP) were estimated by ELISA and ELISPOT, respectively. The microspheres physical properties, such as particle size, protein level and morphology were investigated. RESULTS: All prepared microspheres were found to have a smooth surface morphology from 3.20-4.05 microm in diameter and high encapsulation efficiency from 74.9-82.2 %. No significant correlation in their physical properties was shown, depending on their molecular weight at the similar composition ratio. Immunization with all types of PELA-Hp microspheres elevated the saliva sIgA level at week 3 by approximately 3-4 times that with soluble antigen, which was greatly enhanced after boosting. At one week after last immunization with all types of PELA-Hp microspheres (week 8), the specific sIgA-ASCs, IgG-ASCs and sIgA in salivary rose obviously. In intestinal Peyer's patches, the specific sIgA-ASCs were 5.92-6.98X10(4)/ml cell and IgG-ASCs were 3.47-4.02X10(4)/ml cell, about 5-9 times higher than those with soluble antigen (P<0.01). ASCs in intestine were more than those in stomach and the majority of the ASCs were sIgA-ASCs. The sIgA in gut washing fluid was 1.62-1.85 OD, about 3-6 times tthat of those with soluble antigen. There were significant differences of the ASCs and sIgA in gut washing fluid as compared with those of PBS and MS-0 (P<0.05). There appeared to be good correlation between sIgA level in gut washing fluid and sIgA-ASCs in intestinal Peyer's patches. CONCLUSION: PELA microspheres may be used as vehicle to delivery antigen and adjuvant in designing oral vaccination.

Administration, Oral↗

PubMed2004

CC chemokine ligands 25 and 28 play essential roles in intestinal extravasation of IgA antibody-secreting cells.

CCL25 (also known as thymus-expressed chemokine) and CCL28 (also known as mucosae-associated epithelial chemokine) play important roles in mucosal immunity by recruiting IgA Ab-secreting cells (ASCs) into mucosal lamina propria. However, their exact roles in vivo still remain to be defined. In this study, we first demonstrated in mice that IgA ASCs in small intestine expressed CCR9, CCR10, and CXCR4 on the cell surface and migrated to their respective ligands CCL25, CCL28, and CXCL12 (also known as stromal cell-derived factor 1), whereas IgA ASCs in colon mainly expressed CCR10 and CXCR4 and migrated to CCL28 and CXCL12. Reciprocally, the epithelial cells of small intestine were immunologically positive for CCL25 and CCL28, whereas those of colon were positive for CCL28 and CXCL12. Furthermore, the venular endothelial cells in small intestine were positive for CCL25 and CCL28, whereas those in colon were positive for CCL28, suggesting their direct roles in extravasation of IgA ASCs. Consistently, in mice orally immunized with cholera toxin (CT), anti-CCL25 suppressed homing of CT-specific IgA ASCs into small intestine, whereas anti-CCL28 suppressed homing of CT-specific IgA ASCs into both small intestine and colon. Reciprocally, CT-specific ASCs and IgA titers in the blood were increased in mice treated with anti-CCL25 or anti-CCL28. Anti-CXCL12 had no such effects. Finally, both CCL25 and CCL28 were capable of enhancing alpha4 integrin-dependent adhesion of IgA ASCs to mucosal addressin cell adhesion molecule-1 and VCAM-1. Collectively, CCL25 and CCL28 play essential roles in intestinal homing of IgA ASCs primarily by mediating their extravasation into intestinal lamina propria.

Animals↗

PubMed2000

Acidified sodium chlorite antimicrobial treatment of broiler carcasses.

An acidified sodium chlorite (ASC) solution was investigated for its antimicrobial effects on broiler carcasses processed under conditions similar to those used in U.S. commercial poultry facilities. Of particular interest was the ability of the ASC solution to reduce natural bioburden in a prechill procedure. A number of parameters such as pretreatment washing of carcasses with water (no wash versus water wash), ASC concentration (500, 850, and 1,200 ppm), method of application (spray versus dip), and method of acid activation (phosphoric acid versus citric acid) were explored to evaluate disinfection conditions. ASC dip solutions (18.9 liters) were freshly prepared for groups of five prechill eviscerated carcasses per treatment (n = 10 carcasses). ASC treatment was shown to be an effective method for significantly reducing naturally occurring microbial contamination on carcasses. Reductions following immersion dipping were demonstrated at all disinfectant concentrations for total aerobes (82.9 to 90.7%), Escherichia coli (99.4 to 99.6%), and total coliforms (86.1 to 98.5%). Additionally, testing showed that ASC solutions maintained stable pH and minimal chlorite ion concentration deviations throughout each treatment. The results of the parameter evaluations indicated that maximal antimicrobial activity was achieved in carcasses that were prewashed and then exposed to a 5-s dip in a solution containing phosphoric acid- or citric acid-activated ASC. At 1,200 ppm ASC, a mild but transitory whitening of the skin was noted on dipped carcasses. The results support the methods currently approved by the U.S. Department of Agriculture for the use of ASC solutions as a prechill antimicrobial intervention in U.S. poultry processing plants.

Animals↗

PubMed2005

Use of artificial skin constructs in permeation studies of clindamycin phosphate.

Penetration and permeation of topically applied substances may be studied in vitro either by using excised human and animal skin or with a 3-dimensional artificial skin construct (ASC). In the present study, ASC consisting of dermal and epidermal layers were cultivated with human dermal fibroblasts and spontaneously transformed human epidermal cells from the HaCaT-cell line. For comparative purposes the permeation barrier of ASC was also evaluated using a commercial skin model (AST-2000). Higher drug permeabilities were achieved with ASC in comparison with excised human stratum corneum (EHSC). The factors between permeation coefficients of ASC and EHSC depend on the respective drugs and also on different types of the formulation. Due to higher permeation coefficients obtained, the running time of the experiments could be reduced in the case of ASC. A further advantage of ASC is the independency of skin donations. Additionally, cultivation of ASC for the use in permeation studies is possible in advance, because storage conditions under nitrogen freezing do not affect ASC quality negatively.

Anti-Bacterial Agents↗

PubMed2006

Poor prognosis of patients with stage Ib1 adenosquamous cell carcinoma of the uterine cervix with pelvic lymphnode metastasis.

From January 1990 to December 2004, the prognosis of 28 patients with stage Ib1 adenosquamous cell carcinoma (ASC) were assessed in comparison with those of matched counterparts of pure adenocarcinoma (ADC) and squamous cell carcinoma (SCC). The mean ages were 46.6, 48.3, and 48.5 years for patients with ASC, ADC, and SCC, respectively. All the patients underwent radical hysterectomy with pelvic lymphadenectomy and postoperative adjuvant therapy was given to the patients with positive pathological risk. The incidence of lymph node metastasis for ASC at 21.4% was not significantly different from those for ADC (13.6%) and SCC (15.8%). There was also no significant difference in the incidence of lymphatic or vascular space involvement (LVSI) and depth of stromal invasion between three cell types. Since the tumor sizes of all ASC cases examined in this study were less than 4 cm, the prognoses were compared among stage Ib1 disease according to the classification system of the International Federation of Gynecology and Obstetrics (FIGO). The overall 5-year survival rates of stage Ib1 ASC, ADC, and SCC were 82.4%, 92.4%, and 94.0%, respectively, suggesting poor prognosis of ASC, but there was no significant difference. Patients with stage Ib1 ASC were retrospectively assigned to a low- or high-risk group based on the surgical-pathologic factors including positive lymph node metastasis, 2-4 cm of tumor size, positive LVSI, and/or deep stromal invasion. While all 9 patients in the low-risk group are alive without disease, 7 of the 19 patients in the high-risk group developed recurrence. The overall 5-year survival rates were 100% for a low risk group and 74.8% for a high-risk group, respectively, but this difference did not reach statistical significance. However, the prognosis of high-risk patients with lymph node metastasis was significantly (p=0.01) worse than low-risk group. The present study suggests that ASC histology appears to carry a poor prognosis than SCC, but low-risk group of stage Ib1 ASC has a good prognosis without postoperative adjuvant therapy.

Adenocarcinoma↗