Interleukin-10 (IL-10) mediated suppression of IL-12 production in RAW 264.7 cells also involves c-rel transcription factor

PubMed Central

Rahim, Sheikh Showkat; Khan, Nooruddin; Boddupalli, Chandra Sekhar; Hasnain, Seyed E; Mukhopadhyay, Sangita

2005-01-01

Interleukin-10 (IL-10) is known to inhibit IL-12 production in macrophages primarily at the transcriptional level with the involvement of p50 and p65 nuclear factor-κB (NF-κB). We demonstrate that the c-rel transcription factor also plays a major role in IL-10-mediated IL-12 suppression. Treatment of macrophages with recombinant IL-10 inhibited nuclear c-rel levels, whereas addition of neutralizing anti-IL-10 antibody up-regulated both nuclear c-rel levels and IL-12 production by macrophages. Decreased nuclear c-rel was associated with a reduction in phosphorylation of inhibitory kappa B alpha (IκBα) in the cytoplasm, indicating that IL-10 prevents degradation of IκBα and the subsequent translocation of c-rel into the nucleus. Treatment with leptomycin B, a known inhibitor of c-rel at a concentration of 10 nm, when used with anti-IL-10 antibody, resulted in reduced expression of IL-12. In a complementary experiment, in vitro transient expression of p65 NF-κB could not rescue the inhibitory effect of IL-10 on IL-12 production, suggesting that NF-κB alone was not sufficient to restore IL-12 production during IL-10 treatment. However, over-expression of c-rel resulted in IL-12 restoration upon stimulation with lipopolysaccharide plus interferon-γ during IL-10 treatment. Our studies highlight the involvement of c-rel in IL-10-mediated IL-12 regulation. PMID:15720433

Annual Versus Biannual Mass Azithromycin Distribution and Malaria Parasitemia During the Peak Transmission Season Among Children in Niger.

PubMed

Oldenburg, Catherine E; Amza, Abdou; Kadri, Boubacar; Nassirou, Beido; Cotter, Sun Y; Stoller, Nicole E; West, Sheila K; Bailey, Robin L; Porco, Travis C; Keenan, Jeremy D; Lietman, Thomas M; Gaynor, Bruce D

2018-06-01

Azithromycin has modest efficacy against malaria, and previous cluster randomized trials have suggested that mass azithromycin distribution for trachoma control may play a role in malaria control. We evaluated the effect of annual versus biannual mass azithromycin distribution over a 3-year period on malaria prevalence during the peak transmission season in a region with seasonal malaria transmission in Niger. Twenty-four communities in Matameye, Niger, were randomized to annual mass azithromycin distribution (3 distributions to the entire community during the peak transmission season) or biannual-targeted azithromycin distribution (6 distributions to children <12 years of age, including 3 in the peak transmission season and 3 in the low transmission season). Malaria indices were evaluated at 36 months during the high transmission season. Parasitemia prevalence was 42.6% (95% confidence interval: 31.7%-53.6%) in the biannual distribution arm compared with 50.6% (95% confidence interval: 40.3%-60.8%) in the annual distribution arm (P = 0.29). There was no difference in parasite density or hemoglobin concentration in the 2 treatment arms. Additional rounds of mass azithromycin distribution during low transmission may not have a significant impact on malaria parasitemia measured during the peak transmission season.

Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells

PubMed Central

2011-01-01

Background Peripheral-type benzodiazepine receptor (PBR) expression levels are low in normal human brain, but their levels increase in inflammation, brain injury, neurodegenerative states and gliomas. It has been reported that PBR functions as an immunomodulator. The mechanisms of action of midazolam, a benzodiazepine, in the immune system in the CNS remain to be fully elucidated. We previously reported that interleukin (IL)-1β stimulates IL-6 synthesis from rat C6 glioma cells and that IL-1β induces phosphorylation of inhibitory kappa B (IκB), p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription (STAT)3. It has been shown that p38 MAP kinase is involved in IL-1β-induced IL-6 release from these cells. In the present study, we investigated the effect of midazolam on IL-1β-induced IL-6 release from C6 cells, and the mechanisms of this effect. Methods Cultured C6 cells were stimulated by IL-1β. IL-6 release from C6 cells was measured using an enzyme-linked immunosorbent assay, and phosphorylation of IκB, the MAP kinase superfamily, and STAT3 was analyzed by Western blotting. Results Midazolam, but not propofol, inhibited IL-1β-stimulated IL-6 release from C6 cells. The IL-1β-stimulated levels of IL-6 were suppressed by wedelolactone (an inhibitor of IκB kinase), SP600125 (an inhibitor of SAPK/JNK), and JAK inhibitor I (an inhibitor of JAK 1, 2 and 3). However, IL-6 levels were not affected by PD98059 (an inhibitor of MEK1/2). Midazolam markedly suppressed IL-1β-stimulated STAT3 phosphorylation without affecting the phosphorylation of p38 MAP kinase, SAPK/JNK or IκB. Conclusion These results strongly suggest that midazolam inhibits IL-1β-induced IL-6 release in rat C6 glioma cells via suppression of STAT3 activation. Midazolam may affect immune system function in the CNS. PMID:21682888

Nonsurgical therapy of chronic periodontitis with adjunctive systemic azithromycin or amoxicillin/metronidazole.

PubMed

Jentsch, Holger F R; Buchmann, Andreas; Friedrich, Abel; Eick, Sigrun

2016-09-01

The objective of the present study is to compare the effect of systemic adjunctive use of azithromycin with amoxicillin/metronidazole to scaling and root planing (SRP) in a clinical study. Data from 60 individuals with chronic periodontitis were evaluated after full-mouth SRP. Antibiotics were given from the first day of SRP, in the test group (n = 29), azithromycin for 3 days and, in the control group (n = 31), amoxicillin/metronidazole for7 days. Probing depth (PD), attachment level (AL), and bleeding on probing (BOP) were recorded at baseline and after 3 and 12 months. Gingival crevicular fluid was analyzed for matrix metalloprotease (MMP)-8 and interleukin (IL)-1beta levels. Subgingival plaque was taken for assessment of the major bacteria associated with periodontitis. In both groups, PD, AL, and BOP were significantly reduced (p < 0.001). A few significant differences between the groups were found; AL and BOP were significantly better in the test than in the control group at the end of the study (p = 0.020 and 0.009). Periodontopathogens were reduced most in the test group. A noninferiority of the treatment with azithromycin in comparison with amoxicillin/metronidazole can be stated. The administration of azithromycin could be an alternative to the use of amoxicillin/metronidazole adjunctive to SRP in patients with moderate or severe chronic periodontitis; however, a randomized placebo-controlled multicenter study is needed. Application of azithromycin as a single antibiotic for 3 days might be considered as an additional adjunctive antibiotic to SRP in selected patients.

Suppression of antitumour protective cytotoxic T lymphocyte responses to a human papillomavirus 16 E7 DNA vaccine by coinjection of interleukin-12 complementary DNA: involvement of nitric oxide in immune suppression

PubMed Central

Sin, Jeong-Im

2009-01-01

Interleukin-12 (IL-12) has been shown to enhance cellular immunity in vitro and in vivo. The beneficial roles of IL-12 as a DNA vaccine adjuvant have been commonly observed. Here the impact of IL-12 complementary DNA (cDNA) as an adjuvant for a human papillomavirus (HPV) type 16 E7 DNA vaccine is investigated in a mouse tumour model. Coinjection of E7 DNA vaccine with IL-12 cDNA completely suppressed antigen-specific cytotoxic T-lymphocyte (CTL) responses, leading to a complete loss of antitumour protection from a tumour cell challenge. In addition, antigen-specific antibody and T helper cell proliferative responses were also suppressed by IL-12 cDNA coinjection. This inhibition was observed over different IL-12 cDNA doses. Furthermore, separate leg injections of IL-12 and E7 cDNAs suppressed antigen-specific CTL and tumour protective responses, but not antibody and T helper cell proliferative responses, suggesting different pathways for suppression of these two separate responses. Further knockout animal studies demonstrated that interferon-γ and nitric oxide are not directly associated with suppression of antigen-specific antibody responses by IL-12 cDNA coinjection. However, nitric oxide was found to be involved in suppression of antigen-specific CTL and tumour protective responses by IL-12 cDNA coinjection. These data suggest that coinjection of IL-12 cDNA results in suppression of E7-specific CTL responses through nitric oxide, leading to a loss of antitumour resistance in this DNA vaccine model. This study further shows that the adjuvant effect of IL-12 is dependent on the antigen types tested. PMID:19740332

Suppression of antitumour protective cytotoxic T lymphocyte responses to a human papillomavirus 16 E7 DNA vaccine by coinjection of interleukin-12 complementary DNA: involvement of nitric oxide in immune suppression.

PubMed

Sin, Jeong-Im

2009-09-01

Interleukin-12 (IL-12) has been shown to enhance cellular immunity in vitro and in vivo. The beneficial roles of IL-12 as a DNA vaccine adjuvant have been commonly observed. Here the impact of IL-12 complementary DNA (cDNA) as an adjuvant for a human papillomavirus (HPV) type 16 E7 DNA vaccine is investigated in a mouse tumour model. Coinjection of E7 DNA vaccine with IL-12 cDNA completely suppressed antigen-specific cytotoxic T-lymphocyte (CTL) responses, leading to a complete loss of antitumour protection from a tumour cell challenge. In addition, antigen-specific antibody and T helper cell proliferative responses were also suppressed by IL-12 cDNA coinjection. This inhibition was observed over different IL-12 cDNA doses. Furthermore, separate leg injections of IL-12 and E7 cDNAs suppressed antigen-specific CTL and tumour protective responses, but not antibody and T helper cell proliferative responses, suggesting different pathways for suppression of these two separate responses. Further knockout animal studies demonstrated that interferon-gamma and nitric oxide are not directly associated with suppression of antigen-specific antibody responses by IL-12 cDNA coinjection. However, nitric oxide was found to be involved in suppression of antigen-specific CTL and tumour protective responses by IL-12 cDNA coinjection. These data suggest that coinjection of IL-12 cDNA results in suppression of E7-specific CTL responses through nitric oxide, leading to a loss of antitumour resistance in this DNA vaccine model. This study further shows that the adjuvant effect of IL-12 is dependent on the antigen types tested.

Steady-state plasma and bronchopulmonary concentrations of intravenous levofloxacin and azithromycin in healthy adults.

PubMed

Rodvold, Keith A; Danziger, Larry H; Gotfried, Mark H

2003-08-01

The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (+/- standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 +/- 4.52, 2.50 +/- 0.97, and 1.24 +/- 0.55 micro g/ml; those for 750 mg of levofloxacin were 12.94 +/- 1.21, 6.04 +/- 0.39, and 1.73 +/- 0.78 micro g/ml; and those for azithromycin were 1.70 +/- 0.74, 1.27 +/- 0.47, and 2.86 +/- 1.75 micro g/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 +/- 53.2, 18.3 +/- 6.7, and 5.6 +/- 3.2 micro g/ml; those for 750 mg of levofloxacin were 81.7 +/- 37.0, 78.2 +/- 55.4, and 13.3 +/- 6.5 micro g/ml; and those for azithromycin were 650 +/- 259, 669 +/- 311, and 734 +/- 770 micro g/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of

Steady-State Plasma and Bronchopulmonary Concentrations of Intravenous Levofloxacin and Azithromycin in Healthy Adults

PubMed Central

Rodvold, Keith A.; Danziger, Larry H.; Gotfried, Mark H.

2003-01-01

The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (± standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 ± 4.52, 2.50 ± 0.97, and 1.24 ± 0.55 μg/ml; those for 750 mg of levofloxacin were 12.94 ± 1.21, 6.04 ± 0.39, and 1.73 ± 0.78 μg/ml; and those for azithromycin were 1.70 ± 0.74, 1.27 ± 0.47, and 2.86 ± 1.75 μg/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 ± 53.2, 18.3 ± 6.7, and 5.6 ± 3.2 μg/ml; those for 750 mg of levofloxacin were 81.7 ± 37.0, 78.2 ± 55.4, and 13.3 ± 6.5 μg/ml; and those for azithromycin were 650 ± 259, 669 ± 311, and 734 ± 770 μg/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in

Efficacy of azithromycin in the treatment of bronchiectasis.

PubMed

Lourdesamy Anthony, Albert I; Muthukumaru, Umadevi

2014-11-01

We evaluated the efficacy of a 12-week oral treatment with azithromycin in adult patients with bronchiectasis. The objectives were to demonstrate that this treatment reduces sputum volume, improves quality of life and to assess the lengths of effects after cessation of therapy. Seventy-eight patients with bronchiectasis confirmed by high-resolution computed tomography were included in this study. Subjects received oral azithromycin or placebo in a randomized manner for 12 weeks followed by placebo for another 12 weeks. Sputum volume, St George's Respiratory Questionnaire (SGRQ) score and spirometry were recorded at baseline, 12 weeks and 24 weeks, respectively. End-point measurements were compared from baseline to the end of each study phase. Sixty-eight subjects were included in the analysis. Mean 24-h sputum volume significantly decreased (P < 0.01) during the active treatment phase and remained low during the control phase (P < 0.01). The mean SGRQ total score with azithromycin decreased (i.e. improved health status) from baseline by more than the 4 points at the end of 12 and 24 weeks. Lung functions remained stable during oral azithromycin therapy and the subsequent control phase. Twelve weeks administration of azithromycin in bronchiectasis produces significant reductions in mean sputum volume, health status and stabilization of lung function values. Sputum volume reduction and the improvement of quality of life were sustained for 12 weeks after cessation of azithromycin. (Clinicaltrials.gov number NCT02107274). © 2014 Asian Pacific Society of Respirology.

Human Leukocyte Antigen and Interleukin 2, 10 and 12p40 Cytokine Responses to Measles: Is There Evidence of the HLA Effect?

PubMed Central

Ovsyannikova, Inna G.; Ryan, Jenna E.; Jacobson, Robert M.; Vierkant, Robert A.; Pankratz, V. Shane; Poland, Gregory A.

2007-01-01

HLA class I and class II associations were examined in relation to measles virus-specific cytokine responses in 339 healthy children who had received two doses of live attenuated measles vaccine. Multivariate linear regression modeling analysis revealed suggestions of associations between the expression of DPA1*0201 (p=0.03) and DPA1*0202 (p=0.09) alleles and interleukin-2 (IL-2) cytokine production (global p-value 0.06). Importantly, cytokine production and DQB1 allele associations (global p-value 0.04) revealed that the alleles with the strongest association with IL-10 secretion were DQB1*0302 (p=0.02), DQB1*0303 (p=0.07) and DQB1*0502 (p=0.06). Measles-specific IL-10 secretion associations approached significance with DRB1 and DQA1 loci (both global p-values 0.08). Specifically, suggestive associations were found between DRB1*0701 (p=0.07), DRB1*1103 (p=0.06), DRB1*1302 (p=0.08), DRB1*1303 (p=0.06), DQA1*0101 (p=0.08), and DQA1*0201 (p=0.04) alleles and measles-induced IL-10 secretion. Further, suggestive association was observed between specific DQA1*0505 (p=0.002) alleles and measles-specific IL-12p40 secretion (global p-value 0.09) indicating that cytokine responses to measles antigens are predominantly influenced by HLA class II genes. We found no associations between any of the alleles of HLA A, B, and Cw loci and cytokine secretion. These novel findings suggest that HLA class II genes may influence the level of cytokine production in the adaptive immune responses to measles vaccine. PMID:17234427

Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

PubMed

Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M; Mahdi, Rashid M; Dolinska, Monika B; Sergeev, Yuri V; Wingfield, Paul T; Kim, Sung-Hye; Egwuagu, Charles E

2014-06-01

Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

40 CFR 721.10425 - Substituted alkylamides (generic) (P-12-51 and P-12-52).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Substituted alkylamides (generic) (P-12-51 and P-12-52). 721.10425 Section 721.10425 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.10425 Substituted alkylamides (generic) (P-12-51 and P...

40 CFR 721.10425 - Substituted alkylamides (generic) (P-12-51 and P-12-52).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Substituted alkylamides (generic) (P-12-51 and P-12-52). 721.10425 Section 721.10425 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.10425 Substituted alkylamides (generic) (P-12-51 and P...

40 CFR 721.10425 - Substituted alkylamides (generic) (P-12-51 and P-12-52).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Substituted alkylamides (generic) (P-12-51 and P-12-52). 721.10425 Section 721.10425 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.10425 Substituted alkylamides (generic) (P-12-51 and P...

Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells

PubMed Central

Gerosa, Franca; Baldani-Guerra, Barbara; Lyakh, Lyudmila A.; Batoni, Giovanna; Esin, Semih; Winkler-Pickett, Robin T.; Consolaro, Maria Rita; De Marchi, Mario; Giachino, Daniela; Robbiano, Angela; Astegiano, Marco; Sambataro, Angela; Kastelein, Robert A.; Carra, Giuseppe; Trinchieri, Giorgio

2008-01-01

We analyzed interleukin (IL) 12 and IL-23 production by monocyte-derived dendritic cells (mono-DCs). Mycobacterium tuberculosis H37Rv and zymosan preferentially induced IL-23. IL-23 but not IL-12 was efficiently induced by the combination of nucleotide-binding oligodimerization domain and Toll-like receptor (TLR) 2 ligands, which mimics activation by M. tuberculosis, or by the human dectin-1 ligand β-glucan alone or in combination with TLR2 ligands, mimicking induction by zymosan. TLR2 ligands inhibited IL-12 and increased IL-23 production. DC priming with interferon (IFN) γ strongly increased IL-12 production, but was not required for IL-23 production and inhibited IL-23 production induced by β-glucan. The pattern of IL-12 and IL-23 induction was reflected in accumulation of the IL-12p35 and IL-23p19 transcripts, respectively, but not IL-12/23p40. Although IL-23, transforming growth factor β, and IL-6 contained in the supernatants of activated mono-DCs played a role in the induction of IL-17 by human CD4+ T cells, IL-1β, in combination with one or more of those factors, was required for IL-17 production, and its production determined the differential ability of the stimuli used to elicit mono-DCs to produce soluble factors directing IL-17 production. Thus, the differential ability of pathogens to induce antigen-presenting cells to produce cytokines regulates the immune response to infection. PMID:18490488

In Vivo and In Vitro Antimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine ▿ †

PubMed Central

Pereira, Marcus R.; Henrich, Philipp P.; Sidhu, Amar bir Singh; Johnson, David; Hardink, Joel; Van Deusen, Jeffrey; Lin, Jian; Gore, Katrina; O'Brien, Connor; Wele, Mamadou; Djimde, Abdoulaye; Chandra, Richa; Fidock, David A.

2011-01-01

Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies. PMID:21464242

Interleukin-10 functions in vitro and in vivo to inhibit bacterial DNA-induced secretion of interleukin-12.

PubMed

Anitescu, M; Chace, J H; Tuetken, R; Yi, A K; Berg, D J; Krieg, A M; Cowdery, J S

1997-12-01

Bacterial DNA (bDNA) has a number of biologic properties, including the ability to induce interleukin-12 (IL-12) production by macrophages. We studied the role of the regulatory cytokine IL-10 as a potential inhibitor of bDNA-induced IL-12 production. IL-10 concentrations as low as 0.3 ng/ml profoundly inhibited bDNA-induced macrophage IL-12 production as measured by Elispot analysis of IL-12 p40-secreting cells. Additionally, we found that IL-10 inhibited bDNA-induced IL-12 secretion by the macrophage cell lines J774 and RAW 264. Preincubation of splenic adherent cells with IL-10 markedly reduced bDNA-induced transcription of IL-12 p40 mRNA. Interestingly, after 2 h of exposure, bDNA also induces transcription of IL-10 mRNA by splenic adherent cells. The importance of IL-10 in the in vivo regulation of bDNA-induced cytokine secretion was illustrated by the response of mice with disrupted IL-10 genes (IL-10 ko mice) to i.v. bDNA challenge. Compared to +/+ mice, IL-10 knockout (ko) mice exhibited increased numbers of IL-12 and interferon-gamma (IFN-gamma)-secreting cells following either single or repeated challenge with bDNA. These findings indicate that IL-10 plays a key role in regulating bDNA-induced production of inflammatory cytokines.

Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis

PubMed Central

Kernbauer, Elisabeth; Hölzl, Markus A.; Hofer, Johannes; Gualdoni, Guido A.; Schmetterer, Klaus G.; Miftari, Fitore; Sobanov, Yury; Meshcheryakova, Anastasia; Mechtcheriakova, Diana; Witzeneder, Nadine; Greiner, Georg; Ohradanova-Repic, Anna; Waidhofer-Söllner, Petra; Säemann, Marcus D.; Decker, Thomas

2017-01-01

A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation. PMID:28742108

CXCR1/2 antagonism with CXCL8/Interleukin-8 analogue CXCL8(3–72)K11R/G31P restricts lung cancer growth by inhibiting tumor cell proliferation and suppressing angiogenesis

PubMed Central

Khan, Muhammad Noman; Wang, Bing; Wei, Jing; Zhang, Yingqiu; Li, Qiang; Luan, Xuelin; Cheng, Jya-Wei; Gordon, John R.; Li, Fang; Liu, Han

2015-01-01

CXCR1 and CXCR2 together with cognate chemokines are significantly upregulated in a number of cancers, where they act as key regulators of tumor cell proliferation, metastasis, and angiogenesis. We have previously reported a mutant protein of CXCL8/Interleukin-8, CXCL8(3–72)K11R/G31P (G31P), which can act as a selective antagonist towards CXCR1/2 with therapeutic efficacy in both inflammatory diseases and malignancies. In this study, we investigated the effect of this ELR-CXC chemokine antagonist G31P on human non-small cell lung cancer cells and lung tumor progression in an orthotopic xenograft model. We report increased mRNA levels of CXCR1 and CXCR2 in human lung cancer tissues compared to normal counterparts. Expression levels of CXCR1/2 cognate ligands was determined by ELISA. CXCR1/2 receptor antagonism via G31P leads to decreased H460 and A549 cell proliferation and migration in a dose-dependent manner. G31P also enhanced apoptosis in lung cancer cells as determined by elevated levels of cleaved PARP, Caspase-8, and Bax, together with a reduced expression of the anti-apoptotic protein Bcl-2. In an in vivo orthotopic xenograft mouse model of human lung cancer, G31P treatment suppressed tumor growth, metastasis, and angiogenesis. At the molecular level, G31P treatment was correlated with decreased expression of VEGF and NFкB-p65, in addition to reduced phosphorylation of ERK1/2 and AKT. Our results suggest that G31P blockage of CXCR1 and CXCR2 can inhibit human lung cancer cell growth and metastasis, which offers potential therapeutic opportunities. PMID:26087179

Cloning and characterization of an adenoviral vector for highly efficient and doxycycline – suppressible expression of bioactive human single – chain interleukin 12 in colon cancer

PubMed Central

Wulff, Holger; Krieger, Thorsten; Krüger, Karen; Stahmer, Ingrid; Thaiss, Friedrich; Schäfer, Hansjörg; Block, Andreas

2007-01-01

Background Interleukin-12 (IL-12) is well characterized to induce cellular antitumoral immunity by activation of NK-cells and T-lymphocytes. However, systemic administration of recombinant human IL-12 resulted in severe toxicity without perceptible therapeutic benefit. Even though intratumoral expression of IL-12 leads to tumor regression and long-term survival in a variety of animal models, clinical trials have not yet shown a significant therapeutic benefit. One major obstacle in the treatment with IL-12 is to overcome the relatively low expression of the therapeutic gene without compromising the safety of such an approach. Our objective was to generate an adenoviral vector system enabling the regulated expression of very high levels of bioactive, human IL-12. Results High gene expression was obtained utilizing the VP16 herpes simplex transactivator. Strong regulation of gene expression was realized by fusion of the VP16 to a tetracycline repressor with binding of the fusion protein to a flanking tetracycline operator and further enhanced by auto-regulated expression of its fusion gene within a bicistronic promoter construct. Infection of human colon cancer cells (HT29) at a multiplicity of infection (m.o.i.) of 10 resulted in the production of up to 8000 ng/106 cells in 48 h, thus exceeding any published vector system so far. Doxycycline concentrations as low as 30 ng/ml resulted in up to 5000-fold suppression, enabling significant reduction of gene expression in a possible clinical setting. Bioactivity of the human single-chain IL-12 was similar to purified human heterodimeric IL-12. Frozen sections of human colon cancer showed high expression of the coxsackie adenovirus receptor with significant production of human single chain IL-12 in colon cancer biopsies after infection with 3*107 p.f.u. Ad.3r-scIL12. Doxycycline mediated suppression of gene expression was up to 9000-fold in the infected colon cancer tissue. Conclusion VP16 transactivator-mediated and

Evidence that P12, a specific variant of P16{sup INK4A}, plays a suppressive role in human pancreatic carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poi, Ming J.; Knobloch, Thomas J.; Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH 43210

2013-06-28

Highlights: •P12, a variant of P16{sup INK4A}, inhibits the proliferation of pancreatic cancer cells. •P12 is distinct from P16 in function and structure. •Genetic alterations of p12 are prevalent in human pancreatic carcinoma. •P12 represents a potential pancreas-specific tumor suppressor. -- Abstract: The INK4a-ARF locus plays a central role in the development of pancreatic tumors as evidenced by the fact that up to 98% of pancreatic tumor specimens harbored genetic alterations at the INK4a-ARF locus. Interestingly, in addition to the well-known P16{sup INK4A} (P16) and P14ARF tumor suppressors, the INK4a-ARF locus in pancreas encodes another protein, P12, whose structure, function,more » and contributions to pancreatic carcinogenesis remain to be elucidated. In the current study, we demonstrated that over-expression of p12 in human pancreatic cancer cells led to cell arrest at the G1 phase and such cell cycle arrest was related to down-regulation of a number of oncogenes, such as c-Jun, Fos, and SEI1. Furthermore, unlike P16, P12 did not retain any cyclin-dependent kinase 4 (CDK4)-inhibitory activity. Instead, P12 exhibited a transactivating activity not found in P16. We also examined the genetic status of p12 in a cohort of 40 pancreatic tumor specimens and found that p12 alteration was prevalent in pancreatic tumors with an incidence of 70% (28/40). These results support that P12 is a tumor suppressive protein distinct from P16, and its genetic inactivation is associated with pancreatic carcinogenesis.« less

Azithromycin

MedlinePlus

... taking azithromycin unless you experience the severe side effects described in the SIDE EFFECTS section. If you stop taking azithromycin too soon ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

Expression of biologically active recombinant porcine interleukin-12 from Escherichia coli.

PubMed

Morris, K R; Bruce, M P; Janardhana, V; Thomas, J D; Bean, A G D; Strom, D G

2008-12-15

The control of viral infections is of critical importance to livestock industries worldwide and is highlighted by costly infection outbreaks, such as that seen with foot and mouth disease virus. To ameliorate the impact of increasing problems with viral infections, new vaccine and anti-viral strategies are required and a greater understanding of the anti-viral response is essential. Furthermore, in pigs, evidence is still being gathered on the components of a defined anti-viral immune response. However, this has been greatly improved by the recent cloning and expression of critical cytokines involved in the anti-viral response. To assess the use of recombinant porcine interleukin-12 (rPoIL-12) as an immunotherapeutic and immunomodulator of swine, we have cloned and expressed rPoIL-12 as a single-chain fusion protein from Esherichia coli (E. coli). The fusion encodes the p40 and p35 subunits, linked by a glycine-serine linker and expressed as a C-terminal 6xHis tagged protein. rPoIL-12 stimulated the proliferation of human lymphoblasts and its activity on porcine cells was demonstrated by the ability of rPoIL-12 to increase the mRNA expression of porcine interleukin-18 receptor-alpha (poIL-18Ralpha) from porcine peripheral blood mononuclear cells (PoPMBCs). This data supports the inclusion of E. coli produced rPoIL-12 in immunomodulation strategies in the pig.

Corticosteroid and Azithromycin in Idiopathic Granulomatous Mastitis

PubMed Central

Salehi, Marzieh; Salehi, Maryam; Kalbasi, Nader; Hakamifard, Atousa; Salehi, Hassan; Salehi, Mohammad Mahdi; Sharifian, Jalil

2017-01-01

Background: Mastitis is an inflammatory disorder in breast tissues due to bacterial factors, mycobacterial infections or autoimmune diseases. Idiopathic granulomatous mastitis (IGM) is a form of mastitis which may be affected by systematic diseases such as sarcoidosis, and infectious causes such as mycobacterium and fungus. This study evaluates the efficacy of medical therapy with a combination of corticosteroid and Azithromycin in patients with IGM. Materials and Methods: This study is a clinical trial research carried out in Alzahra Hospital (Isfahan, Iran) in 2013 on granulomatous mastitis patients. It was administered 250 mg of Azithromycin per 12 hour and 60 mg of Prednisolone per day within 2 weeks. Next, they took 40 mg/day within 8 weeks, and this dosage was tapered during 6 months and the patients clinically and radiologically followed up. The studied patients were examined within 1 week, 2 weeks, 1 month, 3 months, and 6 months, from the beginning of treatment. Results: This study investigated granulomatous mastitis patients in Alzahra hospital in 2013. The mean age of these patients was 33.6 ± 8.9, and their age range was 18–56 years old. Among 26 studied patients, 24 persons (92.3%) according to follow-up the patients by physical examination and sonography responded to treatment of corticosteroid and Azithromycin. The remaining (7.7%) underwent surgery. Treatment periods in case of drug use were respectively, 8.5 ± 0.71 months. Conclusion: Treatment with corticosteroid and Azithromycin is an effective and appropriate treatment for IGM. PMID:28217653

Identification of a single p19 gene and three p40 paralogues in grass carp (Ctenopharyngodon idellus): Their potential for the formation of interleukin 23 and inducible expression in vitro and in vivo.

PubMed

Wang, Xinyan; Qin, Lei; Du, Linyong; Chen, Di; Zhang, Anying; Yang, Kun; Zhou, Hong

2017-12-01

Interleukin (IL-) 23, a member of IL-12 family, is a composite cytokine with the subunits of p19 and p40. Although IL-12 and IL-23 share the p40 subunit, they play vastly different roles in immune regulation. In teleost, much emphasis has been placed on the identification of IL-12, but evidence for the existence of IL-23 is still lacking. In the present study, a p19 gene and three p40 paralogues were isolated and identified from grass carp, suggesting multiple assembly of IL-23 molecules in fish species. To address this issue, the existence of different p19/p40 heterodimers were examined by Co-Immunoprecipitation (Co-IP) assay, showing that only co-expression of p19 and each p40 subunit could produce the soluble proteins corresponding to three IL-23 isoforms. Additionally, bacterial infection could up-regulate the mRNA expression of p19, p40a and p40b but not p40c in head kidney, indicating distinct expression patterns of three p40 paralogues. Moreover, in vitro experiments demonstrated that both B-cell stimulator, LPS and T-cell mitogen, PHA markedly increased the mRNA levels of p19 and three p40 paralogues in grass carp periphery blood lymphocytes (PBLs). The simultaneous up-regulation of mRNA expression of p19 and p40 paralogues in response to immune stimuli supports the idea that p19 may form heterodimeric molecules with three p40 subunits in grass carp under immune activation. These findings for the first time highlight the potential of p19 and p40 for dimerization in fish, particularly the existence of three IL-23 isoforms as soluble heterodimeric cytokines in grass carp, thereby providing the basis for further investigating the function of IL-23 in fish immunity. Copyright © 2017 Elsevier Ltd. All rights reserved.

The PPARdelta agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition.

PubMed

Kino, T; Rice, K C; Chrousos, G P

2007-05-01

Interleukin-6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator-activated receptor delta (PPARdelta), which binds to and is activated by a variety of fatty acids, was recently shown to have anti-inflammatory actions. We examined the ability of the synthetic PPARdelta agonist GW501516 to suppress interleukin-6-induced expression of acute phase proteins in human hepatoma HepG2 cells and rat primary hepatocytes. Results GW501516 dose-dependently suppressed interleukin-6-induced mRNA expression of the acute phase protein alpha1-antichymotrypsin in HepG2 cells. The compound also suppressed interleukin-6-induced mRNA expression of alpha2-acid glycoprotein, beta-fibrinogen and alpha2-macroglobulin in and the secretion of C-reactive protein by rat primary hepatocytes. Depletion of the PPARdelta receptor, but not of PPARalpha or gamma, attenuated the suppressive effect of GW501516 on interleukin-6-induced alpha1-antichymotrypsin mRNA expression, indicating that PPARdelta specifically mediated this effect. Since interleukin-6 stimulates the transcriptional activity of the alpha1-antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPARdelta on this promoter. Overexpression of PPARdelta enhanced the suppressive effect of GW501516 on STAT3-activated transcriptional activity of the alpha1-antichymotrypsin promoter, while GW501516 suppressed interleukin-6-induced binding of this transcription factor to this promoter. These findings indicate that agonist-activated PPARdelta interferes with interleukin-6-induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPARdelta agonists might be useful for the suppression of systemic inflammatory reactions in which IL-6 plays a central role.

Localization of azithromycin in Toxoplasma gondii-infected cells.

PubMed Central

Schwab, J C; Cao, Y; Slowik, M R; Joiner, K A

1994-01-01

Agents effective against intracellular pathogens must enter infected cells, crossing vacuolar membranes surrounding the organisms and then penetrating into the microbe and localizing to the microbial target site. We have characterized these parameters for azithromycin entry into Toxoplasma gondii-infected Chinese hamster ovary cells and murine macrophage-like J774 cells. Azithromycin uptake into infected host cells was concentrative and was dependent upon proton gradients. Subcellular fractionation of azithromycin-loaded infected CHO cells demonstrated > 95% intracellular drug in host cell lysosomes and cytosol, with < 5% associated with the parasite. Uptake of azithromycin into the T. gondii vacuole increased if parasites were coated with antibody prior to internalization by murine J774 cells, conditions which result in the formation of acidified phagolysosomes. No redistribution or retention of azithromycin in the parasite was observed when drug efflux from antibiotic-loaded infected CHO cells was monitored. Azithromycin entry into extracellular T. gondii was concentrative, was temperature and pH dependent, and was not different when azithromycin-sensitive and -resistant parasites were compared. These results demonstrate that azithromycin concentrates primarily in acidified compartments in parasites and host cells. The high concentration of azithromycin within these compartments may not be biologically relevant to inhibition of intracellular parasite growth by this agent. PMID:7979295

Azithromycin analogue CSY0073 attenuates lung inflammation induced by LPS challenge

PubMed Central

Balloy, V; Deveaux, A; Lebeaux, D; Tabary, O; le Rouzic, P; Ghigo, J M; Busson, P F; Boëlle, P Y; Guez, J Guez; Hahn, U; Clement, A; Chignard, M; Corvol, H; Burnet, M; Guillot, L

2014-01-01

Background and Purpose Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulating effects. Long-term azithromycin therapy in patients with chronic lung diseases such as cystic fibrosis has been associated with increased antimicrobial resistance, emergence of hypermutable strains, ototoxicity and cardiac toxicity. The aim of this study was to assess the anti-inflammatory effects of the non-antibiotic azithromycin derivative CSY0073. Experimental Approach We compared the effects of CSY0073 with those of azithromycin in experiments on bacterial cultures, Pseudomonas aeruginosa biofilm, lung cells and mice challenged intranasally with P. aeruginosa LPS. Key Results In contrast to azithromycin, CSY0073 did not inhibit the growth of P. aeruginosa, Staphylococcus aureus or Haemophilus influenzae and had no effect on an established P. aeruginosa biofilm. Bronchoalveolar lavage (BAL) fluids and lung homogenates collected after the LPS challenge in mice showed that CSY0073 and azithromycin (200 mg·kg−1, i.p.) decreased neutrophil counts at 24 h and TNF-α, CXCL1 and CXCL2 levels in the BAL fluid after 3 h and IL-6, CXCL2 and IL-1β levels in the lung after 3 h compared with the vehicle. However, only azithromycin reduced IL-1β levels in the lung 24 h post LPS challenge. CSY0073 and azithromycin similarly diminished the production of pro-inflammatory cytokines by macrophages, but not lung epithelial cells, exposed to P. aeruginosa LPS. Conclusions and Implications Unlike azithromycin, CSY0073 had no antibacterial effects but it did have a similar anti-inflammatory profile to that of azithromycin. Hence, CSY0073 may have potential as a long-term treatment for patients with chronic lung diseases. PMID:24417187

Functional analyses of the interaction of chicken interleukin 23 subunit p19 with IL-12 subunit p40 to form the IL-23 complex.

PubMed

Truong, Anh Duc; Hoang, Cong Thanh; Hong, Yeojin; Lee, Janggeun; Lee, Kyungbaek; Lillehoj, Hyun S; Hong, Yeong Ho

2017-12-01

This study represents the first description of the cloning of chicken IL-23p19 (ChIL-23α) and the function of the IL-23 complex in birds. Multiple alignment of ChIL-23α with other known IL-23α amino acid sequences revealed regions of amino acid conservation. The homologies of ChIL-23α, IL-12p35, and similar mammalian subunits ranged between 26% and 42%. ChIL-23α consisted of four exons and three introns; similar to those in humans and mice, and limited conservation of synteny between the human and chicken genomes was observed. Using bioinformatics tools, we identified the NF-κB, C/EBPα-β, c-Jun, c-Rel, AP-1, GATA-1, and ER promoter sites in ChIL-23α. Moreover, IL-23α mRNA was more highly expressed than IL-12p40 and IL-12p35 mRNA in several organs of chickens infected with Salmonella. In addition, ChIL-23 complex are associated with IL-23R, IL-12Rβ1 receptors; activate the JAK2/TYK2, STAT1/3, SOCS1 genes, and induced proinflammatory cytokines in immune cells. Collectively, these results indicate that ChIL-23 is a member of the IL-12 family, has proinflammatory properties related to IL-23R and IL-12Rβ1 receptor expression, and activates the JAK/STAT signaling pathway that results in the interaction of ChIL-23α with ChIL-12p40 to form the novel ChIL-23 complex. Our results provide novel insights into the regulation of immunity, inflammation, and immunopathology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy of azithromycin or clarithromycin for prophylaxis of viridans group streptococcus experimental endocarditis.

PubMed Central

Rouse, M S; Steckelberg, J M; Brandt, C M; Patel, R; Miro, J M; Wilson, W R

1997-01-01

The efficacy of azithromycin or clarithromycin was compared to that of amoxicillin, clindamycin, or erythromycin for the prevention of viridans group streptococcus experimental endocarditis. Rabbits with catheter-induced aortic valve vegetations were given no antibiotics or two doses of amoxicillin at 25 mg/kg of body weight, azithromycin at 10 mg/kg, clarithromycin at 10 mg/kg, clindamycin at 40 mg/kg followed by clindamycin at 20 mg/kg, or erythromycin at 10 mg/kg. Antibiotics were administered 0.5 h before and 5.5 h after intravenous infusion of 5 x 10(5) CFU of Streptococcus milleri. Forty-eight hours after bacterial inoculation, the rabbits were killed and aortic valve vegetations were aseptically removed and cultured for bacteria. Infective endocarditis occurred in 88% of untreated animals, 1% of animals receiving amoxicillin, 9% of animals receiving erythromycin, 0% of animals receiving clindamycin, 2.5% of animals receiving clarithromycin, and 1% of animals receiving azithromycin. All five regimens were more effective (P < 0.001) than no prophylaxis. Erythromycin was less effective (P < 0.05) than amoxicillin or clindamycin. Azithromycin or clarithromycin was as effective as amoxicillin, clindamycin, or erythromycin for the prevention of viridans group streptococcus experimental endocarditis in this model. PMID:9257739

In vitro characterization of pH-sensitive azithromycin-loaded methoxy poly (ethylene glycol)-block-poly (aspartic acid-graft-imidazole) micelles.

PubMed

Teng, Fangfang; Deng, Peizong; Song, Zhimei; Zhou, Feilong; Feng, Runliang; Liu, Na

2017-06-15

In order to improve azithromycin's antibacterial activity in acidic medium, monomethoxy poly (ethylene glycol)-block-poly (aspartic acid-graft-imidazole) copolymer was synthesized through allylation, free radical addition, ring-opening polymerization and amidation reactions with methoxy poly (ethylene glycol) as raw material. Drug loading capacity and encapsulation efficiency of azithromycin-loaded micelles prepared via thin film hydration method were 11.58±0.86% and 96.06±1.93%, respectively. The drug-loaded micelles showed pH-dependent property in the respects of particle size, zeta potential at the range of pH 5.5-7.8. It could control drug in vitro release and demonstrate higher release rate at pH 6.0 than that at pH 7.4. In vitro antibacterial experiment indicated that the activity of azithromycin-loaded micelles against S. aureus was superior to free azithromycin in medium at both pH 6.0 and pH 7.4. Using fluorescein as substitute with pH-dependent fluorescence decrease property, laser confocal fluorescence microscopy analysis confirmed that cellular uptake of micelles was improved due to protonation of copolymer's imidazole groups at pH 6.0. The enhanced cellular uptake and release of drug caused its activity enhancement in acidic medium when compared with free drug. The micellar drug delivery system should be potential application in the field of bacterial infection treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33.

PubMed

Osbourn, Megan; Soares, Dinesh C; Vacca, Francesco; Cohen, E Suzanne; Scott, Ian C; Gregory, William F; Smyth, Danielle J; Toivakka, Matilda; Kemter, Andrea M; le Bihan, Thierry; Wear, Martin; Hoving, Dennis; Filbey, Kara J; Hewitson, James P; Henderson, Holly; Gonzàlez-Cìscar, Andrea; Errington, Claire; Vermeren, Sonja; Astier, Anne L; Wallace, William A; Schwarze, Jürgen; Ivens, Alasdair C; Maizels, Rick M; McSorley, Henry J

2017-10-17

Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Auditing and benchmarking of azithromycin utilization in primary care military clinics.

PubMed

Kopylov, Uri; Admon, Gil; Borer, Abraham; Schlaeffer, Francisc; Aviram, Eliad E; Gilad, Jacob

2007-10-01

Despite widespread azithromycin use, no audit has targeted this drug to date. Azithromycin was audited in primary military clinics between July 1, 2003 and December 31, 2003 (period 1). Consumption (defined daily doses/1000 visits) and economic expenditure of penicillin V, amoxicillin, erythromycin, and azithromycin were evaluated. An educational intervention was performed (dissemination of local guideline regarding indications for azithromycin use) and its impact was assessed between July 1, 2004 and December 31, 2004 (period 2). During periods 1 and 2, 105 and 31 patients were prescribed azithromycin. Azithromycin was appropriately chosen in 5.7% vs. 70.9% of cases (p < 0.0001), but unnecessary in 90.5% vs. 16.2 (p < 0.0001). Azithromycin prescription during period 1 resulted in extrapolated excess expenditure of 420,000 New Israeli shekels/year (1 U.S. dollar = 4.5 New Israeli shekels). There was an attributable decrease of 82.1% in azithromycin consumption (adjusted attributable cost reduction 38.1%), but an increase in amoxicillin consumption (20.2%). Intervention decreased azithromycin consumption and expenditure but its effect was offset by increased consumption of other agents, mainly amoxicillin. Interventions in primary care settings should target prescribing behavior through a multifaceted approach to increase efficacy while preventing a trade-off effect.

Fisetin inhibits the generation of inflammatory mediators in interleukin-1β-induced human lung epithelial cells by suppressing the NF-κB and ERK1/2 pathways.

PubMed

Peng, Hui-Ling; Huang, Wen-Chung; Cheng, Shu-Chen; Liou, Chian-Jiun

2018-07-01

Fisetin, a flavone that can be isolated from fruits and vegetables, has anti-tumor and anti-oxidative properties and ameliorates airway hyperresponsiveness in asthmatic mice. This study investigated whether fisetin can suppress the expression of inflammatory mediators and intercellular adhesion molecule 1 (ICAM-1) in A549 human lung epithelial cells that were stimulated with interleukin-1β (IL-1β) to induce inflammatory responses. A549 cells were treated with fisetin (3-30 μM) and then with IL-1β. Fisetin significantly inhibited COX-2 expression and reduced prostaglandin E 2 production, and it suppressed the levels of IL-8, CCL5, monocyte chemotactic protein 1, tumor necrosis factor α, and IL-6. Fisetin also significantly attenuated the expression of chemokine and inflammatory cytokine genes and decreased the expression of ICAM-1, which mediates THP-1 monocyte adhesion to inflammatory A549 cells. Fisetin decreased the translocation of nuclear transcription factor kappa-B (NF-κB) subunit p65 into the nucleus and inhibited the phosphorylation of proteins in the ERK1/2 pathway. Co-treatment of IL-1β-stimulated A549 cells with ERK1/2 inhibitors plus fisetin reduced ICAM-1 expression. Furthermore, fisetin significantly increased the effects of the protective antioxidant pathway by promoting the expression of nuclear factor erythroid-2-related factor-2 and heme oxygenase 1. Taken together, these data suggest that fisetin has anti-inflammatory effects and that it suppresses the expression of chemokines, inflammatory cytokines, and ICAM-1 by suppressing the NF-κB and ERK1/2 signaling pathways in IL-1β-stimulated human lung epithelial A549 cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Azithromycin and erythromycin ameliorate the extent of colonic damage induced by acetic acid in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahgoub, Afaf; El-Medany, Azza; Mustafa, Ali

2005-05-15

Ulcerative colitis is a common inflammatory bowel disease (IBD) of unknown etiology. Recent studies have revealed the role of some microorganisms in the initiation and perpetuation of IBD. The role of antibiotics in the possible modulation of colon inflammation is still uncertain. In this study, we evaluated the effects of two macrolides, namely azithromycin and erythromycin, at different doses on the extent and severity of ulcerative colitis caused by intracolonic administration of 3% acetic acid in rats. The lesions and the inflammatory response were assessed by histology and measurement of myeloperoxidase (MPO) activity, nitric oxide synthetase (NOS) and tumor necrosismore » factor alpha (TNF{alpha}) in colonic tissues. Inflammation following acetic acid instillation was characterized by oedema, diffuse inflammatory cell infiltration and necrosis. Increase in MPO, NOS and TNF{alpha} was detected in the colonic tissues. Administration of either azithromycin or erythromycin at different dosage (10, 20 and 40 mg/kg orally, daily for 5 consecutive days) significantly (P < 0.05) reduced the colonic damage, MPO and NOS activities as well as TNF{alpha} level. This reduction was highly significant with azithromycin when given at a dose of 40 mg/kg. It is concluded that azithromycin and erythromycin may have a beneficial therapeutic role in ulcerative colitis.« less

Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD.

PubMed

Kent, J R; Almond, M K; Dhillon, S

2001-01-01

Azithromycin is an azalide antibiotic with a similar antibacterial spectrum to erythromycin but with greater gram-negative activity. Azithromycin displays a favorable pharmacokinetic profile, with improved absorption and higher sustained tissue concentrations compared with erythromycin. This results in a prolonged elimination half-life, suggesting a potential for treating continuous ambulatory peritoneal dialysis (CAPD) peritonitis. This study aimed to define the potential role of azithromycin in treating CAPD peritonitis. The pharmacokinetics and peritoneal dialysis (PD) clearance of azithromycin were studied following a single 500-mg oral dose of azithromycin. Blood and dialysate samples were taken over a 10-day period and assayed using high-pressure liquid chromatography. The study took place within the Renal Unit at Southend Hospital NHS Trust, a district general hospital in the United Kingdom. Eight patients with oliguric end-stage renal failure without peritonitis maintained on CAPD (3 x 2 L/day). Peak plasma concentrations occurred at 2-3 hours with 0.35-1.35 microg/mL (mean 0.75). The mean elimination half-life was 84.55 hrs, and plasma clearance was 21.93 L/hour. This compares with values of greater than 40 hours and 40.8 L/hour reported in healthy volunteers. After 8 hours, the mean dialysate concentration was 0.07 microg/mL; PD clearance was 0.06 L/hr. Azithromycin is not substantially removed by CAPD in the absence of peritonitis and cannot be recommended for widespread use in this setting at present. However, the successful use of azithromycin in CAPD peritonitis, due possibly to an intracellular drug transport mechanism, has been reported. Future research should address this possibility.

The Glycogen Synthase Kinase 3α and β Isoforms Differentially Regulates Interleukin-12p40 Expression in Endothelial Cells Stimulated with Peptidoglycan from Staphylococcus aureus.

PubMed

Cortés-Vieyra, Ricarda; Silva-García, Octavio; Oviedo-Boyso, Javier; Huante-Mendoza, Alejandro; Bravo-Patiño, Alejandro; Valdez-Alarcón, Juan J; Finlay, B Brett; Baizabal-Aguirre, Víctor M

2015-01-01

Glycogen synthase kinase 3 (GSK3) is a constitutively active regulatory enzyme that is important in cancer, diabetes, and cardiovascular, neurodegenerative, and psychiatric diseases. While GSK3α is usually important in neurodegenerative and psychiatric diseases GSK3β is fundamental in the inflammatory response caused by bacterial components. Peptidoglycan (PGN), one of the most abundant cell-wall structures of Gram-positive bacteria, is an important inducer of inflammation. To evaluate whether inhibition of GSK3α and GSK3β activity in bovine endothelial cells (BEC) regulates the expression of the pro-inflammatory cytokine IL-12p40, we treated BEC with SDS-purified PGN from Staphylococcus aureus. We found that PGN triggered a TLR2/PI3K/Akt-dependent phosphorylation of GSK3α at Ser21, GSK3β at Ser9, and NF-κB p65 subunit (p65) at Ser536, and the phosphorylation of GSK3α was consistently higher than that of GSK3β. The expression of IL-12p40 was inhibited in BEC stimulated with PGN and pre-treated with a specific neutralizing anti-TLR2 antibody that targets the extracellular domain of TLR2 or by the addition of Akt-i IV (an Akt inhibitor). Inhibition of GSK3α and GSK3β with LiCl or SB216763 induced an increase in IL-12p40 mRNA and protein. The effect of each isoform on IL-12p40 expression was evaluated by siRNA-gene expression silencing of GSK3α and GSK3β. GSK3α gene silencing resulted in a marked increase in IL-12p40 mRNA and protein while GSK3β gene silencing had the opposite effect on IL-12p40 expression. These results indicate that the TLR2/PI3K/Akt-dependent inhibition of GSK3α activity also plays an important role in the inflammatory response caused by stimulation of BEC with PGN from S. aureus.

Thalidomide suppressed interleukin-6 but not tumor necrosis factor-alpha in volunteers with experimental endotoxemia.

PubMed

Shannon, Edward; Noveck, Robert; Sandoval, Felipe; Kamath, Burde; Kearney, Michael

2007-11-01

An early rationale for using thalidomide to treat erythema nodosum leprosum had been based on some reports that it suppresses tumor necrosis factor-alpha (TNF-alpha). However, in vivo and in vitro studies have yielded variable results, having shown that thalidomide can either enhance or suppress TNF-alpha. Since the course of circulating cytokines like TNF-alpha after infusion of endotoxin into volunteers is reproducible and characteristic, we investigated the effect of thalidomide on endotoxin-induced synthesis of TNF-alpha, interleukin (IL)-6, and IL-8. The cytokine response from 18 placebo-treated subjects who had undergone the endotoxin challenge were pooled with a placebo-treated subject from the current study and were compared with 4 subjects who received thalidomide (100 mg) every 6 h for 5 doses before endotoxin challenge. Thirty minutes after the last dose of thalidomide or placebo, volunteers were infused with 4-ng/kg endotoxin. Plasma was collected and assayed for cytokines by enzyme-linked immunosorbent assay. Endotoxin evoked the synthesis of the cytokines in all volunteers. The peak response for TNF-alpha was 1.5 h, 2.5 h for IL-8, and 3.0 h for IL-6. Thalidomide did not significantly delay the release of cytokines into the circulating blood. At the peak response, thalidomide reduced the concentration of the cytokines in the plasma. Using the area under the dose response curve (AUC(0 to 24) h), thalidomide reduced the AUC for IL-6 by 56%, for IL-8 by 30%, and TNF-alpha by 32%. In this model, thalidomide did not suppress TNF-alpha or IL-8, but it did suppress IL-6 at 4-h postinfusion with lipopolysaccharide (P=0.004), at 6 h (P=0.014), at 12 h (P=0.001), and at 16 h (P=0.012).

Azithromycin 1.5g Over 5 Days Compared to 1g Single Dose in Urethral Mycoplasma genitalium: Impact on Treatment Outcome and Resistance.

PubMed

Read, Tim R H; Fairley, Christopher K; Tabrizi, Sepehr N; Bissessor, Melanie; Vodstrcil, Lenka; Chow, Eric P F; Grant, Mieken; Danielewski, Jennifer; Garland, Suzanne M; Hocking, Jane S; Chen, Marcus Y; Bradshaw, Catriona S

2017-02-01

We evaluated the impact of extended azithromycin (1.5g over 5 days) on selection of macrolide resistance and microbiological cure in men with Mycoplasma genitalium urethritis during 2013-2015 and compared this to cases treated with azithromycin 1g in 2012-2013. Microbiological cure was determined for men with M. genitalium urethritis treated with azithromycin 1.5g using quantitative polymerase chain reaction specific for M. genitalium DNA on samples 14-100 days post-treatment. Pre- and post-treatment macrolide resistance mutations were detected by sequencing the 23 S gene. There was no difference in proportions with microbiological cure between azithromycin 1.5g and 1g: 62/106 (58%; 95% confidence interval [CI], 49%, 68%) and 56/107 (52%; 95%CI 42-62%), P = .34, respectively. Also, there was no difference in the proportion of wild-type 23 S rRNA (presumed macrolide sensitive) infections cured after 1.5g and azithromycin 1g: 28/34 (82%; 95%CI 65-92%) and 49/60 (82%; 95%CI 70-90%), P=1.0, respectively. There was no difference between 1.5g and 1g in the proportions of wild-type infections with post-treatment resistance mutations: 4/34 (12%; 95%CI 3-27%) and 11/60 (18%; 95%CI 10-30%), respectively, P = .40. Pre-treatment resistance was present in 51/98 (52%; 95%CI 42-62%) cases in 2013-2015 compared to 47/107 (44%; 95%CI 34-54%) in 2012-2013, P = .25. Extended azithromycin 1.5g was no more effective than a single 1g dose at achieving cure of M. genitalium urethritis and importantly did not reduce the selection of macrolide resistance. Nonmacrolide and new approaches for the treatment of M. genitalium urethritis are required. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

High-Dose Azithromycin versus High-Dose Amoxicillin-Clavulanate for Treatment of Children with Recurrent or Persistent Acute Otitis Media

PubMed Central

Arrieta, Antonio; Arguedas, Adriano; Fernandez, Pilar; Block, Stan L.; Emperanza, Paz; Vargas, Sergio L.; Erhardt, William A.; de Caprariis, Pascal J.; Rothermel, Constance D.

2003-01-01

Infants and young children, especially those in day care, are at risk for recurrent or persistent acute otitis media (AOM). There are no data on oral alternatives to high-dose amoxicillin-clavulanate for treating AOM in these high-risk patients. In this double-blind, double-dummy multicenter clinical trial, we compared a novel, high-dose azithromycin regimen with high-dose amoxicillin-clavulanate for treatment of children with recurrent or persistent AOM. Three hundred four children were randomized; 300 received either high-dose azithromycin (20 mg/kg of body weight once a day for 3 days) or high-dose amoxicillin-clavulanate (90 mg/kg divided twice a day for 10 days). Tympanocentesis was performed at baseline; clinical response was assessed at day 12 to 16 and day 28 to 32. Two-thirds of patients were aged ≤2 years. A history of recurrent, persistent, or recurrent plus persistent AOM was noted in 67, 18, and 14% of patients, respectively. Pathogens were isolated from 163 of 296 intent-to-treat patients (55%). At day 12 to 16, clinical success rates for azithromycin and amoxicillin-clavulanate were comparable for all patients (86 versus 84%, respectively) and for children aged ≤2 years (85 versus 79%, respectively). At day 28 to 32, clinical success rates for azithromycin were superior to those for amoxicillin-clavulanate for all patients (72 versus 61%, respectively; P = 0.047) and for those aged ≤2 years (68 versus 51%, respectively; P = 0.017). Per-pathogen clinical efficacy against Streptococcus pneumoniae and Haemophilus influenzae was comparable between the two regimens. The rates of treatment-related adverse events for azithromycin and amoxicillin-clavulanate were 32 and 42%, respectively (P = 0.095). Corresponding compliance rates were 99 and 93%, respectively (P = 0.018). These data demonstrate the efficacy and safety of high-dose azithromycin for treating recurrent or persistent AOM. PMID:14506028

Efficacy of oral azithromycin versus topical tetracycline in mass treatment of endemic trachoma.

PubMed Central

Fraser-Hurt, N.; Bailey, R. L.; Cousens, S.; Mabey, D.; Faal, H.; Mabey, D. C.

2001-01-01

OBJECTIVE: To compare the impact of mass treatment with oral azithromycin and topical tetracycline on the prevalence of active trachoma. METHODS: A total of 1803 inhabitants from 106 households of eight Gambian villages were randomized, in pairs, to receive either three doses of azithromycin at weekly intervals, or daily topical tetracycline over 6 weeks. Ocular examinations were conducted before treatment, and 2, 6 and 12 months after treatment. FINDINGS: Prior to treatment, 16% of the study participants had active trachoma. Two months after treatment, the prevalence of trachoma was 4.6% and 5.1% in the azithromycin and the tetracycline groups, respectively (adjusted odds ratio (OR) = 1.09; 95% confidence interval (CI) = 0.53, 2.02). Subsequently, the prevalence rose to 16% in the tetracycline group, while remaining at 7.7% in the azithromycin group (adjusted OR at 12 months = 0.52; 95% CI = 0.34, 0.80). At 12 months post-treatment, there were fewer new prevalent cases in the azithromycin group, and trachoma resolution was significantly better for this group (adjusted OR = 2.02; 95% CI = 1.42, 3.50). CONCLUSION: Oral azithromycin therefore appears to offer a means for controlling blinding trachoma. It is easy to administer and higher coverages may be possible than have been achieved hitherto. PMID:11477966

Does Mass Azithromycin Distribution Impact Child Growth and Nutrition in Niger? A Cluster-Randomized Trial

PubMed Central

Amza, Abdou; Yu, Sun N.; Kadri, Boubacar; Nassirou, Baido; Stoller, Nicole E.; Zhou, Zhaoxia; West, Sheila K.; Bailey, Robin L.; Gaynor, Bruce D.; Keenan, Jeremy D.; Porco, Travis C.; Lietman, Thomas M.

2014-01-01

Background Antibiotic use on animals demonstrates improved growth regardless of whether or not there is clinical evidence of infectious disease. Antibiotics used for trachoma control may play an unintended benefit of improving child growth. Methodology In this sub-study of a larger randomized controlled trial, we assess anthropometry of pre-school children in a community-randomized trial of mass oral azithromycin distributions for trachoma in Niger. We measured height, weight, and mid-upper arm circumference (MUAC) in 12 communities randomized to receive annual mass azithromycin treatment of everyone versus 12 communities randomized to receive biannual mass azithromycin treatments for children, 3 years after the initial mass treatment. We collected measurements in 1,034 children aged 6–60 months of age. Principal Findings We found no difference in the prevalence of wasting among children in the 12 annually treated communities that received three mass azithromycin distributions compared to the 12 biannually treated communities that received six mass azithromycin distributions (odds ratio = 0.88, 95% confidence interval = 0.53 to 1.49). Conclusions/Significance We were unable to demonstrate a statistically significant difference in stunting, underweight, and low MUAC of pre-school children in communities randomized to annual mass azithromycin treatment or biannual mass azithromycin treatment. The role of antibiotics on child growth and nutrition remains unclear, but larger studies and longitudinal trials may help determine any association. PMID:25210836

Intermittent androgen suppression in the LuCaP 23.12 prostate cancer xenograft model.

PubMed

Buhler, K R; Santucci, R A; Royai, R A; Whitney, S C; Vessella, R L; Lange, P H; Ellis, W J

2000-04-01

Intermittent androgen suppression (IAS) has been proposed as a method of delaying the onset of androgen-independent growth in prostate cancer. While several pilot studies have demonstrated the feasibility of such a treatment, no study to date has defined the effect of IAS on survival. We developed an IAS protocol for mice bearing the LuCaP 23.12 human prostate cancer xenograft, with each cycle consisting of 1 week of androgen replacement with a testosterone pellet followed by 3 weeks of androgen withdrawal. Mice that responded to castration with a 40% or greater decrease in serum prostate-specific antigen (PSA) were randomized to treatment with either continuous androgen suppression (CAS) or IAS. Serum PSA, tumor volume, and overall survival were monitored. A total of 75 mice met the randomization criteria. There was no significant difference of survival between animals treated with CAS or IAS (185 vs. 239 days, P = 0.1835). Serum PSA showed evidence of cycling with hormonal manipulation. No cycling was noted in tumor volume. IAS is not associated with a decrease in survival compared to CAS, yet in patients may offer quality-of-life improvements. Further studies of IAS in the setting of Institutional Review Board (IRB) approved clinical trials should be encouraged. Prostate 43:63-70, 2000. Published 2000 Wiley-Liss, Inc.

Comparing azithromycin and doxycycline for the treatment of rectal chlamydial infection: a retrospective cohort study

PubMed Central

Khosropour, Christine M.; Dombrowski, Julia C.; Barbee, Lindley A.; Manhart, Lisa E.; Golden, Matthew R.

2015-01-01

Background Centers for Disease Control and Prevention (CDC) guidelines recommend azithromycin or doxycycline for treatment of rectal chlamydial infection. Methods We created a retrospective cohort of male patients diagnosed with rectal chlamydia 1993-2012 at a sexually transmitted disease clinic in Seattle, Washington. Men were included in the analysis if they were treated with azithromycin (1g single dose) or doxycycline (100mg BID x 7 days) within 60 days of chlamydia diagnosis and returned for repeat testing 14-180 days post-treatment. We compared the risk of persistent/recurrent rectal chlamydial infection among recipients of the two drug regimens using four follow-up testing time intervals (14 to 30, 60, 90, and 180 days). Results Of 1,835 cases of rectal chlamydia diagnosed in the study period, 1,480 (81%) were treated with azithromycin or doxycycline without a second drug active against C. trachomatis. Of these, 407 (33%) of 1231 azithromycin-treated men and 95 (38%) of 249 doxycycline-treated men were re-tested 14-180 days after treatment (P=0.12); 88 (22%) and 8 (8%), respectively, had persistent/recurrent infection (P=0.002). Persistent/recurrent infection was higher among men treated with azithromycin compared to doxycycline at 14-30 days (4/53 (8%) vs. 0/20 (0%)), 14-60 days (23/136 (17%) vs. 0/36 (0%)), and 14-90 days (50/230 (22%) vs. 2/56 (4%)). In multivariate analysis, azithromycin-treated men had a significantly higher risk of persistent/recurrent infection in the 14-90 days (aRR=5.2, 95% CI=1.3-21.0) and 14-180 days (aRR=2.4, 95% CI=1.2-4.8) after treatment. Conclusions These data suggest that doxycycline may be more effective than azithromycin in the treatment of rectal chlamydial infections. PMID:24413484

Recombinant interleukin-12 and interleukin-18 antitumor therapy in a guinea-pig hepatoma cell implant model.

PubMed

Shiratori, Ikuo; Suzuki, Yasuhiko; Oshiumi, Hiroyuki; Begum, Nasim A; Ebihara, Takashi; Matsumoto, Misako; Hazeki, Kaoru; Kodama, Ken; Kashiwazaki, Yasuo; Seya, Tsukasa

2007-12-01

Interleukin (IL)-12 and IL-18 are secreted by myeloid cells activated with adjuvants such as Bacillus Calmette-Guérin (BCG) cell wall. They induce T-helper 1 polarization in the host immune system and upregulate production of lymphocyte interferon-gamma, which leads to the induction of an antitumor gene program. It has been reported that humans have an immune system that more closely resembles that of the guinea pig in adjuvant-response features rather than the mouse system, which prevents the mouse results being extrapolated to human immunotherapy. Here we have constructed a tumor-implant system in guinea pigs to evaluate the antitumor potential of guinea pig IL-12 (gpIL-12) and guinea pig IL-18 (gpIL-18). Purified recombinant gpIL-12 and gpIL-18 were prepared and applied intraperitoneally to tumor-bearing (line 10 hepatoma) guinea pigs as the basis of the adjuvant immunotherapy. Intraperitoneal administration of gpIL-12 and gpIL-18 led to retardation of primary tumor growth and suppression of lymph-node metastasis in tumor-bearing guinea pigs. The permissible range of IL-12 appeared wider in guinea pigs than in mice. Even at an IL-12 dose higher than that in mice, there was no evidence of side-effects until day 26, when the guinea pigs were killed. gpIL-18 augmented the antitumor effect of gpIL-12 but exerted less ability to suppress lymph-node metastasis. The effects of gpIL-12 and gpIL-18 on the tumors implanted in guinea pigs will encourage us to use IL-12- and IL-18-inducible adjuvants for immunotherapy in human patients with solid cancer.

A quantitative systems approach to identify paracrine mechanisms that locally suppress immune response to Interleukin-12 in the B16 melanoma model

PubMed Central

Kulkarni, Yogesh M.; Chambers, Emily; McGray, A. J. Robert; Ware, Jason S.; Bramson, Jonathan L.

2012-01-01

Interleukin-12 (IL12) enhances anti-tumor immunity when delivered to the tumor microenvironment. However, local immunoregulatory elements dampen the efficacy of IL12. The identity of these local mechanisms used by tumors to suppress immunosurveillance represents a key knowledge gap for improving tumor immunotherapy. From a systems perspective, local suppression of anti-tumor immunity is a closed-loop system - where system response is determined by an unknown combination of external inputs and local cellular cross-talk. Here, we recreated this closed-loop system in vitro and combined quantitative high content assays, in silico model-based inference, and a proteomic workflow to identify the biochemical cues responsible for immunosuppression. Following an induction period, the B16 melanoma cell model, a transplantable model for spontaneous malignant melanoma, inhibited the response of a T helper cell model to IL12. This paracrine effect was not explained by induction of apoptosis or creation of a cytokine sink, despite both mechanisms present within the co-culture assay. Tumor-derived Wnt-inducible signaling protein-1 (WISP-1) was identified to exert paracrine action on immune cells by inhibiting their response to IL12. Moreover, WISP-1 was expressed in vivo following intradermal challenge with B16F10 cells and was inferred to be expressed at the tumor periphery. Collectively, the data suggest that (1) biochemical cues associated with epithelial-to-mesenchymal transition can shape anti-tumor immunity through paracrine action and (2) remnants of the immunoselective pressure associated with evolution in cancer include both sculpting of tumor antigens and expression of proteins that proactively shape anti-tumor immunity. PMID:22777646

Macrophage IL-12p70 Signaling Prevents HSV-1–Induced CNS Autoimmunity Triggered by Autoaggressive CD4+ Tregs

PubMed Central

Mott, Kevin R.; Gate, David; Zandian, Mandana; Allen, Sariah J.; Rajasagi, Naveen Kumar; van Rooijen, Nico; Chen, Shuang; Arditi, Moshe; Rouse, Barry T.; Flavell, Richard A.; Town, Terrence; Ghiasi, Homayon

2011-01-01

Purpose. CD4+CD25+FoxP3+ naturally occurring regulatory T cells (Tregs) maintain self-tolerance and function to suppress overly exuberant immune responses. However, it is unclear whether innate immune cells modulate Treg function. Here the authors examined the role of innate immunity in lymphomyeloid homeostasis. Methods. The involvement of B cells, dendritic cells (DCs), macrophages, natural killer (NK) cells, and T cells in central nervous system (CNS) demyelination in different strains of mice infected ocularly with herpes simplex virus type 1 (HSV-1) was investigated. Results. The authors found that depletion of macrophages, but not DCs, B cells, NK cells, CD4+ T cells, or CD8+ T cells, induced CNS demyelination irrespective of virus or mouse strain. As with macrophage depletion, mice deficient in interleukin (IL)-12p35 or IL-12p40 showed CNS demyelination after HSV-1 infection, whereas demyelination was undetectable in HSV-1–infected, IL-23p19–deficient, or Epstein-Barr virus–induced gene 3-deficient mice. Demyelination could be rescued in macrophage-depleted mice after the injection of IL-12p70 DNA and in IL-12p35−/− or IL-12p40−/− mice after injection with IL-12p35 or IL-12p40 DNA or with recombinant viruses expressing IL-12p35 or IL-12p40. Using FoxP3-, CD4-, CD8-, or CD25-depletion and gene-deficient mouse approaches, the authors demonstrated that HSV-1–induced demyelination was blocked in the absence of CD4, CD25, or FoxP3 in macrophage-depleted mice. Flow cytometry showed an elevation of CD4+CD25+FoxP3+ T cells in the spleens of infected macrophage-depleted mice, and adoptive transfer of CD4+CD25+ T cells to infected macrophage-depleted severe combined immunodeficient mice induced CNS demyelination. Conclusions. The authors demonstrated that macrophage IL-12p70 signaling plays an important role in maintaining immune homeostasis in the CNS by preventing the development of autoaggressive CD4+ Tregs. PMID:21220560

Randomized Clinical Trial of Azithromycin vs. Erythromycin for the Treatment of Chlamydia Cervicitis in Pregnancy

PubMed Central

Edwards, M. S.; Carter, S. G.; LeBoeuf, F. W.; Menard, M. K.; Rainwater, K. P.

1996-01-01

Objective: The purpose of this study was to prospectively test the null hypothesis that there is no difference in the clinical effectiveness of azithromycin and erythromycin for the treatment of chlamydia cervicitis in pregnancy. Methods: All antepartum obstetrical patients underwent routine screening for chlamydia cervicitis using a DNA probe assay (Gen-Probe Pace, San Diego, CA). Women who tested positive for chlamydia cervicitis were prospectively randomized to receive either azithromycin 1 g orally at enrollment, or erythromycin 500 mg orally 4 times a day for 7 days. Sexual partners were referred to the county health department for evaluation and treatment. A test of cure was repeated in 2 weeks. Results were analyzed by chi-square analysis and Fisher's exact test when indicated. Results: One hundred forty women tested positive for chlamydia cervicitis and agreed to randomization. There were 4 (6.2%) treatment failures in the azithromycin group and 18 (27.7%) in the erythromycin group (P = 0.005). Gastrointestinal side effects were reported by 42 (65.5%) of the women taking erythromycin, but only 12 (19.4%) of those taking azithromycin (P < 0.002). Gastrointestinal side effects and resultant noncompliance were significantly related to treatment failure with erythromycin. Conclusions: The findings of this study support the conclusion that a single dose of azithromycin is a significantly more effective and better tolerated treatment regimen for chlamydia cervicitis in pregnancy than erythromycin which is currently recommended. PMID:18476121

Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial.

PubMed

Wong, Conroy; Jayaram, Lata; Karalus, Noel; Eaton, Tam; Tong, Cecilia; Hockey, Hans; Milne, David; Fergusson, Wendy; Tuffery, Christine; Sexton, Paul; Storey, Louanne; Ashton, Toni

2012-08-18

Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis. We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV(1)) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493. 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26-0·54; p<0·0001). Prebronchodilator FEV(1) did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI -0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (-5·17 units) and placebo groups (-1·92 units; difference -3·25, 95% CI -7

Signaling pathways of interleukin-1 actions in the brain: anatomical distribution of phospho-ERK1/2 in the brain of rat treated systemically with interleukin-1beta.

PubMed

Nadjar, A; Combe, C; Busquet, P; Dantzer, R; Parnet, P

2005-01-01

Interleukin-1beta is released at the periphery during infection and acts on the nervous system to induce fever, neuroendocrine activation, and behavioral changes. These effects are mediated by brain type I IL-1 receptors. In vitro studies have shown the ability of interleukin-1beta to activate mitogen-activated protein kinase signaling pathways including p38, c-Jun N-terminal kinase and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In contrast to other mitogen-activated protein kinases, little is known about ERK1/2 activation in the rat brain in response to interleukin-1beta. The aim of the present study was therefore to investigate spatial and temporal activation of ERK1/2 in the rat brain after peripheral administration of interleukin-1beta using immunohistochemistry to detect the phosphorylated form of the kinase. In non-stimulated conditions, phosphorylated ERK1/2 immunoreactivity was observed in neurons throughout the brain. Administration of interleukin-1beta (60 microg/kg, i.p.) induced the phosphorylation of ERK1/2 in areas at the interface between brain and blood or cerebrospinal fluid: meninges, circumventricular organs, endothelial like cells of the blood vessels, and in brain nuclei involved in behavioral depression, fever and neuroendocrine activation: paraventricular nucleus of the hypothalamus, supraoptic nucleus, central amygdala and arcuate nucleus. Double labeling of phosphorylated ERK1/2 and cell markers revealed the expression of phosphorylated ERK1/2 in neurons, astrocytes and microglia. Since phosphorylated ERK1/2 was found in structures in which type I IL-1 receptor has already been identified as well as in structures lacking this receptor, activation of ERK1/2 is likely to occur in response to both direct and indirect action of interleukin-1beta on its target cells.

Childhood mortality in a cohort treated with mass azithromycin for trachoma.

PubMed

Keenan, Jeremy D; Ayele, Berhan; Gebre, Teshome; Zerihun, Mulat; Zhou, Zhaoxia; House, Jenafir I; Gaynor, Bruce D; Porco, Travis C; Emerson, Paul M; Lietman, Thomas M

2011-04-01

Mass azithromycin distributions are used to clear ocular strains of chlamydia that cause trachoma, but treatments may also affect respiratory infections, diarrhea, and malaria. Here, we monitor a large cohort in which almost 90% of individuals received azithromycin. We assess whether receiving treatment is associated with reduced all-cause and infectious childhood mortality. As part of a clinical trial for trachoma, a census was conducted in 24 communities in rural Ethiopia. All individuals ≥1 year of age were eligible for single-dose oral azithromycin, although antibiotic coverage was not universal. A follow-up census was performed 26 months after treatment to estimate all-cause mortality among children 1-5 years of age, and verbal autopsies were performed to identify infectious mortality. The cohort included 35,052 individuals ≥1 year of age and 5507 children 1-5 years of age, of whom 4914 received a dose of azithromycin. All-cause mortality was significantly lower among those 1-5-year-old children who received azithromycin (odds ratio [OR]=0.35 [95% confidence interval {CI}, 0.17-0.74]), as was infectious mortality (OR=0.20 [95% CI, 0.07-0.58]). When individuals were compared only with members of the same household, azithromycin treatment was still associated with reduced all-cause mortality in children 1-5 years of age (OR=0.40 [95% CI, 0.16-0.96]), although this relationship was not statistically significant for infectious mortality (OR=0.35 [95% CI, 0.10-1.28]). This study demonstrated an association between mass oral azithromycin treatment and reduced all-cause and infectious childhood mortality. This relationship could not be attributed to bias at the level of the household. Mass azithromycin distributions may have benefits unrelated to trachoma. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

Radiation Inhibits Interleukin-12 Production via Inhibition of C-Rel through the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Signaling Pathway in Dendritic Cells

PubMed Central

Lee, Eun-Jung; Lee, Seo Jin; Kim, Ji-Hye; Kim, Kyoung-Jin; Yang, Seung-Hyun; Jeong, Keun-Yeong; Seong, Jinsil

2016-01-01

Radiotherapy (RT) is a potent anti-tumor modality. However, unwanted effects including increased recurrence and metastasis that involve factors such as cytokines, which induce complex molecular mechanisms, have also been reported. In a previous study, we showed that interleukin (IL)-12 and radiotherapy combination treatment suppressed tumor growth and metastasis in a hepatoma mouse model. In this study, we investigated the mechanism underlying the IL-12 anti-tumor effect during radiotherapy. In tumor-bearing mice, irradiation decreased IL-12 expression in the tumors and spleens. However, a number of dendritic cells infiltrated into the tumors in which IL-12 expression did not decrease. To further study the underlying detailed mechanism for this decrease in IL-12, LPS-stimulated bone marrow–derived dendritic cells (BMDCs) were irradiated, and then IL-12– and IL-6–associated molecules were examined in irradiated tumors and BMDCs. Irradiation resulted in IL-12 suppression and IL-6 increase. IL-6 and signal transducer and activator of transcription 3 (STAT3) inhibitors restored the irradiation-induced IL-12 decrease via suppression of C-Rel activation. Taken together, our study suggests that irradiation-induced IL-6 can decrease IL-12 production through the inhibition of C-Rel phosphorylation by the IL-6/STAT3 signaling pathway. PMID:26745884

Suppression of Cartilage Degradation by Zingerone Involving the p38 and JNK MAPK Signaling Pathway.

PubMed

Ruangsuriya, Jetsada; Budprom, Piyaporn; Viriyakhasem, Nawarat; Kongdang, Patiwat; Chokchaitaweesuk, Chatchadawalai; Sirikaew, Nutnicha; Chomdej, Siriwadee; Nganvongpanit, Korakot; Ongchai, Siriwan

2017-02-01

Zingerone, an active compound that is present in cooked ginger, has been claimed to be a bioactive ingredient that holds the potential of preventing and/or treating diseases involving inflammation. In this study, zingerone was used to discover its properties against joint inflammation using interleukin-1 β -induced osteoarthritis in cartilage explant and cell culture models. Zingerone was supplemented into the cartilage explant and cell culture media at different concentrations along with the presence of interleukin-1 β , an inducer of osteoarthritis. Markers indicating cartilage degradation, inflammation, and the signaling molecules involved in the inflammatory induction were investigated. Diacerien, an anti-osteoarthritic drug, was used as a positive control. Zingerone at a concentration of 40 µM reduced the level of matrix metalloproteinase-13 to about 31.95 ± 4.33 % compared with the interleukin-1 β -treated group and halted cartilage explant degradation as indicated by reducing the accumulative release of sulfated glycosaminoglycans by falling to the control concomitantly with an elevation of the remaining contents of uronic acid and collagen in the explant tissues when zingerone was added. In the SW1353 cell line model, zingerone efficiently suppressed the expression of TNF- α , interleukin-6, and interleukin-8 mRNA levels and tended to reduce the levels of both p38 and c-Jun N-terminal kinase phosphorylation. From the results of this study, it can be concluded that zingerone potentially reduced cartilage degradation, which is partially involved in p38 and c-Jun N-terminal kinases of the mitogen activator protein kinase signaling pathway leading to the reduction of proinflammatory cytokine amplification effects and cartilage-degrading enzyme syntheses. This finding supports the contention that ginger holds positive pharmaceutical effects against osteoarthritis. Georg Thieme Verlag KG Stuttgart · New York.

MicroRNA-130a-3p suppresses cell viability, proliferation and invasion in nasopharyngeal carcinoma by inhibiting CXCL12.

PubMed

Qu, Rongfeng; Sun, Yan; Li, Yarong; Hu, Chunmei; Shi, Guang; Tang, Yan; Guo, Dongrui

2017-01-01

Incidence of nasopharyngeal carcinoma (NPC) has remained high worldwide, posing a serious health problem. MicroRNAs (miRNAs) are a family of about 20-23 nucleotides small non-coding molecules, which play a significant role in NPC. In this study, we explored the molecular mechanisms of miR-130a-3p in inhibiting viability, proliferation, migration and invasion of NPC cells by suppressing CXCL12 . The relative expression of miR-130a-3p and CXCL12 mRNA expression in tissues and cells was measured by qRT-PCR. NPC cell line CNE-2Z was transfected with miR-130a-3p mimics, CXCL12 siRNA, cDNA- CXCL12 and negative control. Western Blot was performed to detect CXCL12 expression. The MTT assay was performed to study cell viability. The colony formation assay was done to test cell growth. Flow cytometry was conducted to analyze cell cycle and apoptosis. The Transwell assay was used to investigate cell migration and invasion. The results found that the up-regulation of miR-130a-3p or down-regulation of CXCL12 could inhibit viability, proliferation, migration and invasion of CNE-2Z cells. Luciferase-reporting system assay was performed to investigate miR-130a-3p could bind to the 3'UTR region of CXCL12 and the overexpression of miR-130a-3p could suppress CXCL12 expression. Collectively, our finding suggested demonstrated that miR-130a-3p could prohibit the progression of NPC by suppressing CXCL12 , which might serve as potential therapeutic targets for NPC.

Protective Effects of Carvedilol and Vitamin C against Azithromycin-Induced Cardiotoxicity in Rats via Decreasing ROS, IL1-β, and TNF-α Production and Inhibiting NF-κB and Caspase-3 Expression

PubMed Central

El-Shitany, Nagla A.; El-Desoky, Karema

2016-01-01

The Food and Drug Administration recently warned of the fatal cardiovascular risks of azithromycin in humans. In addition, a recently published study documented azithromycin-induced cardiotoxicity in rats. This study aimed to justify the exact cardiovascular events accompanying azithromycin administration in rats, focusing on electrocardiographic, biochemical, and histopathological changes. In addition, the underlying mechanisms were studied regarding reactive oxygen species production, cytokine release, and apoptotic cell-death. Finally, the supposed protective effects of both carvedilol and vitamin C were assessed. Four groups of rats were used: (1) control, (2) azithromycin, (3) azithromycin + carvedilol, and (4) azithromycin + vitamin C. Azithromycin resulted in marked atrophy of cardiac muscle fibers and electrocardiographic segment alteration. It increased the heart rate, lactate dehydrogenase, creatine phosphokinase, malondialdehyde, nitric oxide, interleukin-1 beta (IL1-β), tumor necrosis factor alpha (TNF-α), nuclear factor kappa beta (NF-κB), and caspase-3. It decreased reduced glutathione, glutathione peroxidase, and superoxide dismutase. Carvedilol and vitamin C prevented most of the azithromycin-induced electrocardiographic and histopathological changes. Carvedilol and vitamin C decreased lactate dehydrogenase, malondialdehyde, IL1-β, TNF-α, NF-κB, and caspase-3. Both agents increased glutathione peroxidase. This study shows that both carvedilol and vitamin C protect against azithromycin-induced cardiotoxicity through antioxidant, immunomodulatory, and antiapoptotic mechanisms. PMID:27274777

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses

PubMed Central

Mauger, David T.; Boehmer, Susan; Beigelman, Avraham; Fitzpatrick, Anne M.; Jackson, Daniel J.; Baxi, Sachin N.; Benson, Mindy; Burnham, Carey-Ann D.; Cabana, Michael; Castro, Mario; Chmiel, James F.; Covar, Ronina; Daines, Michael; Gaffin, Jonathan M.; Gentile, Deborah Ann; Holguin, Fernando; Israel, Elliot; Kelly, H. William; Lazarus, Stephen C.; Lemanske, Robert F.; Ly, Ngoc; Meade, Kelley; Morgan, Wayne; Moy, James; Olin, Tod; Peters, Stephen P.; Phipatanakul, Wanda; Pongracic, Jacqueline A.; Raissy, Hengameh H.; Ross, Kristie; Sheehan, William J.; Sorkness, Christine; Szefler, Stanley J.; Teague, W. Gerald; Thyne, Shannon; Martinez, Fernando D.

2016-01-01

IMPORTANCE Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed. OBJECTIVE To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment. INTERVENTION Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child’s signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12-through 18-month period. MAIN OUTCOMES AND MEASURES The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures. RESULTS A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for

Development and validation of a reversed-phase HPLC method for simultaneous estimation of ambroxol hydrochloride and azithromycin in tablet dosage form.

PubMed

Shaikh, K A; Patil, S D; Devkhile, A B

2008-12-15

A simple, precise and accurate reversed-phase liquid chromatographic method has been developed for the simultaneous estimation of ambroxol hydrochloride and azithromycin in tablet formulations. The chromatographic separation was achieved on a Xterra RP18 (250 mm x 4.6 mm, 5 microm) analytical column. A Mixture of acetonitrile-dipotassium phosphate (30 mM) (50:50, v/v) (pH 9.0) was used as the mobile phase, at a flow rate of 1.7 ml/min and detector wavelength at 215 nm. The retention time of ambroxol and azithromycin was found to be 5.0 and 11.5 min, respectively. The validation of the proposed method was carried out for specificity, linearity, accuracy, precision, limit of detection, limit of quantitation and robustness. The linear dynamic ranges were from 30-180 to 250-1500 microg/ml for ambroxol hydrochloride and azithromycin, respectively. The percentage recovery obtained for ambroxol hydrochloride and azithromycin were 99.40 and 99.90%, respectively. Limit of detection and quantification for azithromycin were 0.8 and 2.3 microg/ml, for ambroxol hydrochloride 0.004 and 0.01 microg/ml, respectively. The developed method can be used for routine quality control analysis of titled drugs in combination in tablet formulation.

Bradycardia and Hypothermia Complicating Azithromycin Treatment.

PubMed

Benn, Kerri; Salman, Sam; Page-Sharp, Madhu; Davis, Timothy M E; Buttery, Jim P

2017-08-11

BACKGROUND Azithromycin is a macrolide antibiotic widely used to treat respiratory, urogenital, and other infections. Gastrointestinal upset, headache, and dizziness are common adverse effects, and prolongation of the rate-corrected electrocardiographic QT interval and malignant arrhythmias have been reported. There are rare reports of bradycardia and hypothermia but not in the same patient. CASE REPORT A 4-year-old boy given intravenous azithromycin as part of treatment for febrile neutropenia complicating leukemia chemotherapy developed hypothermia (rectal temperature 35.2°C) and bradycardia (65 beats/minute) after the second dose, which resolved over several days post-treatment, consistent with persistence of high tissue azithromycin concentrations relative to those in plasma. A sigmoid Emax pharmacokinetic/pharmacodynamic model suggested a maximal azithromycin-associated reduction in heart rate of 23 beats/minute. Monitoring for these potential adverse effects should facilitate appropriate supportive care in similar cases. CONCLUSIONS Recommended azithromycin doses can cause at least moderate bradycardia and hypothermia in vulnerable pediatric patients, adverse effects that should prompt appropriate monitoring and which may take many days to resolve.

Large dosage amoxicillin/clavulanate, compared with azithromycin, for the treatment of bacterial acute otitis media in children.

PubMed

Hoberman, Alejandro; Dagan, Ron; Leibovitz, Eugene; Rosenblut, Andres; Johnson, Candice E; Huff, Anne; Bandekar, Rajesh; Wynne, Brian

2005-06-01

A large dosage pediatric formulation of amoxicillin/clavulanate with an improved pharmacokinetic/pharmacodynamic profile was developed to eradicate many penicillin-resistant strains of Streptococcus pneumoniae and Haemophilus influenzae (including beta-lactamase-producing strains). This randomized, investigator-blinded, multicenter trial examined treatment of bacterial acute otitis media (AOM) in children 6-30 months of age with amoxicillin/clavulanate (90/6.4 mg/kg/d in 2 divided doses for 10 days) versus azithromycin (10 mg/kg for 1 day followed by 5 mg/kg/d for 4 days). Tympanocentesis was performed at entry for bacteriologic assessment, at the on-therapy visit (day 4-6) to determine bacterial eradication and at any time before the end-of-therapy visit (day 12-14) if the child was categorized as experiencing clinical failure. Clinical assessments were performed at the on-therapy, end-of-therapy and follow-up (day 21-25) visits. We enrolled 730 children; AOM pathogens were isolated at baseline for 249 of the amoxicillin/clavulanate group and 245 of the azithromycin group. For children with AOM pathogens at baseline, clinical success rates at the end-of-therapy visit were 90.5% for amoxicillin/clavulanate versus 80.9% for azithromycin (P < 0.01), and those at the on-therapy and follow-up visits were 94.9% versus 88.0% and 80.3% versus 71.1%, respectively (all P < 0.05). At the on-therapy visit, pretherapy pathogens were eradicated for 94.2% of children receiving amoxicillin/clavulanate versus 70.3% of those receiving azithromycin (P < 0.001). Amoxicillin/clavulanate eradicated 96.0% of S. pneumoniae (92.0% of fully penicillin-resistant S. pneumoniae) and 89.7% of H. influenzae (85.7% [6 of 7 cases] of beta-lactamase-positive H. influenzae). Corresponding rates for azithromycin were 80.4% (54.5%) for S. pneumoniae and 49.1% (100% [1 of 1 case]) for H. influenzae (all P < 0.01 for between-drug comparisons). Amoxicillin/clavulanate was clinically and

Long-term azithromycin for Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease (Bronchiectasis Intervention Study): a multicentre, double-blind, randomised controlled trial.

PubMed

Valery, Patricia C; Morris, Peter S; Byrnes, Catherine A; Grimwood, Keith; Torzillo, Paul J; Bauert, Paul A; Masters, I Brent; Diaz, Abbey; McCallum, Gabrielle B; Mobberley, Charmaine; Tjhung, Irene; Hare, Kim M; Ware, Robert S; Chang, Anne B

2013-10-01

Indigenous children in high-income countries have a heavy burden of bronchiectasis unrelated to cystic fibrosis. We aimed to establish whether long-term azithromycin reduced pulmonary exacerbations in Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease. Between Nov 12, 2008, and Dec 23, 2010, we enrolled Indigenous Australian, Maori, and Pacific Island children aged 1-8 years with either bronchiectasis or chronic suppurative lung disease into a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial. Eligible children had had at least one pulmonary exacerbation in the previous 12 months. Children were randomised (1:1 ratio, by computer-generated sequence with permuted block design, stratified by study site and exacerbation frequency [1-2 vs ≥3 episodes in the preceding 12 months]) to receive either azithromycin (30 mg/kg) or placebo once a week for up to 24 months. Allocation concealment was achieved by double-sealed, opaque envelopes; participants, caregivers, and study personnel were masked to assignment until after data analysis. The primary outcome was exacerbation (respiratory episodes treated with antibiotics) rate. Analysis of the primary endpoint was by intention to treat. At enrolment and at their final clinic visits, children had deep nasal swabs collected, which we analysed for antibiotic-resistant bacteria. This study is registered with the Australian New Zealand Clinical Trials Registry; ACTRN12610000383066. 45 children were assigned to azithromycin and 44 to placebo. The study was stopped early for feasibility reasons on Dec 31, 2011, thus children received the intervention for 12-24 months. The mean treatment duration was 20·7 months (SD 5·7), with a total of 902 child-months in the azithromycin group and 875 child-months in the placebo group. Compared with the placebo group, children receiving azithromycin had significantly lower exacerbation rates (incidence rate ratio 0·50

[Susceptibility to azithromycin and other antibiotics in recent isolates of Salmonella, Shigella and Yersinia].

PubMed

Martín-Pozo, Angeles; Arana, David M; Fuentes, Miriam; Alós, Juan-Ignacio

2014-01-01

Azithromycin represents an alternative option to treat bacterial diarrhea when the antibiotic therapy is indicated. Little is known regarding the susceptibility to azithromycin in enteropathogens in Spain. The MICs of azithromycin were determined by E-test against Salmonella non-typhi (SNT), Shigella and Yersinia isolates collected over the last three years (2010-2012). In addition, the susceptibility to other antibiotics usually used to treat gastrointestinal diseases was determined in these isolates by using a microdilution method. A total of 139 strains of SNT, Shigella and Yersinia were studied. All of them, except one strain, had a MIC≤16mg/L of azithromycin. In the adult population, 14.7% and 40.6% of SNT and Shigella isolates, respectively, were resistant to at least 2 of following antibiotics: amoxicillin, trimethoprim-sulfamethoxazole and ciprofloxacin. In the pediatric population, 10% of SNT clinical isolates and 28.6% (2/7) of Shigella isolates were resistant to amoxicillin and trimethoprim-sulfamethoxazole. In our experience, azithromycin would be a useful antibiotic alternative to treat bacterial diarrhea. Copyright © 2013 Elsevier España, S.L. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

IL-12p40-dependent agonistic effects on the development of protective innate and adaptive immunity against Salmonella enteritidis.

PubMed

Lehmann, J; Bellmann, S; Werner, C; Schröder, R; Schütze, N; Alber, G

2001-11-01

To study a potential IL-12p40-dependent but IL-12p75-independent agonistic activity regulating the immune response against Salmonella Enteritidis, the course of infection in IL-12p35-deficient mice (IL-12p35(-/-), capable of producing IL-12p40) was compared with that of IL-12p40(-/-) mice. Mice lacking IL-12p40 revealed a higher mortality rate and higher bacterial organ burden than mice capable of producing IL-12p40. This phenotype was found in both genetically susceptible (BALB/c, Ity(s)) and resistant mice (129Sv/Ev, Ity(r)) indicating Ity-independent mechanisms. The more effective control of bacteria in the IL-12p35(-/-) mice was associated with elevated serum IFN-gamma and TNF-alpha levels. In contrast, IL-12p40(-/-) mice showed reduced IFN-gamma production, which was associated with significantly elevated serum IgE levels. Early during infection (days 3 and 4 postinfection), as well as late (day 20 postinfection), the number of infected phagocytes was strongly increased in the absence of IL-12p40 indicating impaired bactericidal activity when IL-12p40 was missing. Liver histopathology revealed a decreased number of mononuclear granulomas in IL-12p40(-/-) mice. Depletion of CD4(+) or CD8(+) T lymphocytes in vivo suggested that both T cell subpopulations contribute to the IL-12p40-dependent protective functions. Analysis of IL-12p40 vs IL-23p19 mRNA expression revealed an up-regulation of only IL-12p40 mRNA during Salmonella infection. Together these data indicate that IL-12p40 can induce protective mechanisms during both the innate and the adaptive type 1 immune response in Salmonella infection. This novel activity of IL-12p40 complements the well described dominant and essential role of IL-12p75 in protective immunity to Salmonella infection.

Identification and expression analysis of two interleukin-23α (p19) isoforms, in rainbow trout Oncorhynchus mykiss and Atlantic salmon Salmo salar.

PubMed

Jiang, Yousheng; Husain, Mansourah; Qi, Zhitao; Bird, Steve; Wang, Tiehui

2015-08-01

Interleukin (IL)-23 is a heterodimeric IL-12 family cytokine composed of a p19 α-chain, linked to a p40 β-chain that is shared with IL-12. IL-23 is distinguished functionally from IL-12 by its ability to induce the production of IL-17, and differentiation of Th17 cells in mammals. Three isoforms of p40 (p40a, p40b and p40c) have been found in some 3R teleosts. Salmonids also possess three p40 isoforms (p40b1, p40b2 and p40c) although p40a is missing, and two copies (paralogues) of p40b are present that have presumably been retained following the 4R duplication in this fish lineage. Teleost p19 has been discovered recently in zebrafish, but to date there is limited information on expression and modulation of this molecule. In this report we have cloned two p19 paralogues (p19a and p19b) in salmonids, suggesting that a salmonid can possess six potential IL-23 isoforms. Whilst Atlantic salmon has two active p19 genes, the rainbow trout p19b gene may have been pseudogenized. The salmonid p19 translations share moderate identities (22.8-29.9%) to zebrafish and mammalian p19 molecules, but their identity was supported by structural features, a conserved 4 exon/3 intron gene organisation, and phylogenetic tree analysis. The active salmonid p19 genes are highly expressed in blood and gonad. Bacterial (Yersinia ruckeri) and viral infection in rainbow trout induces the expression of p19a, suggesting pathogen-specific induction of IL-23 isoforms. Trout p19a expression was also induced by PAMPs (poly IC and peptidoglycan) and the proinflammatory cytokine IL-1β in primary head kidney macrophages. These data may indicate diverse functional roles of trout IL-23 isoforms in regulating the immune response in fish. Copyright © 2015 Elsevier Ltd. All rights reserved.

Levofloxacin versus azithromycin for treating legionella pneumonia: a propensity score analysis.

PubMed

Garcia-Vidal, C; Sanchez-Rodriguez, I; Simonetti, A F; Burgos, J; Viasus, D; Martin, M T; Falco, V; Carratalà, J

2017-09-01

Concerns have arisen regarding the equivalence of levofloxacin and some macrolides for treating community-acquired legionella pneumonia (LP). We aimed to compare the outcomes of current patients with LP treated with levofloxacin, azithromycin and clarithromycin. Observational retrospective multicentre study of consecutive patients with LP requiring hospitalization (2000-2014) conducted in two hospitals. The primary outcome assessed was 30-day mortality. To control for confounding, therapy was assessed by multivariate analysis. We documented 446 patients with LP, of which 175 were treated with levofloxacin, 177 with azithromycin and 58 with clarithromycin. No significant differences in time to defervescence (2 (interquartile range (IQR) 1-4) versus 2 (IQR 1-3) days; p 0.453), time to achieve clinical stability (3 (2-5) versus 3 (2-5) days; p 0.486), length of intravenous therapy (3 (2-5.25) versus 4 (3-6) days; p 0.058) and length of hospital stay (7 (5-10) versus 6 (5-9) days; p 0.088) were found between patients treated with levofloxacin and those treated with azithromycin. Patients treated with clarithromycin had longer intravenous antibiotic treatment (3 (2-5.25) versus 5 (3-6.25) days; p 0.002) and longer hospital stay (7 (5-10) versus 9 (7-14) days; p 0.043) compared with those treated with levofloxacin. The overall mortality was 4.3% (19 patients). Neither univariate nor multivariate analysis showed a significant association of levofloxacin versus azithromycin on mortality (4 (2.3%) versus 9 (5.1%) deaths; p 0.164). The results did not change after incorporation of the propensity score into the models. In our study, no significant differences in most outcomes were found between patients treated with levofloxacin and those treated with azithromycin. Due to the small number of deaths, results regarding mortality should be interpreted with caution. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All

Sigma Receptor 1 activation attenuates release of inflammatory cytokines MIP1γ, MIP2, MIP3α and IL12 (p40/p70) by retinal Müller glial cells

PubMed Central

Shanmugam, A.; Wang, J.; Markand, S.; Perry, R.L.; Tawfik, A.; Zorrilla, E.; Ganapathy, V.; Smith, S.B.

2015-01-01

The high affinity Sigma Receptor 1 (σR1) ligand (+)-pentazocine ((+)-PTZ) affords profound retinal neuroprotection in vitro and in vivo by a yet-unknown mechanism. A common feature of retinal disease is Müller cell reactive gliosis, which includes cytokine release. Here we investigated whether LPS stimulates cytokine release by primary mouse Müller cells and whether (+)-PTZ alters release. Using a highly sensitive inflammatory antibody array we observed significant release of macrophage inflammatory proteins (MIP1γ, MIP2, MIP3α) and interleukin-12 (IL12 (p40/p70)) in LPS-treated cells compared to controls, and a significant decrease in secretion upon (+)-PTZ treatment. Müller cells from σR1 knockout mice demonstrated increased MIP1γ, MIP2, MIP3α and IL12 (p40/p70) secretion when exposed to LPS compared to LPS-stimulated WT cells. We investigated whether cytokine secretion was accompanied by cytosolic-to-nuclear NFκB translocation and whether endothelial cell adhesion/migration was altered by released cytokines. Cells exposed to LPS demonstrated increased NFκB nuclear location, which was reduced significantly in (+)-PTZ-treated cells. Media conditioned by LPS-stimulated-Müller cells induced leukocyte-endothelial cell adhesion and endothelial cell migration, which was attenuated by (+)-PTZ treatment. The findings suggest that release of certain inflammatory cytokines by Müller cells can be attenuated by σR1 ligands providing insights into the retinal neuroprotective role of this receptor. PMID:25439327

Central Interleukin-1β Suppresses the Nocturnal Secretion of Melatonin

PubMed Central

Herman, A. P.; Bochenek, J.; Król, K.; Krawczyńska, A.; Antushevich, H.; Pawlina, B.; Herman, A.; Romanowicz, K.; Tomaszewska-Zaremba, D.

2016-01-01

In vertebrates, numerous processes occur in a rhythmic manner. The hormonal signal reliably reflecting the environmental light conditions is melatonin. Nocturnal melatonin secretion patterns could be disturbed in pathophysiological states, including inflammation, Alzheimer's disease, and depression. All of these states share common elements in their aetiology, including the overexpression of interleukin- (IL-) 1β in the central nervous system. Therefore, the present study was designed to determine the effect of the central injection of exogenous IL-1β on melatonin release and on the expression of the enzymes of the melatonin biosynthetic pathway in the pineal gland of ewe. It was found that intracerebroventricular injections of IL-1β (50 µg/animal) suppressed (P < 0.05) nocturnal melatonin secretion in sheep regardless of the photoperiod. This may have resulted from decreased (P < 0.05) synthesis of the melatonin intermediate serotonin, which may have resulted, at least partially, from a reduced expression of tryptophan hydroxylase. IL-1β also inhibited (P < 0.05) the expression of the melatonin rhythm enzyme arylalkylamine-N-acetyltransferase and hydroxyindole-O-methyltransferase. However, the ability of IL-1β to affect the expression of these enzymes was dependent upon the photoperiod. Our study may shed new light on the role of central IL-1β in the aetiology of disruptions in melatonin secretion. PMID:27212805

Chronic Azithromycin Use in Cystic Fibrosis and Risk of Treatment-Emergent Respiratory Pathogens.

PubMed

Cogen, Jonathan D; Onchiri, Frankline; Emerson, Julia; Gibson, Ronald L; Hoffman, Lucas R; Nichols, David P; Rosenfeld, Margaret

2018-02-23

Azithromycin has been shown to improve lung function and reduce the number of pulmonary exacerbations in cystic fibrosis patients. Concerns remain, however, regarding the potential emergence of treatment-related respiratory pathogens. To determine if chronic azithromycin use (defined as thrice weekly administration) is associated with increased rates of detection of eight specific respiratory pathogens. We performed a new-user, propensity-score matched retrospective cohort study utilizing data from the Cystic Fibrosis Foundation Patient Registry. Incident azithromycin users were propensity-score matched 1:1 with contemporaneous non-users. Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate the association between chronic azithromycin use and incident respiratory pathogen detection. Analyses were performed separately for each pathogen, limited to patients among whom that pathogen had not been isolated in the two years prior to cohort entry. After propensity score matching, mean age of the cohorts was ~12 years. Chronic azithromycin users had a significantly lower risk of detection of new methicillin-resistant Staphylococcus aureus, non-tuberculous mycobacteria, and Burkholderia cepacia complex compared to non-users. The risk of acquiring the remaining five pathogens was not significantly different between users and non-users. Using an innovative new-user, propensity-score matched study design to minimize indication and selection biases, we found in a predominantly pediatric cohort that chronic azithromycin users had a lower risk of acquiring several cystic fibrosis-related respiratory pathogens. These results may ease concerns that chronic azithromycin exposure increases the risk of acquiring new respiratory pathogens among pediatric cystic fibrosis patients.

Mechanistic study of the azithromycin dosage-form-dependent food effect.

PubMed

Curatolo, William; Foulds, George; Labadie, Robert

2010-07-01

Azithromycin capsules are known to exhibit a negative food effect, manifest as a decrease in azithromycin bioavailability in the fed state. Azithromycin tablets are known to be bioequivalent to capsules in the fasted state, but do not exhibit a food effect. In the present study, the involvement of gastric degradation of azithromycin to des-cladinose azithromycin (DCA) has been investigated as a possible mechanism for the observed capsule food effect. Healthy volunteers were dosed with azithromycin tablets and capsules, fasted and fed, in a four-way randomized crossover study. Serum levels of DCA were measured as a function of time post-dose. Natural log-transformed PK parameters were statistically analyzed using an ANOVA model appropriate for the study design. When capsules were dosed to fed subjects, the systemic AUC for DCA was 243% of the value observed after fasted-state dosing, and the DCA C(max) was 270% of the value observed after fasted-state dosing. When azithromycin tablets were dosed in the fasted and fed states, there was no significant difference in systemic DCA. Gastric degradation of azithromycin to DCA is the likely mechanism for the observed negative food effect observed for azithromycin capsules. This effect is not observed for tablets. These observations suggest that azithromycin capsules exhibit slow and/or delayed disintegration in the fed stomach, resulting in extended gastric residence and degradation of a portion of the gastrically retained azithromycin.

Dehydroepiandrosterone sulfate (DHEAS) suppresses P2X purinoceptor-coupled responses in PC12 cells.

PubMed

Liu, P S; Hsieh, H L; Lin, C M

2001-09-01

Some steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels in addition to their well-known genomic effects via intracellular steroid receptors. Such effects were found in GABA receptor, nicotinic receptors, yet not investigated in P2X purinoceptors. In this study, the effects of dehydroepiandrosterone sulfate on the P2 purinoceptor was investigated. Results show that dehydroepiandrosterone sulfate acutely inhibits P2X purinoceptor functions in PC12 cells. Dehydroepiandrosterone sulfate suppressed ATP-induced cytosolic free calcium concentration ([Ca(2+)](i)) rise, cytosolic free sodium concentration ([Na(+)](i)) rise, and dopamine secretion in the presence of external calcium, but had no effect on ATP-induced [Ca(2+)](i) rise in the absence of external calcium or on UTP-induced [Ca(2+)](i) rise in the absence or presence of external calcium. Our data show that dehydroepiandrosterone sulfate exerted its effect on P2X, but not on the P2Y purinoceptors found in PC12 cells. Estradiol and estrone have similar effects on P2X purinoceptor, but dehydroepiandrosterone and progesterone do not.

pH-Dependent stability of azithromycin in aqueous solution and structure identification of two new degradation products.

PubMed

Saita, Maria Grazia; Aleo, Danilo; Melilli, Barbara; Mangiafico, Sergio; Cro, Melina; Sanfilippo, Claudia; Patti, Angela

2018-05-28

The degradation profile of azithromycin in buffered solutions was investigated using HPLC and found to be pH dependent in the range of 6.0-7.2. Desosaminylazitromycin, derived from hydrolytic loss of cladinose of the parent molecule, was the major degradation product at pH 6.0 but its amount progressively decreased moving toward pH 7.2. Two additional unreported degradation products were also observed and their structures were fully elucidated by MS- and NMR-spectroscopy to be associated with opening of the macrocyclic lactone ring. Copyright © 2018. Published by Elsevier B.V.

Continuous release of interleukin 12 from microencapsulated engineered cells for colon cancer therapy

PubMed Central

Zheng, Shu; Xiao, Zuo-Xiang; Pan, Yue-Long; Han, Ming-Yong; Dong, Qi

2003-01-01

AIM: To explore the anti-tumor immunity against CT26 colon tumor of the microencapsulated cells modified with murine interleukine-12 (mIL-12) gene. METHODS: Mouse fibroblasts (NIH3T3) were stably transfected to express mIL-12 using expression plasmids carrying mIL-12 gene (p35 and p40), and NIH3T3-mIL-12 cells were encapsulated in alginate microcapsules for long-term delivery of mIL-12. mIL-12 released from the microencapsulated NIH3T3-mIL-12 cells was confirmed using ELISA assay. Transplantation of the microencapsulated NIH3T3-mIL-12 cells was performed in the tumor-bearing mice with CT26 cells. The anti-tumor responses and the anti-tumor activities of the microencapsulated NIH3T3-mIL-12 cells were evaluated. RESULTS: Microencapsulated NIH3T3-mIL-12 cells could release mIL-12 continuously and stably for a long time. After the microencapsulated NIH3T3-mIL-12 cells were transplanted subcutaneously into the tumor-bearing mice for 21 d, the serum concentrations of mIL-12, mIL-2 and mIFN-γ, the cytotoxicity of the CTL from the splenocytes and the NK activity in the treatment group were significantly higher than those in the controls. Moreover, mIL-12 released from the microencapsulated NIH3T3-mIL-12 cells resulted in a significant inhibition of tumor proliferation and a prolonged survival of tumor-bearing mice. CONCLUSION: The microencapsulated NIH3T3-mIL-12 cells have a significant therapeutic effect on the experimental colon tumor by activating anti-tumor immune responses in vivo. Microencapsulated and genetically engineered cells may be an extremely versatile tool for tumor gene therapy. PMID:12717836

Azithromycin versus Doxycycline for Urogenital Chlamydia trachomatis Infection.

PubMed

Geisler, William M; Uniyal, Apurva; Lee, Jeannette Y; Lensing, Shelly Y; Johnson, Shacondra; Perry, Raymond C W; Kadrnka, Carmel M; Kerndt, Peter R

2015-12-24

Urogenital Chlamydia trachomatis infection remains prevalent and causes substantial reproductive morbidity. Recent studies have raised concern about the efficacy of azithromycin for the treatment of chlamydia infection. We conducted a randomized trial comparing oral azithromycin with doxycycline for the treatment of urogenital chlamydia infection among adolescents in youth correctional facilities, to evaluate the noninferiority of azithromycin (1 g in one dose) to doxycycline (100 mg twice daily for 7 days). The treatment was directly observed. The primary end point was treatment failure at 28 days after treatment initiation, with treatment failure determined on the basis of nucleic acid amplification testing, sexual history, and outer membrane protein A (OmpA) genotyping of C. trachomatis strains. Among the 567 participants enrolled, 284 were randomly assigned to receive azithromycin, and 283 were randomly assigned to receive doxycycline. A total of 155 participants in each treatment group (65% male) made up the per-protocol population. There were no treatment failures in the doxycycline group. In the azithromycin group, treatment failure occurred in 5 participants (3.2%; 95% confidence interval, 0.4 to 7.4%). The observed difference in failure rates between the treatment groups was 3.2 percentage points, with an upper boundary of the 90% confidence interval of 5.9 percentage points, which exceeded the prespecified absolute 5-percentage-point cutoff for establishing the noninferiority of azithromycin. In the context of a closed population receiving directly observed treatment for urogenital chlamydia infection, the efficacy of azithromycin was 97%, and the efficacy of doxycycline was 100%. The noninferiority of azithromycin was not established in this setting. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00980148.).

Comparison of minocycline and azithromycin for the treatment of mild scrub typhus in northern China.

PubMed

Zhao, Minxing; Wang, Ting; Yuan, Xiaoyu; Du, Weiming; Lin, Miaoxin; Shen, Yanbo

2016-09-01

Scrub typhus, caused by Orientia tsutsugamushi, has recently emerged in northern China where the disease had not been known to exist. Although doxycycline and azithromycin are the recommended agents for the treatment of scrub typhus, clinical responses depend both on the susceptibilities of various O. tsutsugamushi strains and the severity of the disease. A retrospective analysis was conducted on patients diagnosed with mild scrub typhus from August 2013 to January 2016 in the Affiliated Hospital of Nantong University, northern China. A total of 40 patients who received minocycline treatment and 34 patients who received azithromycin treatment were included in the analysis. All patients except one defervesced within 120 h after initiating antimicrobial therapy. Kaplan-Meier curves in association with log-rank test showed that the median time to defervescence was significantly shorter for the minocycline-treated group than the azithromycin-treated group (P = 0.003). There were no serious adverse events during treatment. No relapse occurred in either group during the 1-month follow-up period. In conclusion, both minocycline and azithromycin are effective and safe for the treatment of mild scrub typhus, but minocycline is more active than azithromycin against O. tsutsugamushi infection acquired in northern China. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Haloperidol Suppresses NF-kappaB to Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Response in RAW 264 Cells

PubMed Central

Yamamoto, Shunsuke; Ohta, Noriyuki; Matsumoto, Atsuhiro; Horiguchi, Yu; Koide, Moe; Fujino, Yuji

2016-01-01

Background Haloperidol, a tranquilizing agent, is administered both to treat symptoms of psychotic disorders and to sedate agitated and delirious patients. Notably, haloperidol has been suggested to inhibit the immune response through unknown mechanisms. We hypothesized that the sedative modulates the immune response via NF-κB. Material/Methods Using flow cytometry, we analyzed the effects of haloperidol on expression CD80 and CD86 in RAW 264 cells and in primary macrophages derived from bone marrow. Secretion of interleukin (IL)-1β, IL-6, and IL-12 p40 was measured by enzyme-linked immunosorbent assay. In addition, NF-κB activation was evaluated using a reporter assay based on secretory embryonic alkaline phosphatase. Finally, synthetic antagonists were used to identify the dopamine receptor that mediates the effects of haloperidol. Results Haloperidol inhibited NF-κB activation, and thereby suppressed expression of CD80, as well as secretion of IL-1β, IL-6, and IL-12 p40. CD80 and IL-6 levels were similarly attenuated by a D2-like receptor antagonist, but not by a D1-like receptor antagonist. Conclusions The data strongly suggest that haloperidol inhibits the immune response by suppressing NF-κB signaling via the dopamine D2 receptor. PMID:26842661

Haloperidol Suppresses NF-kappaB to Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Response in RAW 264 Cells.

PubMed

Yamamoto, Shunsuke; Ohta, Noriyuki; Matsumoto, Atsuhiro; Horiguchi, Yu; Koide, Moe; Fujino, Yuji

2016-02-04

BACKGROUND Haloperidol, a tranquilizing agent, is administered both to treat symptoms of psychotic disorders and to sedate agitated and delirious patients. Notably, haloperidol has been suggested to inhibit the immune response through unknown mechanisms. We hypothesized that the sedative modulates the immune response via NF-κB. MATERIAL AND METHODS Using flow cytometry, we analyzed the effects of haloperidol on expression CD80 and CD86 in RAW 264 cells and in primary macrophages derived from bone marrow. Secretion of interleukin (IL)-1β, IL-6, and IL-12 p40 was measured by enzyme-linked immunosorbent assay. In addition, NF-κB activation was evaluated using a reporter assay based on secretory embryonic alkaline phosphatase. Finally, synthetic antagonists were used to identify the dopamine receptor that mediates the effects of haloperidol. RESULTS Haloperidol inhibited NF-κB activation, and thereby suppressed expression of CD80, as well as secretion of IL-1β, IL-6, and IL-12 p40. CD80 and IL-6 levels were similarly attenuated by a D2-like receptor antagonist, but not by a D1-like receptor antagonist. CONCLUSIONS The data strongly suggest that haloperidol inhibits the immune response by suppressing NF-kB signaling via the dopamine D2 receptor.

Subantibiotic dose of azithromycin attenuates alveolar bone destruction and improves trabecular microarchitectures in a rat model of experimental periodontitis: A study using micro-computed tomography.

PubMed

Park, Hye-Shin; Lee, Yong Sun; Choi, Eun-Young; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

2017-06-01

Azithromycin, a macrolide antibiotic, has anti-inflammatory and immunomodulatory activities apart from its antibacterial properties. In this study, we examined the efficacy of subantibiotic dose of azithromycin on ligature-induced periodontitis in rats using micro-computed tomography (micro-CT) imaging and bone parameter analysis. Male Sprague-Dawley rats were allocated to the following four groups: non-ligation (NL) group; ligation-only (L) group; ligation-plus-subantibiotic dose azithromycin (SA) group; and 4) ligation-plus-antibiotic dose azithromycin (AA) group. The rats from Groups L, SA and AA were subjected to periodontitis by placing a ligature around lower right first molar. Immediately after ligation, the rats in SA and AA groups received daily intraperitoneal injections of azithromycin at a dosage of 3.5 or 10mg/kg body weight, respectively. The ligatures were maintained for 2weeks at which time the rats had their mandibles hemisected for micro-CT analysis. Subantibiotic dose of azithromycin strongly suppressed reductions in alveolar bone height and bone volume fraction caused by experimental periodontitis. When subantibiotic dosage of azithromycin was administered to rats, ligature-induced alterations in microarchitectural parameters of trabecular bone were significantly reversed. Rats treated with subantibiotic dose of azithromycin presented no significant difference compared to rats with antibiotic dosage in all parameters. While further studies are necessary, subantibiotic dose of azithromycin could be utilized as a host modulator for the treatment of periodontitis. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of interleukins 2 and 12 on TBT-induced alterations of MAP kinases p38 and p44/42 in human natural killer cells.

PubMed

Aluoch, Aloice O; Whalen, Margaret M

2006-01-01

NK cells are lymphocytes in the non-adaptive immune system that protect the body against intracellular pathogens and eliminate tumor cells. Tributyltin (TBT) is a toxic chemical that has been detected in human foods as well as in human blood. The role of TBT in immunosuppression has been described, including inhibition of the human NK-cell cytotoxic function. Previous studies indicated that exposure of NK cells to TBT for 1 h induced progressive and irreversible inhibition of cytotoxic function. However, it was found that if NK cells were incubated in TBT-free media with either IL-2 or IL-12, loss of cytotoxic function was prevented/reversed within 24 h. Molecular studies established that loss of cytotoxic function is accompanied by alteration of MAP kinases (MAPKs) p38 and p44/42 phosphorylation. This study examined whether interleukin-mediated recovery of cytotoxicity involved reversal of tributyltin-altered p38 and p44/42 phosphorylation. The results indicated that there was no substantial IL-2 prevention/reversal of the TBT-induced alteration of phosphorylation of either p38 or p44/42 after either a 24 or 48 h recovery period. Additionally, IL-12 caused no substantial prevention/reversal of the TBT-induced alteration of phosphorylation of the MAPKs seen after either 24 or 48 h. These data suggest that IL-2 and/or IL-12-mediated recovery of NK cytotoxic function is not a result of prevention/reversal of TBT-induced phosphorylation of p38 and p44/42 MAPKs at the 24 or 48 h time points. Copyright 2005 John Wiley & Sons, Ltd.

A comparative study of single-dose treatment of chancroid using thiamphenicol versus Azithromycin.

PubMed

Belda, Walter; Di Chiacchio, Nilton G; Di Chiacchio, Nilton; Romiti, Ricardo; Criado, Paulo R; Velho, Paulo Eduardo N Ferreira

2009-06-01

A study was conducted in São Paulo, Brazil, to compare azithromycin with thiamphenicol for the single-dose treatment of chancroid. In all, 54 men with chancroid were tested. The etiology was determined by clinical characterization and direct bacterioscopy with Gram staining. None of the patients had positive serology or dark-field examination indicating active infection with Treponema pallidum. Genital infections due to Neisseria gonorrhoeae and herpes simplex virus were excluded by polymerase chain reaction testing. For 54 patients with chancroid, cure rates with single-dose treatment were 73% with azithromycin and 89% with thiamphenicol. HIV seropositivity was found to be associated with treatment failure (p=0.001). The treatment failed in all HIV positive patients treated with azithromycin (p=0.002) and this drug should be avoided in these co-infected patients. In the view of the authors, thiamphenicol is the most indicated single-dose regimen for chancroid treatment.

Minocycline Suppresses Interleukine-6, Its Receptor System and Signaling Pathways and Impairs Migration, Invasion and Adhesion Capacity of Ovarian Cancer Cells: In Vitro and In Vivo Studies

PubMed Central

Ataie-Kachoie, Parvin; Morris, David L.; Pourgholami, Mohammad H.

2013-01-01

Interleukin (IL)-6 has been shown to be a major contributing factor in growth and progression of ovarian cancer. The cytokine exerts pro-tumorigenic activity through activation of several signaling pathways in particular signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK)1/2. Hence, targeting IL-6 is becoming increasingly attractive as a treatment option in ovarian cancer. Here, we investigated the effects of minocycline on IL-6 and its signaling pathways in ovarian cancer. In vitro, minocycline was found to significantly suppress both constitutive and IL-1β or 4-hydroxyestradiol (4-OH-E2)-stimulated IL-6 expression in human ovarian cancer cells; OVCAR-3, SKOV-3 and CAOV-3. Moreover, minocycline down-regulated two major components of IL-6 receptor system (IL-6Rα and gp130) and blocked the activation of STAT3 and ERK1/2 pathways leading to suppression of the downstream product MCL-1. In female nude mice bearing intraperitoneal OVCAR-3 tumors, acute administration (4 and 24 h) of minocycline (30 mg/kg) led to suppression of IL-6. Even single dose of minocycline was effective at significantly lowering plasma and tumor IL-6 levels. In line with this, tumoral expression of p-STAT3, p-ERK1/2 and MCL-1 were decreased in minocycline-treated mice. Evaluation of the functional implication of minocycline on metastatic activity revealed the capacity of minocycline to inhibit cellular migration, invasion and adhesion associated with down-regulation of matrix metalloproteinases (MMP)-2 and 9. Thus, the data suggest a potential role for minocycline in suppressing IL-6 expression and activity. These effects may prove to be an important attribute to the upcoming clinical trials of minocycline in ovarian cancer. PMID:23593315

Mass drug administration of azithromycin for trachoma reduces the prevalence of genital Chlamydia trachomatis infection in the Solomon Islands.

PubMed

Marks, M; Bottomley, C; Tome, H; Pitakaka, R; Butcher, R; Sokana, O; Kako, H; Solomon, A W; Mabey, D C

2016-06-01

Chlamydia trachomatis is the most common bacterial sexually transmitted infection and is frequently asymptomatic; ocular C. trachomatis strains cause trachoma. Mass drug administration (MDA) of azithromycin for trachoma might also reduce the prevalence of genital C. trachomatis. In a survey conducted in the Solomon Islands in 2014, prior to MDA, the prevalence of genital C. trachomatis was 20.3% (95% CI 15.9% to 25.4%). We conducted a survey to establish the impact of MDA with azithromycin on genital C. trachomatis. Women attending three community outpatient clinics, predominantly for antenatal care, 10 months after MDA with azithromycin given for trachoma elimination, were enrolled in this survey. Self-taken high vaginal swabs were for C. trachomatis and Neisseria gonorrhoeae using the BD Probetec strand displacement assay. 298 women were enrolled. C. trachomatis infection was diagnosed in 43 women (14.4%, 95% CI 10.6% to 18.9%) and N. gonorrhoeae in 9 (3%, 95% CI 1.4% to 5.7%). The age-adjusted OR for C. trachomatis infection was consistent with a significant decrease in the prevalence of C. trachomatis following MDA (OR 0.58, 95% CI 0.37 to 0.94, p=0.027). There was no change in the prevalence of N. gonorrhoeae between following MDA (OR 0.51, 95% CI 0.22 to 1.22, p=0.13). This study demonstrated a 40% reduction in the age-adjusted prevalence of genital C. trachomatis infection following azithromycin MDA for trachoma elimination. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Murine bone marrow-derived mesenchymal stem cells as vehicles for interleukin-12 gene delivery into Ewing sarcoma tumors.

PubMed

Duan, Xiaoping; Guan, Hui; Cao, Ying; Kleinerman, Eugenie S

2009-01-01

This study evaluated the therapeutic efficacy of interleukin 12 (IL-12) gene therapy in Ewing sarcoma and whether murine mesenchymal stem cells (MSCs) could serve as vehicles for IL-12 gene delivery. MSCs were isolated from murine bone marrow cells. Cells were phenotyped using flow cytometry. Cultured MSCs differentiated into osteocytes and adipocytes using the appropriate media. Freshly isolated MSCs were transfected with adenoviral vectors containing either the beta-galactosidase (Ad:beta-gal) or the IL-12 (Ad:IL-12) gene. Expression of IL-12 was confirmed using reverse transcription polymerase chain reaction. Mice with TC71 Ewing sarcoma tumors were then treated intravenously with MSCs transfected with Ad:beta-gal or Ad:IL-12. Tumors were measured and analyzed by immunohistochemical analysis for expression of IL-12 protein. Expression of both p35 and p40 IL-12 subunits was demonstrated in MSCs transfected in vitro with Ad:IL-12. IL-12 expression was seen in tumors from mice treated with MSCs transfected with Ad:IL-12. Tumor growth was also significantly inhibited compared with that in mice treated with MSCs transfected with Ad:beta-gal. MSCs can be transfected with the IL-12 gene. These transfected cells localize to tumors after intravenous injection and induce local IL-12 protein production and the regression of established tumors. Copyright (c) 2008 American Cancer Society.

Oral azithromycin for treatment of posterior blepharitis.

PubMed

Igami, Thais Zamudio; Holzchuh, Ricardo; Osaki, Tammy Hentona; Santo, Ruth Miyuki; Kara-Jose, Newton; Hida, Richard Y

2011-10-01

To evaluate the effects of oral azithromycin in patients with posterior blepharitis. Twenty-six eyes of 13 patients with posterior blepharitis diagnosed by a qualified ophthalmologist were enrolled in this study. Patients were instructed to use oral azithromycin 500 mg per day for 3 days in 3 cycles with 7-day intervals. Subjective clinical outcomes were graded and scored 1 day before and 30 days after the end of the treatment (53 days after initiating the treatment) based on severity scores of: (1) eyelid debris; (2) eyelid telangiectasia; (3) swelling of the eyelid margin; (4) redness of the eyelid margin; and (5) ocular mucus secretion. For the assessment of global efficacy, patients were asked by the investigator to rate the subjective symptoms (eyelid itching, ocular itching, eyelid hyperemia, ocular hyperemia, ocular mucus secretion, photophobia, foreign body sensation, and dry eye sensation) on a scale of 0 (no symptoms) to 5 (severe symptoms). Break-up time, Schirmer I test, corneal fluorescein staining score, and rose bengal staining score were also performed in all patients. All clinical outcomes scoring showed statistically significant improvement after oral azithromycin, except for eyelid swelling. Average subjective symptom grading improved statistically after treatment with oral azithromycin, except for eyelid hyperemia, photophobia, and foreign body sensation. Average tear film break-up time values showed statistically significant improvement after the treatment with oral azithromycin. No statistically significant improvement was observed on average values of Schirmer I test, corneal fluorescein staining score, and rose bengal staining score. The combination of multiple clinical parameters shown in this study supports the clinical efficacy of pulsed oral azithromycin therapy for the management of posterior blepharitis.

Azithromycin is more allergenic than clarithromycin in children with suspected hypersensitivity reaction to macrolides.

PubMed

Barni, S; Butti, D; Mori, F; Pucci, N; Rossi, M E; Cianferoni, A; Novembre, E

2015-01-01

Macrolides are considered safe antibiotics with reduced allergenic activity. However, studies on the safety of macrolides are scarce, particularly in children. The aim of this study was to assess the frequency of hypersensitivity reactions to clarithromycin and azithromycin in a group of children referred to our allergy unit for suspected macrolide allergy. We retrospectively reviewed the charts of 90 children aged 1-17 years with symptoms suggestive of hypersensitivity reaction to clarithromycin or azithromycin between December 31, 2008 and December 31, 2013. The allergy workup included skin tests (ie, skin prick tests and/or intradermal tests), determination of serum specific IgE (sIgE) to clarithromycin and azithromycin, and, if necessary to reach a diagnosis, oral provocation tests. Seventy-seven children completed the allergy workup. A reaction to clarithromycin was recorded in 58 children (75.3%): 21 (36.2%) had a history of immediate reactions, and 37 (63.8%) had a history of nonimmediate reactions. A reaction to azithromycin was recorded in 19 children (24.6%): 6 (31.5%) had a history of immediate reaction, and 13 (68.42%) had a history of nonimmediate reaction. Positive results in skin tests and oral provocation tests with the suspect drug confirmed the diagnosis in 15.5% of reactions to clarithromycin (9 of 58) and in 47.3% of reactions to azithromycin (9 of 19) (P = .004). A complete allergy workup enabled us to confirm a diagnosis of clarithromycin and azithromycin allergy in 15.5% and 47.3% of cases, respectively. Azithromycin was more allergenic than clarithromycin in children.

Clinically and Microbiologically Derived Azithromycin Susceptibility Breakpoints for Salmonella enterica Serovars Typhi and Paratyphi A

PubMed Central

Thieu, Nga Tran Vu; Dolecek, Christiane; Karkey, Abhilasha; Gupta, Ruchi; Turner, Paul; Dance, David; Maude, Rapeephan R.; Ha, Vinh; Tran, Chinh Nguyen; Thi, Phuong Le; Be, Bay Pham Van; Phi, La Tran Thi; Ngoc, Rang Nguyen; Ghose, Aniruddha; Dongol, Sabina; Campbell, James I.; Thanh, Duy Pham; Thanh, Tuyen Ha; Moore, Catrin E.; Sona, Soeng; Gaind, Rajni; Deb, Monorama; Anh, Ho Van; Van, Sach Nguyen; Tinh, Hien Tran; Day, Nicholas P. J.; Dondorp, Arjen; Thwaites, Guy; Faiz, Mohamed Abul; Phetsouvanh, Rattanaphone; Newton, Paul; Basnyat, Buddha; Farrar, Jeremy J.; Baker, Stephen

2015-01-01

Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 S. Typhi and S. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 μg/ml. The proportion of Asian enteric fever isolates with an MIC of ≤16 μg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) for S. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P < 0.001) for S. Paratyphi A. A zone size of ≥13 mm to a 5-μg azithromycin disk identified S. Typhi isolates with an MIC of ≤16 μg/ml with a sensitivity of 99.7%. An azithromycin MIC of ≤16 μg/ml or disk inhibition zone size of ≥13 mm enabled the detection of susceptible S. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in S. Typhi isolates with an azithromycin MIC of >16 μg/ml and to determine MIC and disk breakpoints for S. Paratyphi A. PMID:25733500

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

PubMed

Lee, Dhong Hyun; Zandian, Mandana; Kuo, Jane; Mott, Kevin R; Chen, Shuang; Arditi, Moshe; Ghiasi, Homayon

2017-05-01

We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

PubMed Central

Lee, Dhong Hyun; Zandian, Mandana; Mott, Kevin R.; Chen, Shuang

2017-01-01

We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice. PMID:28542613

Sustained transmission of high-level azithromycin-resistant Neisseria gonorrhoeae in England: an observational study.

PubMed

Fifer, Helen; Cole, Michelle; Hughes, Gwenda; Padfield, Simon; Smolarchuk, Christa; Woodford, Neil; Wensley, Adrian; Mustafa, Nazim; Schaefer, Ulf; Myers, Richard; Templeton, Kate; Shepherd, Jill; Underwood, Anthony

2018-05-01

Between Nov 3, 2014, and Feb 24, 2017, 70 cases of high-level azithromycin-resistant (HL-AziR; minimum inhibitory concentration [MIC] ≥256 mg/L) Neisseria gonorrhoeae were reported from across England. Whole-genome sequencing was done to investigate this outbreak to determine whether the ongoing outbreak represented clonal spread of an HL-AziR N gonorrhoeae strain identified in Leeds. We also wanted to elucidate the molecular mechanisms of azithromycin resistance in N gonorrhoeae in the UK. In this observational study, whole-genome sequencing was done on the HL-AziR N gonorrhoeae isolates from England. As comparators, 110 isolates from the UK and Ireland with a range of azithromycin MICs were also sequenced, including eight isolates from Scotland with azithromycin MICs ranging from 0·12 mg/L to 1·00 mg/L that were N gonorrhoeae multi-antigen sequence type 9768 (ST9768), which was the sequence type initially responsible for the outbreak. The presence of mutations or genes associated with azithromycin resistance was also investigated. 37 of the 60 HL-AziR isolates from England belonged to ST9768, and were genetically similar (mean 4·3 single-nucleotide polymorphisms). A 2059A→G mutation was detected in three or all four alleles of the 23S rRNA gene. Five susceptible ST9768 isolates had one mutated 23S rRNA allele and one low-level resistant ST9768 isolate had two mutated alleles. Sustained transmission of a successful HL-AziR clone was seen across England. Mutation 2059A→G was found in isolates with lower azithromycin MICs. Azithromycin exposure might have provided the selection pressure for one or two mutated copies of the 23S rRNA gene to recombine with wild-type copies, leading to three or four mutated copies and the HL-AziR phenotype. HL-AziR could emerge in isolates with low azithromycin MICs and eliminate the effectiveness of azithromycin as part of dual therapy for the treatment of gonorrhoea. Public Health England. Copyright © 2018 Elsevier Ltd. All

Comparison effect of azithromycin gel 2% with clindamycin gel 1% in patients with acne.

PubMed

Mokhtari, Fatemeh; Faghihi, Gita; Basiri, Akram; Farhadi, Sadaf; Nilforoushzadeh, Mohammadali; Behfar, Shadi

2016-01-01

Acne vulgaris is the most common skin disease. Local and systemic antimicrobial drugs are used for its treatment. But increasing resistance of Propionibacterium acnes to antibiotics has been reported. In a double-blind clinical trial, 40 patients with mild to moderate acne vulgaris were recruited. one side of the face was treated with Clindamycin Gel 1% and the other side with Azithromycin Topical Gel 2% BID for 8 weeks and then they were assessed. Average age was 21. 8 ± 7 years. 82.5% of them were female. Average number of papules, pustules and comedones was similarly reduced in both groups and, no significant difference was observed between the two groups (P > 0.05, repeated measurs ANOVA). The mean indexes of ASI and TLC also significantly decreased during treatment in both groups, no significant difference was observed between the two groups. (P > 0.05, repeated measurs ANOVA). Also, impact of both drugs on papules and pustules was 2-3 times greater than the effect on comedones. Average satisfaction score was not significant between the two groups (P = 0.6, repeated measurs ANOVA). finally, frequency distribution of complications was not significant between the two groups (P > 0.05, Fisher Exact test). Azithromycin gel has medical impact at least similar to Clindamycin Gel in treatment of mild to moderate acne vulgaris, and it may be consider as suitable drug for resistant acne to conventional topical therapy.

Thalidomide reduces tumour necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn's disease.

PubMed

Bauditz, J; Wedel, S; Lochs, H

2002-02-01

Thalidomide improves clinical symptoms in patients with therapy refractory Crohn's disease, as shown in two recent studies. The mechanism of this effect however is still unknown. Suppression of tumour necrosis factor alpha (TNF-alpha) by thalidomide has been suggested as a possible mechanism. However, effects on other cytokines have not been adequately investigated. The aim of our study was to investigate the effects of thalidomide on cytokine production in patients with inflammatory bowel disease (IBD). Ten patients with therapy refractory IBD (nine Crohn's disease, one ulcerative colitis) received thalidomide 300 mg daily in a 12 week open label study. Production of TNF-alpha, interleukin (IL)-1 beta, IL-6, and IL-12 was investigated in short term cultures of stimulated colonic lamina propria mononuclear cells (LPMC) and peripheral blood monocytes (PBMC) before and after 12 weeks of treatment. LPMC were also cultured with graded doses of thalidomide. Three patients discontinued treatment because of sedative side effects. In the other patients, disease activity decreased significantly, with four patients achieving remission. Production of TNF-alpha and IL-12 decreased during treatment with thalidomide: LPMC (TNF-alpha: 42.3 (8.3) pg/ml v 16.4 (6.3); IL-12: 9.7 (3.3) v 5.0 (2.5); p<0.04) and PBMC (TNF-alpha: 62.8 (14.6) v 22.5 (9.2); p<0.02). Production of IL-1 beta and IL-6 did not change significantly. Culturing of LPMC with thalidomide showed a dose dependent decrease in TNF-alpha and IL-12 production. The clinical effects of thalidomide in Crohn's disease may be mediated by reduction of both TNF-alpha and IL-12.

Clinical effect of azithromycin as an adjunct to non-surgical treatment of chronic periodontitis: a meta-analysis of randomized controlled clinical trials.

PubMed

Zhang, Z; Zheng, Y; Bian, X

2016-06-01

The results of recent published studies focusing on the effect of azithromycin as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis are inconsistent. We conducted a meta-analysis of randomized controlled clinical trials to examine the effect of azithromycin combined with SRP on periodontal clinical parameters as compared to SRP alone. An electronic search was carried out on Pubmed, Embase and the Cochrane Central Register of Controlled Trials from their earliest records through December 28, 2014 to identify studies that met pre-stated inclusion criteria. Reference lists of retrieved articles were also reviewed. Data were extracted independently by two authors. Either a fixed- or random-effects model was used to calculate the overall effect sizes of azithromycin on probing depth, attachment level (AL) and bleeding on probing (BOP). Heterogeneity was evaluated using the Q test and I(2) statistic. Publication bias was evaluated by Begg's test and Egger's test. A total of 14 trials were included in the meta-analysis. Compared with SRP alone, locally delivered azithromycin plus SRP statistically significantly reduced probing depth by 0.99 mm (95% CI 0.42-1.57) and increased AL by 1.12 mm (95% CI 0.31-1.92). In addition, systemically administered azithromycin plus SRP statistically significantly reduced probing depth by 0.21 mm (95% CI 0.12-0.29), BOP by 4.50% (95% CI 1.45-7.56) and increased AL by 0.23 mm (95% CI 0.07-0.39). Sensitivity analysis yielded similar results. No evidence of publication bias was observed. The additional benefit of systemic azithromycin was shown at the initially deep probing depth sites, but not at shallow or moderate sites. The overall effect sizes of systemic azithromycin showed a tendency to decrease with time, and meta-regression analysis suggested a negative relation between the length of follow-up and net change in probing depth (r = -0.05, p = 0.02). This meta-analysis provides further

Change in pneumococcal susceptibility to azithromycin during treatment for acute otitis media.

PubMed

Toltzis, Philip; Dul, Michael; Blumer, Jeffrey

2007-07-01

Authorities have suggested restriction of azithromycin use as a principal strategy to contain the spread of azithromycin-nonsusceptible Streptococcus pneumoniae (ANSP). In 83 children persistently colonized by pneumococcus during and after treatment of acute otitis media, 17 acquired a new strain, 9 of which were less susceptible to azithromycin than the original isolate. New appearance of ANSP was documented after both beta-lactam and azithromycin exposure. ANSP is likely to disseminate even with significant reduction of azithromycin use unless other antibiotic use is decreased as well.

Targeted mass treatment for syphilis with oral azithromycin.

PubMed

Rekart, Michael L; Patrick, David M; Chakraborty, Bubli; Maginley, Juanita J L; Jones, H D; Bajdik, Chris D; Pourbohloul, Babak; Brunham, Robert C

2003-01-25

From mid 1997 to end of 1999, there was a sexually-transmitted infectious syphilis outbreak mainly in heterosexual people in British Columbia, Canada, that was concentrated in Vancouver. The rate across the province increased from less than 0.5 to 3.4 per 100000, and the rate in Vancouver reached 12.9 per 100000. We aimed to eliminate the syphillis outbreak by treating people at risk of infection. In 2000, a targeted mass treatment programme provided azithromycin (1.8 g orally) to 4384 at-risk residents in this city. After the programme, syphilis frequency fell significantly for 6 months (p=0.016), but rose again in 2001. Results from curve fitting analyses showed that the number of cases in 2001 (177) was higher than expected (0.0001<p<0.0044). This rate rebound and the absence of a sustained effect suggest that targeted mass treatment for syphilis, even though feasible, should not be done routinely.

Luteolin, a flavonoid, inhibits CD40 ligand expression by activated human basophils.

PubMed

Hirano, Toru; Arimitsu, Junsuke; Higa, Shinji; Naka, Tetsuji; Ogata, Atsushi; Shima, Yoshihito; Fujimoto, Minoru; Yamadori, Tomoki; Ohkawara, Tomoharu; Kuwabara, Yusuke; Kawai, Mari; Kawase, Ichiro; Tanaka, Toshio

2006-01-01

We have previously shown that flavonoids such as luteolin, apigenin and fisetin inhibit interleukin 4 and interleukin 13 production. In this study, we investigated whether luteolin can suppress CD40 ligand expression by basophils. A human basophilic cell line, KU812, was stimulated with A23187 and phorbol myristate acetate (PMA) with or without various concentrations of luteolin or other flavonoids for 12 h, and CD40 ligand expression was analyzed by FACS. The effect of luteolin on CD40 ligand mRNA expression was studied by semiquantitative reverse transcription PCR analysis. In addition, CD40 ligand expression was also measured in purified basophils that had been stimulated for 12 h with A23187 plus PMA with or without various concentrations of luteolin. CD40 ligand expression by KU812 cells was enhanced noticeably in response to A23187 and even more strikingly augmented by A23187 plus PMA. The expression was significantly suppressed by 10 or 30 microM of luteolin, whereas myricetin failed to inhibit. Reverse transcription PCR analyses demonstrated that luteolin inhibited CD40 ligand mRNA expression by stimulated KU812 cells. Of the six flavonoids examined, luteolin, apigenin, fisetin and quercetin at 30 microM showed a significant inhibitory effect on CD40 ligand expression. The incubation of purified basophils with A23187 plus PMA significantly enhanced CD40 ligand expression, and the presence of luteolin again had an inhibitory effect. Luteolin inhibits CD40 ligand expression by activated basophils.

Curcumin suppresses the production of interleukin-6 in Prevotella intermedia lipopolysaccharide-activated RAW 264.7 cells

PubMed Central

2011-01-01

Purpose Curcumin is known to exert numerous biological effects including anti-inflammatory activity. In this study, we investigated the effects of curcumin on the production of interleukin-6 (IL-6) by murine macrophage-like RAW 264.7 cells stimulated with lipopolysaccharide (LPS) from Prevotella intermedia, a major cause of inflammatory periodontal disease, and sought to determine the underlying mechanisms of action. Methods LPS was prepared from lyophilized P. intermedia ATCC 25611 cells by the standard hot phenol-water method. Culture supernatants were collected and assayed for IL-6. We used real-time polymerase chain reaction to detect IL-6 mRNA expression. IκB-α degradation, nuclear translocation of NF-κB subunits, and STAT1 phosphorylation were characterized via immunoblotting. DNA-binding of NF-κB was also analyzed. Results Curcumin strongly suppressed the production of IL-6 at both gene transcription and translation levels in P. intermedia LPS-activated RAW 264.7 cells. Curcumin did not inhibit the degradation of IκB-α induced by P. intermedia LPS. Curcumin blocked NF-κB signaling through the inhibition of nuclear translocation of NF-κB p50 subunit. Curcumin also attenuated DNA binding activity of p50 and p65 subunits and suppressed STAT1 phosphorylation. Conclusions Although further study is required to explore the detailed mechanism of action, curcumin may contribute to blockade of the host-destructive processes mediated by IL-6 and appears to have potential therapeutic values in the treatment of inflammatory periodontal disease. PMID:21811692

Effects of Caffeine Supplementation on Plasma and Blood Mononuclear Cell Interleukin-10 Levels After Exercise.

PubMed

Tauler, Pedro; Martinez, Sonia; Martinez, Pau; Lozano, Leticia; Moreno, Carlos; Aguiló, Antoni

2016-02-01

This study compared the response of interleukin (IL)-10, and also of IL-6 and IL-12 p40, to exercise and caffeine supplementation between plasma and blood mononuclear cells (BMNCs). Participants in the study (n = 28) were randomly allocated in a double-blind fashion to either caffeine (n = 14) or placebo (n = 14) treatments. One hour before completing a 15-km run competition, athletes took 6 mg/kg body mass of caffeine or a placebo. Plasma and BMNCs were purified from blood samples taken before and after competition. Concentrations of interleukins (IL-10, IL-6, and IL-12 p40), cyclic adenosine monophosphate (cAMP), caffeine, adrenaline, and cortisol were measured in plasma. IL-10, IL-6, and IL-12 p40 and cAMP levels were also determined in BMNCs. Exercise induced significant increases in IL-6 and IL-10 plasma levels, with higher increases in the caffeine-supplemented group. After 2-hr recovery, these levels returned to almost preexercise values. However, no effect of caffeine on BMNC cytokines was observed. IL-10, IL-6, and IL-12 p40 levels in BMNCs increased mainly at 2 hr postexercise. cAMP levels increased postexercise in plasma and after recovery in BMNCs, but no effects of caffeine were observed. In conclusion, caffeine did not modify cytokine levels in BMNCs in response to exercise. However, higher increases of IL-10 were observed in plasma after exercise in the supplemented participants, which could suppose an enhancement of the anti-inflammatory properties of exercise.

Josamycin suppresses Prevotella intermedia lipopolysaccharide-induced production of nitric oxide and interleukin-1β in murine macrophages.

PubMed

Choi, Eun-Young; Choe, So-Hui; Hyeon, Jin-Yi; Park, Hae Ryoun; Choi, In Soon; Kim, Sung-Jo

2018-06-05

Josamycin has immunomodulatory properties independent of its antibacterial actions. This study was designed to explore the influences and associated mechanisms of josamycin upon the generation of proinflammatory mediators in murine macrophages activated with lipopolysaccharide (LPS) from Prevotella intermedia, a pathogenic bacterium associated with periodontal disease. LPS was purified by employing phenol-water extraction protocol. Culture supernatants were analyzed for nitric oxide (NO) and interleukin (IL)-1β. Real-time PCR and immunoblotting were conducted to quantify mRNA and protein expression, respectively. The expression levels of IL-1β were analyzed by confocal laser scanning microscopy. NF-κB-dependent SEAP levels were estimated by reporter assay. Josamycin significantly attenuated NO production elicited by P. intermedia LPS as well as induction of iNOS protein and mRNA in RAW264.7 cells. While the release of IL-1β from cells stimulated by LPS was suppressed in the presence of josamycin, josamycin failed to reduce the degree of IL-1β mRNA expression. Josamycin did not reduce the stability of IL-1β mRNA induced by P. intermedia LPS, at the same time josamycin also failed to suppress the LPS-induced intracellular IL-1β expression. Josamycin augmented HO-1 induction in cells exposed to P. intermedia LPS, and SnPP, an inhibitor of HO-1 activity, reversed the suppressive impact of josamycin upon NO generation induced by LPS. Josamycin diminished NF-κB transcriptional activity induced by P. intermedia LPS. Further, josamycin enhanced SOCS1 mRNA level in cells activated with LPS. Josamycin suppressed P. intermedia LPS-induced generation of NO and IL-1β in RAW264.7 macrophages via the inhibition of NF-κB activation as well as HO-1 and SOCS1 induction. Josamycin may have benefits as a host modulatory agent in treating periodontal disease. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Human serum activity of telithromycin, azithromycin and amoxicillin/clavulanate against common aerobic and anaerobic respiratory pathogens.

PubMed

Stein, Gary E; Schooley, Sharon; Tyrrell, Kerin L; Citron, Diane M; Goldstein, Ellie J C

2007-01-01

Telithromycin is a new ketolide antimicrobial with a good in vitro activity against both aerobic and anaerobic respiratory pathogens. In this study, we evaluated the antibacterial activity over time of telithromycin (800mg), azithromycin (500mg), and amoxicillin/clavulanate (875/125mg) in serum following single oral doses of these agents to 10 healthy subjects. Inhibitory and bactericidal titers were determined at 2, 6, 12, and 24h after each dose and the median titer was used to determine antibacterial activity. Against two azithromycin-resistant strains of Streptococcus pneumoniae, both telithromycin (MIC=0.25 and 0.5 microg/mL) and amoxicillin/clavulanate exhibited inhibitory and cidal activity for at least 6h. All three antibiotics provided prolonged (>or=12h) inhibitory activity against strains of Hemophilus influenzae (telithromycin MIC=4.0 microg/ml). Both telithromycin and amoxicillin/clavulanate exhibited rapid and prolonged inhibitory activity (>or=12h) against each of the anaerobes studied (Finegoldia [Peptostreptococcus] magna Peptostreptococcus micros, Prevotella bivia, and Prevotella melaninogenica). Moreover, both agents provided bactericidal activity against both Prevotella species. In this ex vivo pharmacodynamic study, we found that telithromycin provided rapid and prolonged antibacterial activity in serum against macrolide-resistant strains of S. pneumoniae, beta-lactamase-positive and -negative strains of H. influenzae, and common respiratory anaerobic pathogens. These findings suggest that telithromycin could have clinical utility in the treatment of community-acquired mixed aerobic-anaerobic respiratory tract infections, including chronic sinusitis and aspiration pneumonia.

[Prevalence of potential drug interactions with azithromycin in Colombia, 2012-2013].

PubMed

Machado-Alba, Jorge E; Martínez-Pulgarín, Dayron F; Gómez-Suta, Daniela

2015-05-01

Objective To determine the prevalence of potential drug interactions between azithromycin and different IA and III antiarrhythmic groups in a national database of drug prescriptions in 2012-2013. Methods Retrospective study based on a population database of medicine dispensation. Data from patients who received azithromycin between January 1, 2012 and June 30, 2013 were extracted along with data from patients who received azithromycin in combination with other medications shown to cause heart arrhythmias when used concomitantly. Frequencies and proportions were established. Results 13 859 patients receiving azithromycin alone or in combination with other drugs were identified. The average time of use was 4.5 ± 0.9 days. A total of 702 patients (5.1 %) received azithromycin plus 19 other potentially risky drugs. The most frequently associated were loratadine (77.1 %), diphenhydramine (16.5 %) and amitriptyline (8.1 %). Combinations with a single drug were the most frequent (n=533, 75.9 %), predominantly azithromycin+loratadine. The maximum number of combined drugs was six (n=2, 0.3 %). Conclusions Identification of drug prescriptions through population databases is an effective way to find potential drug interactions. The frequency of potential interactions between azithromycin and other drugs is common in Colombian patients. Future research should assess the risk of occurrence of adverse cardiac events.

Ketamine suppresses the substance P-induced production of IL-6 and IL-8 by human U373MG glioblastoma/astrocytoma cells.

PubMed

Yamaguchi, Keisuke; Kumakura, Seiichiro; Murakami, Taisuke; Someya, Akimasa; Inada, Eiichi; Nagaoka, Isao

2017-03-01

The neuropeptide substance P (SP) is an important mediator of neurogenic inflammation within the central and peripheral nervous systems. SP has been shown to induce the expression of pro-inflammatory cytokines implicated in the pathogenesis of several disorders of the human brain via the neurokinin-1 receptor (NK-1R). Ketamine, an intravenous anesthetic agent, functions as a competitive antagonist of the excitatory neurotransmission N-methyl-D‑aspartate (NMDA) receptor, and also antagonizes the NK-1R by interfering with the binding of SP. In the present study, we investigated the anti-inflammatory effects of ketamine on the SP-induced activation of a human astrocytoma cell line, U373MG, which expresses high levels of NK-1R. The results from our experiments indicated that ketamine suppressed the production of interleukin (IL)-6 and IL-8 by the U373MG cells. Furthermore, ketamine inhibited the SP-induced activation of extracellular signal‑regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). Taken together, these observations suggest that ketamine may suppress the SP-induced activation (IL-6 and IL-8 production) of U373MG cells by inhibiting the phosphorylation of signaling molecules (namely ERK1/2, p38 MAPK and NF-κB), thereby exerting anti‑inflammatory effects. Thus, ketamine may modulate SP-induced inflammatory responses by NK-1R‑expressing cells through the suppression of signaling molecules (such as ERK1/2, p38 MAPK and NF-κB).

Substance P Receptor Antagonist Suppresses Inflammatory Cytokine Expression in Human Disc Cells.

PubMed

Kepler, Christopher K; Markova, Dessislava Z; Koerner, John D; Mendelis, Joseph; Chen, Chiu-Ming; Vaccaro, Alexander R; Risbud, Makarand V; Albert, Todd J; Anderson, D Greg

2015-08-15

Laboratory study. To evaluate whether blockade of the Substance P (SP) NK1R attenuates its proinflammatory effect on human intervertebral disc cells (IVD), and to evaluate the signaling pathways associated with SP. SP and its receptors are expressed in human IVD cells, and cause upregulation of inflammatory mediators; however, the effects of blocking these receptors have not been studied in human IVD cells. Human annulus fibrosus (AF) and nucleus pulposus (NP) cells were expanded in monolayer, and then suspended in alginate beads. The alginate beads were treated with culture medium first containing a high affinity NK1R antagonist (L-760735) at different concentrations, and then with medium containing both NK1R antagonist and SP at 2 concentrations. Ribonucleic acid was isolated and transcribed into cDNA. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to evaluate expression of interleukin (IL)-1β, IL-6, and IL-8. Western blot analysis was performed to examine levels of the phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase 1/2 (ERK1/2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB p65). The cells were pretreated with specific inhibitors of p38 (SB203580), ERK1/2 (PD98059), and p65 (SM7368) and then stimulated with SP. We detected expression of NK1R, neurokinin receptor 2 (NK2R), and neurokinin receptor 3 (NK3R) in AF and NP cells. Treatment of disc cells with the NK1R antagonist was able to suppress expression of IL-1β, IL-6, and IL-8 in a dose-dependent manner. SP stimulation increased phosphorylation of p38-MAPK and ERK1/2, but not of NFκB p65. This indicates that p38-MAPK and ERK1/2 control SP-induced cytokine expression independently from NF-kB p65. Inhibition of p38 and ERK1/2 activation reduced SP-induced IL-6 production in human disc cells. NK1R is responsible for the proinflammatory effect of SP on IVD cells and this effect can be blocked by

Increased Interleukin-23 in Hashimoto's Thyroiditis Disease Induces Autophagy Suppression and Reactive Oxygen Species Accumulation.

PubMed

Zheng, Tingting; Xu, Chengcheng; Mao, Chaoming; Mou, Xiao; Wu, Fei; Wang, Xuefeng; Bu, Ling; Zhou, Yuepeng; Luo, Xuan; Lu, Qingyan; Liu, Hongli; Yuan, Guoyue; Wang, Shengjun; Chen, Deyu; Xiao, Yichuan

2018-01-01

Hashimoto's thyroiditis (HT) represents the most common organ-specific autoimmune disease. Inflammatory factors and reactive oxygen species (ROS) play detrimental roles during the pathogenesis of HT. In this study, we found that thyroid follicular cells (TFCs) from HT patients expressed an elevated level of interleukin-23 (IL-23), which contributed to autophagy suppression and ROS accumulation. Additionally, IL-23-induced autophagy suppression and ROS accumulation in human TFCs was attributed to AKT/mTOR/NF-κB signaling pathway activation. Inhibition of either IL-23 by a specific neutralization antibody, or mTOR by rapamycin, or NF-κB by IKK-16, significantly reversed the autophagy suppression and ROS accumulation. These results demonstrate a key role for IL-23 in HT pathogenesis and provide a potential therapeutic strategy against IL-23 or its signaling pathway in HT.

Thalidomide reduces tumour necrosis factor α and interleukin 12 production in patients with chronic active Crohn's disease

PubMed Central

Bauditz, J; Wedel, S; Lochs, H

2002-01-01

Background: Thalidomide improves clinical symptoms in patients with therapy refractory Crohn's disease, as shown in two recent studies. The mechanism of this effect however is still unknown. Suppression of tumour necrosis factor α (TNF-α) by thalidomide has been suggested as a possible mechanism. However, effects on other cytokines have not been adequately investigated. Aim: The aim of our study was to investigate the effects of thalidomide on cytokine production in patients with inflammatory bowel disease (IBD). Methods: Ten patients with therapy refractory IBD (nine Crohn's disease, one ulcerative colitis) received thalidomide 300 mg daily in a 12 week open label study. Production of TNF-α, interleukin (IL)-1β, IL-6, and IL-12 was investigated in short term cultures of stimulated colonic lamina propria mononuclear cells (LPMC) and peripheral blood monocytes (PBMC) before and after 12 weeks of treatment. LPMC were also cultured with graded doses of thalidomide. Results: Three patients discontinued treatment because of sedative side effects. In the other patients, disease activity decreased significantly, with four patients achieving remission. Production of TNF-α and IL-12 decreased during treatment with thalidomide: LPMC (TNF-α: 42.3 (8.3) pg/ml v 16.4 (6.3); IL-12: 9.7 (3.3) v 5.0 (2.5); p<0.04) and PBMC (TNF-α: 62.8 (14.6) v 22.5 (9.2); p<0.02). Production of IL-1β and IL-6 did not change significantly. Culturing of LPMC with thalidomide showed a dose dependent decrease in TNF-α and IL-12 production. Conclusion: The clinical effects of thalidomide in Crohn's disease may be mediated by reduction of both TNF-α and IL-12. PMID:11788559

P50 suppression in children with selective mutism: a preliminary report.

PubMed

Henkin, Yael; Feinholz, Maya; Arie, Miri; Bar-Haim, Yair

2010-01-01

Evidence suggests that children with selective mutism (SM) display significant aberrations in auditory efferent activity at the brainstem level that may underlie inefficient auditory processing during vocalization, and lead to speech avoidance. The objective of the present study was to explore auditory filtering processes at the cortical level in children with SM. The classic paired-click paradigm was utilized to assess suppression of the P50 event-related potential to the second, of two sequentially-presented clicks, in ten children with SM and 10 control children. A significant suppression of P50 to the second click was evident in the SM group, whereas no suppression effect was observed in controls. Suppression was evident in 90% of the SM group and in 40% of controls, whereas augmentation was found in 10% and 60%, respectively, yielding a significant association between group and suppression of P50. P50 to the first click was comparable in children with SM and controls. The adult-like, mature P50 suppression effect exhibited by children with SM may reflect a cortical mechanism of compensatory inhibition of irrelevant repetitive information that was not properly suppressed at lower levels of their auditory system. The current data extends our previous findings suggesting that differential auditory processing may be involved in speech selectivity in SM.

Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa.

PubMed

Keenan, Jeremy D; Bailey, Robin L; West, Sheila K; Arzika, Ahmed M; Hart, John; Weaver, Jerusha; Kalua, Khumbo; Mrango, Zakayo; Ray, Kathryn J; Cook, Catherine; Lebas, Elodie; O'Brien, Kieran S; Emerson, Paul M; Porco, Travis C; Lietman, Thomas M

2018-04-26

We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations. In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses. A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial.

PubMed

Bacharier, Leonard B; Guilbert, Theresa W; Mauger, David T; Boehmer, Susan; Beigelman, Avraham; Fitzpatrick, Anne M; Jackson, Daniel J; Baxi, Sachin N; Benson, Mindy; Burnham, Carey-Ann D; Cabana, Michael; Castro, Mario; Chmiel, James F; Covar, Ronina; Daines, Michael; Gaffin, Jonathan M; Gentile, Deborah Ann; Holguin, Fernando; Israel, Elliot; Kelly, H William; Lazarus, Stephen C; Lemanske, Robert F; Ly, Ngoc; Meade, Kelley; Morgan, Wayne; Moy, James; Olin, Tod; Peters, Stephen P; Phipatanakul, Wanda; Pongracic, Jacqueline A; Raissy, Hengameh H; Ross, Kristie; Sheehan, William J; Sorkness, Christine; Szefler, Stanley J; Teague, W Gerald; Thyne, Shannon; Martinez, Fernando D

2015-11-17

Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed. To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes. A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment. Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child's signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period. The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures. A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0

Comparison of Mass Azithromycin Coverage Targets of Children in Niger: A Cluster-Randomized Trachoma Trial.

PubMed

Oldenburg, Catherine E; Amza, Abdou; Kadri, Boubacar; Nassirou, Beido; Cotter, Sun Y; Stoller, Nicole E; West, Sheila K; Bailey, Robin L; Porco, Travis C; Gaynor, Bruce D; Keenan, Jeremy D; Lietman, Thomas M

2018-02-01

Repeated oral azithromycin distribution targeted only to children has proven effective in reducing the ocular Chlamydia that causes trachoma. Here, we assess whether an enhanced coverage target of at least 90% of children is superior to the World Health Organization recommendation of at least 80%. Twenty-four trachoma-endemic communities in Matamèye, Niger, were randomized to a single day of azithromycin distribution aiming for at least 80% coverage or up to 4 days of treatment and > 90% coverage of children under age 12. All distributions were biannual. Children < 5 years of age and adults > 15 years were monitored for ocular Chlamydia infection by polymerase chain reaction every 6 months for 36 months in children and at baseline and 36 months in adults. Ocular Chlamydia prevalence in children decreased from 24.9% (95% confidence interval [CI] 15.9-33.8%) to 4.4% (95% CI 0.6-8.2%, P < 0.001) at 36 months in the standard coverage arm and from 15.6% (95% CI 10.0-21.2%) to 3.3% (95% CI 1.0-5.5%; P < 0.001) in the enhanced coverage arm. Enhanced coverage reduced ocular Chlamydia prevalence in children more quickly over time compared with standard ( P = 0.04). There was no difference between arms at 36 months in children (2.4% lower with enhanced coverage, 95% CI 7.7-12.5%; P = 0.60). No infection was detected in adults at 36 months. Increasing antibiotic coverage among children from 80% to 90% may yield only short term improvements for trachoma control programs. Targeting treatment to children alone may be sufficient for trachoma control in this setting.

Impact of Community Mass Treatment with Azithromycin for Trachoma Elimination on the Prevalence of Yaws

PubMed Central

Marks, Michael; Vahi, Ventis; Sokana, Oliver; Chi, Kai-Hua; Puiahi, Elliot; Kilua, Georgina; Pillay, Allan; Dalipanda, Tenneth; Bottomley, Christian; Solomon, Anthony W.; Mabey, David C.

2015-01-01

Background Community mass treatment with 30mg/kg azithromycin is central to the new WHO strategy for eradicating yaws. Both yaws and trachoma— which is earmarked for elimination by 2020 using a strategy that includes mass treatment with 20mg/kg azithromycin—are endemic in the Pacific, raising the possibility of an integrated approach to disease control. Community mass treatment with azithromycin for trachoma elimination was conducted in the Solomon Islands in 2014. Methods We conducted a study to assess the impact of mass treatment with 20mg/kg azithromycin on yaws. We examined children aged 5-14 years and took blood and lesion samples for yaws diagnosis. Results We recruited 897 children, 6 months after mass treatment. There were no cases of active yaws. Serological evidence of current infection was found in 3.6% (95% CI= 2.5-5.0%). This differed significantly between individuals who had and had not received azithromycin (2.8% vs 6.5%, p=0.015); the prevalence of positive serology in 5-14 year-olds had been 21.7% (95% CI=14.6%-30.9%) 6 months prior to mass treatment. Not receiving azithromycin was associated with an odds of 3.9 for infection (p=0.001). National figures showed a 57% reduction in reported cases of yaws following mass treatment. Discussion Following a single round of treatment we did not identify any cases of active yaws in a previously endemic population. We found a significant reduction in latent infection. Our data support expansion of the WHO eradication strategy and suggest an integrated approach to the control of yaws and trachoma in the Pacific may be viable. PMID:26241484

Suppression of chronic experimental autoimmune neuritis by nasally administered recombinant rat interleukin-6

PubMed Central

DERETZI, G; PELIDOU, S-H; ZOU, L-P; QUIDING, C; MIX, E; LEVI, M; WAHREN, B; ZHU, J

1999-01-01

Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated demyelinating disease of the peripheral nervous system (PNS) and serves as experimental model for human immune-demyelinating neurophathies, especially the Guillain–Barré syndrome. In this study, we examined the effect of recombinant rat interleukin-6 (rrIL-6) on chronic EAN in Lewis rats induced by immunization with P2 peptide 57-81 and Freund’s complete adjuvant (FCA). Nasal administration of rat rIL-6 (1 μg/rat/day) beginning in the initial phase of EAN as a therapeutic agent, decreased the severity and the duration of clinical EAN. Low-grade inflammation and suppression of regional demyelination within the sciatic nerves were seen in rrIL-6-treated rats. Hyporesponsiveness of lymph node T cells, down-regulation of serum tumour necrosis factor-α (TNF-α) and increased levels of P2-specific immunoglobulin G1 (IgG1) antibodies document that nasal administration of rrIL-6 was effective systemically. However, because of the non-specific nature of the treatment and multiple effects of IL-6, more experience and great caution are needed, before nasal administration of IL-6 can be considered as a treatment of human autoimmune demyelinating neurophathies. PMID:10447716

A Randomized Controlled Comparison of Azithromycin and Ofloxacin for Treatment of Multidrug-Resistant or Nalidixic Acid-Resistant Enteric Fever

PubMed Central

Chinh, Nguyen Tran; Parry, Christopher M.; Ly, Nguyen Thi; Ha, Huynh Duy; Thong, Mai Xuan; Diep, To Song; Wain, John; White, Nicholas J.; Farrar, Jeremy J.

2000-01-01

To examine the efficacy and safety of short courses of azithromycin and ofloxacin for treating multidrug-resistant (MDR, i.e., resistant to chloramphenicol, ampicillin, and cotrimoxazole) and nalidixic acid-resistant enteric fever, azithromycin (1 g once daily for 5 days at 20 mg/kg/day) and ofloxacin (200 mg orally twice a day for 5 days at 8 mg/kg/day) were compared in an open randomized study in adults admitted to a hospital with uncomplicated enteric fever. A total of 88 blood culture-confirmed patients were enrolled in the study (86 with Salmonella enterica serovar Typhi and 2 with S. enterica serovar Paratyphi A). Of these, 44 received azithromycin and 44 ofloxacin. A total of 68 of 87 (78%) isolates were MDR serovar Typhi, and 46 of 87 (53%) were nalidixic acid resistant. The MIC90 (range) of azithromycin was 8 (4 to 16) μg/ml for the isolates. The MIC90 (range) of ofloxacin for the nalidixic acid-sensitive isolates was 0.03 (0.015 to 0.06) μg/ml and for the nalidixic acid-resistant isolates it was 0.5 (0.25 to 1.0) μg/ml. There was no significant difference in the overall clinical cure rate with ofloxacin and azithromycin (38 of 44 [86.4%] versus 42 of 44 [95.5%]; P = 0.27) or in the patients infected with nalidixic acid-resistant typhoid (17 of 21 [81.0%] versus 24 of 25 [96.0%]; P = 0.16). However, patients with nalidixic acid-resistant typhoid treated with ofloxacin had a longer fever clearance time compared with those treated with azithromycin (174 [60 to 264] versus 135 [72 to 186] h; P = 0.004) and had positive fecal cultures after the end of treatment (7 of 17 [41%] versus 0 of 19 [0%]; P = 0.002). Both antibiotics were well tolerated. A 5-day course of azithromycin was effective for the treatment of enteric fever due to MDR and nalidixic-acid-resistant serovar Typhi, whereas the ofloxacin regimen chosen was less satisfactory for these strains. PMID:10858343

Azithromycin in the treatment of uncomplicated genital chlamydial infections.

PubMed

Stamm, W E

1991-09-12

Chlamydia trachomatis is among the most prevalent of sexually transmitted diseases and causes serious sequelae, especially in women. A major difficulty facing the clinician has been the effective treatment of patients with chlamydial infections, since existing drugs require 7 or more days of multidose therapy, and hence considerable commitment from the patient. Many patients, especially those who are minimally symptomatic or asymptomatic, are likely to be noncompliant when given such multiple day regimens and thus may fail therapy. Azithromycin is an azalide antibiotic that has a minimum inhibitory concentration against C. trachomatis of between 0.03 and 0.25 mg/L, as well as good in vitro activity against other sexually transmitted pathogens that are often present concurrently. Azithromycin also achieves high intracellular concentrations, which may be beneficial in eradicating Chlamydia, an obligate intracellular pathogen. More importantly, azithromycin has high tissue bioavailability and a tissue half-life of between 2 and 4 days. These pharmacokinetic properties imply that the dosing period for azithromycin can be greatly reduced while still achieving high antimicrobial activity at sites of infection. Clinical experience to date shows that a single 1 g oral dose of azithromycin is as effective as a standard 7-day twice daily regimen of doxycycline and more effective than 7 days of ciprofloxacin in eradicating uncomplicated chlamydial genital infections. As such, azithromycin is the first single-dose therapy for the treatment of urethritis and cervicitis due to C. trachomatis. Single-dose therapy for chlamydial infection, which could be administered under supervision in the clinic, would be a significant advance in the management and public health control of chlamydial infections.

Systematic review of interleukin-12, interleukin-17, and interleukin-23 pathway inhibitors for the treatment of moderate-to-severe chronic plaque psoriasis: ustekinumab, briakinumab, tildrakizumab, guselkumab, secukinumab, ixekizumab, and brodalumab.

PubMed

Tausend, William; Downing, Christopher; Tyring, Stephen

2014-01-01

Monoclonal antibodies known as biologic agents specifically targeted against interleukin-12 (IL-12), interleukin-17A (IL-17), and interleukin-23 (IL-23) have been the focus of research for moderate-to-severe chronic plaque psoriasis in recent years. To discuss the immune-mediated model of psoriasis and to summarize current knowledge of the clinical efficacy and safety of new biologic agents for moderate-to-severe chronic plaque psoriasis. The PubMed database was searched for relevant articles on ustekinumab, briakinumab, tildrakizumab (MK-322), guselkumab, secukinumab, ixekizumab, and brodalumab published between January 2005 and July 2013. Fifty-five articles were identified. These studies suggest that the biologic agents specifically targeting IL-12, IL-17, and IL-23 are efficacious and safe in the treatment of moderate-to-severe psoriasis in adults. Current data from clinical trials suggest that biologic agents targeting IL-12, IL-17, and IL-23 are safe and efficacious drugs for use in moderate-to-severe chronic plaque psoriasis. Long-term data still need to be established.

Increased Interleukin-23 in Hashimoto’s Thyroiditis Disease Induces Autophagy Suppression and Reactive Oxygen Species Accumulation

PubMed Central

Zheng, Tingting; Xu, Chengcheng; Mao, Chaoming; Mou, Xiao; Wu, Fei; Wang, Xuefeng; Bu, Ling; Zhou, Yuepeng; Luo, Xuan; Lu, Qingyan; Liu, Hongli; Yuan, Guoyue; Wang, Shengjun; Chen, Deyu; Xiao, Yichuan

2018-01-01

Hashimoto’s thyroiditis (HT) represents the most common organ-specific autoimmune disease. Inflammatory factors and reactive oxygen species (ROS) play detrimental roles during the pathogenesis of HT. In this study, we found that thyroid follicular cells (TFCs) from HT patients expressed an elevated level of interleukin-23 (IL-23), which contributed to autophagy suppression and ROS accumulation. Additionally, IL-23-induced autophagy suppression and ROS accumulation in human TFCs was attributed to AKT/mTOR/NF-κB signaling pathway activation. Inhibition of either IL-23 by a specific neutralization antibody, or mTOR by rapamycin, or NF-κB by IKK-16, significantly reversed the autophagy suppression and ROS accumulation. These results demonstrate a key role for IL-23 in HT pathogenesis and provide a potential therapeutic strategy against IL-23 or its signaling pathway in HT. PMID:29434604

Neutrophil elastase enhances IL-12p40 production by lipopolysaccharide-stimulated macrophages via transactivation of the PAR-2/EGFR/TLR4 signaling pathway.

PubMed

Yamaguchi, Rui; Yamamoto, Takatoshi; Sakamoto, Arisa; Narahara, Shinji; Sugiuchi, Hiroyuki; Yamaguchi, Yasuo

2016-07-01

Proteinase-activated receptor 2 (PAR-2) and toll-like receptor 4 (TLR4) are involved in innate immune responses and signaling cross-talk between these receptor molecules has the potential to augment an ongoing inflammatory response. The aim of this study was to evaluate the possible cooperative influence of PAR-2 and TLR4 on IL-12p40 production by macrophages after stimulation with lipopolysaccharide (LPS). During culture, GM-CSF upregulated PAR-2 expression by macrophages in a time-dependent manner. Stimulation with LPS enhanced IL-12p40 production by macrophages in a concentration-dependent manner. While human neutrophil elastase (HNE) did not induce IL-12p40 production, pretreatment of macrophages with HNE synergistically increased the IL-12p40 protein level after LPS exposure. Silencing of TLR4 with small interfering RNA blunted the synergistic enhancement of IL-12p40 by HNE combined with LPS. Silencing of β-arrestin 2, p22phox, or ERK1/2 also inhibited an increase of IL-12p40. Interestingly, transfection of macrophages with small interfering RNA duplexes for DUOX-2, EGFR, TLR4, or TRAF6 significantly blunted the increase of IL-12p40 in response to treatment with HNE plus LPS. U73122 and Rottlerin also inhibited the increased production of IL-12p40. In conclusion, HNE is involved in transactivation of TLR4 through activation of DUOX-2/EGFR and synergistically enhances IL-12p40 production by macrophages stimulated with LPS. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparison of doxycycline with azithromycin in treatment of pharyngeal chlamydia infection.

PubMed

Manavi, K; Hettiarachchi, N; Hodson, J

2016-12-01

Recent data suggest that azithromycin may not be as effective as doxycycline in eradication of genital chlamydial infection. The aim of this study was to compare the eradication rate of pharyngeal Chlamydia trachomatis infection after treatment with azithromycin 1 g stat with that of doxycycline 100 mg twice a day for seven days. A prospective open-label observational study was conducted on patients with pharyngeal Chlamydia trachomatis diagnosed at Whittall Street Clinic, University Hospitals Birmingham, Birmingham, UK, between July 2012 and July 2013. We confirmed eradication of pharyngeal Chlamydia trachomatis with a negative test of cure. We treated all our patients with azithromycin 1 g stat until February 2013. At that stage, we offered doxycycline to patients with pharyngeal Chlamydia trachomatis A total of 398 patients (52 men, 346 women) were diagnosed with pharyngeal Chlamydia trachomatis during the study period. Of the 172 patients included in the final analysis, 78 were treated with azithromycin and 64 with doxycycline. Treatment failure was identified among 8/78 (10%) patients treated with azithromycin and 1/64 (2%) treated with doxycycline (absolute difference: 8 percentage points, 95% CI: 0-17%, p = 0.041). In our study, doxycycline 100 mg twice a day for seven days was associated with less treatment failure of oropharyngeal chlamydia compared with azithromycin 1 g stat Future randomised studies should investigate whether patients with pharyngeal Chlamydia trachomatis should be followed up with a test of cure when treated with azithromycin, or be treated with doxycycline. © The Author(s) 2016.

IL-1α and MMP-9 Tear Levels of Patients with Active Ocular Rosacea before and after Treatment with Systemic Azithromycin or Doxycycline.

PubMed

Lam-Franco, Lorena; Perfecto-Avalos, Yocanxochitl; Patiño-Ramírez, Beatriz E; Rodríguez García, Alejandro

2018-06-06

The purpose of this paper was to determine the lacrimal concentration of IL-1α and MMP-9 in patients with active ocular rosacea before and after systemic treatment with azithromycin or doxycycline. After 4 weeks of therapy with azithromycin (500 mg/day, 3 days a week PO) or doxycycline (200 mg/day PO), lacrimal samples were analyzed using an enzyme-linked immunosorbent assay multiplex. There was a significant difference between baseline IL-1α (37.9 pg/mL) and MMP-9 (26.7 ng/mL) in rosacea eyes compared to controls (0.001 pg/mL for IL-1α and 0.2 ng/mL for MMP-9) (p < 0.001). IL-1α decreased from 47.0 pg/mL before azithromycin to 23.5 pg/mL after treatment (p = 0.024), but not after doxycycline therapy. On the contrary, baseline MMP-9 tear levels (10.28 ng/mL) decreased after treatment (8.36 pg/mL) with doxycycline (p = 0.054) but not with azithromycin. There was a strong clinical correlation of higher baseline IL-1α tear levels between patients who responded to doxycycline therapy and those who failed (p = 0.043). Patients unresponsive to azithromycin had significantly higher baseline MMP-9 levels than those with doxycycline (p = 0.040). While IL-1α levels decreased after azithromycin therapy, MMP-9 did so after doxycycline treatment. Baseline cytokine tear levels tend to be markedly elevated in patients with antibiotic failure, suggesting their potential role as therapeutic biomarkers for the disease. © 2018 S. Karger AG, Basel.

Antimicrobial Susceptibility to Azithromycin among Salmonella enterica Isolates from the United States▿

PubMed Central

Sjölund-Karlsson, Maria; Joyce, Kevin; Blickenstaff, Karen; Ball, Takiyah; Haro, Jovita; Medalla, Felicita M.; Fedorka-Cray, Paula; Zhao, Shaohua; Crump, John A.; Whichard, Jean M.

2011-01-01

Due to emerging resistance to traditional antimicrobial agents, such as ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol, azithromycin is increasingly used for the treatment of invasive Salmonella infections. In the present study, 696 isolates of non-Typhi Salmonella collected from humans, food animals, and retail meats in the United States were investigated for antimicrobial susceptibility to azithromycin. Seventy-two Salmonella enterica serotype Typhi isolates from humans were also tested. For each isolate, MICs of azithromycin and 15 other antimicrobial agents were determined by broth microdilution. Among the non-Typhi Salmonella isolates, azithromycin MICs among human isolates ranged from 1 to 32 μg/ml, whereas the MICs among the animal and retail meat isolates ranged from 2 to 16 μg/ml and 4 to 16 μg/ml, respectively. Among Salmonella serotype Typhi isolates, the azithromycin MICs ranged from 4 to 16 μg/ml. The highest MIC observed in the present study was 32 μg/ml, and it was detected in three human isolates belonging to serotypes Kentucky, Montevideo, and Paratyphi A. Based on our findings, we propose an epidemiological cutoff value (ECOFF) for wild-type Salmonella of ≤16 μg/ml of azithromycin. The susceptibility data provided could be used in combination with clinical outcome data to determine tentative clinical breakpoints for azithromycin and Salmonella enterica. PMID:21690279

Carbon monoxide-releasing molecule-3 suppresses Prevotella intermedia lipopolysaccharide-induced production of nitric oxide and interleukin-1β in murine macrophages.

PubMed

Choi, Eun-Young; Choe, So-Hui; Hyeon, Jin-Yi; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

2015-10-05

This study was performed to analyze the effect of carbon monoxide (CO)-releasing molecule-3 (CORM-3) in alleviating the production of proinflammatory mediators in macrophages treated with lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen associated with periodontal disease, and its possible mechanisms of action. LPS was isolated using the hot phenol-water method. Culture supernatants were assayed for nitric oxide (NO) and interleukin-1β (IL-1β). Gene expression was quantified by real-time PCR, and protein expression by immunoblotting. DNA-binding activities of NF-κB subunits were determined using an ELISA-based kit. CORM-3 suppressed the production of inducible NO synthase (iNOS)-derived NO and IL-1β at both gene transcription and translation levels in P. intermedia LPS-activated RAW264.7 cells. CORM-3 enhanced heme oxygenase-1 (HO-1) expression in cells stimulated with P. intermedia LPS, and inhibition of HO-1 activity by SnPP notably reversed the suppressive effect of CORM-3 on LPS-induced production of NO. LPS-induced phosphorylation of p38 and JNK was not affected by CORM-3. CORM-3 did not influence P. intermedia LPS-induced degradation of IκB-α. Instead, nuclear translocation of NF-κB p65 and p50 subunits was blocked by CORM-3 in LPS-treated cells. In addition, CORM-3 reduced LPS-induced p65 and p50 binding to DNA. Besides, CORM-3 significantly suppressed P. intermedia LPS-induced phosphorylation of STAT1. Overall, this study indicates that CORM-3 suppresses the production of NO and IL-1β in P. intermedia LPS-activated murine macrophages via HO-1 induction and inhibition of NF-κB and STAT1 pathways. The modulation of host inflammatory response by CORM-3 would be an attractive therapeutic approach to attenuate the progression of periodontal disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Interleukin-12 Induces a Th1-Like Response to Burkholderia mallei and Limited Protection in BALB/c Mice

DTIC Science & Technology

2006-01-01

sublethal and lethal intraperitoneal glanders ( Burkholderia mallei ). Vet Pathol 2000;37:626–36. [34] Jankovic D, Caspar P, Zweig M, Garcia-Moll M...Vaccine 24 (2006) 1413–1420 Interleukin-12 induces a Th1-like response to Burkholderia mallei and limited protection in BALB/c mice Kei Amemiya...IL)-12 on the immune response to Burkholderia mallei in BALB/c mice. Mice were vaccinated with non-viable B. mallei cells with or without IL-12

Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya.

PubMed

Zhang, Lyna; Prather, Donald; Vanden Eng, Jodi; Crawford, Sara; Kariuki, Simon; ter Kuile, Feiko; Terlouw, Dianne; Nahlen, Bernard; Lal, Altaf A; Slutsker, Laurence; Udhayakumar, Venkatachalam; Shi, Ya Ping

2010-03-29

Malarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined. Fifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya. An increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21). This study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients.

The mechanism of retrovirus suppression of human T cell proliferation in vitro.

PubMed

Copelan, E A; Rinehart, J J; Lewis, M; Mathes, L; Olsen, R; Sagone, A

1983-10-01

Immunosuppression is commonly associated with retrovirus-induced animal tumors. Studies in the murine and feline retrovirus systems suggest that the 15,000-dalton envelope protein (p15E) of the virion may contribute to immunosuppression by interfering with normal lymphocyte function. We examined the effect of inactivated feline leukemia virus (UV-FeLV) and p15E derived from this virus on concanavalin A (Con A) driven human T cell proliferation. Virus and p15E markedly suppressed mononuclear cell proliferative response to Con A. Suppression was not due to inhibition of monocyte accessory cell function, or interleukin 1 (IL 1) secretion. In fact, the presence of monocytes partially protected T cells from UV-FeLV suppression. UV-FeLV, however, suppressed T cell secretion of and response to interleukin 2 (IL 2). We conclude that UV-FeLV and derived p15E inhibit T cell proliferation by direct inhibition of T cell function. These findings, extended to the in vivo situations, suggest that retrovirus-associated suppression of the immune response involves the induction of T cell but not monocyte dysfunction.

Azithromycin Resistance in Shigella spp. in Southeast Asia

PubMed Central

Darton, Thomas C.; Tuyen, Ha Thanh; The, Hao Chung; Newton, Paul N.; Phetsouvanh, Rattanaphone; Davong, Viengmon; Campbell, James I.; Hoang, Nguyen Van Minh; Thwaites, Guy E.; Parry, Christopher M.; Thanh, Duy Pham

2018-01-01

ABSTRACT Infection by Shigella spp. is a common cause of dysentery in Southeast Asia. Antimicrobials are thought to be beneficial for treatment; however, antimicrobial resistance in Shigella spp. is becoming widespread. We aimed to assess the frequency and mechanisms associated with decreased susceptibility to azithromycin in Southeast Asian Shigella isolates and use these data to assess appropriate susceptibility breakpoints. Shigella isolates recovered in Vietnam and Laos were screened for susceptibility to azithromycin (15 μg) by disc diffusion and MIC. Phenotypic resistance was confirmed by PCR amplification of macrolide resistance loci. We compared the genetic relationships and plasmid contents of azithromycin-resistant Shigella sonnei isolates using whole-genome sequences. From 475 available Shigella spp. isolated in Vietnam and Laos between 1994 and 2012, 6/181 S. flexneri isolates (3.3%, MIC ≥ 16 g/liter) and 16/294 S. sonnei isolates (5.4%, MIC ≥ 32 g/liter) were phenotypically resistant to azithromycin. PCR amplification confirmed a resistance mechanism in 22/475 (4.6%) isolates (mphA in 19 isolates and ermB in 3 isolates). The susceptibility data demonstrated the acceptability of the S. flexneri (MIC ≥ 16 g/liter, zone diameter ≤ 15 mm) and S. sonnei (MIC ≥ 32 g/liter, zone diameter ≤ 11 mm) breakpoints with a <3% discrepancy. Phylogenetic analysis demonstrated that decreased susceptibility has arisen sporadically in Vietnamese S. sonnei isolates on at least seven occasions between 2000 and 2009 but failed to become established. While the proposed susceptibility breakpoints may allow better recognition of resistant isolates, additional studies are required to assess the impact on the clinical outcome. The potential emergence of azithromycin resistance highlights the need for alternative options for management of Shigella infections in countries where Shigella is endemic. PMID:29378707

Pregabalin- and azithromycin-induced rhabdomyolysis with purpura: An unrecognized interaction: A case report.

PubMed

Kato, Kazuya; Iwasaki, Yoshiaki; Onodera, Kazuhiko; Higuchi, Mineko; Kato, Kimitaka; Kato, Yurina; Tsutsui, Masato; Taniguchi, Masahiko; Furukawa, Hiroyuki

2016-01-01

Rhabdomyolysis associated with the use of pregabalin or azithromycin has been demonstrated to be a rare but potentially life-threatening adverse event. Here, we report an extremely rare case of rhabdomyolysis with purpura in a patient who had used pregabalin and azithromycin. We present the case of a 75-year-old woman with a history of fibromyalgia who was admitted with mild limb weakness and lower abdominal purpura. She was prescribed pregabalin (75mg, twice daily) for almost 3 months to treat chronic back pain. Her medical history revealed that 3days before admission, she began experiencing acute bronchitis and was treated with a single dose of azithromycin (500mg). She had developed rapid onset severe myalgia, mild whole body edema, muscle weakness leading to gait instability, abdominal purpura and tender purpura on the lower extremities. Laboratory values included a white blood cell count of 25,400/mL and a creatinine phosphokinase (CPK) concentration of 1250 IU/L. Based on these findings and the patient's clinical history, a diagnosis of pregabalin- and azithromycin-induced rhabdomyolysis was made. The long-term use of pregabalin and the initiation azithromycin therapy followed by a rapid onset of rhabdomyolysis is indicative of a drug interaction between pregabalin and azithromycin. We report an extremely rare case of rhabdomyolysis with purpura caused by a drug interaction between pregabalin and azithromycin. However, the mechanisms of the interactions between azithromycin on the pregabalin are still unknown. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Interleukin-12 (IL-12)-driven alloimmune responses in vitro and in vivo: requirement for beta1 subunit of the IL-12 receptor.

PubMed

Piccotti, J R; Li, K; Chan, S Y; Eichwald, E J; Bishop, D K

1999-06-15

Interleukin-12 (IL-12) mediates its biologic activities via binding high-affinity receptors on T and natural killer cells. Although emphasis has been placed on the requirement for IL-12Rbeta2 in IL-12 bioactivity, the role of IL-12Rbeta1 is less well defined. The current study evaluated the effects of exogenous IL-12 on alloantigen-specific immune responses and determined the requirement for IL-12Rbeta1 in IL-12-mediated alloimmunity. The mouse heterotopic cardiac transplant model was employed to evaluate the effects of IL-12 on alloantigen-specific immune responses in vivo. In addition, IFN-gamma production in mixed lymphocyte cultures (MLC) supplemented with IL-12 was measured to assess the effects of IL-12 on Th1 function in vitro. Mice deficient in IL-12Rbeta1 (IL-12Rbeta1-/-) were used to determine the requirement for this receptor component in IL-12-driven alloimmune responses. Addition of IL-12 to MLC consisting of wild-type splenocytes enhanced alloantigen-specific proliferative responses and Th1 development. In contrast, IL-12 did not alter these in vitro immune parameters in IL-12Rbeta1-/- MLC. Treatment of wild-type cardiac allograft recipients with IL-12 resulted in high concentrations of serum interferon-gamma (IFN-gamma) and a 10-fold increase in IFN-gamma production by recipient splenocytes after restimulation in vitro. However, this fulminate Th1 response did not accelerate allograft rejection. Importantly, IL-12 had no effect on serum IFN-gamma or in vivo priming of Thl in IL-12Rbeta1-/- recipients. Finally, administration of IL-12 to WT allograft recipients resulted in a bimodal alloantibody response: antibody production was suppressed at high doses of IL-12, and enhanced at lower doses. IL-12 markedly enhances alloantigen-specific immune function; however, these exaggerated Th1-driven responses do not culminate in accelerated allograft rejection. Further, these data indicate that IL-12Rbeta1 is essential for the enhancement of both in vitro and

Levofloxacin versus azithromycin on the oropharyngeal carriage and selection of antibacterial- resistant streptococci in the microflora of healthy adults.

PubMed

Nord, Carl Erik; Peterson, Janet; Ambruzs, Mary; Fisher, Alan C

2009-06-01

To determine the proportion of subjects with oropharyngeal streptococci resistant to either levofloxacin or azithromycin prior to and during antibacterial exposure, and to follow temporal changes in the proportion of resistant and susceptible isolates through 6 weeks post-exposure. This randomized, open-label, single-center study is registered with ClinicalTrials.gov (identifier: NCT00821782). A total of 143 healthy volunteers (levofloxacin, n = 71; azithromycin, n = 72) without antibacterial exposure in the previous 90 days received either levofloxacin 750 mg once daily for 5 days or azithromycin 500 mg once daily on day 1 and 250 mg once daily on days 2 through 5. Oropharyngeal cultures were obtained pre-exposure, at day 5, and at 2, 4, and 6 weeks post-dosing. Bacterial strains were identified and the minimum inhibitory concentrations for levofloxacin and azithromycin were determined. At study entry 117 streptococci were isolated from 72 subjects randomized to azithromycin and 53 (45.3%) were azithromycin-resistant. None of the 121 streptococci isolated from 71 subjects randomized to.levofloxacin were colonized by a levofloxacin-resistant microorganism prior to dosing. At the end of dosing, the number of subjects with resistant streptococci (S. mitis, S. salivarius, S. sanguis, or alpha streptococcus species [spp.]) increased in azithromycin-exposed subjects and resistant isolates remained through 6 weeks post-dosing. In contrast, a small number of levofloxacin-resistant streptococci were observed at the end of dosing but decreased by week 2 post-dosing and continued to decrease through the 6-week evaluation period (p < 0.001 azithromycin vs. levofloxacin for S. mitis, S. salivarius, S. sanguis and alpha streptococcus spp. at week 6). Limitations of this study included the fact that, since previous antibiotic use was self-reported, genetic typing was not done. The results of this study may not be completely generalizable, because subjects in this study received

Notes from the field: Shigella with decreased susceptibility to azithromycin among men who have sex with men - United States, 2002-2013.

PubMed

Heiman, Katherine E; Karlsson, Maria; Grass, Julian; Howie, Becca; Kirkcaldy, Robert D; Mahon, Barbara; Brooks, John T; Bowen, Anna

2014-02-14

Bacteria of the genus Shigella cause approximately 500,000 illnesses each year in the United States. Diarrhea (sometimes bloody), fever, and stomach cramps typically start 1-2 days after exposure and usually resolve in 5-7 days. For patients with severe disease, bloody diarrhea, or compromised immune systems, antibiotic treatment is recommended, but resistance to traditional first-line antibiotics (e.g., ampicillin and trimethoprim-sulfamethoxazole) is common. For multidrugresistant cases, azithromycin, the most frequently prescribed antibiotic in the United States, is recommended for both children and adults. However, not all Shigellae are susceptible to azithromycin. Nonsusceptible isolates exist but are not usually identified because there are no clinical laboratory guidelines for azithromycin susceptibility testing. However, to monitor susceptibility of Shigellae in the United States, CDC's National Antimicrobial Resistance Monitoring System (NARMS) has, since 2011, routinely measured the azithromycin minimum inhibitory concentration (MIC) for every 20th Shigella isolate submitted from public health laboratories to CDC, as well as outbreak-associated isolates. All known U.S. Shigella isolates with decreased susceptibility to azithromycin (DSA-Shigella), and the illnesses caused by them, are described in this report.

Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration.

PubMed

Meyer, Nuala J; Reilly, John P; Anderson, Brian J; Palakshappa, Jessica A; Jones, Tiffanie K; Dunn, Thomas G; Shashaty, Michael G S; Feng, Rui; Christie, Jason D; Opal, Steven M

2018-01-01

Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration. Retrospective subgroup analysis of randomized controlled trial. Multicenter North American and European clinical trial. Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population. Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours. We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human

Sphingosine 1-phosphate (S1P) suppresses the collagen-induced activation of human platelets via S1P4 receptor.

PubMed

Onuma, Takashi; Tanabe, Kumiko; Kito, Yuko; Tsujimoto, Masanori; Uematsu, Kodai; Enomoto, Yukiko; Matsushima-Nishiwaki, Rie; Doi, Tomoaki; Nagase, Kiyoshi; Akamatsu, Shigeru; Tokuda, Haruhiko; Ogura, Shinji; Iwama, Toru; Kozawa, Osamu; Iida, Hiroki

2017-08-01

Sphingosine 1-phosphate (S1P) is as an extracellular factor that acts as a potent lipid mediator by binding to specific receptors, S1P receptors (S1PRs). However, the precise role of S1P in human platelets that express S1PRs has not yet been fully clarified. We previously reported that heat shock protein 27 (HSP27) is released from human platelets accompanied by its phosphorylation stimulated by collagen. In the present study, we investigated the effect of S1P on the collagen-induced platelet activation. S1P pretreatment markedly attenuated the collagen-induced aggregation. Co-stimulation with S1P and collagen suppressed collagen-induced platelet activation, but the effect was weaker than that of S1P-pretreatment. The collagen-stimulated secretion of platelet-derived growth factor (PDGF)-AB and the soluble CD40 ligand (sCD40L) release were significantly reduced by S1P. In addition, S1P suppressed the collagen-induced release of HSP27 as well as the phosphorylation of HSP27. S1P significantly suppressed the collagen-induced phosphorylation of p38 mitogen-activated protein kinase. S1P increased the levels of GTP-bound Gαi and GTP-bound Gα13 coupled to S1PPR1 and/or S1PR4. CYM50260, a selective S1PR4 agonist, but not SEW2871, a selective S1PR1 agonist, suppressed the collagen-stimulated platelet aggregation, PDGF-AB secretion and sCD40L release. In addition, CYM50260 reduced the release of phosphorylated-HSP27 by collagen as well as the phosphorylation of HSP27. The selective S1PR4 antagonist CYM50358, which failed to affect collagen-induced HSP27 phosphorylation, reversed the S1P-induced attenuation of HSP27 phosphorylation by collagen. These results strongly suggest that S1P inhibits the collagen-induced human platelet activation through S1PR4 but not S1PR1. Copyright © 2017 Elsevier Ltd. All rights reserved.

Analysis of the activation profile of dendritic cells derived from the bone marrow of interleukin-12/interleukin-23-deficient mice

PubMed Central

Bastos, Karina R B; de Deus Vieira de Moraes, Luciana; Zago, Cláudia A; Marinho, Cláudio R F; Russo, Momtchilo; Alvarez, José M M; D'Império Lima, Maria R

2005-01-01

We have previously shown that macrophages from interleukin (IL)-12p40 gene knockout (IL-12/IL-23−/−) mice have a bias towards the M2 activation profile, spontaneously secreting large quantities of transforming growth factor-β1 (TGF-β1) and producing low levels of nitric oxide (NO) in response to lipopolysaccharide (LPS) and interferon-γ (IFN-γ). To verify whether the activation profile of dendritic cells (DCs) is also influenced by the absence of IL-12/IL-23, bone marrow-derived DCs from IL-12/IL-23−/− and C57BL/6 mice were evaluated. At first we noticed that ≈ 50% of the C57BL/6 DCs were dead after LPS-induced maturation, whereas the mortality of IL-12/IL-23−/− DCs was < 10%, a protective effect that diminished when recombinant IL-12 (rIL-12) was added during maturation. Similarly to macrophages, mature IL-12/IL-23−/− DCs (mDCs) produced higher levels of TGF-β1 and lower levels of NO than C57BL/6 mDCs. NO release was IFN-γ-dependent, as evidenced by the poor response of IFN-γ−/− and IL-12/IL-23−/−IFN-γ−/− mDCs. Nevertheless, IFN-γ deficiency was not the sole reason for the weak NO response observed in the absence of IL-12/IL-23. The high level of TGF-β1 secretion by IL-12/IL-23−/− mDCs could explain why exogenous IFN-γ partially restored the NO production of IFN-γ−/− mDCs, while IL-12/IL-23−/− IFN-γ−/− mDCs remained unresponsive. We also showed that CD4+ T-cell proliferation was inhibited by C57BL/6 mDCs, but not by IL-12/IL-23−/− mDCs. IFN-γ and NO appear to mediate this antiproliferative effect because this effect was not observed in the presence of mDCs from IFN-γ−/− or IL-12/IL-23−/− IFN-γ−/− mice and it was attenuated by aminoguanidine. We conclude that the presence of IL-12/IL-23 during LPS-induced maturation influences the activation profile of DCs by a mechanism that is, only in part, IFN-γ dependent. PMID:15804287

Calcium hydroxide suppresses Porphyromonas endodontalis lipopolysaccharide-induced bone destruction.

PubMed

Guo, J; Yang, D; Okamura, H; Teramachi, J; Ochiai, K; Qiu, L; Haneji, T

2014-05-01

Porphyromonas endodontalis and its main virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical diseases and alveolar bone loss. Calcium hydroxide is commonly used for endodontic therapy. However, the effects of calcium hydroxide on the virulence of P. endodontalis LPS and the mechanism of P. endodontalis LPS-induced bone destruction are not clear. Calcium hydroxide rescued the P. endodontalis LPS-suppressed viability of MC3T3-E1 cells and activity of nuclear factor-κB (NF-κB) in these cells, resulting in the reduced expression of interleukin-6 and tumor necrosis factor-α. In addition, calcium hydroxide inhibited P. endodontalis LPS-induced osteoclastogenesis by decreasing the activities of NF-κB, p38, and ERK1/2 and the expression of nuclear factor of activated T-cell cytoplasmic 1 in RAW264.7 cells. Calcium hydroxide also rescued the P. endodontalis LPS-induced osteoclastogenesis and bone destruction in mouse calvaria. Taken together, our present results indicate that calcium hydroxide suppressed bone destruction by attenuating the virulence of P. endodontalis LPS on bone cells.

Per a 10 protease activity modulates CD40 expression on dendritic cell surface by nuclear factor-kappaB pathway.

PubMed

Goel, C; Kalra, N; Dwarakanath, B S; Gaur, S N; Arora, N

2015-05-01

Serine protease activity of Per a 10 from Periplaneta americana modulates dendritic cell (DC) functions by a mechanism(s) that remains unclear. In the present study, Per a 10 protease activity on CD40 expression and downstream signalling was evaluated in DCs. Monocyte-derived DCs from cockroach-allergic patients were treated with proteolytically active/heat-inactivated Per a 10. Stimulation with active Per a 10 demonstrated low CD40 expression on DCs surface (P < 0·05), while enhanced soluble CD40 level in the culture supernatant (P < 0·05) compared to the heat-inactivated Per a 10, suggesting cleavage of CD40. Per a 10 activity reduced the interleukin (IL)-12 and interferon (IFN)-γ secretion by DCs (P < 0·05) compared to heat-inactivated Per a 10, indicating that low CD40 expression is associated with low levels of IL-12 secretion. Active Per a 10 stimulation caused low nuclear factor-kappa B (NF-κB) activation in DCs compared to heat-inactivated Per a 10. Inhibition of the NF-κB pathway suppressed the CD40 expression and IL-12 secretion by DCs, further indicating that NF-κB is required for CD40 up-regulation. CD40 expression activated the tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), thereby suggesting its involvement in NF-κB activation. Protease activity of Per a 10 induced p38 mitogen-activated protein kinase (MAPK) activation that showed no significant effect on CD40 expression by DCs. However, inhibiting p38 MAPK or NF-κB suppressed the secretion of IL-12, IFN-γ, IL-6 and TNF-α by DCs. Such DCs further reduced the secretion of IL-4, IL-6, IL-12 and TNF-α by CD4(+) T cells. In conclusion, protease activity of Per a 10 reduces CD40 expression on DCs. CD40 down-regulation leads to low NF-κB levels, thereby modulating DC-mediated immune responses. © 2014 British Society for Immunology.

Per a 10 protease activity modulates CD40 expression on dendritic cell surface by nuclear factor-kappaB pathway

PubMed Central

Goel, C; Kalra, N; Dwarakanath, B S; Gaur, S N; Arora, N

2015-01-01

Serine protease activity of Per a 10 from Periplaneta americana modulates dendritic cell (DC) functions by a mechanism(s) that remains unclear. In the present study, Per a 10 protease activity on CD40 expression and downstream signalling was evaluated in DCs. Monocyte-derived DCs from cockroach-allergic patients were treated with proteolytically active/heat-inactivated Per a 10. Stimulation with active Per a 10 demonstrated low CD40 expression on DCs surface (P < 0·05), while enhanced soluble CD40 level in the culture supernatant (P < 0·05) compared to the heat-inactivated Per a 10, suggesting cleavage of CD40. Per a 10 activity reduced the interleukin (IL)-12 and interferon (IFN)-γ secretion by DCs (P < 0·05) compared to heat-inactivated Per a 10, indicating that low CD40 expression is associated with low levels of IL-12 secretion. Active Per a 10 stimulation caused low nuclear factor-kappa B (NF-κB) activation in DCs compared to heat-inactivated Per a 10. Inhibition of the NF-κB pathway suppressed the CD40 expression and IL-12 secretion by DCs, further indicating that NF-κB is required for CD40 up-regulation. CD40 expression activated the tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), thereby suggesting its involvement in NF-κB activation. Protease activity of Per a 10 induced p38 mitogen-activated protein kinase (MAPK) activation that showed no significant effect on CD40 expression by DCs. However, inhibiting p38 MAPK or NF-κB suppressed the secretion of IL-12, IFN-γ, IL-6 and TNF-α by DCs. Such DCs further reduced the secretion of IL-4, IL-6, IL-12 and TNF-α by CD4+ T cells. In conclusion, protease activity of Per a 10 reduces CD40 expression on DCs. CD40 down-regulation leads to low NF-κB levels, thereby modulating DC-mediated immune responses. PMID:25492061

A Case-Control Study of Molecular Epidemiology in Relation to Azithromycin Resistance in Neisseria gonorrhoeae Isolates Collected in Amsterdam, the Netherlands, between 2008 and 2015

PubMed Central

Wind, Carolien M.; Bruisten, Sylvia M.; Schim van der Loeff, Maarten F.; Dierdorp, Mirjam; de Vries, Henry J. C.

2017-01-01

ABSTRACT Neisseria gonorrhoeae resistance to ceftriaxone and azithromycin is increasing, which threatens the recommended dual therapy. We used molecular epidemiology to identify N. gonorrhoeae clusters and associations with azithromycin resistance in Amsterdam, the Netherlands. N. gonorrhoeae isolates (n = 143) were selected from patients visiting the Amsterdam STI Outpatient Clinic from January 2008 through September 2015. We included all 69 azithromycin-resistant isolates (MIC ≥ 2.0 mg/liter) and 74 frequency-matched susceptible controls (MIC ≤ 0.25 mg/liter). The methods used were 23S rRNA and mtrR sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), N. gonorrhoeae multilocus variable-number tandem-repeat analysis (NG-MLVA), and a specific PCR to detect mosaic penA genes. A hierarchical cluster analysis of NG-MLVA related to resistance and epidemiological characteristics was performed. Azithromycin-resistant isolates had C2611T mutations in 23S rRNA (n = 62, 89.9%, P < 0.001) and were NG-MAST genogroup G2992 (P < 0.001), G5108 (P < 0.001), or G359 (P = 0.02) significantly more often than susceptible isolates and were more often part of NG-MLVA clusters (P < 0.001). Two resistant isolates (2.9%) had A2059G mutations, and five (7.3%) had wild-type 23S rRNA. No association between mtrR mutations and azithromycin resistance was found. Twenty-four isolates, including 10 azithromycin-resistant isolates, showed reduced susceptibility to extended-spectrum cephalosporins. Of these, five contained a penA mosaic gene. Four of the five NG-MLVA clusters contained resistant and susceptible isolates. Two clusters consisting mainly of resistant isolates included strains from men who have sex with men and from heterosexual males and females. The co-occurrence of resistant and susceptible strains in NG-MLVA clusters and the frequent occurrence of resistant strains outside of clusters suggest that azithromycin resistance develops independently from the background

The suppression of enhanced bitterness intensity of macrolide dry syrup mixed with an acidic powder.

PubMed

Ishizaka, Toshihiko; Okada, Sachie; Takemoto, Eri; Tokuyama, Emi; Tsuji, Eriko; Mukai, Junji; Uchida, Takahiro

2007-10-01

The aim of the present study was to identify a medicine which strongly enhanced the bitterness of clarithromycin dry syrup (CAMD) when administered concomitantly and to develop a method to suppress this enhanced bitterness. The bitterness enhancement was evaluated not only by gustatory sensation tests but also using pH and taste sensor measurements of the mixed sample. A remarkable bitterness enhancement was found when CAMD was mixed with the acidic powder L-carbocysteine. The acidic pH (pH 3.40) of the suspension made from these two preparations, seemed to be due to enhanced release of clarithromycin caused by the dissolution of the alkaline polymer film-coating. Several methods for preventing this bitterness enhancement were investigated. Neither increasing the volume of water taken with the mixture, nor changing the ratio of CAMD:L-carbocysteine in the mixture, were effective in reducing the bitterness intensity of the CAMD/L-carbocysteine mixture. The best way to achieve taste masking was to first administer CAMD mixed with chocolate jelly, which has a neutral pH, followed by the L-carbocysteine suspension. Similar results were obtained for the bitterness suppression of azithromycin fine granules with L-carbocysteine. The chocolate jelly will be useful for taste masking of bitter macrolide drug formulations, when they need to be administered together with acidic drug formulations.

Effects of food on a gastrically degraded drug: azithromycin fast-dissolving gelatin capsules and HPMC capsules.

PubMed

Curatolo, William; Liu, Ping; Johnson, Barbara A; Hausberger, Angela; Quan, Ernest; Vendola, Thomas; Vatsaraj, Neha; Foulds, George; Vincent, John; Chandra, Richa

2011-07-01

Commercial azithromycin gelatin capsules (Zithromax®) are known to be bioequivalent to commercial azithromycin tablets (Zithromax®) when dosed in the fasted state. These capsules exhibit a reduced bioavailability when dosed in the fed state, while tablets do not. This gelatin capsule negative food effect was previously proposed to be due to slow and/or delayed capsule disintegration in the fed stomach, resulting in extended exposure of the drug to gastric acid, leading to degradation to des-cladinose-azithromycin (DCA). Azithromycin gelatin capsules were formulated with "superdisintegrants" to provide fast-dissolving capsules, and HPMC capsule shells were substituted for gelatin capsule shells, in an effort to eliminate the food effect. Healthy volunteers were dosed with these dosage forms under fasted and fed conditions; pharmacokinetics were evaluated. DCA pharmacokinetics were also evaluated for the HPMC capsule subjects. In vitro disintegration of azithromycin HPMC capsules in media containing food was evaluated and compared with commercial tablets and commercial gelatin capsules. When the two fast-dissolving capsule formulations were dosed to fed subjects, the azithromycin AUC was 38.9% and 52.1% lower than after fasted-state dosing. When HPMC capsules were dosed to fed subjects, the azithromycin AUC was 65.5% lower than after fasted-state dosing. For HPMC capsules, the absolute fasting-state to fed-state decrease in azithromycin AUC (on a molar basis) was similar to the increase in DCA AUC. In vitro capsule disintegration studies revealed extended disintegration times for commercial azithromycin gelatin capsules and HPMC capsules in media containing the liquid foods milk and Ensure®. Interaction of azithromycin gelatin and HPMC capsules with food results in slowed disintegration in vitro and decreased bioavailability in vivo. Concurrent measurement of serum azithromycin and the acid-degradation product DCA demonstrates that the loss of azithromycin

Interleukin-12 plasmid DNA delivery using l-thyroxine-conjugated polyethylenimine nanocarriers

NASA Astrophysics Data System (ADS)

Dehshahri, Ali; Sadeghpour, Hossein; Kazemi Oskuee, Reza; Fadaei, Mahin; Sabahi, Zahra; Alhashemi, Samira Hossaini; Mohazabieh, Erfaneh

2014-05-01

In this study, l-thyroxine was covalently grafted on 25 kDa branched polyethylenimine (PEI), and the ability of the nano-sized polyplexes for transferring plasmid encoding interleukin-12 (IL-12) gene was evaluated. As there are several problems in systemic administration of recombinant IL-12 protein, local expression of the plasmid encoding IL-12 gene inside the tumor tissue has been considered as an effective alternative approach. The l-thyroxine-conjugated PEI polyplexes were prepared using pUMVC3-hIL12 plasmid, and their transfection activity was determined in HepG2 human liver carcinoma and Neuro2A neuroblastoma cell lines. The polyplexes characterized in terms of DNA condensation ability, particle size, zeta potential, and buffering capacity as well as cytotoxicity and resistance to enzyme digestion. The results revealed that l-thyroxine conjugation of PEI increased gene transfer ability by up to two fold relative to unmodified 25 kDa PEI, the gold standard for non-viral gene delivery, with the highest increase occurring at degrees of conjugation around 10 %. pDNA condensation tests and dynamic light scattering measurements exhibited the ability of PEI conjugates to optimally condense the plasmid DNA into polyplexes in the size range around 200 nm. The modified polymers showed remarkable buffering capacity and protection against enzymatic degradation comparable to that of unmodified PEI. These results suggest that l-thyroxine conjugation of PEI is a simple modification strategy for future investigations aimed at developing a targeting gene vehicle.

Interleukin‑12B is upregulated by decoy receptor 3 in rheumatoid synovial fibroblasts.

PubMed

Fukuda, Koji; Miura, Yasushi; Maeda, Toshihisa; Hayashi, Shinya; Kurosaka, Masahiro

2016-04-01

Decoy receptor 3 (DcR3) competitively binds to three ligands, Fas ligand, lymphotoxin‑related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells and tumor necrosis factor‑like ligand 1A (TL1A), to prevent their effects. Recent studies have suggested that DcR3 directly affects cells as a ligand. Using a microarray assay, our group newly identified interleukin (IL)‑12B, which encodes the p40 subunit common to IL‑12 and IL‑23, as one of the genes for which expression in fibroblast‑like synoviocytes from patients with rheumatoid arthritis (RA‑FLS) is induced by DcR3. The present study demonstrated that IL‑12B mRNA expression was upregulated by DcR3‑Fc in RA‑FLS in a dose‑dependent manner, but not in OA‑FLS. IL‑12B p40 protein in RA‑FLS was increased when stimulated with DcR3‑Fc. Pre‑treatment with anti‑TL1A antibody suppressed the upregulation of IL‑12B mRNA in RA‑FLS stimulated with DcR3‑Fc. DcR3 mRNA expression in RA‑FLS was induced by IL‑23, but not by IL‑12. These results indicated that DcR3 may increase IL‑12 or IL‑23 by inducing IL‑12B p40 expression via membrane‑bound TL1A on RA‑FLS and that IL‑23 reciprocally induces DcR3 expression in RA‑FLS. DcR3 and IL‑23 may interact in a feedback loop that aggravates local inflammation in patients with RA.

Azithromycin Treatment Failure for Chlamydia trachomatis Among Heterosexual Men With Nongonococcal Urethritis.

PubMed

Kissinger, Patricia J; White, Scott; Manhart, Lisa E; Schwebke, Jane; Taylor, Stephanie N; Mena, Leandro; Khosropour, Christine M; Wilcox, Larissa; Schmidt, Norine; Martin, David H

2016-10-01

Three recent prospective studies have suggested that the 1-g dose of azithromycin for Chlamydia trachomatis (Ct) was less effective than expected, reporting a wide range of treatment failure rates (5.8%-22.6%). Reasons for the disparate results could be attributed to geographic or methodological differences. The purpose of this study was to reexamine the studies and attempt to harmonize methodologies to reduce misclassification as a result of false positives from early test-of-cure (TOC) or reinfection as a result of sexual exposure rather than treatment failure. Men who had sex with women, who received 1-g azithromycin under directly observed therapy for presumptive treatment of nongonococcal urethritis with confirmed Ct were included. Baseline screening was performed on urethral swabs or urine, and TOC screening was performed on urine using nucleic acid amplification tests. Posttreatment vaginal sexual exposure was elicited at TOC. Data from the 3 studies were obtained and reanalyzed. Rates of Ct retest positive were examined for all cases, and a sensitivity analysis was conducted to either reclassify potential false positives/reinfections as negative or remove them from the analysis. The crude treatment failure rate was 12.8% (31/242). The rate when potential false positives/reinfections were reclassified as negative was 6.2% (15/242) or when these were excluded from analysis was 10.9% (15/138). In these samples of men who have sex with women with Ct-related nongonococcal urethritis, azithromycin treatment failure was between 6.2% and 12.8%. This range of failure is lower than previously published but higher than the desired World Health Organization's target chlamydia treatment failure rate of < 5%.

Limited Azithromycin Localization to Rabbit Meibomian Glands Revealed by LC-MS-Based Bioanalysis and DESI Imaging.

PubMed

Asano, Nagayoshi; Wiseman, Justin Michael; Tsuji, Fumio; Kawazu, Kouichi

2017-01-01

Meibomian gland dysfunction (MGD) is the leading cause of dry eye, and although it affects approximately 4% of the population, treatment options remain limited. Topical azithromycin is one of the most promising pharmacological agents because of its multiple mechanisms of action and long sustainability. Azithromycin is frequently used as an off-label medication in the U.S. However, although azithromycin is presumed to act directly on meibomian gland cells, the mechanisms of action that contribute to its clinical efficacy remain unclear because no studies using a pharmacokinetic approach have been performed. Therefore, we aimed to clarify whether topical azithromycin reaches the meibomian glands sufficiently to generate a biological effect. We measured azithromycin concentrations in rabbit meibomian glands collected using a recently developed method. Moreover, we also visualized the azithromycin micro-distribution using desorption electrospray ionization (DESI) imaging. Azithromycin concentration in the meibomian glands reached only 0.8 µg/g tissue following a single application of a 1% azithromycin ophthalmic solution and was 1000-fold lower than the concentration in conjunctival epithelium. Similarly, no signal was observed in the meibomian glands on DESI images. Our results clearly demonstrated that topical azithromycin had limited access to the meibomian glands and was predominantly distributed in ocular surface tissues such as the palpebral conjunctiva and lid margins. These findings provide new insight into the clinical responses to topical azithromycin therapy and will aid in the further development of effective drugs with more suitable pharmacokinetic properties.

Clinical features of Candidiasis in patients with inherited interleukin 12 receptor β1 deficiency.

PubMed

Ouederni, Monia; Sanal, Ozden; Ikinciogullari, Aydan; Tezcan, Ilhan; Dogu, Figen; Sologuren, Ithaisa; Pedraza-Sánchez, Sigifredo; Keser, Melike; Tanir, Gonul; Nieuwhof, Chris; Colino, Elena; Kumararatne, Dinakantha; Levy, Jacov; Kutukculer, Necil; Aytekin, Caner; Herrera-Ramos, Estefanía; Bhatti, Micah; Karaca, Neslihan; Barbouche, Ridha; Broides, Arnon; Goudouris, Ekaterini; Franco, José Luis; Parvaneh, Nima; Reisli, Ismail; Strickler, Alexis; Shcherbina, Anna; Somer, Ayper; Segal, Anthony; Angel-Moreno, Alfonso; Lezana-Fernandez, José Luis; Bejaoui, Mohamed; Bobadilla-Del Valle, Miriam; Kachboura, Salem; Sentongo, Timothy; Ben-Mustapha, Imen; Bustamante, Jacinta; Picard, Capucine; Puel, Anne; Boisson-Dupuis, Stéphanie; Abel, Laurent; Casanova, Jean-Laurent; Rodríguez-Gallego, Carlos

2014-01-01

Interleukin 12Rβ1 (IL-12Rβ1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rβ1 deficiency. Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.

Clinical Features of Candidiasis in Patients With Inherited Interleukin 12 Receptor β1 Deficiency

PubMed Central

Ouederni, Monia; Sanal, Ozden; Ikincioğullari, Aydan; Tezcan, Ilhan; Dogu, Figen; Sologuren, Ithaisa; Pedraza-Sánchez, Sigifredo; Keser, Melike; Tanir, Gonul; Nieuwhof, Chris; Colino, Elena; Kumararatne, Dinakantha; Levy, Jacov; Kutukculer, Necil; Aytekin, Caner; Herrera-Ramos, Estefanía; Bhatti, Micah; Karaca, Neslihan; Barbouche, Ridha; Broides, Arnon; Goudouris, Ekaterini; Franco, José Luis; Parvaneh, Nima; Reisli, Ismail; Strickler, Alexis; Shcherbina, Anna; Somer, Ayper; Segal, Anthony; Angel-Moreno, Alfonso; Lezana-Fernandez, José Luis; Bejaoui, Mohamed; Bobadilla-Del Valle, Miriam; Kachboura, Salem; Sentongo, Timothy; Ben-Mustapha, Imen; Bustamante, Jacinta; Picard, Capucine; Puel, Anne; Boisson-Dupuis, Stéphanie; Abel, Laurent; Casanova, Jean-Laurent; Rodríguez-Gallego, Carlos

2014-01-01

Background. Interleukin 12Rβ1 (IL-12Rβ1)–deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12–dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23–dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rβ1 deficiency. Results. Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. Conclusions. Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients. PMID:24186907

Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer.

PubMed

Gounder, Anshu P; Yokoyama, Christine C; Jarjour, Nicholas N; Bricker, Traci L; Edelson, Brian T; Boon, Adrianus C M

2018-04-01

Pro-inflammatory cytokinemia is a hallmark of highly pathogenic H5N1 influenza virus (IAV) disease yet little is known about the role of host proteins in modulating a pathogenic innate immune response. The host Interferon Induced Protein 35 (Ifi35) has been implicated in increased susceptibility to H5N1-IAV infection. Here, we show that Ifi35 deficiency leads to reduced morbidity in mouse models of highly pathogenic H5N1- and pandemic H1N1-IAV infection. Reduced weight loss in Ifi35-/- mice following H5N1-IAV challenge was associated with reduced cellular infiltration and decreased production of specific cytokines and chemokines including IL-12p40. Expression of Ifi35 by the hematopoietic cell compartment in bone-marrow chimeric mice contributed to increased immune cell recruitment and IL-12p40 production. In addition, Ifi35 deficient primary macrophages produce less IL-12p40 following TLR-3, TLR-4, and TLR-7 stimulation in vitro. Decreased levels of IL-12p40 and its homodimer, IL-12p80, were found in bronchoalveolar lavage fluid of H5N1-IAV infected Ifi35 deficient mice. Specific antibody blockade of IL-12p80 ameliorated weight loss and reduced cellular infiltration following H5N1-IAV infection in wild-type mice; suggesting that increased levels of IL-12p80 alters the immune response to promote inflammation and IAV disease. These data establish a role for Ifi35 in modulating cytokine production and exacerbating inflammation during IAV infection.

Impact of Azithromycin on Pregnancy Prolongation in Women at Risk of Preterm Labor: A Time-to-Event Analysis.

PubMed

Goyer, Isabelle; Ferland, Gabrielle; Ruo, Ni; Morin, Caroline; Brochet, Marie-Sophie; Morin, Lucie; Ferreira, Ema

2016-09-13

Since 2006, the empiric use of azithromycin in women at risk of premature birth has become prevalent in our institution without any evidence of its efficacy. Although antibiotics can prolong pregnancy in preterm prolonged rupture of membranes, no published data are available for women with intact membranes. To describe the purpose of adding azithromycin to the usual treatments (cerclage, tocolysis, rest, etc.) to prolong pregnancy in women with intact membranes who are at risk of or already in preterm labour. A retrospective observational cohort study was done at a Mother-Child University Hospital Centre. Patients admitted to obstetric ward who received azithromycin between January 1 st , 2006 and August 1 st , 2010 were included. A total of 127 exposed women were matched to 127 controls through medical records and pharmacy software. A time-to-event analysis was done to compare gestational age at the time of the recorded composite event (delivery, or rupture of membranes, or second intervention to prolong pregnancy). To compare proportions of composite event at different time points, χ 2 tests were used. Patients who received azithromycin had a more severe condition at presentation. Once adjusted for confounding factors, prolongation of pregnancy (HR =1.049; CI 95%: 0.774-1.421 [p=0.758]) and gestational age at the event (HR=1.200; CI 95%: 0.894-1.609 [p=0.225]) did not differ between the groups. The proportions of women with an event ≥7 days post-diagnosis or ≥37 gestational weeks were similar. Azithromycin was added to medical therapy in a more at-risk population and no clear benefit was measured.

Expression, purification and characterisation of recombinant Escherichia coli derived chicken interleukin-12.

PubMed

Thomas, Jesse D; Morris, Kirsten R; Godfrey, Dale I; Lowenthal, John W; Bean, Andrew G D

2008-12-15

Zoonotic viruses, such as H5N1 Avian Influenza, pose major threats to both animals and humans, and with this in mind there is a need for the development of new anti-viral strategies. The cytokine interleukin-12 (IL-12) is known to play a pivotal regulatory role in the anti-viral response due to its role in the induction of the key anti-viral cytokine IFN-gamma. Therefore, strategies which provide a means for the production of therapeutic quantities of IL-12 may be of major benefit. Here we describe the development of biologically active Escherichia coli (E. coli) derived chicken IL-12 (ChIL-12). The single chain ChIL-12 gene was cloned into the pET32b expression vector, transformed into the BL-21 E. coli strain and expression induced with IPTG. Over expressed protein was solubilised with zwittergent detergent and isolated utilising Nickel ion affinity chromatography. Biological activity was determined as ChIL-12 stimulated proliferation of pre-treated T-cells in vitro. This study is the first example of a biologically active E. coli derived IL-12 from a non-mammalian vertebrate subsequently providing a means for testing the anti-viral therapeutic potential of ChIL-12 in an in vivo model.

Mangiferin inhibits lipopolysaccharide-induced production of interleukin-6 in human oral epithelial cells by suppressing toll-like receptor signaling.

PubMed

Li, Hao; Wang, Qi; Chen, Xinmin; Ding, Yi; Li, Wei

2016-11-01

Oral epithelial cells have currently been found to play an important role in inflammatory modulation in periodontitis. Mangiferin is a natural glucosylxanthone with anti-inflammatory activity. The aim of this study was to investigate the regulatory effect of mangiferin on lipopolysaccharide (LPS)-induced production of proinflammatory cytokine interleukin-6 (IL-6) in oral epithelial cells and the underlying mechanisms. The levels of LPS-induced IL-6 production in OKF6/TERT-2 oral keratinocytes were detected using enzyme-linked immunosorbent assay (ELISA). The expression of Toll-like receptor (TLR) 2 and TLR4 was determined using western blot analysis. And the phosphorylation of TLR downstream nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) was examined using cell-based protein phosphorylation ELISA kits. We found that mangiferin reduced LPS-upregulated IL-6 production in OKF6/TERT-2 cells. Additionally, mangiferin inhibited LPS-induced TLR2 and TLR4 overexpression, and suppressed the phosphorylation of NF-κB, p38 MAPK and JNK. Moreover, mangiferin repressed IL-6 production and TLR signaling activation in a dose-dependent manner after 24h treatment. Mangiferin decreases LPS-induced production of IL-6 in human oral epithelial cells by suppressing TLR signaling, and this glucosylxanthone may have potential for the treatment of periodontitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Role of interleukin 12 in experimental neonatal sepsis caused by group B streptococci.

PubMed Central

Mancuso, G; Cusumano, V; Genovese, F; Gambuzza, M; Beninati, C; Teti, G

1997-01-01

Cytokines are suspected to play an important role in systemic infections by group B streptococci (GBS), an important cause of neonatal sepsis. This work was undertaken to determine if interleukin 12 (IL-12) is produced in mouse pups infected with GBS and has a role in this sepsis model. IL-12 elevations were measured by both an enzyme-linked immunosorbent assay and a bioassay in plasma samples obtained from 12 to 72 h after GBS challenge. Pretreatment with neutralizing anti-IL-12 antibodies significantly increased lethality and blood CFU (P < 0.05). Conversely, either prophylactically or therapeutically administered recombinant IL-12 (rIL-12) significantly improved survival time and decreased blood CFU. Since these beneficial effects were associated with increased spleen gamma interferon (IFN-gamma) production, we examined whether the latter cytokine mediated the observed rIL-12 effects. Pretreatment with neutralizing anti-IFN-gamma monoclonal antibodies significantly counteracted the beneficial effects of rIL-12 on lethality. Our data indicate that rIL-12 is a possible candidate for treatment of GBS sepsis and that its activities in this model are at least partially mediated by IFN-gamma. PMID:9284145

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation.

PubMed

Mangal, Sharad; Nie, Haichen; Xu, Rongkun; Guo, Rui; Cavallaro, Alex; Zemlyanov, Dmitry; Zhou, Qi Tony

2018-01-08

Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution. The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated. The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations. We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.

Azithromycin treatment failure for Chlamydia trachomatis among heterosexual men with nongonococcal urethritis

PubMed Central

Kissinger, Patricia; White, Scott; Manhart, Lisa E.; Schwebke, Jane; Taylor, Stephanie N; Mena, Leandro; Khosropour, Christine M; Wilcox, Larissa; Schmidt, Norine; Martin, David H

2016-01-01

Background Three recent prospective studies have suggested that the 1 g dose of azithromycin for Chlamydia trachomatis (Ct) was less effective than expected, reporting a wide range of treatment failure rates (5.8%–22.6%). Reasons for the disparate results could be attributed to geographic or methodological differences. The purpose of this study was to re-examine the studies and attempt to harmonize methodologies to reduce misclassification as a result of false positives from early test-of-cure (TOC) or reinfection as a result of sexual exposure rather than treatment failure. Methods Men who had sex with women, who received 1 g azithromycin under directly observed therapy (DOT) for presumptive treatment of nongonococcal urethritis (NGU) with confirmed Ct were included. Baseline screening was performed on urethral swabs or urine and TOC screening was performed on urine using nucleic acid amplification tests (NAAT). Post-treatment vaginal sexual exposure was elicited at TOC. Data from the three studies was obtained and re-analyzed. Rates of Ct re-test positive were examined for all cases and a sensitivity analysis was conducted to either reclassify potential false positives/reinfections as negative or remove them from the analysis. Results The crude treatment failure rate was 12.8% (31/242). The rate when potential false positives/reinfections were reclassified as negative was 6.2% (15/242) or when these were excluded from analysis was 10.9% (15/138). Conclusion In these samples of men who have sex with women with Ct-related NGU, azithromycin treatment failure was between 6.2% and 12.8%. This range of failure is lower than previously published but higher than the desired World Health Organization’s target chlamydia treatment failure rate of < 5%. PMID:27631353

One man's poison is another man's meat: using azithromycin-induced phospholipidosis to promote ocular surface health.

PubMed

Liu, Yang; Kam, Wendy R; Ding, Juan; Sullivan, David A

2014-06-05

Drug-induced phospholipidosis (PLD) is a common adverse effect which has led to the termination of clinical trials for many candidate pharmaceuticals. However, this lipid-inducing effect may be beneficial in the treatment of meibomian gland dysfunction (MGD). MGD is the major cause of dry eye disease (DED), which affects 40 million people in the USA and has no cure. Azithromycin (AZM) is a PLD-inducing antibiotic that is used off-label to treat MGD, and is presumably effective because it suppresses the MGD-associated conjunctival inflammation (i.e. posterior blepharitis) and growth of lid bacteria. We hypothesize that AZM can act directly to promote the function of human meibomian gland epithelial cells by inducing PLD in these cells, characterized by the accumulation of lipids and lysosomes. Immortalized human meibomian gland epithelial cells (HMGEC) were cultured with or without azithromycin for 5 days. Cells were evaluated for cholesterol (Filipin) and neutral lipid (LipidTox) staining, as well as the appearance of lysosomes (LysoTracker) and lamellar bodies (transmission electron microscopy, TEM). The lipid composition of cellular lysates was analyzed by high performance thin-layer chromatography. Our findings demonstrate that AZM stimulates the accumulation of free cholesterol, neutral lipids and lysosomes in HMGEC. This AZM-induced increase of neutral lipid content occurred predominantly within lysosomes. Many of these vesicles appeared to be lamellar bodies by TEM, which is the characteristic of PLD. Our findings also show that AZM promotes an accumulation of free and esterified cholesterol, as well as phospholipids in HMGECimmortalized. Our results support our hypothesis and confirm the beneficial effect of PLD induced by AZM on HMGEC. Our discovery reveals a new potential use of PLD-inducing drugs, and makes this adverse effect a beneficial effect. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

PubMed Central

Mangal, Sharad; Nie, Haichen; Xu, Rongkun; Guo, Rui; Cavallaro, Alex; Zemlyanov, Dmitry; Zhou, Qi (Tony)

2018-01-01

Purpose Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution. Methods The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated. Results The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations. Conclusions We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine. PMID:29374368

Benefits of additional courses of systemic azithromycin in periodontal disease case report.

PubMed

Schmidt, Edgard F; Bretz, Walter A

2007-01-01

The strong association of subgingival anaerobic bacteria, such as Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, with destructive periodontal disease has been well documented in the literature. Several double-blind studies have also shown the beneficial use of systemic antimicrobials that are active against these microorganisms in conjunction with conventional periodontal treatment, especially when periodontal abscesses and/or suppuration upon probing are present. Four cases with periodontal abscesses were treated with scaling/root planing in conjunction with systemic azithromycin. Partial improvement led to retreatment with two additional courses of azithromycin. Bone formation was noted on periapical radiographs after the patients took additional courses of azithromycin. In view of the benefits of using additional courses of azithromycin in the treatment of destructive periodontal disease, we conclude that the single course of systemic antimicrobials currently used in periodontal therapy may be insufficient to reach necessary therapeutic levels in infected sites.

Outcome of Intravenous Azithromycin Therapy in Patients with Complicated Scrub Typhus Compared with That of Doxycycline Therapy Using Propensity-Matched Analysis

PubMed Central

Jang, Mi-Ok; Jang, Hee-Chang; Kim, Uh Jin; Ahn, Joon Hwan; Kang, Seung-Ji; Jung, Sook-In; Shin, Hee-Young

2014-01-01

There are no well-matched, controlled studies comparing azithromycin with doxycycline for the treatment of complicated scrub typhus. A retrospective propensity score-matched case-control study was performed for patients who presented with complicated scrub typhus and were treated with doxycycline or azithromycin between 2001 and 2011. Data on comorbidities, clinical manifestations, laboratory studies, treatments, and outcomes were extracted for analysis. The clinical characteristics and outcomes of the azithromycin-treated group (n = 73) were compared to those of the doxycycline-treated group (n = 108). Of 181 patients, 73 from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment success and survival rates were not significantly different (89% [65/73 patients] versus 96% [70/73 patients] and 96% [70/73 patients] versus 96% [70/73 patients], respectively [P > 0.05]). No difference was observed in the time to defervescence or length of hospital stay between the two groups (P > 0.05). In complicated scrub typhus patients (n = 181), multivariate analysis showed that only APACHE II score was an independent risk factor for mortality (95% confidence interval, 1.11 to 1.56; P < 0.001). Our data suggest that outcomes of azithromycin therapy are comparable to those of doxycycline therapy in patients with complicated scrub typhus. PMID:24366734

Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells.

PubMed

Poznanski, Sophie M; Lee, Amanda J; Nham, Tina; Lusty, Evan; Larché, Margaret J; Lee, Dean A; Ashkar, Ali A

2017-01-01

The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation. © 2017 S. Karger AG, Basel.

Retreatment rates for uncomplicated gonorrhea infection: comparing ceftriaxone and azithromycin versus ceftriaxone and doxycycline.

PubMed

Schumacher, Christina M; Ghanem, Khalil G

2013-07-01

The current recommended first-line regimen to treat gonorrhea is ceftriaxone in combination with either azithromycin or doxycycline. Azithromycin is the preferred second agent. We retrospectively measured and compared gonorrhea retreatment rates between patients receiving ceftriaxone plus azithromycin and those receiving ceftriaxone plus doxycycline. Using data from public sexually transmitted disease clinics for patients treated for gonorrhea in Baltimore, Maryland, between January 2004 and December 2011, we measured time to retreatment from the date the ceftriaxone regimen was received. Censoring occurred on the earlier of 2 years posttreatment or March 31, 2012. Survival analysis methods were used to compare retreatment rates. One tenth (9.9%; n = 4457) of patients were retreated within 2 years. Treatment regimen was not related to time to retreatment (adjusted hazard ratio [aHR], 0.88; 95% confidence interval, 0.69-1.12). Patients receiving expedited partner therapy (EPT) were 45% less likely to be retreated (aHR, 0.55 [0.31-0.96]) compared with patients treated before EPT became available. A subanalysis among patients retested for gonorrhea within 90 and 30 days found retreatment rates of 18.8% (n = 91/485) and 13.5% (n = 19/140), respectively. The 90-day cohort showed no association with treatment regimen (aHR, 0.95 [0.55-1.65]); however, all of the retreated patients in the 30-day cohort had received the doxycycline regimen. Gonorrhea retreatment was common, highlighting the need for rescreening and better partner therapies. The protective effect of EPT further underscores the need for effective oral therapies. Azithromycin may be preferable as the second agent to treat gonorrhea, although doxycycline seems to be a reasonable alternative.

Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model1

PubMed Central

Dickerson, Erin B; Steinberg, Howard; Breen, Matthew; Auerbach, Robert; Helfand, Stuart C

2004-01-01

Abstract We established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in a dog to provide a renewable source of endothelial cells for studies of angiogenesis in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously in a bg/nu/XID mouse allowing the tumor cells to expand in vivo. A cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular endothelial growth factor (VEGF) receptors 1 and 2, CD31, CD146, and αvβ3 integrin, and produced several growth factors and cytokines, including VEGF, basic fibroblast growth factor, and interleukin (IL)-8 that are stimulatory to endothelial cell growth. These results indicated that the cells recapitulated features of mitotically activated endothelia. In vivo, SB-HSA cells stimulated robust angiogenic responses in mice and formed tumor masses composed of aberrant vascular channels in immunocompromised mice providing novel opportunities for investigating the effectiveness of antiangiogenic agents. Using this model, we determined that IL-12, a cytokine with both immunostimulatory and antiangiogenic effects, suppressed angiogenesis induced by, and tumor growth of, SB-HSA cells. The endothelial cell model we have described offers unique opportunities to pursue further investigations with IL-12, as well as other antiangiogenic approaches in cancer therapy. PMID:15140399

Suppression of allergic airway inflammation in a mouse model by Der p2 recombined BCG.

PubMed

Ou-Yang, Hai-Feng; Hu, Xing-Bin; Ti, Xin-Yu; Shi, Jie-Ran; Li, Shu-Jun; Qi, Hao-Wen; Wu, Chang-Gui

2009-09-01

Allergic asthma is a chronic inflammatory disease mediated by T helper (Th)2 cell immune responses. Currently, immunotherapies based on both immune deviation and immune suppression, including the development of recombinant mycobacteria as immunoregulatory vaccines, are attractive treatment strategies for asthma. In our previous studies, we created a genetically recombinant form of bacille Calmette-Guerin (rBCG) that expressed Der p2 of house dust mites and established that it induced a shift from a Th2 response to a Th1 response in naive mice. However, it is unclear whether rBCG could suppress allergic airway inflammation in a mouse model. In this article we report that rBCG dramatically inhibited airway inflammation, eosinophilia, mucus production and mast cell degranulation in allergic mice. Analysis of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels in bronchoalveolar lavage fluid (BALF) and lung tissue revealed that the suppression was associated with a shift from a Th2 response to a Th1 response. At the same time, rBCG induced a CD4(+) CD25(+) Foxp3(+) T-cell subtype that could suppress the proliferation of Th2 effector cells in vitro in an antigen-specific manner. Moreover, suppression of CD4(+) CD25(+) T cells could be adoptively transferred. Thus, our results demonstrate that rBCG induces both generic and specific immune responses. The generic immune response is associated with a shift from a Th2 to a Th1 cytokine response, whereas the specific immune response against Der p2 appears to be related to the expansion of transforming growth factor-beta (TGF-beta)-producing CD4(+) CD25(+) Foxp3(+) regulatory T cells. rBCG can suppress asthmatic airway inflammation through both immune deviation and immune suppression and may be a feasible, efficient immunotherapy for asthma.

Azithromycin induced hepatocellular toxicity and hepatic encephalopathy in asymptomatic dilated cardiomyopathy

PubMed Central

Das, Bidyut Kumar

2011-01-01

Azithromycin is a widely used macrolide derivative and has generally been considered to be a very safe medication. Though gastrointestinal symptoms and reversible hearing loss are common, potentially serious side effects including angioedema and cholestatic jaundice occurred in less than one percent of patients. We report a case of asymptomatic dilated cardiomyopathy with Azithromycin induced severe hepatocellular toxicity and hepatic encephalopathy. PMID:22144789

Interleukin-6 and soluble interleukin-6 receptor suppress osteoclastic differentiation by inducing PGE(2) production in chondrocytes.

PubMed

Honda, Kazuhiro

2011-03-01

This study examined how interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6r) influence osteoclastic differentiation through the function of chondrocytes. Chondrocytes were cultured with or without IL-6 and/or sIL-6r in the presence or absence of NS398, a specific inhibitor of cyclooxygenase (COX)-2, for up to 28 days. Chondrocytes were also cultured with or without IL-6 and sIL-6r for 28 days, and the conditioned medium from cells cultured without IL-6 and sIL-6r was used to induce differentiation of RAW264.7 cells into osteoclast precursors. Osteoclastic differentiation was assessed by tartrate-resistant acid phosphatase (TRAP) staining. Expression of osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), COX-2, and prostaglandin E(2) (PGE(2)) increased in cells exposed to IL-6 and sIL-6r, whereas expression of macrophage colony-stimulating factor (M-CSF) and bone resorption-related enzymes decreased. NS398 blocked the stimulatory/suppressive effects of IL-6 and sIL-6r on the expression of OPG, RANKL, and M-CSF. Fewer TRAP-positive multinucleated cells were detected after treatment with conditioned medium from IL-6- and sIL-6r-treated chondrocytes than after treatment with conditioned medium from untreated chondrocytes. These results suggest that IL-6 and sIL-6r interfere with osteoclast function through the involvement of chondrocytes. Specifically, they appear to suppress the differentiation of osteoclast precursors into osteoclasts by inducing chondrocytic PGE(2) production, which, in turn, increases OPG secretion and decreases M-CSF secretion by chondrocytes.

Occurrence of congenital syphilis after maternal treatment with azithromycin during pregnancy.

PubMed

Zhou, Pingyu; Qian, Yihong; Xu, Jinhua; Gu, Zhiying; Liao, Kanghuang

2007-07-01

To evaluate the efficacy of azithromycin in preventing congenital syphilis. Five pregnant women with syphilis who were allergic to penicillin were given azithromycin, 1 g daily orally or intravenously, in different hospitals. The duration of the therapy ranged from 1 day to 10 days. A second course of therapy was provided at 28 weeks gestation. The babies were given a physical examination and blood test for serum rapid plasma reagin test (RPR), treponema pallidum hemagglutination test (TPHA), and fluorescent treponemal antibody adsorption test (FTA-ABS-19-sIgM) within three months after birth. Five infants born to these mothers developed skin rashes. Four of the infants had hepatomegaly and one showed osteochondritis. The tests RPR, TPHA, and FTA-ABS-19-sIgM were positive. The RPR titers varied from 1:64 to 1:256 and the babies were diagnosed with congenital syphilis. They were successfully treated with penicillin. Successful therapy for syphilis during pregnancy demands maternal care as well as prevention or cure of congenital infection. The failure of azithromycin in preventing congenital syphilis in our report suggests that azithromycin should not be recommended as an alternative in treating syphilitic pregnant women or fetal syphilis.

Interleukin-12 Induces a Th1-like Response to Burkholderia mallei and Limited Protection in BALB/c Mice

DTIC Science & Technology

2005-09-02

protection from a lethal challenge. 15. SUBJECT TERMS Burkholderia mallei , glanders , cytokines, immune response, humoral, cellular, laboratory animals...model of sublethal and lethal intraperitoneal glanders ( Burkholderia mallei ). Vet Pathol 2000;37:626–36. [34] Jankovic D, Caspar P, Zweig M, Garcia...Vaccine 24 (2006) 1413–1420 Interleukin-12 induces a Th1-like response to Burkholderia mallei and limited protection in BALB/c mice Kei Amemiya

Enhanced Control of Pathogenic Simian Immunodeficiency Virus SIVmac239 Replication in Macaques Immunized with an Interleukin-12 Plasmid and a DNA Prime-Viral Vector Boost Vaccine Regimen ▿ §

PubMed Central

Winstone, Nicola; Wilson, Aaron J.; Morrow, Gavin; Boggiano, Cesar; Chiuchiolo, Maria J.; Lopez, Mary; Kemelman, Marina; Ginsberg, Arielle A.; Mullen, Karl; Coleman, John W.; Wu, Chih-Da; Narpala, Sandeep; Ouellette, Ian; Dean, Hansi J.; Lin, Feng; Sardesai, Niranjan Y.; Cassamasa, Holly; McBride, Dawn; Felber, Barbara K.; Pavlakis, George N.; Schultz, Alan; Hudgens, Michael G.; King, C. Richter; Zamb, Timothy J.; Parks, Christopher L.; McDermott, Adrian B.

2011-01-01

DNA priming has previously been shown to elicit augmented immune responses when administered by electroporation (EP) or codelivered with a plasmid encoding interleukin-12 (pIL-12). We hypothesized that the efficacy of a DNA prime and recombinant adenovirus 5 boost vaccination regimen (DNA/rAd5) would be improved when incorporating these vaccination strategies into the DNA priming phase, as determined by pathogenic simian immunodeficiency virus SIVmac239 challenge outcome. The whole SIVmac239 proteome was delivered in 5 separate DNA plasmids (pDNA-SIV) by EP with or without pIL-12, followed by boosting 4 months later with corresponding rAd5-SIV vaccine vectors. Remarkably, after repeated low-dose SIVmac239 mucosal challenge, we demonstrate 2.6 and 4.4 log reductions of the median SIV peak and set point viral loads in rhesus macaques (RMs) that received pDNA-SIV by EP with pIL-12 compared to the median peak and set point viral loads in mock-immunized controls (P < 0.01). In 5 out of 6 infected RMs, strong suppression of viremia was observed, with intermittent “blips” in virus replication. In 2 RMs, we could not detect the presence of SIV RNA in tissue and lymph nodes, even after 13 viral challenges. RMs immunized without pIL-12 demonstrated a typical maximum of 1.5 log reduction in virus load. There was no significant difference in the overall magnitude of SIV-specific antibodies or CD8 T-cell responses between groups; however, pDNA delivery by EP with pIL-12 induced a greater magnitude of SIV-specific CD4 T cells that produced multiple cytokines. This vaccine strategy is relevant for existing vaccine candidates entering clinical evaluation, and this model may provide insights into control of retrovirus replication. PMID:21734035

Jarisch-Herxheimer reaction among HIV-positive patients with early syphilis: azithromycin versus benzathine penicillin G therapy

PubMed Central

Tsai, Mao-Song; Yang, Chia-Jui; Lee, Nan-Yao; Hsieh, Szu-Min; Lin, Yu-Hui; Sun, Hsin-Yun; Sheng, Wang-Huei; Lee, Kuan-Yeh; Yang, Shan-Ping; Liu, Wen-Chun; Wu, Pei-Ying; Ko, Wen-Chien; Hung, Chien-Ching

2014-01-01

Introduction The Jarisch-Herxheimer reaction, a febrile inflammatory reaction that often occurs after the first dose of chemotherapy in spirochetal diseases, may result in deleterious effects to patients with neurosyphilis and to pregnant women. A single 2-g oral dose of azithromycin is an alternative treatment to benzathine penicillin G for early syphilis in areas with low macrolide resistance. With its potential anti-inflammatory activity, the impact of azithromycin on the incidence of the Jarisch-Herxheimer reaction in HIV-positive patients with early syphilis has rarely been investigated. Methods In HIV-positive patients with early syphilis, the Jarisch-Herxheimer reaction was prospectively investigated using the same data collection form in 119 patients who received benzathine penicillin G between 2007 and 2009 and 198 who received azithromycin between 2012 and 2013, when shortage of benzathine penicillin G occurred in Taiwan. Between 2012 and 2013, polymerase chain reaction (PCR) assay was performed to detect Treponema pallidum DNA in clinical specimens, and PCR restriction fragment length polymorphism of the 23S ribosomal RNA was performed to detect point mutations (2058G or A2059G) that are associated with macrolide resistance. Results The overall incidence of the Jarisch-Herxheimer reaction was significantly lower in patients receiving azithromycin than those receiving benzathine penicillin G (14.1% vs. 56.3%, p<0.001). The risk increased with higher rapid plasma reagin (RPR) titres (adjusted odds ratio [AOR] per 1-log2 increase, 1.21; confidence interval [CI], 1.04–1.41), but decreased with prior penicillin therapy for syphilis (AOR, 0.37; 95% CI, 0.19–0.71) and azithromycin treatment (AOR, 0.15; 95% CI, 0.08–0.29). During the study period, 310 specimens were obtained from 198 patients with syphilis for PCR assays, from whom T. pallidum was identified in 76 patients, one of whom (1.3%) was found to be infected with T. pallidum harbouring the

Effects of long-term azithromycin therapy on airway oxidative stress markers in non-cystic fibrosis bronchiectasis.

PubMed

Diego, Afredo De; Milara, Javier; Martinez-Moragón, Eva; Palop, Marta; León, Montse; Cortijo, Julio

2013-10-01

To explore the effect of long-term therapy with azithromycin in regards to airway oxidative stress markers in exhaled breath condensate (EBC) of adult patients with stable non-cystic fibrosis (CF) bronchiectasis. Open-label prospective study of 30 patients randomized to azithromycin 250 mg three times per week during 3 months (16 patients) or control (14 patients). Primary outcome were changes in nitric oxide, 8-isoprostane, pH, nitrites and nitrates in EBC. Secondary outcomes were changes in exacerbation rates, dyspnoea (Borg scale), sputum volume (cc), sputum colour (15-point scale), bacterial infection, health-related quality of life (St George's Respiratory Questionnaire), lung function and radiological extension. Azithromycin produced a significant decrease in sputum volume (8.9 (1.8) mL vs 2.1 (3.4) mL) and number of exacerbations (0.1 (0.6) vs 1.2 (0.9)). Dyspnoea (0.4 (0.1) vs 0.1 (0.2)) and health-related quality of life also improved after therapy. However, oxidative stress markers in EBC, systemic inflammatory markers as well as functional respiratory tests did not differ from the control group after therapy. A post-hoc analysis comparing patients infected or not with Pseudomonas aeruginosa revealed that these effects were more pronounced in infected patients. In this subgroup, treatment was followed by a significant reduction in sputum volume, number of exacerbations, dyspnoea and St George's Respiratory Questionnaire total score. Of all airway oxidative stress markers, only nitrates in EBC were reduced after therapy. Long-term azythromicin treatment has some clinical benefits in patients with non-CF stable bronchiectasis, but it does not affect airway oxidative stress markers. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

Co-operative suppression of inflammatory responses in human dendritic cells by plant proanthocyanidins and products from the parasitic nematode Trichuris suis.

PubMed

Williams, Andrew R; Klaver, Elsenoor J; Laan, Lisa C; Ramsay, Aina; Fryganas, Christos; Difborg, Rolf; Kringel, Helene; Reed, Jess D; Mueller-Harvey, Irene; Skov, Søren; van Die, Irma; Thamsborg, Stig M

2017-03-01

Interactions between dendritic cells (DCs) and environmental, dietary and pathogen antigens play a key role in immune homeostasis and regulation of inflammation. Dietary polyphenols such as proanthocyanidins (PAC) may reduce inflammation, and we therefore hypothesized that PAC may suppress lipopolysaccharide (LPS) -induced responses in human DCs and subsequent T helper type 1 (Th1) -type responses in naive T cells. Moreover, we proposed that, because DCs are likely to be exposed to multiple stimuli, the activity of PAC may synergise with other bioactive molecules that have anti-inflammatory activity, e.g. soluble products from the helminth parasite Trichuris suis (TsSP). We show that PAC are endocytosed by monocyte-derived DCs and selectively induce CD86 expression. Subsequently, PAC suppress the LPS-induced secretion of interleukin-6 (IL-6) and IL-12p70, while enhancing secretion of IL-10. Incubation of DCs with PAC did not affect lymphocyte proliferation; however, subsequent interferon-γ production was markedly suppressed, while IL-4 production was unaffected. The activity of PAC was confined to oligomers (degree of polymerization ≥ 4). Co-pulsing DCs with TsSP and PAC synergistically reduced secretion of tumour necrosis factor-α, IL-6 and IL-12p70 while increasing IL-10 secretion. Moreover, both TsSP and PAC alone induced Th2-associated OX40L expression in DCs, and together synergized to up-regulate OX40L. These data suggest that PAC induce an anti-inflammatory phenotype in human DCs that selectively down-regulates Th1 response in naive T cells, and that they also act cooperatively with TsSP. Our results indicate a novel interaction between dietary compounds and parasite products to influence immune function, and may suggest that combinations of PAC and TsSP can have therapeutic potential for inflammatory disorders. © 2016 John Wiley & Sons Ltd.

Dose-dependent suppression by ethanol of transient auditory 40-Hz response.

PubMed

Jääskeläinen, I P; Hirvonen, J; Saher, M; Pekkonen, E; Sillanaukee, P; Näätänen, R; Tiitinen, H

2000-02-01

Acute alcohol (ethanol) challenge is known to induce various cognitive disturbances, yet the neural basis of the effect is poorly known. The auditory transient evoked gamma-band (40-Hz) oscillatory responses have been suggested to be associated with various perceptual and cognitive functions in humans; however, alcohol effects on auditory 40-Hz responses have not been investigated to date. The objective of the study was to test the dose-related impact of alcohol on auditory transient evoked 40-Hz responses during a selective-attention task. Ten healthy social drinkers ingested, in four separate sessions, 0.00, 0. 25, 0.50, or 0.75 g/kg of 10% (v/v) alcohol solution. The order of the sessions was randomized and a double-blind procedure was employed. During a selective attention task, 300-Hz standard and 330-Hz deviant tones were presented to the left ear, and 1000-Hz standards and 1100-Hz deviants to the right ear of the subjects (P=0. 425 for each standard, P=0.075 for each deviant). The subjects attended to a designated ear, and were to detect the deviants therein while ignoring tones to the other ear. The auditory transient evoked 40-Hz responses elicited by both the attended and unattended standard tones were significantly suppressed by the 0.50 and 0.75 g/kg alcohol doses. Alcohol suppresses auditory transient evoked 40-Hz oscillations already with moderate blood alcohol concentrations. Given the putative role of gamma-band oscillations in cognition, this finding could be associated with certain alcohol-induced cognitive deficits.

Gypenoside IX Suppresses p38 MAPK/Akt/NFκB Signaling Pathway Activation and Inflammatory Responses in Astrocytes Stimulated by Proinflammatory Mediators.

PubMed

Wang, Xiaoshuang; Yang, Liu; Yang, Li; Xing, Faping; Yang, Hua; Qin, Liyue; Lan, Yunyi; Wu, Hui; Zhang, Beibei; Shi, Hailian; Lu, Cheng; Huang, Fei; Wu, Xiaojun; Wang, Zhengtao

2017-12-01

Gypenoside IX (GP IX) is a pure compound isolated from Panax notoginseng. Gypenosides have been implicated to benefit the recovery of enormous neurological disorders. By suppressing the activation of astrocytes, gypenosides can improve the cognitive impairment. However, so far, little is known about whether GP IX could restrain the inflammatory responses in astrocytes or reactive astrogliosis. In present study, the anti-inflammatory effects of GP IX were investigated in reactive astrocytes induced by proinflammatory mediators both in vitro and in vivo. GP IX significantly reduced the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) at either protein or mRNA level in glial cell line C6 cells stimulated by lipopolysaccharide (LPS)/TNF-α combination. It also alleviated the astrogliosis and decreased the production of inflammatory mediators in brain cortex of LPS-treated mice. Further study disclosed that GP IX inhibited nuclear translocation of nuclear factor kappa B (NFκB) and reduced its transcriptional activity. Meanwhile, GP IX significantly attenuated the phosphorylation of NFκB, inhibitor of kappa B (IκB), Akt, and p38 mitogen-activated protein kinase (MAPK) under inflammatory conditions both in vitro and in vivo. These findings indicated that GP IX might suppress reactive astrogliosis by suppressing Akt/p38 MAPK/NFκB signaling pathways. And GP IX might be a promising drug candidate or prodrug for the therapy of neuroinflammatory disorders characterized with reactive astrogliosis.

Hydrocortisone prevents immunosuppression by interleukin-10+ natural killer cells after trauma-hemorrhage.

PubMed

Roquilly, Antoine; Broquet, Alexis; Jacqueline, Cédric; Masson, Damien; Segain, Jean Pierre; Braudeau, Cecile; Vourc'h, Mickael; Caillon, Jocelyne; Altare, Frédéric; Josien, Regis; Retière, Christelle; Villadangos, Jose; Asehnoune, Karim

2014-12-01

Trauma induces a state of immunosuppression, which is responsible for the development of nosocomial infections. Hydrocortisone reduces the rate of pneumonia in patients with trauma. Because alterations of dendritic cells and natural killer cells play a central role in trauma-induced immunosuppression, we investigated whether hydrocortisone modulates the dendritic cell/natural killer cell cross talk in the context of posttraumatic pneumonia. Experimental study. Research laboratory from an university hospital. Bagg Albino/cJ mice (weight, 20-24 g). First, in an a priori substudy of a multicenter, randomized, double-blind, placebo-controlled trial of hydrocortisone (200 mg/d for 7 d) in patients with severe trauma, we have measured the blood levels of five cytokines (tumor necrosis factor-α, interleukin-6, interleukin-10, interleukin-12, interleukin-17) at day 1 and day 8. In a second step, the effects of hydrocortisone on dendritic cell/natural killer cell cross talk were studied in a mouse model of posttraumatic pneumonia. Hydrocortisone (0.6 mg/mice i.p.) was administered immediately after hemorrhage. Twenty-four hours later, the mice were challenged with Staphylococcus aureus (7 × 10 colony-forming units). Using sera collected during a multicenter study in patients with trauma, we found that hydrocortisone decreased the blood level of interleukin-10, a cytokine centrally involved in the regulation of dendritic cell/natural killer cell cluster. In a mouse model of trauma-hemorrhage-induced immunosuppression, splenic natural killer cells induced an interleukin-10-dependent elimination of splenic dendritic cell. Hydrocortisone treatment reduced this suppressive function of natural killer cells and increased survival of mice with posthemorrhage pneumonia. The reduction of the interleukin-10 level in natural killer cells by hydrocortisone was partially dependent on the up-regulation of glucocorticoid-induced tumor necrosis factor receptor-ligand (TNFsf18) on

Mangiferin suppresses CIA by suppressing the expression of TNF-α, IL-6, IL-1β, and RANKL through inhibiting the activation of NF-κB and ERK1/2.

PubMed

Tsubaki, Masanobu; Takeda, Tomoya; Kino, Toshiki; Itoh, Tatsuki; Imano, Motohiro; Tanabe, Genzo; Muraoka, Osamu; Satou, Takao; Nishida, Shozo

2015-01-01

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of synovial joints, ultimately leading to a progressive and irreversible joint destruction. Activation of nuclear factor-kappa B (NF-κB) promotes production of proinflammatory cytokines in various inflammatory diseases including rheumatoid arthritis. Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside (C-glucosyl xanthone), is a naturally occurring polyphenol. Our previous results showed that mangiferin suppressed NF-κB activation. However, it is unclear, whether mangiferin can prevent rheumatoid arthritis through suppression of NF-κB activation and expression of various cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), which play a critical role in the pathogenesis of rheumatoid arthritis. In the present study, we found that mangiferin suppressed the progression and incidence of CIA in DBA1/J mice. In CIA mice, mangiferin inhibited the mRNA expression of cytokine genes in thymus and spleen of CIA mie and led to decreased serum levels of IL-1β, IL-6, TNF-α, and receptor activator NF-κB ligand (RANKL) via inhibition of NF-κB and activation of extracellular signal-regulated kinase 1/2 (ERK1/2). In addition, mangiferin markedly inhibited not only developing but also clinically evident CIA. These findings suggest that mangiferin has potential clinical applications for the treatment of rheumatoid arthritis.

Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease

PubMed Central

Molle, Céline; Zhang, Tong; Ysebrant de Lendonck, Laure; Gueydan, Cyril; Andrianne, Mathieu; Sherer, Félicie; Van Simaeys, Gaetan; Blackshear, Perry J.; Leo, Oberdan

2013-01-01

Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine–rich element (ARE)–binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow–derived dendritic cells (BMDCs) from TTP−/− mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3′ untranslated region. TTP−/− mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23–IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation. PMID:23940256

Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease.

PubMed

Molle, Céline; Zhang, Tong; Ysebrant de Lendonck, Laure; Gueydan, Cyril; Andrianne, Mathieu; Sherer, Félicie; Van Simaeys, Gaetan; Blackshear, Perry J; Leo, Oberdan; Goriely, Stanislas

2013-08-26

Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine-rich element (ARE)-binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow-derived dendritic cells (BMDCs) from TTP(-/-) mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3' untranslated region. TTP(-/-) mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23-IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation.

The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin

PubMed Central

Broad, John; Sanger, Gareth J

2013-01-01

Background and Purpose The antibiotic azithromycin is a suggested alternative to erythromycin for treating patients with delayed gastric emptying. However, although hypothesized to activate motilin receptors, supportive evidence is unavailable. This was investigated using recombinant and naturally expressed motilin receptors in human stomach, comparing azithromycin with erythromycin. Experimental Approach [125I]-motilin binding and calcium flux experiments were conducted using human recombinant motilin receptors in CHO cells. Neuromuscular activities were studied using circular muscle of human gastric antrum, after electrical field stimulation (EFS) of intrinsic nerves. Key Results Azithromycin (1–100 μM) and erythromycin (3–30 μM) concentration-dependently displaced [125I]-motilin binding to the motilin receptor (52 ± 7 and 58 ± 18% displacement at 100 and 30 μM respectively). Azithromycin, erythromycin and motilin concentration-dependently caused short-lived increases in intracellular [Ca2+] in cells expressing the motilin receptor. EC50 values were, respectively, 2.9, 0.92 and 0.036 μM (n = 3 each); and maximal activities were similar. In human stomach, EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. Azithromycin and erythromycin lactobionate (30–300 μM each) facilitated these contractions (apparent Emax values of 2007 ± 396 and 1924 ± 1375%, n = 3–4 each concentration, respectively). These actions were slow in onset and faded slowly. The higher concentrations also evoked short-lived muscle contraction. Contractions to a submaximally effective concentration of carbachol were unaffected by either drug. Conclusions and Implications Azithromcyin activates human recombinant motilin receptors in therapeutically relevant concentrations, similar to erythromycin. In humans, gastric antrum azithromycin caused long-lasting facilitation of cholinergic activity. These actions explain the gastric prokinetic

Regulation of Memory T Cells by Interleukin-23.

PubMed

Li, Yanchun; Wang, Hongbo; Lu, Honghua; Hua, Shucheng

2016-01-01

Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, is a heterodimeric cytokine. It is composed of subunits p40 (shared with IL-12) and p19 (an IL-12 p35-related subunit) and is secreted by several types of immune cells, such as natural killer cells and dendritic cells. The IL-23 receptor is composed of the subunit IL-12Rβ1 and the IL-23-specific subunit IL-23R. The binding of IL-23 to its specific cell surface receptor regulates a number of functions, including proliferation and differentiation of cells and secretion of cell factors. Memory T cells are a subset of T cells that secrete numerous important cell factors, and they function in the immune response to infection and diseases like cancer, autoimmune disease and bronchial asthma. IL-23R is expressed on the surface of memory T cells, which suggests that it can specifically regulate memory T cell function. IL-23 has been widely used as a clinical indicator in immune-related diseases and shows potential for use in disease treatment. Here we review the current progress in the study of the role of IL-23 in the regulation of memory T cells. © 2016 S. Karger AG, Basel.

An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.

PubMed

Morita, Hideaki; Arae, Ken; Unno, Hirotoshi; Miyauchi, Kousuke; Toyama, Sumika; Nambu, Aya; Oboki, Keisuke; Ohno, Tatsukuni; Motomura, Kenichiro; Matsuda, Akira; Yamaguchi, Sachiko; Narushima, Seiko; Kajiwara, Naoki; Iikura, Motoyasu; Suto, Hajime; McKenzie, Andrew N J; Takahashi, Takao; Karasuyama, Hajime; Okumura, Ko; Azuma, Miyuki; Moro, Kazuyo; Akdis, Cezmi A; Galli, Stephen J; Koyasu, Shigeo; Kubo, Masato; Sudo, Katsuko; Saito, Hirohisa; Matsumoto, Kenji; Nakae, Susumu

2015-07-21

House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Contribution of Bordetella Filamentous Hemagglutinin and Adenylate Cyclase Toxin to Suppression and Evasion of Interleukin-17-Mediated Inflammation

PubMed Central

Henderson, Michael W.; Inatsuka, Carol S.; Sheets, Amanda J.; Williams, Corinne L.; Benaron, David J.; Donato, Gina M.; Gray, Mary C.; Hewlett, Erik L.

2012-01-01

Bordetella pertussis and Bordetella bronchiseptica establish respiratory infections with notorious efficiency. Our previous studies showed that the fhaB genes of B. pertussis and B. bronchiseptica, which encode filamentous hemagglutinin (FHA), are functionally interchangeable and provided evidence that FHA-deficient B. bronchiseptica induces more inflammation in the lungs of mice than wild-type B. bronchiseptica. We show here that the robust inflammatory response to FHA-deficient B. bronchiseptica is characterized by the early and sustained influx of interleukin-17 (IL-17)-positive neutrophils and macrophages and, at 72 h postinoculation, IL-17-positive CD4+ T cells, suggesting that FHA allows the bacteria to suppress the development of an IL-17-mediated inflammatory response. We also show that the cyaA genes of B. pertussis and B. bronchiseptica, which encode adenylate cyclase toxin (ACT), are functionally interchangeable and that ACT, specifically its catalytic activity, is required for B. bronchiseptica to resist phagocytic clearance but is neither required for nor inhibitory of the induction of inflammation if bacteria are present in numbers sufficient to persist during the first 3 days postinoculation. Incubation of bone marrow-derived macrophages with a ΔcyaA strain caused decreased production of IL-1β and increased production of tumor necrosis factor alpha (TNF-α) and IL-12, while incubation with a ΔcyaA ΔfhaB strain caused increased production of IL-23. These data suggest that FHA and ACT both contribute to suppress the recruitment of neutrophils and the development of an IL-17-mediated immune response. To our knowledge, this is the first demonstration of a microbial pathogen suppressing IL-17-mediated inflammation in vivo as a strategy to evade innate immunity. PMID:22473603

Isotope shift of 40,42,44,48Ca in the 4s 2S1/2 → 4p 2P3/2 transition

NASA Astrophysics Data System (ADS)

Gorges, C.; Blaum, K.; Frömmgen, N.; Geppert, Ch; Hammen, M.; Kaufmann, S.; Krämer, J.; Krieger, A.; Neugart, R.; Sánchez, R.; Nörtershäuser, W.

2015-12-01

We report on improved isotope shift measurements of the isotopes {}{40,42,{44,48}}Ca in the 4{{s}}{ }2{{{S}}}1/2\\to 4{{p}}{ }2{{{P}}}3/2 (D2) transition using collinear laser spectroscopy. Accurately known isotope shifts in the 4{{s}}{ }2{{{S}}}1/2\\to 4{{p}}{ }2{{{P}}}1/2(D1) transition were used to calibrate the ion beam energy with an uncertainty of {{Δ }}U≈ +/- 0.25 {{V}}. The accuracy in the D2 transition was improved by a factor of 5-10. A King-plot analysis of the two transitions revealed that the field shift factor in the D2 line is about 1.8(13)% larger than in the D1 transition which is ascribed to relativistic contributions of the 4{{{p}}}1/2 wave function.

[Allergic asthma and interleukins 2, 4, 5, 6 and 12 and gamma interferon levels].

PubMed

Bastida Segura, Diana Lyzbeth; López Velásquez, Benjamin; Castrejón Vázquez, María Isabel; Galicia Tapía, Jorge; Cano Altamirano, Silvia; Miranda Feria, Alfonso Javier

2004-01-01

Asthma is an inflammatory chronic illness, in which mastocyt cells, basophils, T lymphocytes, eosinophils and cytokines play a role. Its association with the production of TH2 cytokines is not well known, but it is considered an aberrant immune response, yielding the activation and recruitment of a number of effector cells (mastocyts/eosinophils) and the appearance of clinical symptoms. To determine the serum values of the interleukins 2, 4, 5, 6 and 12 and gamma interferon in relation to the severity degree of asthma and the time of immunotherapy in patients with stable chronic allergic bronchial asthma. Clinical records of allergic asthmatic patients from the external consultation at Servicio de Alergia e Immunología Clínica were reviewed in a period of 12 months (1st January 2002 to 1st January 2003) and those of healthy volunteers, forming three groups: Group 1, allergic asthmatics with immunotherapy less than 24 months; Group 2, allergic asthmatics with more than 24 months of immunotherapy, and Group 3, healthy volunteers (control group). Previous informed consent, a serum sample was taken of all subjects. Ninety-two subjects were included: 41 (45%) allergic asthmatics and 51 (55%) healthy volunteers. Significant differences were found in interleukins 2, 4, 5, 6 and 12 levels between healthy volunteers and asthmatics without relating the immunotherapy time. In the total group gamma interferon levels were not found. A relation of interleukins Th2 levels with the severity degree of asthma was not found. Differences of serum interleukins Th1 and Th2 in allergic patients related to immunotherapy time were not significant; even though, irrespective of immunotherapy time, IgG levels were always high. Patients with allergic asthma have a predominance of serum interleukins Th2 and, despite of the immunotherapy, in the maintaining phase, these continue high, which may be due to an immune system dysregulation maybe including other factors. Immunotherapy continues

[Clinical effect of Saccharomyces boulardii powder combined with azithromycin sequential therapy in treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia].

PubMed

Chen, Qi-Fen; Zhang, Yi-Wei

2018-02-01

To investigate the clinical effect of Saccharomyces boulardii powder combined with azithromycin sequential therapy in the treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia. A total of 88 children with diarrhea secondary to Mycoplasma pneumoniae pneumonia between June 2015 and March 2017 were divided into control group and study group using a random number table, with 44 children in each group. The children in the control group were given routine treatment combined with azithromycin sequential therapy, and those in the study group were given oral Saccharomyces boulardii powder in addition to the treatment in the control group until the end of azithromycin sequential therapy. After the treatment ended, the two groups were compared in terms of time to improvement of clinical symptoms, length of hospital stay, clinical outcome, defecation frequency before and after treatment, condition of intestinal dysbacteriosis, and incidence of adverse events. Compared with the control group, the study group had significantly shorter time to improvement of clinical symptoms and length of hospital stay (P<0.05). The study group had a significantly higher response rate than the control group (P<0.05). On days 3 and 5 of treatment, the study group had a significant reduction in defecation frequency compared with the control group (P<0.05). The study group had a significantly lower rate of intestinal dysbacteriosis than the control group (P<0.05). There was no significant difference in the incidence of adverse events between the two groups (P>0.05). In the treatment of children with diarrhea secondary to Mycoplasma pneumoniae pneumonia, Saccharomyces boulardii powder combined with azithromycin sequential therapy can improve clinical symptoms, shorten the length of hospital stay, reduce defecation frequency and the incidence of intestinal dysbacteriosis, and improve clinical outcomes, and does not increase the risk of adverse events.

Interleukin-1 Receptor Antagonist and Interleukin-4 Genes Variable Number Tandem Repeats Are Associated with Adiposity in Malaysian Subjects

PubMed Central

Kok, Yung-Yean; Ong, Hing-Huat

2017-01-01

Interleukin-1 receptor antagonist (IL1RA) intron 2 86 bp repeat and interleukin-4 (IL4) intron 3 70 bp repeat are variable number tandem repeats (VNTRs) that have been associated with various diseases, but their role in obesity is elusive. The objective of this study was to investigate the association of IL1RA and IL4 VNTRs with obesity and adiposity in 315 Malaysian subjects (128 M/187 F; 23 Malays/251 ethnic Chinese/41 ethnic Indians). The allelic distributions of IL1RA and IL4 were significantly different among ethnicities, and the alleles were associated with total body fat (TBF) classes. Individuals with IL1RA I/II genotype or allele II had greater risk of having higher overall adiposity, relative to those having the I/I genotype or I allele, respectively, even after controlling for ethnicity [Odds Ratio (OR) of I/II genotype = 12.21 (CI = 2.54, 58.79; p = 0.002); II allele = 5.78 (CI = 1.73, 19.29; p = 0.004)]. However, IL4 VNTR B2 allele was only significantly associated with overall adiposity status before adjusting for ethnicity [OR = 1.53 (CI = 1.04, 2.23; p = 0.03)]. Individuals with IL1RA II allele had significantly higher TBF than those with I allele (31.79 ± 2.52 versus 23.51 ± 0.40; p = 0.005). Taken together, IL1RA intron 2 VNTR seems to be a genetic marker for overall adiposity status in Malaysian subjects. PMID:28293435

Interleukin-1 Receptor Antagonist and Interleukin-4 Genes Variable Number Tandem Repeats Are Associated with Adiposity in Malaysian Subjects.

PubMed

Kok, Yung-Yean; Ong, Hing-Huat; Say, Yee-How

2017-01-01

Interleukin-1 receptor antagonist ( IL1RA ) intron 2 86 bp repeat and interleukin-4 ( IL4 ) intron 3 70 bp repeat are variable number tandem repeats (VNTRs) that have been associated with various diseases, but their role in obesity is elusive. The objective of this study was to investigate the association of IL1RA and IL4 VNTRs with obesity and adiposity in 315 Malaysian subjects (128 M/187 F; 23 Malays/251 ethnic Chinese/41 ethnic Indians). The allelic distributions of IL1RA and IL4 were significantly different among ethnicities, and the alleles were associated with total body fat (TBF) classes. Individuals with IL1RA I/II genotype or allele II had greater risk of having higher overall adiposity, relative to those having the I/I genotype or I allele, respectively, even after controlling for ethnicity [Odds Ratio (OR) of I/II genotype = 12.21 (CI = 2.54, 58.79; p = 0.002); II allele = 5.78 (CI = 1.73, 19.29; p = 0.004)]. However, IL4 VNTR B2 allele was only significantly associated with overall adiposity status before adjusting for ethnicity [OR = 1.53 (CI = 1.04, 2.23; p = 0.03)]. Individuals with IL1RA II allele had significantly higher TBF than those with I allele (31.79 ± 2.52 versus 23.51 ± 0.40; p = 0.005). Taken together, IL1RA intron 2 VNTR seems to be a genetic marker for overall adiposity status in Malaysian subjects.

Gut Microbial Diversity in Antibiotic-Naive Children After Systemic Antibiotic Exposure: A Randomized Controlled Trial.

PubMed

Doan, Thuy; Arzika, Ahmed M; Ray, Kathryn J; Cotter, Sun Y; Kim, Jessica; Maliki, Ramatou; Zhong, Lina; Zhou, Zhaoxia; Porco, Travis C; Vanderschelden, Benjamin; Keenan, Jeremy D; Lietman, Thomas M

2017-05-01

Antibiotic exposure can alter the gut microbiome. We evaluate the effects of azithromycin on the gut microbiome diversity of children from an antibiotic-naive community in Niger. A population-based sample of 80 children aged 1-60 months in the Dosso region of Niger was randomized to receive a single dose of either oral azithromycin or placebo. Fecal samples were collected immediately before treatment and 5 days after treatment for 16S rRNA gene sequencing. The prespecified outcome was α-diversity (inverse Simpson's α-diversity index), with secondary outcomes of β and γ Simpson's and Shannon's diversities. At 5 days after treatment, 40 children aged 1-60 months were analyzed in the azithromycin-treated group and 40 children in the placebo-treated group. Diversity of the gut microbiome was significantly lower in the treated group (inverse Simpson's α-diversity, 5.03; 95% confidence interval [CI], 4.08-6.14) than in the placebo group (6.91; 95% CI, 5.82-8.21; P = .03). Similarly, the Shannon's α-diversity was lower in the treated group (10.60; 95% CI, 8.82-12.36) than the placebo group (15.42; 95% CI, 13.24-17.80; P = .004). Simpson's community-level (γ) diversity decreased with azithromycin exposure from 17.72 (95% CI, 13.80-20.21) to 10.10 (95% CI, 7.80-11.40; P = .00008), although β-diversity was not significantly reduced (2.56, 95% CI, 1.88-3.12; to 2.01, 95% CI, 1.46-2.51; P = .26). Oral administration of azithromycin definitively decreases the diversity of the gut microbiome of children in an antibiotic-naive community. NCT02048007. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

New Interleukins in Psoriasis and Psoriatic Arthritis Patients: The Possible Roles of Interleukin-33 to Interleukin-38 in Disease Activities and Bone Erosions.

PubMed

Li, Jiang; Liu, Lei; Rui, Wenlong; Li, Xiangyu; Xuan, Dandan; Zheng, Shucong; Yu, Yiyun; Zhang, Jiong; Kong, Ning; Zhu, Xiaoxia; Zou, Hejian; Wan, Weiguo; Xue, Yu

2017-01-01

New interleukins (ILs), especially members of IL-1 and IL-12 families, have recently been reported to be involved in the development and regulation of autoimmune and inflammatory diseases. In this study, we aimed to explore the impact of these new ILs in psoriasis (Ps) and psoriatic arthritis (PsA). Forty PsA patients, 20 Ps patients, and 20 healthy controls (HCs) were recruited. Blood samples were obtained for detecting the levels of ILs, IL-12/23p40, and tumor necrosis factor α (TNF-α). The severity of skin lesions was assessed by the Psoriasis Area and Severity Index (PASI). Arthritis activities of PsA patients were assessed by the PsA Joint Activity Index. For PsA patients, circulating osteoclastogenesis-related cytokines (osteoprotegerin and receptor activator of nuclear factor-κB ligand) and numbers of osteoclast precursors were evaluated. Radiographic features of affected joints in these patients were scored for erosion, joint-space narrowing, osteolysis, and new bone formation. Correlations among levels of these ILs, Ps, and PsA disease activities and bone erosions were studied. Ps and PsA patients had higher serum levels of TNF-α, IL-12/23p40, and IL-33. Serum levels of IL-34 and IL-35 were higher in PsA patients than in Ps patients and HCs. Patients with pustular Ps had higher serum levels of IL-36α and IL-38 than patients with Ps vulgaris or HCs. Increased serum levels of IL-36α were positively correlated with PASI. Certain ILs were elevated in the circulation of patients with Ps and PsA, which might contribute to the pathogenesis of skin lesions and arthritis. © 2017 S. Karger AG, Basel.

Thalidomide suppressed IL-1beta while enhancing TNF-alpha and IL-10, when cells in whole blood were stimulated with lipopolysaccharide.

PubMed

Shannon, Edward; Noveck, Robert; Sandoval, Felipe; Kamath, Burde

2008-01-01

Thalidomide is used to treat erythema nodosum leprosum (ENL). The events that precipitate this inflammatory reaction, which may occur in multibacillary leprosy patients, and the mechanism by which thalidomide arrest ENL, are not known. Thalidomide's ability to inhibit tumor necrosis factor alpha (TNF-alpha) in vitro has been proposed as a partial explanation of its effective treatment of ENL. In in vitro assays, thalidomide can enhance or suppress TNF-alpha. This is dependent on the stimulant used to evoke TNF-alpha; the procedure used to isolate the mononuclear cells from blood, and the predominant mononuclear cell type in the culture. To avoid artifacts that may occur during isolation of mononuclear cells from blood, we stimulated normal human blood with LPS and evaluated the effect of thalidomide and dexamethasone on TNF-alpha, and other inflammatory cytokines and biomarkers. Thalidomide suppressed interleukin 1 beta (IL-1beta) (p = 0.007), and it enhanced TNF-alpha (p = 0.007) and interleukin 10 (IL-10) (p = 0.031). Dexamethasone enhanced IL-10 (p = 0.013) and suppressed IL-1beta, TNF-alpha, interleukin 6 (IL-6), and interleukin 8 (IL-8) (p = 0.013). The two drugs did not suppress: C-reactive protein (CRP), Ig-superfamily cell-adhesion molecule 1 (ICAM 1), tumor necrosis factor receptor 1 (TNFR1), tumor necrosis factor receptor 2 (TNFR2), or amyloid A. In vitro and in vivo evidence is accumulating that TNF-alpha is not the primary cytokine targeted by thalidomide in ENL and other inflammatory conditions.

Gene gun-mediated delivery of an interleukin-12 expression plasmid protects against infections with the intracellular protozoan parasites Leishmania major and Trypanosoma cruzi in mice

PubMed Central

Sakai, T; Hisaeda, H; Nakano, Y; Ishikawa, H; Maekawa, Y; Ishii, K; Nitta, Y; Miyazaki, J; Himeno, K

2000-01-01

An interleukin-12 (IL-12) expression plasmid was transferred, using a gene gun, to mice infected with Leishmania major or Trypanosoma cruzi. Transfer of the IL-12 gene to susceptible BALB/c mice resulted in regression of lesion size and reduced the number of parasites in draining lymph nodes (LN) at the site of L. major infection. Coincident with these protective effects, the T-helper type (Th) response shifted towards Th1, as evaluated by cytokine production in vitro and L. major-specific antibody responses. Protective effects of the IL-12 gene were also observed in T. cruzi infection. Treatment of BALB/c mice infected with T. cruzi enhanced the production of interferon-γ (IFN-γ) by spleen cells, while suppressed production of interleukin-10 (IL-10) compared with control mice. Administration of anti-CD4 or anti-CD8 monoclonal antibody (mAb) abolished the protective immunity against T. cruzi infection, and treatment with the IL-12 gene could not restore the resistance in these mice. Mice depleted of natural killer (NK) cells with anti-asialo GM1 also became susceptible to infection, while the resistance was restored when these mice were treated with the IL-12 gene. Thus, target cells for the treatment appear to be CD4+ and CD8+ T cells, which are ordinarily activated by NK cells. These results suggest that the transfer of cytokine genes using a gene gun is an effective method for investigating the roles of cytokines and gene therapy in infectious diseases. PMID:10792510

22 CFR 40.12-40.19 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false [Reserved] 40.12-40.19 Section 40.12-40.19 Foreign Relations DEPARTMENT OF STATE VISAS REGULATIONS PERTAINING TO BOTH NONIMMIGRANTS AND IMMIGRANTS UNDER THE IMMIGRATION AND NATIONALITY ACT, AS AMENDED Medical Grounds of Ineligibility §§ 40.12-40.19...

Case report: failure under azithromycin treatment in a case of bacteremia due to Salmonella enterica Paratyphi A.

PubMed

Kobayashi, Tetsuro; Hayakawa, Kayoko; Mawatari, Momoko; Mezaki, Kazuhisa; Takeshita, Nozomi; Kutsuna, Satoshi; Fujiya, Yoshihiro; Kanagawa, Shuzo; Ohmagari, Norio; Kato, Yasuyuki; Morita, Masatomo

2014-07-20

Limited information is available regarding the clinical efficacy of azithromycin for the treatment of enteric fever due to fluoroquinolone-resistant Salmonella Typhi and Salmonella Paratyphi among travelers returning to their home countries. We report a case of a 52-year-old Japanese man who returned from India, who developed a fever of 39°C with no accompanying symptoms 10 days after returning to Japan from a 1-month business trip to Delhi, India. His blood culture results were positive for Salmonella Paratyphi A. He was treated with 14 days of ceftriaxone, after which he remained afebrile for 18 days before his body temperature again rose to 39°C with no apparent symptoms. He was then empirically given 500 mg of azithromycin, but experienced clinical and microbiological failure of azithromycin treatment for enteric fever due to Salmonella Paratyphi A. However, the minimum inhibitory concentration (MIC) of azithromycin was not elevated (8 mg/L). He was again given ceftriaxone for 14 days with no signs of recurrence during the follow-up. There are limited data available for the treatment of enteric fever using azithromycin in travelers from developed countries who are not immune to the disease, and thus, careful follow-up is necessary. In our case, the low azithromycin dose might have contributed the treatment failure. Additional clinical data are needed to determine the rate of success, MIC, and contributing factors for success and/or failure of azithromycin treatment for both Salmonella Typhi and Salmonella Paratyphi infections.

Suppression of the PI3K subunit p85α delays embryoid body development and inhibits cell adhesion.

PubMed

Gurney, Susan M R; Forster, Peter; Just, Ursula; Schwanbeck, Ralf

2011-12-01

Phosphatidylinositol-3-kinases (PI3Ks) exert a variety of signaling functions in eukaryotes. We suppressed the PI3K regulatory subunit p85α using a small interfering RNA (Pik3r1 siRNA) and examined the effects on embryoid body (EB) development in hanging drop culture. We observed a 150% increase in the volume of the treated EBs within 24 h, compared to the negative controls. Fluorescence Activated Cell Sorting (FACS) assays showed that this increase in volume is not due to increased cellular proliferation. Instead, the increase in volume appears to be due to reduced cellular aggregation and adherence. This is further shown by our observation that 40% of treated EBs form twin instead of single EBs, and that they have a significantly reduced ability to adhere to culture dishes when plated. A time course over the first 96 h reveals that the impaired adherence is transient and explained by an initial 12-hour delay in EB development. Quantitative PCR expression analysis suggests that the adhesion molecule integrin-β1 (ITGB1) is transiently downregulated by the p85α suppression. In conclusion we found that suppressing p85α leads to a delay in forming compact EBs, accompanied by a transient inability of the EBs to undergo normal cell-cell and cell-substrate adhesion. Copyright © 2011 Wiley Periodicals, Inc.

Myxoma Virus Expressing Human Interleukin-12 Does Not Induce Myxomatosis in European Rabbits▿

PubMed Central

Stanford, Marianne M.; Barrett, John W.; Gilbert, Philippe-Alexandre; Bankert, Richard; McFadden, Grant

2007-01-01

Myxoma virus (MV) is a candidate for oncolytic virotherapy due to its ability to selectively infect and kill tumor cells, yet MV is a species-specific pathogen that causes disease only in European rabbits. To assess the ability of MV to deliver cytokines to tumors, we created an MV (vMyxIL-12) that expresses human interleukin-12 (IL-12). vMyxIL-12 replicates similarly to wild-type MV, and virus-infected cells secrete bioactive IL-12. Yet, vMyxIL-12 does not cause myxomatosis, despite expressing the complete repertoire of MV proteins. Thus, vMyxIL-12 exhibits promise as an oncolytic candidate and is safe in all known vertebrate hosts, including lagomorphs. PMID:17728229

Myxoma virus expressing human interleukin-12 does not induce myxomatosis in European rabbits.

PubMed

Stanford, Marianne M; Barrett, John W; Gilbert, Philippe-Alexandre; Bankert, Richard; McFadden, Grant

2007-11-01

Myxoma virus (MV) is a candidate for oncolytic virotherapy due to its ability to selectively infect and kill tumor cells, yet MV is a species-specific pathogen that causes disease only in European rabbits. To assess the ability of MV to deliver cytokines to tumors, we created an MV (vMyxIL-12) that expresses human interleukin-12 (IL-12). vMyxIL-12 replicates similarly to wild-type MV, and virus-infected cells secrete bioactive IL-12. Yet, vMyxIL-12 does not cause myxomatosis, despite expressing the complete repertoire of MV proteins. Thus, vMyxIL-12 exhibits promise as an oncolytic candidate and is safe in all known vertebrate hosts, including lagomorphs.

Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines in mouse hepatocellular carcinoma.

PubMed

Tatsumi, T; Takehara, T; Kanto, T; Miyagi, T; Kuzushita, N; Sugimoto, Y; Jinushi, M; Kasahara, A; Sasaki, Y; Hori, M; Hayashi, N

2001-10-15

Dendritic cells (DCs) are potent antigen-presenting cells that are capable of priming systemic antitumor immune response. Here, we evaluated the combined effectiveness of tumor lysate-pulsed DC immunization and interleukin (IL)-12 administration on the induction of antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. Mouse DCs were pulsed with lysate of BNL 1ME A.7R.1 (BNL), a BALB/c-derived HCC cell line, and then injected into syngeneic mice in combination with systemic administration of IL-12. Lymphocytes from mice treated with BNL lysate-pulsed DCs and IL-12 showed stronger cytolytic activity and produced higher amounts of IFN-gamma than those from mice treated with BNL lysate-pulsed DCs alone. Although immunization with BNL lysate-pulsed DCs alone did not lead to complete regression of established tumors, it significantly inhibited tumor growth compared with vehicle injection. Importantly, the combined therapy of BNL lysate-pulsed DCs and IL-12 resulted in tumor rejection or significant inhibition of tumor growth compared with mice treated with BNL lysate-pulsed DCs alone. In vivo lymphocyte depletion experiments demonstrated that this combination was dependent on both CD8+ and CD4+ T cells, but not natural killer cells. These results demonstrated that IL-12 administration enhanced the therapeutic effect of immunization of tumor lysate-pulsed DCs against HCC in mice. This combination of IL-12 and DCs may be useful for suppressing the growth of residual tumor after primary therapy of human HCC.

Pharmaceutical development and optimization of azithromycin suppository for paediatric use.

PubMed

Kauss, Tina; Gaubert, Alexandra; Boyer, Chantal; Ba, Boubakar B; Manse, Muriel; Massip, Stephane; Léger, Jean-Michel; Fawaz, Fawaz; Lembege, Martine; Boiron, Jean-Michel; Lafarge, Xavier; Lindegardh, Niklas; White, Nicholas J; Olliaro, Piero; Millet, Pascal; Gaudin, Karen

2013-01-30

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought. Copyright © 2012 Elsevier B.V. All rights reserved.

Pharmaceutical development and optimization of azithromycin suppository for paediatric use

PubMed Central

Kauss, Tina; Gaubert, Alexandra; Boyer, Chantal; Ba, Boubakar B.; Manse, Muriel; Massip, Stephane; Léger, Jean-Michel; Fawaz, Fawaz; Lembege, Martine; Boiron, Jean-Michel; Lafarge, Xavier; Lindegardh, Niklas; White, Nicholas J.; Olliaro, Piero; Millet, Pascal; Gaudin, Karen

2013-01-01

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought. PMID:23220079

40 CFR 279.82 - Use as a dust suppressant.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 28 2012-07-01 2012-07-01 false Use as a dust suppressant. 279.82 Section 279.82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES..., such programs must minimize the impacts of use as a dust suppressant on the environment. (c) List of...

40 CFR 279.82 - Use as a dust suppressant.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 27 2014-07-01 2014-07-01 false Use as a dust suppressant. 279.82 Section 279.82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF USED OIL Standards for Use as a Dust Suppressant and Disposal of...

40 CFR 279.82 - Use as a dust suppressant.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 28 2013-07-01 2013-07-01 false Use as a dust suppressant. 279.82 Section 279.82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF USED OIL Standards for Use as a Dust Suppressant and Disposal of...

40 CFR 279.82 - Use as a dust suppressant.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 27 2011-07-01 2011-07-01 false Use as a dust suppressant. 279.82 Section 279.82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF USED OIL Standards for Use as a Dust Suppressant and Disposal of...

40 CFR 279.82 - Use as a dust suppressant.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 26 2010-07-01 2010-07-01 false Use as a dust suppressant. 279.82 Section 279.82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR THE MANAGEMENT OF USED OIL Standards for Use as a Dust Suppressant and Disposal of...

Interleukin-1beta-induced hyperresponsiveness to [Sar9,Met(O2)11]substance P in isolated human bronchi.

PubMed

Barchasz, E; Naline, E; Molimard, M; Moreau, J; Georges, O; Emonds-Alt, X; Advenier, C

1999-08-20

Interleukin-1beta has been reported to induce airway hyperresponsiveness in several animal models. In this study, we have investigated whether interleukin-1beta was able to potentiate the contractions of human isolated small bronchi (internal diameter < or = 1 mm) provoked by a specific tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P. Pre-incubation of human isolated small bronchi with interleukin-1beta (10 ng/ml, in Krebs-Henseleit solution, at 21 degrees C for 15 h) potentiated the contractile response to [Sar9,Met(O2)11]substance P. It also increased the [Sar9,Met(O2)11]substance P-induced release of thromboxane B2, the stable metabolite of thromboxane A2. Indomethacin (10(-6) M), a non-specific cyclooxygenase inhibitor, or GR 32191 ((1R-(1alpha(Z)),2beta,3beta,5alpha))-(+)-7-(5-(((1,1' -biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-hept enoic acid, hydrochloride) (10(-6) M), a prostanoid TP-receptor antagonist, blocked the contractions induced by [Sar9,Met(O2)11]substance P both in control experiments and after interleukin-1beta pre-treatment, indicating that prostanoids and thromboxane receptors are directly implicated in the [Sar9,Met(O2)11]substance P-induced contractile response. The thromboxane mimetic U-46619 (10(-8)-10(-6) M) (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F2alpha)-induced contractions of human isolated small bronchi were not enhanced by interleukin-1beta pre-treatment, suggesting that no up-regulation of thromboxane receptors occurred. Furthermore, the cyclooxygenase-2 inhibitor CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanon e) (10(-6) M) had no direct effect on [Sar9,Met(O2)11]substance P-provoked contractions, but inhibited the interleukin-1beta-induced potentiation of [Sar9,Met(O2)11]substance P response. In conclusion, our results show that interleukin-1beta pre-treatment is able to potentiate the contractions of isolated human small bronchi provoked by [Sar9,Met(O2

Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1β-treated hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoshigai, Emi; Ritsumeikan Global Innovation Research Organization; Machida, Toru

Highlights: •Nobiletin is a polymethoxylated flavone that is abundant in citrus peels. •Nobiletin is a major constituent of the Citrus unshiu peel extract. •Nobiletin suppresses induction of NO and reduces iNOS expression in hepatocytes. •Nobiletin reduces the iNOS promoter activity and the DNA-binding activity of NF-κB. -- Abstract: Background: Nobiletin is a polymethoxylated flavone that is abundant in the peels of citrus fruits, such as Citrus unshiu (Satsuma mandarin) and Citrus sinensis. The dried peels of C. unshiu (chinpi) have been included in several formulae of Japanese Kampo medicines. Nobiletin may suppress the induction of inducible nitric oxide synthase (iNOS),more » which synthesizes the inflammatory mediator nitric oxide (NO) in hepatocytes. Methods: A C. unshiu peel (CUP) extract was prepared. Primary cultured rat hepatocytes were treated with the CUP extract or nobiletin in the presence of interleukin 1β (IL-1β), which induces iNOS expression. NO production and iNOS gene expression were analyzed. Results: High-performance liquid chromatography analyses revealed that the nobiletin content in the CUP extract was 0.14%. Nobiletin dose-dependently reduced the NO levels and decreased iNOS expression at the protein, mRNA and antisense transcript levels. Flavone, which does not contain any methoxy groups, also suppressed iNOS induction. Nobiletin reduced the transcriptional activity of iNOS promoter-luciferase constructs and the DNA-binding activity of nuclear factor κB (NF-κB) in the nuclei. Conclusions: The suppression of iNOS induction by nobiletin suggests that nobiletin may be responsible for the anti-inflammatory effects of citrus peels and have a therapeutic potential for liver diseases.« less

Regulation of 1-alpha, 25-dihydroxyvitamin D3 on interleukin-6 and interleukin-8 induced by sulfur mustard (HD) on human skin cells.

PubMed

Arroyo, Carmen M; Kan, Robert K; Burman, Damon L; Kahler, David W; Nelson, Marian R; Corun, Charlene M; Guzman, Juanita J; Broomfield, Clarence A

2003-05-01

The regulatory effects of the active form of vitamin D, 1-alpha, 25-dihydroxyvitamin D3 (1-alpha, 25 (OH)2D3) were assessed on the cytokine and chemokine secretion induced by sulfur mustard on human skin fibroblasts and human epidermal keratinocytes. Stimulation of human skin fibroblasts with sulfur mustard (10(-4) M for 24 hr at 37 degrees ) resulted in approximately a 5 times increase in the secretion of interleukin-6 and over a 10 times increase for interleukin-8, which was inhibited by 1-alpha, 25 (OH)2D3, at suppressed interleukin-8 secretion by 5 times and interleukin-6 by 4 times on sulfur mustard-stimulated human epidermal keratinocytes at concentrations suppression of interleukin-6 and interleukin-8 induced by sulfur mustard on human skin fibroblasts/human epidermal keratinocytes, apparent at nanomolar concentrations. Our results indicate that the suppression of these inflammatory mediators by 1-alpha, 25 (OH)2D3 is dependent on the source of the primary cultures, cell densities, and kinetics of pretreatments. In contrast to the inhibition of cytokine/chemokine production, cell proliferation was enhanced by almost 1.7 times on treated human epidermal keratinocytes with 1-alpha, 25 (OH)2D3 (1 x 10(-9) M) after sulfur mustard-stimulation (10(-4) M for 24 hr at 37 degrees C). The observed enhancement diversified based on cell density, and kinetics of pretreatment with a maximal synergism (s) observed at 1 x 10(-9) M. Photomicrographs show typical signs of cellular degeneration caused by sulfur mustard such as chromatin condensation. The observed cellular degeneration was lessened when human epidermal keratinocytes were treated with 1-alpha, 25 (OH)2D3 (2 x 10(-9) M). 1-alpha, 25(OH)2D3 could be an alternative treatment for cutaneous inflammation disorders caused by sulfur mustard because we have demonstrated its ability to suppress inflammatory

Insulin resistance and serum levels of interleukin-17 and interleukin-18 in normal pregnancy.

PubMed

Jahromi, Abdolreza Sotoodeh; Shojaei, Mohammad; Ghobadifar, Mohamed Amin

2014-06-01

We performed this study to evaluate the role of Interleukin-17 (IL-17) and Interleukin-18 (IL-18) in insulin resistance during normal pregnancy. This descriptive cross sectional study was carried out on 97 healthy pregnant women including 32, 25, and 40 individuals in the first, second, and third trimesters, respectively, and on 28 healthy non pregnant women between the autumn of 2012 and the spring of 2013. We analyzed the serum concentrations of IL-17 and IL-18 by using the enzyme linked immunosorbent assay (ELISA). Insulin resistance was measured by homeostasis model assessment of insulin resistance equation. No significant differences between the demographic data of the pregnant and non pregnant groups were observed. Insulin resistant in pregnant women was significantly higher than the controls (p=0.006). Serum IL-17 concentration was significantly different in non pregnant women and pregnant women in all gestational ages (p<0.05). Serum IL-18 level was significantly lower in subjects with first, second, and third trimesters of pregnancy in compared to non pregnant women (p<0.05). No significant correlations were found between serum IL-17 and IL-18 levels with insulin resistance (r=0.08, p=0.34 vs. r=0.01, p=0.91, respectively). Our data suggested that IL-17 and IL-18 do not appear to attribute greatly to pregnancy deduced insulin resistance during normal pregnancy.

Transverse-momentum and collision-energy dependence of high-pT hadron suppression in Au+Au collisions at ultrarelativistic energies.

PubMed

Adams, J; Adler, C; Aggarwal, M M; Ahammed, Z; Amonett, J; Anderson, B D; Anderson, M; Arkhipkin, D; Averichev, G S; Badyal, S K; Balewski, J; Barannikova, O; Barnby, L S; Baudot, J; Bekele, S; Belaga, V V; Bellwied, R; Berger, J; Bezverkhny, B I; Bhardwaj, S; Bhaskar, P; Bhati, A K; Bichsel, H; Billmeier, A; Bland, L C; Blyth, C O; Bonner, B E; Botje, M; Boucham, A; Brandin, A; Bravar, A; Cadman, R V; Cai, X Z; Caines, H; Calderón de la Barca Sánchez, M; Carroll, J; Castillo, J; Castro, M; Cebra, D; Chaloupka, P; Chattopadhyay, S; Chen, H F; Chen, Y; Chernenko, S P; Cherney, M; Chikanian, A; Choi, B; Christie, W; Coffin, J P; Cormier, T M; Cramer, J G; Crawford, H J; Das, D; Das, S; Derevschikov, A A; Didenko, L; Dietel, T; Dong, X; Draper, J E; Drees, K A; Du, F; Dubey, A K; Dunin, V B; Dunlop, J C; Dutta Majumdar, M R; Eckardt, V; Efimov, L G; Emelianov, V; Engelage, J; Eppley, G; Erazmus, B; Fachini, P; Faine, V; Faivre, J; Fatemi, R; Filimonov, K; Filip, P; Finch, E; Fisyak, Y; Flierl, D; Foley, K J; Fu, J; Gagliardi, C A; Ganti, M S; Gagunashvili, N; Gans, J; Gaudichet, L; Germain, M; Geurts, F; Ghazikhanian, V; Ghosh, P; Gonzalez, J E; Grachov, O; Grigoriev, V; Gronstal, S; Grosnick, D; Guedon, M; Guertin, S M; Gupta, A; Gushin, E; Gutierrez, T D; Hallman, T J; Hardtke, D; Harris, J W; Heinz, M; Henry, T W; Heppelmann, S; Herston, T; Hippolyte, B; Hirsch, A; Hjort, E; Hoffmann, G W; Horsley, M; Huang, H Z; Huang, S L; Humanic, T J; Igo, G; Ishihara, A; Jacobs, P; Jacobs, W W; Janik, M; Johnson, I; Jones, P G; Judd, E G; Kabana, S; Kaneta, M; Kaplan, M; Keane, D; Kiryluk, J; Kisiel, A; Klay, J; Klein, S R; Klyachko, A; Kollegger, T; Konstantinov, A S; Kopytine, M; Kotchenda, L; Kovalenko, A D; Kramer, M; Kravtsov, P; Krueger, K; Kuhn, C; Kulikov, A I; Kumar, A; Kunde, G J; Kunz, C L; Kutuev, R Kh; Kuznetsov, A A; Lamont, M A C; Landgraf, J M; Lange, S; Lansdell, C P; Lasiuk, B; Laue, F; Lauret, J; Lebedev, A; Lednický, R; Leontiev, V M; LeVine, M J; Li, C; Li, Q; Lindenbaum, S J; Lisa, M A; Liu, F; Liu, L; Liu, Z; Liu, Q J; Ljubicic, T; Llope, W J; Long, H; Longacre, R S; Lopez-Noriega, M; Love, W A; Ludlam, T; Lynn, D; Ma, J; Ma, Y G; Magestro, D; Mahajan, S; Mangotra, L K; Mahapatra, D P; Majka, R; Manweiler, R; Margetis, S; Markert, C; Martin, L; Marx, J; Matis, H S; Matulenko, Yu A; McShane, T S; Meissner, F; Melnick, Yu; Meschanin, A; Messer, M; Miller, M L; Milosevich, Z; Minaev, N G; Mironov, C; Mishra, D; Mitchell, J; Mohanty, B; Molnar, L; Moore, C F; Mora-Corral, M J; Morozov, V; de Moura, M M; Munhoz, M G; Nandi, B K; Nayak, S K; Nayak, T K; Nelson, J M; Nevski, P; Nikitin, V A; Nogach, L V; Norman, B; Nurushev, S B; Odyniec, G; Ogawa, A; Okorokov, V; Oldenburg, M; Olson, D; Paic, G; Pandey, S U; Pal, S K; Panebratsev, Y; Panitkin, S Y; Pavlinov, A I; Pawlak, T; Perevoztchikov, V; Peryt, W; Petrov, V A; Phatak, S C; Picha, R; Planinic, M; Pluta, J; Porile, N; Porter, J; Poskanzer, A M; Potekhin, M; Potrebenikova, E; Potukuchi, B V K S; Prindle, D; Pruneau, C; Putschke, J; Rai, G; Rakness, G; Raniwala, R; Raniwala, S; Ravel, O; Ray, R L; Razin, S V; Reichhold, D; Reid, J G; Renault, G; Retiere, F; Ridiger, A; Ritter, H G; Roberts, J B; Rogachevski, O V; Romero, J L; Rose, A; Roy, C; Ruan, L J; Rykov, V; Sahoo, R; Sakrejda, I; Salur, S; Sandweiss, J; Savin, I; Schambach, J; Scharenberg, R P; Schmitz, N; Schroeder, L S; Schweda, K; Seger, J; Seliverstov, D; Seyboth, P; Shahaliev, E; Shao, M; Sharma, M; Shestermanov, K E; Shimanskii, S S; Singaraju, R N; Simon, F; Skoro, G; Smirnov, N; Snellings, R; Sood, G; Sorensen, P; Sowinski, J; Spinka, H M; Srivastava, B; Stanislaus, S; Stock, R; Stolpovsky, A; Strikhanov, M; Stringfellow, B; Struck, C; Suaide, A A P; Sugarbaker, E; Suire, C; Sumbera, M; Surrow, B; Symons, T J M; Szanto de Toledo, A; Szarwas, P; Tai, A; Takahashi, J; Tang, A H; Thein, D; Thomas, J H; Tikhomirov, V; Tokarev, M; Tonjes, M B; Trainor, T A; Trentalange, S; Tribble, R E; Trivedi, M D; Trofimov, V; Tsai, O; Ullrich, T; Underwood, D G; Van Buren, G; VanderMolen, A M; Vasiliev, A N; Vasiliev, M; Vigdor, S E; Viyogi, Y P; Voloshin, S A; Waggoner, W; Wang, F; Wang, G; Wang, X L; Wang, Z M; Ward, H; Watson, J W; Wells, R; Westfall, G D; Whitten, C; Wieman, H; Willson, R; Wissink, S W; Witt, R; Wood, J; Wu, J; Xu, N; Xu, Z; Xu, Z Z; Yakutin, A E; Yamamoto, E; Yang, J; Yepes, P; Yurevich, V I; Zanevski, Y V; Zborovský, I; Zhang, H; Zhang, H Y; Zhang, W M; Zhang, Z P; Zołnierczuk, P A; Zoulkarneev, R; Zoulkarneeva, J; Zubarev, A N

2003-10-24

We report high statistics measurements of inclusive charged hadron production in Au+Au and p+p collisions at sqrt[s(NN)]=200 GeV. A large, approximately constant hadron suppression is observed in central Au+Au collisions for 5<p(T)<12 GeV/c. The collision energy dependence of the yields and the centrality and p(T) dependence of the suppression provide stringent constraints on theoretical models of suppression. Models incorporating initial-state gluon saturation or partonic energy loss in dense matter are largely consistent with observations. We observe no evidence of p(T)-dependent suppression, which may be expected from models incorporating jet attenuation in cold nuclear matter or scattering of fragmentation hadrons.

Pharmacokinetics, microbial response, and pulmonary outcomes of multidose intravenous azithromycin in preterm infants at risk for Ureaplasma respiratory colonization.

PubMed

Merchan, L Marcela; Hassan, Hazem E; Terrin, Michael L; Waites, Ken B; Kaufman, David A; Ambalavanan, Namasivayam; Donohue, Pamela; Dulkerian, Susan J; Schelonka, Robert; Magder, Laurence S; Shukla, Sagar; Eddington, Natalie D; Viscardi, Rose M

2015-01-01

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg(0.75), 1.88 liters · kg, 1.79 liters/h · kg(0.75), and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼ 4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating

Pharmacokinetics, Microbial Response, and Pulmonary Outcomes of Multidose Intravenous Azithromycin in Preterm Infants at Risk for Ureaplasma Respiratory Colonization

PubMed Central

Merchan, L. Marcela; Hassan, Hazem E.; Terrin, Michael L.; Waites, Ken B.; Kaufman, David A.; Ambalavanan, Namasivayam; Donohue, Pamela; Dulkerian, Susan J.; Schelonka, Robert; Magder, Laurence S.; Shukla, Sagar; Eddington, Natalie D.

2014-01-01

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg0.75, 1.88 liters · kg, 1.79 liters/h · kg0.75, and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp

Heparinoid suppresses Der p-induced IL-1β production by inhibiting ERK and p38 MAPK pathways in keratinocytes.

PubMed

Utsunomiya, Ryo; Dai, Xiuju; Murakami, Masamoto; Okazaki, Hidenori; Tsuda, Teruko; Mori, Hideki; Shiraishi, Ken; Tohyama, Mikiko; Sayama, Koji

2018-05-13

Epidermal keratinocytes initiate skin inflammation by activating immune cells. The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NLRP3 inflammasome of keratinocytes, thereby releasing pro-inflammatory cytokines. Heparinoid is an effective moisturizer for atopic dry skin. However, a recent report showed that heparinoid treatment can improve inflammation of lichen planus. Therefore, we hypothesized that it acts on epidermal keratinocytes not only as a moisturizer, but also as a suppressant of the triggers of skin inflammation. We found that HDM allergen-induced interleukin (IL)-1β release from keratinocytes was inhibited significantly by heparinoid pretreatment without affecting cell viability. However, heparinoid did not affect caspase-1 release, suggesting that heparinoid did not affect HDM allergen-induced inflammasome activation. Heparinoid treatment not only decreased intracellular levels of pro-IL-1β, but also suppressed IL-1β messenger RNA (mRNA) expression in keratinocytes. Among the intracellular signaling pathways, the activation of extracellular signal-regulated kinase and p38 pathways, which are required for IL-1β expression in keratinocytes, was inhibited by heparinoid treatment. The inhibitory effect of heparinoid on IL-1β mRNA expression was also confirmed with living skin equivalents. Our results demonstrated that heparinoid suppresses the initiation of keratinocyte-mediated skin inflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Creatinine-based non-phospholipid vesicular carrier for improved oral bioavailability of Azithromycin.

PubMed

Ullah, Shafi; Shah, Muhammad Raza; Shoaib, Mohammad; Imran, Muhammad; Shah, Syed Wadood Ali; Ali, Imdad; Ahmed, Farid

2017-06-01

Novel, safe, efficient and cost effective nano-carriers from renewable resources have got greater interest for enhancing solubility and bioavailability of hydrophobic dugs. This study reports the synthesis of a novel biocompatible non-phospholipid human metabolite "Creatinine" based niosomal delivery system for Azithromycin improved oral bioavailability. Synthesized surfactant was characterized through spectroscopic and spectrometric techniques and then the potential for niosomal vesicle formation was evaluated using Azithromycin as model drug. Drug loaded vesicles were characterized for size, polydispersity index (PDI), shape, drug encapsulation efficiency (EE), in vitro release and drug-excipient interaction using zetasizer, atomic force microscope (AFM), LC-MS/MS and FTIR. The biocompatibility of surfactant was investigated through cells cytotoxicity, blood hemolysis and acute toxicity. Azithromycin encapsulated in niosomes was investigated for in vivo bioavailability in rabbits. The vesicles were spherical with 247 ± 4.67 nm diameter hosting 73.29 ± 3.51% of the drug. Surfactant was nontoxic against cell cultures and caused 5.80 ± 0.51% hemolysis at 1000 µg/mL. It was also found safe in mice up to 2.5 g/kg body weight. Synthesized surfactant based niosomal vesicles revealed enhanced oral bioavailability of Azithromycin in rabbits. The results of the present study confirm that the novel surfactant is highly biocompatible and the niosomal vesicles can be efficiently used for improving the oral bioavailability of poor water soluble drugs.

Single-dose extended-release azithromycin versus a 10-day regimen of amoxicillin/clavulanate for the treatment of children with acute otitis media.

PubMed

Arguedas, Adriano; Soley, Carolina; Kamicker, Barbara J; Jorgensen, Daniel M

2011-04-01

A randomized, double-blind, double-dummy, multicenter international study was conducted to assess the clinical and bacteriologic response, safety, and compliance of a single 60-mg/kg dose of azithromycin extended-release (ER) versus a 10-day regimen of amoxicillin/clavulanate 90/6.4 mg/kg per day in children with acute otitis media at high risk of persistent or recurrent middle ear infection. Children aged 3 to 48 months were enrolled and stratified into two age groups (≤ 24 months and >24 months). Pretreatment tympanocentesis was performed at all sites and was repeated during treatment at selected sites. The primary endpoint, clinical response at the test-of-cure visit in the bacteriologic eligible population, was achieved in 80.5% of children in the azithromycin ER group and 84.5% of children in the amoxicillin/clavulanate group (difference-3.9%; 95% confidence interval-10.4, 2.6). Bacteriologic eradication was 82.6% in the azithromycin ER group and 92% in the amoxicillin/clavulanate group (p=0.050). Children who received amoxicillin/clavulanate had significantly higher rates of dermatitis and diarrhea, a greater burden of adverse events, and a lower rate of compliance to study drug compared to those who received azithromycin ER. A single 60-mg/kg dose of azithromycin ER provides near equivalent effectiveness to a 10-day regimen of amoxicillin/clavulanate 90/6.4 mg/kg per day in the treatment of children with acute otitis media. Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Azithromycin in a triple therapy for H.pylori eradication in active duodenal ulcer

PubMed Central

Ivashkin, Vladimir T.; Lapina, Tatiana L.; Bondarenko, Oksana Yu.; Sklanskaya, Olga A.; Grigoriev, Petr Ya.; Vasiliev, Yuri V.; Yakovenko, Emilia P.; Gulyaev, Pavel V.; Fedchenko, Valeri I.

2002-01-01

AIM: To assess and compare the efficacy and safety of two triple regimes: A) metronidazole, amoxicillin and omeprazole, which is still widely used in Russia, and B) azithromycin, amoxicillin and omeprazole in healing active duodenal ulcer and H. pylori eradication. METHODS: 100 patients with active duodenal ulcer were included in the open, multicentre, randomized study with comparative groups. Patients were randomly assigned to one of the following one-week triple regimes: A) metronidazole 500 mg bid, amoxicillin 1 g bid and omeprazole 20 mg bid (OAM, n = 50) and B) azithromycin 1 g od for the first 3 d (total dose 3 g), amoxicillin 1 g bid and omeprazole 20 mg bid (OAA, n = 50). Omeprazole 20 mg od was given after the eradication course as a monotherapy for three weeks. The control endoscopy was performed 8 wk after the entry. H. pylori infection was determined in the entry of the study and four weeks after the cessation of treatment by means of histology and CLO-test. RESULTS: 97 patients completed the study according to the protocol (1 patient of the OAM group did not come to the control endoscopy, 2 patients of the OAA group stopped the treatment because of mild allergic urticaria). Duodenal ulcers were healed in 48 patients of the OAM group (96%; CI 90.5%-100%) and in 46 patients of the OAA group (92%; CI 89.5%-94.5%) (p = ns). H. pylori infection was eradicated in 15 out of 50 patients with OAM (30%; CI 17%-43%) and in 36 out of 50 patients treated with OAA (72%; CI 59%-85%) (P < 0.001) - ITT analysis. CONCLUSION: The triple therapy with omeprazole, amoxicillin and metronidazole failed to eradicate H. pylori in the majority of patients, which is an essential argument to withdraw this regimen out of the national recommendations. Macrolide with amoxicillin are preferable to achieve higher eradication rates. Azithromycin (1 g od for the first 3 d) can be considered as a successful component of the triple PPI-based regimen. PMID:12378634

Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study.

PubMed

Foulks, Gary N; Borchman, Douglas; Yappert, Marta; Kakar, Shelley

2013-01-01

Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment. Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer. Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal. Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels

The effects of Lactobacillus reuteri probiotics combined with azithromycin on peri-implantitis: A randomized placebo-controlled study.

PubMed

Tada, Hiroaki; Masaki, Chihiro; Tsuka, Shintaro; Mukaibo, Taro; Kondo, Yusuke; Hosokawa, Ryuji

2018-01-01

The aim of this randomized placebo-controlled clinical study was to investigate the effects of a probiotic tablet containing Lactobacillus reuteri in peri-implantitis patients. Subjects comprised 30 patients with mild to moderate peri-implantitis. A baseline clinical examination and microbiological assessment were conducted, followed by an antibiotics treatment (azithromycin, 500mg, once a day for 3 days). Subjects were divided into probiotic and placebo groups. The clinical examination and bacterial sampling were performed 0, 4, 12 and 24 weeks after the intake of probiotics. The clinical examination included probing pocket depth (PPD), bleeding on probing (BOP), the modified plaque index (mPI), and modified bleeding index (mBI). The number of bacteria was assessed using the PCR-invader method. The Wilcoxon rank-sum test and Wilcoxon signed-rank test with Bonferroni corrections were used for data analyses. Although the number of bacteria decreased after the administration of azithromycin in both groups, they increased again thereafter. No significant difference was observed in bacterial numbers between the two groups. Although PPD in the probiotics group was significantly lower at 4 and 24 weeks than at 0 weeks (p<0.05), a significant decrease did not occur in the placebo group. The mBI score at 24 weeks was significantly lower in the probiotics group than in the placebo group (p<0.05). No significant difference was observed in BOP or mPI between the two groups. These results suggested that probiotics prevent inflammation by affecting host responses rather than improving microbial flora in peri-implant sulci in peri-implantitis patients. Copyright © 2017 Japan Prosthodontic Society. Published by Elsevier Ltd. All rights reserved.

Azithromycin-induced rash in a patient of infectious mononucleosis - a case report with review of literature.

PubMed

Banerjee, Indranil; Mondal, Somnath; Sen, Sukanta; Tripathi, Santanu Kumar; Banerjee, Gautam

2014-08-01

Antibiotic induced skin rash in setting of infectious mononucleosis is often encountered in clinical practice. However, macrolides like azithromycin are considered relatively safe and till date only two cases of azithromycin induced rash in setting of infectious mononucleosis have been reported. The following report illustrates the case of a 23-year-old man suffering from infectious mononucleosis who exhibited a generalized cutaneous rash following treatment with azithromycin. Using the Naranjo ADR probability scale, this case of acute onset rash following azithromycin administration was found to be in 'probable' category. The mechanism of antibiotic-induced rash in patients suffering from infectious mononucleosis is incompletely understood. It has been suggested that the rash could result from virus mediated immunomodulation or due to altered drug metabolism. The report calls for cautious use of antibiotics in the setting of suspected viral infections like infectious mononucleosis as injudicious use might increase the risk of deleterious skin reactions and increase the cost of healthcare.

The diphtheria toxin transmembrane domain as a pH sensitive membrane anchor for human interleukin-2 and murine interleukin-3.

PubMed

Liger, D; Nizard, P; Gaillard, C; vanderSpek, J C; Murphy, J R; Pitard, B; Gillet, D

1998-11-01

We have constructed two fusion proteins T-hIL-2 and T-mIL-3 in which human interleukin-2 (hIL-2) or murine interleukin-3 (mIL-3) are fused to the C-terminus of the diphtheria toxin transmembrane domain (T domain). Two additional fusion proteins, T-(Gly4-Ser)2-hIL-2 and T-(Gly4-Ser)2-mIL-3, were derived by introduction of the (Gly4-Ser)2 spacer between the T domain and cytokine components. Recognition of the hIL-2 receptor or the mIL-3 receptor by the corresponding recombinant proteins was demonstrated by their capacity to stimulate cytokine-dependent cell lines. All proteins retained the capacity of the T domain to insert into phospholipid membranes at acidic pH. Finally, anchoring of both cytokines to the membrane of lipid vesicles or living cells was assessed by specific antibody recognition. Our results show that the T domain fused to the N-terminus of a given protein can function as a pH sensitive membrane anchor for that protein.

Retinoid acid-induced microRNA-27b-3p impairs C2C12 myoblast proliferation and differentiation by suppressing α-dystrobrevin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Nan; Tang, Yi; Liu, Bo

We previously reported that excess retinoic acid (RA) resulted in hypoplastic and derangement of myofilaments in embryonic tongue by inhibiting myogenic proliferation and differentiation through CamKIID pathway. Our further studies revealed that the expression of a series of miRNAs was altered by RA administration in embryonic tongue as well as in C2C12 cells. Thus, if excess RA impairs myogenic proliferation and differentiation through miRNAs is taken into account. In present study, miR-27b-3p was found up-regulated in RA-treated C2C12 cells as in embryonic tongue, and predicted to target the 3′UTR of α-dystrobrevin (DTNA). Luciferase reporter assays confirmed the direct interaction betweenmore » miR-27b-3p and the 3′UTR of DTNA. MiR-27b-3p mimics recapitulated the RA repression on DTNA expression, C2C12 proliferation and differentiation, while the miR-27b-3p inhibitor circumvented these defects resulting from excess RA. As expected, the effects of siDTNA on C2C12 were coincided with those by RA treatment or miR-27b-3p mimics. Therefore, these findings indicated that excess RA inhibited the myoblast proliferation and differentiation by up-regulating miR-27b-3p to target DTNA, which implied a new mechanism in myogenic hypoplasia. - Highlights: • A mechanism that RA results in tongue deformity by disrupting the myogenesis. • A non-muscle specific miR mediating the RA suppression on tongue myogenesis. • A target gene of non-muscle specific miR involved in RA induced tongue deformity.« less

Pilot study of the use of community volunteers to distribute azithromycin for trachoma control in Ghana.

PubMed Central

Solomon, A. W.; Akudibillah, J.; Abugri, P.; Hagan, M.; Foster, A.; Bailey, R. L.; Mabey, D. C.

2001-01-01

OBJECTIVE: To assess the skills of community health volunteers in diagnosing active trachoma and distributing azithromycin in the Northern Region of Ghana. METHODS: Six community health volunteers from Daboya were trained to diagnose trachoma and to treat the disease using azithromycin. They were also informed of the drug's possible side-effects. Under supervision, each volunteer then examined, and if necessary treated, 15 households. The dose of azithromycin was determined by weight; height was also measured. Tablets were given in preference to suspension when possible. RESULTS: The volunteers' diagnostic sensitivity for active trachoma was 63%; their specificity was 96%. At the household level, their "decision to treat" was correct in 83% of households. In 344 treatment episodes, volunteers planned a dose of azithromycin outside the range 15-30 mg/kg on only seven occasions (2.0% of all planned treatments). The volunteers' drug management skills were good, the response of the community was excellent, and adverse reactions were infrequent. Diagnosis of active trachoma, record-keeping skills, and knowledge of side-effects were found to need greater emphasis in any future education programme. Most people aged four years or older were able to swallow tablets. For those taking tablets, the correlation between the data gathered for height and weight shows that calculating azithromycin doses by height is a valid alternative to calculating it by weight. CONCLUSION: Trained community health volunteers have a potential role in identifying active trachoma and distributing azithromycin. To simplify training and logistics, it may be better to base dosage schedules on height rather than weight for those taking tablets, which included most people aged four years or more in the population studied. PMID:11217675

Human monocytes and gingival fibroblasts release tumor necrosis factor-alpha, interleukin-1 alpha and interleukin-6 in response to particulate and soluble fractions of Prevotella melaninogenica and Fusobacterium nucleatum.

PubMed

Rossano, F; Rizzo, A; Sanges, M R; Cipollaro de L'Ero, G; Tufano, M A

1993-01-01

In this study we provide evidence that structural and soluble components of periodontopathogenic bacteria, such as Prevotella melaninogenica and Fusobacterium nucleatum, induce the release of cytokines in vitro known to cause in vivo necrotic inflammatory phenomena and bone resorption (tumor necrosis factor-alpha, interleukin-1 alpha and interleukin-6). Human monocytes and gingival fibroblasts were cultivated in vitro in the presence of both particulate and soluble bacterial fractions. A dose-dependent production of tumor necrosis factor-alpha by monocytes and gingival fibroblasts was observed in the presence of fractions of P. melaninogenica and F. nucleatum. Interleukin-1 alpha was produced in approximately the same quantities in the presence of soluble fractions of either P. melaninogenica or F. nucleatum, but in greater quantities in response to particulate fractions of P. melaninogenica. Monocytes released larger amounts of interleukin-1 alpha (about 3000 pg/ml) than gingival fibroblasts (about 1500 pg/ml). Interleukin-6 was released in greater quantities by monocytes in the presence of the pellet fraction of P. melaninogenica (about 5.5 ng/ml), but gingival fibroblasts released larger amounts of interleukin-6, especially in the presence of particulate and soluble components of F. nucleatum (about 12 ng/ml). The ability to induce the release of these cytokines notably increases the pathogenic potential of the bacteria involved in the damage of periodontal tissue.

[Experimental study of interleukin-12 gene vaccines in the treatment of low-load malignant lymphoma (EL4)].

PubMed

Jiang, Q; Da, W; Ou, Y

2001-11-01

Two kinds of murine interleukin-12 (mIL-12) fusion gene vaccines were used to treat the murine low-load malignant T cell lymphoma EL4 as minimal residual disease (MRD) model. C57BL/6 synergistical mice were subcutaneously inoculated with 1 x 10(6) wild-type (wt) EL4 tumor cells as low-load lymphoma model treated with two mIL-12 gene vaccines. Package cell line PA317/12 producing mIL-12 retrovirus (RV) was used as in vivo vaccine and EL4 tumor cells transferred with mIL-12 gene as ex vivo vaccine. In both mIL-12 gene vaccine-treated groups, there was no tumor growth in 50% mice 60 days after inoculation. Nine of these no tumor growth mice were re-challenged with 5 x 10(5) wt EL4 cells, and 5 of them survived without tumors in another 60 days. All control mice died with tumors within one month after inoculation. Among those developed tumors in both vaccine-treated groups, the development of tumors was delayed, the survival period prolonged (P < 0.01), and the tumors size at death smaller (P < 0.05) as compared with the controls. In the long-survived vaccine-treated mice, no residual tumor cells were found by morphological examination. Both IL-12 gene vaccines can efficiently eliminate wt EL4 MRD in C57BL/6 mice.

Cluster of Neisseria gonorrhoeae Isolates With High-level Azithromycin Resistance and Decreased Ceftriaxone Susceptibility, Hawaii, 2016.

PubMed

Katz, Alan R; Komeya, Alan Y; Kirkcaldy, Robert D; Whelen, A Christian; Soge, Olusegun O; Papp, John R; Kersh, Ellen N; Wasserman, Glenn M; O'Connor, Norman P; O'Brien, Pamela S; Sato, Douglas T; Maningas, Eloisa V; Kunimoto, Gail Y; Tomas, Juval E

2017-09-15

The Centers for Disease Control and Prevention (CDC) currently recommends dual therapy with ceftriaxone and azithromycin for gonorrhea to ensure effective treatment and slow emergence of antimicrobial resistance. Since 2013, the prevalence of reduced azithromycin susceptibility increased in the United States; however, these strains were highly susceptible to cephalosporins. We identified a cluster of Neisseria gonorrhoeae isolates with high-level azithromycin resistance, several of which also demonstrated decreased ceftriaxone susceptibility. Eight N. gonorrhoeae isolates collected from 7 patients on Oahu, Hawaii, seen 21 April 2016 through 10 May 2016 underwent routine Etest antimicrobial susceptibility testing by the Hawaii Department of Health. All demonstrated elevated azithromycin minimum inhibitory concentrations (MICs) >256 μg/mL and elevated ceftriaxone MICs (≥0.125 μg/mL). Isolates were sent to the University of Washington and CDC for confirmatory agar dilution testing; sequence data were sent to CDC for analysis. All patients were interviewed and treated, and when possible, partners were interviewed, tested, and treated. All isolates had azithromycin MICs >16 µg/mL and 5 had ceftriaxone MICs = 0.125 µg/mL by agar dilution. All isolates were β-lactamase positive and were resistant to penicillin, tetracycline, and ciprofloxacin. Genomic analysis revealed genetic relatedness. No patients reported recent travel or antibiotic use, and no male patients reported male sex partners. All patients were successfully treated. This cluster of genetically related gonococcal isolates with decreased ceftriaxone susceptibility and high-level azithromycin resistance may bring the threat of treatment failure in the United States with the current recommended dual therapy one step closer. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Decreased production of interleukin-12 and type 2 immune responses are marked in cachectic patients with colorectal and gastric cancer.

PubMed

Shibata, Masahiko; Nezu, Takeshi; Kanou, Hisao; Abe, Hideo; Takekawa, Motoo; Fukuzawa, Masahiro

2002-04-01

Balance of the two types of T helper cells is one of the most important factors for regulation of the immune system. This study examines the production of interleukin (IL)-4, -6, -10, -12, and interferon-gamma by peripheral blood mononuclear cells stimulated with phytohemagglutinin or Staphylococcus aureus. Sixty-one patients, including 25 with gastric and 39 with colorectal cancer, and 39 normal volunteers were entered. The production of IL-12 decreased significantly with advancing disease and was lowest in the patients with distant metastases and cachexia. Compared with normal donors, the production of interferon-gamma decreased in all categories of patients, with no difference among patient groups. Levels of Th2 cytokines, such as IL-4, IL-6, and IL-10, also showed no difference among patient groups. However, production of all these cytokines had increased by 2.5 months after sequential testing in the same cachectic patients. The authors' findings indicate that the induction of Th1 cells seems to be suppressed at a relatively early stage of disease, whereas that of Th2 cells seems to increase in the terminal stage.

Azithromycin-Induced Rash in a Patient of Infectious Mononucleosis – A Case Report with Review of Literature

PubMed Central

Mondal, Somnath; Sen, Sukanta; Tripathi, Santanu Kumar; Banerjee, Gautam

2014-01-01

Antibiotic induced skin rash in setting of infectious mononucleosis is often encountered in clinical practice. However, macrolides like azithromycin are considered relatively safe and till date only two cases of azithromycin induced rash in setting of infectious mononucleosis have been reported. The following report illustrates the case of a 23-year-old man suffering from infectious mononucleosis who exhibited a generalized cutaneous rash following treatment with azithromycin. Using the Naranjo ADR probability scale, this case of acute onset rash following azithromycin administration was found to be in ‘probable’ category. The mechanism of antibiotic-induced rash in patients suffering from infectious mononucleosis is incompletely understood. It has been suggested that the rash could result from virus mediated immunomodulation or due to altered drug metabolism. The report calls for cautious use of antibiotics in the setting of suspected viral infections like infectious mononucleosis as injudicious use might increase the risk of deleterious skin reactions and increase the cost of healthcare. PMID:25302218

Generation and characterization of a potent fully human monoclonal antibody against the interleukin-23 receptor.

PubMed

Sasaki-Iwaoka, Haruna; Ohori, Makoto; Imasato, Akira; Taguchi, Katsunari; Minoura, Kyoko; Saito, Tetsu; Kushima, Kiyoshi; Imamura, Emiko; Kubo, Satoshi; Furukawa, Shigetada; Morokata, Tatsuaki

2018-06-05

Interleukin (IL)-12 and IL-23 share a common subunit (p40) and function in T-helper (Th) 1 and Th17 immunity, respectively. Anti-IL-12/23p40 and specific anti-IL-23 antibodies are currently in clinical use for psoriasis and undergoing trials for autoimmune diseases. Since expression levels of the IL-23 receptor are likely to be much lower than those of IL-23, an anti-IL-23 receptor antibody might offer greater promise in inhibiting the IL-23-IL-17 pathways involved in inflammatory disorders. To our knowledge, no anti-IL-23 receptor antibody has been trialed in clinical studies to date. This study describes the generation and characterization of AS2762900-00, a fully human monoclonal antibody against the IL-23 receptor. AS2762900-00 bound both human and cynomolgus monkey IL-23 receptors. AS2762900-00 showed potent inhibitory effects on IL-23-induced Kit-225 cell proliferation compared to the existing anti-IL-12/23p40 antibody, ustekinumab. In a single dose administration pharmacodynamics study in cynomolgus monkeys, 1 mg/kg of AS2762900-00 significantly inhibited (> 85%) IL-23-induced STAT3 phosphorylation in blood for up to 84 days. Therefore, AS2762900-00 represents a potent novel IL-23-IL-17 pathway inhibitor with the potential to be developed into a new therapy for the treatment of autoimmune diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation.

PubMed

Lovell, M; Lott, S T; Wong, P; El-Naggar, A; Tucker, S; Killary, A M

1999-05-01

Human chromosome 3p cytogenetic abnormalities and loss of heterozygosity have been observed at high frequency in the nonpapillary form of sporadic renal cell carcinoma (RCC). The von Hippel-Lindau (VHL) gene has been identified as a tumor suppressor gene for RCC at 3p25, and functional studies as well as molecular genetic and cytogenetic analyses have suggested as many as two or three additional regions of 3p that could harbor tumor suppressor genes for sporadic RCC. We have previously functionally defined a novel genetic locus nonpapillary renal carcinoma-1 (NRC-1) within chromosome 3p12, distinct from the VHL gene, that mediates tumor suppression and rapid cell death of RCC cells in vivo. We now report the suppression of tumorigenicity of RCC cells in vivo after the transfer of a defined centric 3p fragment into different histological types of RCC. Results document the functional involvement of NRC-1 in not only different cell types of RCC (i.e., clear cell, mixed granular cell/clear cell, and sarcomatoid types) but also in papillary RCC, a less frequent histological type of RCC for which chromosome 3p LOH and genetic aberrations have only rarely been observed. We also report that the tumor suppression observed in functional genetic screens was independent of the microenvironment of the tumor, further supporting a role for NRC-1 as a more general mediator of in vivo growth control. Furthermore, this report demonstrates the first functional evidence for a VHL-independent pathway to tumorigenesis in the kidney via the genetic locus NRC-1.

p53 Mutation suppresses adult neurogenesis in medaka fish (Oryzias latipes)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Isoe, Yasuko; Okuyama, Teruhiro; Taniguchi, Yoshihito

2012-07-13

Highlights: Black-Right-Pointing-Pointer Progenitor migration is accompanied by an increase in their numbers in the adult brain. Black-Right-Pointing-Pointer p53 Mutation suppressed an increase in the number of the migrated progenitors. Black-Right-Pointing-Pointer The decreased progenitor number is not due to enhanced cell death. Black-Right-Pointing-Pointer p53 Mutation did not affect proliferation of stem cells. -- Abstract: Tumor suppressor p53 negatively regulates self-renewal of neural stem cells in the adult murine brain. Here, we report that the p53 null mutation in medaka fish (Oryzias latipes) suppressed neurogenesis in the telencephalon, independent of cell death. By using 5-bromo-29-deoxyuridine (BrdU) immunohistochemistry, we identified 18 proliferation zonesmore » in the brains of young medaka fish; in situ hybridization showed that p53 was expressed selectively in at least 12 proliferation zones. We also compared the number of BrdU-positive cells present in the whole telencephalon of wild-type (WT) and p53 mutant fish. Immediately after BrdU exposure, the number of BrdU-positive cells did not differ significantly between them. One week after BrdU-exposure, the BrdU-positive cells migrated from the proliferation zone, which was accompanied by an increased number in the WT brain. In contrast, no significant increase was observed in the p53 mutant brain. Terminal deoxynucleotidyl transferase (dUTP) nick end-labeling revealed that there was no significant difference in the number of apoptotic cells in the telencephalon of p53 mutant and WT medaka, suggesting that the decreased number of BrdU-positive cells in the mutant may be due to the suppression of proliferation rather than the enhancement of neural cell death. These results suggest that p53 positively regulates neurogenesis via cell proliferation.« less

Screening paediatric rectal forms of azithromycin as an alternative to oral or injectable treatment.

PubMed

Kauss, Tina; Gaudin, Karen; Gaubert, Alexandra; Ba, Boubakar; Tagliaferri, Serena; Fawaz, Fawaz; Fabre, Jean-Louis; Boiron, Jean-Michel; Lafarge, Xavier; White, Nicholas J; Olliaro, Piero L; Millet, Pascal

2012-10-15

The aim of this study was to identify a candidate formulation for further development of a home or near-home administrable paediatric rectal form of a broad-spectrum antibiotic - specially intended for (emergency) use in tropical rural settings, in particular for children who cannot take medications orally and far from health facilities where injectable treatments can be given. Azithromycin, a broad-spectrum macrolide used orally or intravenously for the treatment of respiratory tract, skin and soft tissue infections, was selected because of its pharmacokinetic and therapeutic properties. Azithromycin in vitro solubility and stability in physiologically relevant conditions were studied. Various pharmaceutical forms, i.e. rectal suspension, two different rectal gels, polyethylene glycol (PEG) suppository and hard gelatin capsule (HGC) were assessed for in vitro dissolution and in vivo bioavailability in the rabbit. Azithromycin PEG suppository appears to be a promising candidate. Copyright © 2012 Elsevier B.V. All rights reserved.

Screening paediatric rectal forms of azithromycin as an alternative to oral or injectable treatment

PubMed Central

Kauss, Tina; Gaudin, Karen; Gaubert, Alexandra; Ba, Boubakar; Tagliaferri, Serena; Fawaz, Fawaz; Fabre, Jean-Louis; Boiron, Jean-Michel; Lafarge, Xavier; White, Nicholas J.; Olliaro, Piero L.; Millet, Pascal

2012-01-01

The aim of this study was to identify a candidate formulation for further development of a home or near-home administrable paediatric rectal form of a broad-spectrum antibiotic – specially intended for (emergency) use in tropical rural settings, in particular for children who cannot take medications orally and far from health facilities where injectable treatments can be given. Azithromycin, a broad-spectrum macrolide used orally or intravenously for the treatment of respiratory tract, skin and soft tissue infections, was selected because of its pharmacokinetic and therapeutic properties. Azithromycin in vitro solubility and stability in physiologically relevant conditions were studied. Various pharmaceutical forms, i.e. rectal suspension, two different rectal gels, polyethylene glycol (PEG) suppository and hard gelatin capsule (HGC) were assessed for in vitro dissolution and in vivo bioavailability in the rabbit. Azithromycin PEG suppository appears to be a promising candidate. PMID:22868232

Intravenous azithromycin as salvage therapy in a patient with Legionnaire's disease

PubMed Central

Dorrell, L; Fulton, B; Ong, E L C

1994-01-01

A patient with proven Legionnaire's disease is described whose clinical condition improved with intravenous azithromycin after failure to respond to treatment with erythromycin and rifampicin. Images PMID:8016806

Comparison of azithromycin and clarithromycin triple therapy regimens for helicobacter pylori eradication in hemodialysis patients.

PubMed

Jalalzadeh, Mojgan; Nazarian, Morteza; Vafaeimanesh, Jamshid; Mirzamohammadi, Fatemeh

2012-01-01

Helicobacter pylori eradication with clarithromycin is more expensive than with azithromycin. This study aimed to compare the effectiveness of these two antibiotics in eradicating H. pylori in hemodialysis (HD) patients. This is a prospective, randomized, double-blinded clinical trial analysis of HD patients. Patients who had dyspepsia and showed positive results for two of three tests, anti-H. pylori serology, H. pylori stool antigen (HpSAg), or Urease Breath Test (UBT), were included in the study. The subjects consisted of 39 dialysis patients who were randomly divided into two groups that received medication twice daily. Group OAC received 20 mg omeprazol, 500 mg amoxycilin, and 250 mg clarithromycin, and Group OAAz received 20 mg omeprazol, 500 mg amoxicillin, and 250 mg azithromycin. Both regimens were administered for 14 days. Eradication was investigated by performing the UBT and the HpSAg test eight weeks later. This study began with 39 patients, 37 of which completed the treatment schedule (20 males and 17 females, mean age 59 years). Two patients died due to MI before beginning treatment. In the OAC group, negative results on the UBT and HpSAg tests were found in 82.4% and 88.2% of the participants, respectively. In the OAAz group, these values were 80% and 85%, respectively. The data showed that the difference between the two regimens was not significant (P = 1.0). According to the data, no differences in eradication rates were apparent between the azitromycin and the claritromycin regimens. However, lower cost and fewer complaints could be considered as an advantage of the triple therapy with azithromycin.

40 CFR 721.2584 - Dodecanoic acid, 12-amino-.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Dodecanoic acid, 12-amino-. 721.2584... Substances § 721.2584 Dodecanoic acid, 12-amino-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as dodecanoic acid, 12-amino- (PMN P-98-0823; CAS No. 693...

40 CFR 721.2584 - Dodecanoic acid, 12-amino-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Dodecanoic acid, 12-amino-. 721.2584... Substances § 721.2584 Dodecanoic acid, 12-amino-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as dodecanoic acid, 12-amino- (PMN P-98-0823; CAS No. 693...

Surface plasmon resonance based selective and sensitive colorimetric determination of azithromycin using unmodified silver nanoparticles in pharmaceuticals and human plasma

NASA Astrophysics Data System (ADS)

Chavada, Vijay D.; Bhatt, Nejal M.; Sanyal, Mallika; Shrivastav, Pranav S.

2017-01-01

In this article we report a novel method for colorimetric sensing and selective determination of a non-chromophoric drug-azithromycin, which lacks native absorbance in the UV-Visible region using unmodified silver nanoparticles (AgNPs). The citrate-capped AgNps dispersed in water afforded a bright yellow colour owing to the electrostatic repulsion between the particles due to the presence of negatively charged surface and showed surface plasmon resonance (SPR) band at 394 nm. Addition of positively charged azithromycin at a concentration as low as 0.2 μM induced rapid aggregation of AgNPs by neutralizing the negative charge on the particle surface. This phenomenon resulted in the colour change from bright yellow to purple which could be easily observed by the naked eye. This provided a simple platform for rapid determination of azithromycin based on colorimetric measurements. The factors affecting the colorimetric response like pH, volume of AgNPs suspension and incubation time were suitably optimized. The validated method was found to work efficiently in the established concentration range of 0.2-100.0 μM using two different calibration models. The selectivity of the method was also evaluated by analysis of nanoparticles-aggregation response upon addition of several anions, cations and some commonly prescribed antibiotics. The method was successfully applied for the analysis of azithromycin in pharmaceuticals and spiked human plasma samples with good accuracy and precision. The simplicity, efficiency and cost-effectiveness of the method hold tremendous potential for the analysis of such non-chromophoric pharmaceuticals.

Cancer Therapeutic Based on T Cell Receptors Designed to Regiospecifically Release Interleukin-12 | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute's Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize a potential cancer therapeutic based on T cells genetically engineered to express the human interleukin 12 (IL-12) cytokine only in the tumor environment.

Effect of azithromycin on the LPS-induced production and secretion of phospholipase A2 in lung cells.

PubMed

Kitsiouli, Eirini; Antoniou, Georgia; Gotzou, Helen; Karagiannopoulos, Michalis; Basagiannis, Dimitris; Christoforidis, Savvas; Nakos, George; Lekka, Marilena E

2015-07-01

Azithromycin is a member of macrolides, utilized in the treatment of infections. Independently, these antibiotics also possess anti-inflammatory and immunomodulatory properties. Phospholipase A2 isotypes, which are implicated in the pathophysiology of inflammatory lung disorders, are produced by alveolar macrophages and other lung cells during inflammatory response and can promote lung injury by destructing lung surfactant. The aim of the study was to investigate whether in lung cells azithromycin can inhibit secretory and cytosolic phospholipases A2, (sPLA2) and (cPLA2), respectively, which are induced by an inflammatory trigger. In this respect, we studied the lipopolysaccharide (LPS)-mediated production or secretion of sPLA2 and cPLA2 from A549 cells, a cancer bronchial epithelial cell line, and alveolar macrophages, isolated from bronchoalveolar lavage fluid of ARDS and control patients without cardiopulmonary disease or sepsis. Pre-treatment of cells with azithromycin caused a dose-dependent decrease in the LPS-induced sPLA2-IIA levels in A549 cells. This inhibition was rather due to reduced PLA2G2A mRNA expression and secretion of sPLA2-IIA protein levels, as observed by western blotting and indirect immunofluorescence by confocal microscopy, respectively, than to the inhibition of the enzymic activity per se. On the contrary, azithromycin had no effect on the LPS-induced production or secretion of sPLA2-IIA from alveolar macrophages. The levels of LPS-induced c-PLA2 were not significantly affected by azithromycin in either cell type. We conclude that azithromycin exerts anti-inflammatory properties on lung epithelial cells through the inhibition of both the expression and secretion of LPS-induced sPLA2-IIA, while it does not affect alveolar macrophages. Copyright © 2015 Elsevier B.V. All rights reserved.

Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats.

PubMed

Harper, Curt E; Cook, Leah M; Patel, Brijesh B; Wang, Jun; Eltoum, Isam A; Arabshahi, Ali; Shirai, Tomoyuki; Lamartiniere, Coral A

2009-11-01

Chemoprevention utilizing dietary agents is an effective means to slow the development of prostate cancer. We evaluated the potential additive and synergistic effects of genistein and resveratrol for suppressing prostate cancer in the Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model, a transgenic model of spontaneously developing prostate cancer. Rats were fed genistein or resveratrol (250 mg/kg AIN-76A diet) alone and in combination, and a low-dose combination (83 mg genistein + 83 mg resveratrol/kg diet). Histopathology and mechanisms of action studies were conducted at 30 and 12 weeks of age, respectively. Genistein, resveratrol, and the high-dose combination treatments suppressed prostate cancer. The low-dose combination did not elicit protection against prostate cancer and was most likely below the effective dose for causing significant histopathological changes. Total genistein and resveratrol concentrations in the blood reached 2,160 and 211 nM, respectively in rats exposed to the single treatments. Polyphenol treatments decreased cell proliferation and insulin-like growth factor-1 (IGF-1) protein expression in the prostate. In addition, genistein as a single agent induced apoptosis and decreased steroid receptor coactivator-3 (SRC-3) in the ventral prostate (VP). Genistein and resveratrol, alone and in combination, suppress prostate cancer development in the SV-40 Tag model. Regulation of SRC-3 and growth factor signaling proteins are consistent with these nutritional polyphenols reducing cell proliferation and increasing apoptosis in the prostate.

Hypothermia increases interleukin-6 and interleukin-10 in juvenile endotoxemic mice.

PubMed

Stewart, Corrine R; Landseadel, Jessica P; Gurka, Matthew J; Fairchild, Karen D

2010-01-01

To develop a juvenile mouse model to establish effects of in vivo hypothermia on expression of the inflammation-modulating cytokines tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-10. Although induced hypothermia is neuroprotective in some patients, the mechanisms of protection are not well understood and concerns remain over potential detrimental effects, particularly in the setting of infection. We previously showed that in vitro hypothermia increases production of tumor necrosis factor-alpha and interleukin-1beta in lipopolysaccharide-treated monocytes. : Laboratory investigation. Research laboratory. Juvenile (4-wk) male C57BL/6 mice. : Mice were given chlorpromazine to suspend thermoregulation and lipopolysaccharide to stimulate cytokine production. Core temperature was maintained at 32 degrees C or 37 degrees C for 6 hrs by adjusting environmental temperature. In separate experiments, lipopolysaccharide-treated mice were kept in a cooling chamber without chlorpromazine treatment. Plasma and organs were collected for cytokine quantitation. Chlorpromazine-treated hypothermic mice had 2.3-fold and 1.8-fold higher plasma interleukin-6 and interleukin-10 levels at 6 hrs compared with identically treated normothermic mice (p < .05), whereas plasma tumor necrosis factor-alpha and interleukin-1beta were not significantly different at 2 hrs or 6 hrs. Liver tumor necrosis factor-alpha and interleukin-6 were significantly higher in hypothermic vs. normothermic mice, but lung and brain cytokines were not different. Lipopolysaccharide-treated mice kept in a cooling chamber without chlorpromazine treatment developed varying degrees of hypothermia with associated increases in plasma interleukin-6 and interleukin-10. A nonspecific marker of stress (plasma corticosterone) was not affected by hypothermia in lipopolysaccharide-treated mice. Further studies are necessary to determine the mechanism and physiologic consequences of augmented systemic

Toxoplasma gondii infection inhibits Th17-mediated spontaneous development of arthritis in interleukin-1 receptor antagonist-deficient mice.

PubMed

Washino, Takuya; Moroda, Masataka; Iwakura, Yoichiro; Aosai, Fumie

2012-04-01

Interleukin 1 receptor antagonist (IL-1Ra)-deficient BALB/c mice develop spontaneous arthritis resembling human rheumatoid arthritis. We herein report that infection with Toxoplasma gondii, an intracellular protozoan, is capable of ameliorating the spontaneous development of arthritis in IL-1Ra-deficient mice. The onset of arthritis development was delayed and the severity score of arthritis was significantly suppressed in T. gondii-infected mice. Expression of IL-12p40 mRNA from CD11c(+) cells of mesenteric lymph nodes (mLN) and spleen markedly increased at 1 week after peroral infection. While CD11c(+) cells also produced IL-10, IL-1β, and IL-6, CD4(+) T cells from T. gondii-infected mice expressed significantly high levels of T-bet and gamma interferon (IFN-γ) mRNA in both mLN and spleen. Levels of GATA-3/IL-4 mRNA or RORγt/IL-17 mRNA decreased in the infected mice, indicating Th1 cell polarization and the reduction of Th2 and Th17 cell polarization. The severity of arthritis was related to Th1 cell polarization accompanied by Th17 cell reduction, demonstrating the protective role of the T. gondii-derived Th1 response against Th17 cell-mediated arthritis in IL-1Ra-deficient mice.

Failure of azithromycin 2.0 g in the treatment of gonococcal urethritis caused by high-level resistance in California.

PubMed

Gose, Severin O; Soge, Olusegun O; Beebe, James L; Nguyen, Duylinh; Stoltey, Juliet E; Bauer, Heidi M

2015-05-01

We report a treatment failure to azithromycin 2.0 g caused by a urethral Neisseria gonorrhoeae isolate with high-level azithromycin resistance in California. This report describes the epidemiological case investigation and phenotypic and genetic characterization of the treatment failure isolate.

Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-kappa B transcription factors.

PubMed

Ma, Wei; Gee, Katrina; Lim, Wilfred; Chambers, Kelly; Angel, Jonathan B; Kozlowski, Maya; Kumar, Ashok

2004-01-01

IL-12 plays a critical role in the development of cell-mediated immune responses and in the pathogenesis of inflammatory and autoimmune disorders. Dexamethasone (DXM), an anti-inflammatory glucocorticoid, has been shown to inhibit IL-12p40 production in LPS-stimulated monocytic cells. In this study, we investigated the molecular mechanism by which DXM inhibits IL-12p40 production by studying the role of the mitogen-activated protein kinases (MAPKs), and the key transcription factors involved in human IL-12p40 production in LPS-stimulated monocytic cells. A role for c-Jun N-terminal kinase (JNK) MAPK in LPS-induced IL-12p40 regulation in a promonocytic THP-1/CD14 cell line was demonstrated by using specific inhibitors of JNK activation, SP600125 and a dominant-negative stress-activated protein/extracellular signal-regulated kinase kinase-1 mutant. To identify transcription factors regulating IL-12p40 gene transcription, extensive deletion analyses of the IL-12p40 promoter was performed. The results revealed the involvement of a sequence encompassing the AP-1-binding site, in addition to that of NF-kappaB. The role of AP-1 in IL-12p40 transcription was confirmed by using antisense c-fos and c-jun oligonucleotides. Studies conducted to understand the regulation of AP-1 and NF-kappaB activation by JNK MAPK revealed that both DXM and SP600125 inhibited IL-12p40 gene transcription by inhibiting the activation of AP-1 and NF-kappaB transcription factors as revealed by luciferase reporter and gel mobility shift assays. Taken together, our results suggest that DXM may inhibit IL-12p40 production in LPS-stimulated human monocytic cells by down-regulating the activation of JNK MAPK, the AP-1, and NF-kappaB transcription factors.

Intravenous anesthetic propofol suppresses prostaglandin E2 production in murine dendritic cells.

PubMed

Inada, Takefumi; Kubo, Kozue; Ueshima, Hironobu; Shingu, Koh

2011-01-01

Propofol is an intravenous anesthetic that is widely used for anesthesia and sedation. Dendritic cells (DC) are one of the crucial immune cells that bridge innate and adaptive immunity, in which DC process antigens during innate immune responses to present them to naïve T-cells, leading to an establishment of adaptive immunity. Prostaglandin (PG)-E(2) may be secreted by DC into the microenvironment, considerably influencing DC phenotype and function, and thus determining the fate of adaptive immunity. Since propofol suppresses PGE(2) production in murine macrophages, the primary purpose of the present study was to determine whether propofol also suppresses PGE(2) production in DC. Assuming a positive finding of such suppression, we tested whether this also leads to alterations of interleukin (IL)-12 and IL-10 production and DC surface marker expression, both of which can be modulated by PGE(2). In bone marrow-derived DC, propofol significantly suppressed the PGE(2) production after lipopolysaccharide stimulation. Cyclo-oxygenase (COX) protein expression and arachidonic acid release were unaffected, while COX enzyme activity was significantly inhibited by propofol. The propofol-induced COX inhibition did not lead to the increased production of cysteinyl leukotrienes and leukotriene-B(4). Endogenous COX inhibition with propofol, as well as with the selective COX-2 inhibitor, NS-398, did not affect IL-12 and IL-10 production from DC. The surface expression of I-A(b) and CD40 on DC was not changed, while that of CD86 slightly increased, with both propofol and NS-398; expression of CD80 was not affected with propofol, but increased slightly with NS-398. Finally, endogenous COX inhibition with either propofol or NS-398 did not significantly affect the ability of DC to induce allogeneic T-cell proliferation. It is concluded that the intravenous anesthetic propofol suppresses COX enzyme activity in DC, with no consequences with respect to IL-12/IL-10 production and

IDO-expressing Fibroblasts Suppress the Development of Imiquimod-induced Psoriasis-like Dermatitis.

PubMed

Elizei, Sanam Salimi; Pakyari, Mohammadreza; Ghoreishi, Mehraneh; Kilani, Ruhangiz; Mahmoudi, Sanaz; Ghahary, Aziz

2018-01-01

Psoriasis is a chronic skin condition whose pathogenesis is reported to be due to the activation of the interleukin-23/interleukin-17 (IL-23/IL-17) pathway. Here, we report that indoleamine 2,3-dioxygenase (IDO)-expressing fibroblasts reduce the activity of this pathway in activated immune cells. The findings showed that intralesional injection of IDO-expressing fibroblasts in imiquimod-induced psoriasis-like dermatitis on the back and ear (Pso. ear group) in mice significantly improves the clinical lesional appearance by reducing the number of skin-infiltrated IL-17+ CD4+ T cells (1.9% ± 0.3% vs. 6.9% ± 0.6%, n = 3, P value < 0.01), IL-17+ γδ+ T cells (2.8% ± 0.3% vs. 11.6% ± 1.2%, n = 3, P value < 0.01), IL-23+ activated dendritic cells (7.6% ± 0.9% vs. 14.0% ± 0.5%, n = 3, P < 0.01), macrophages (4.3% ± 0.1% vs. 11.3% ± 1.0%, n = 3, P value < 0.01), and granulocytes (2.5% ± 0.4% vs. 4.5% ± 0.3%, n = 3, P value < 0.01) as compared to untreated psoriatic mice. This finding suggests that IDO-expressing fibroblasts, and to a lesser extent, non-IDO primary fibroblasts suppress the psoriatic-like symptoms by inhibiting the infiltration of key immune cells involved in the development of psoriasis.

Effects of clarithromycin treatment in scrub typhus in children: comparison with chloramphenicol and azithromycin.

PubMed

Lee, Min; Kim, June; Jo, Dae Sun

2017-04-01

Chloramphenicol and tetracycline are not recommended for treating scrub typhus in pediatric patients because of potential side effects, such as aplastic anemia or tooth discoloration. While clarithromycin has recently been used in adults, few reports have been published on its effects in pediatric patients. We report the clinical profiles of pediatric scrub typhus and the effects of clarithromycin on scrub typhus in children. We retrospectively analyzed medical records of 56 children with scrub typhus who were admitted between 2004 and 2013 to Chonbuk National University Hospital, Jeonju, Korea. Cases were divided into 3 groups based on thetreatment drug (chloramphenicol, azithromycin, and clarithromycin). We compared their clinical manifestations and laboratory findings. All patients exhibited fever and rash. Other common clinical manifestations were eschars (66%), lymphadenopathy (48%), upper respiratory symptoms (42%), abdominal pain (32%), and hepatosplenomegaly (14%). Elevated levels of C-reactive protein, erythrocyte sedimentation rates, aspartate transaminase, and alanine transaminase were detected in 95%, 96%, 84%, and 77% of patients, respectively. Additionally, decreased platelet and white blood cell levels were observed in 43% and 36% of patients, respectively. There were no statistical differences between the treatment groups in mean age ( P =0.114) or sex ( P =0.507). However, time to defervescence after the treatments differed significantly, being the shortest in the clarithromycin group ( P =0.019). All patients recovered without complications related to the disease or drugs. Clarithromycin was as effective as chloramphenicol and azithromycin in pediatric scrub typhus patients and may be used as a first-line treatment drug.

A Case of Community-Acquired Pneumonia Due to Legionella pneumophila Serogroup 9 Wherein Initial Treatment with Single-Dose Oral Azithromycin Appeared Useful.

PubMed

Ito, Akihiro; Ishida, Tadashi; Tachibana, Hiromasa; Ito, Yuhei; Takaiwa, Takuya; Fujii, Hiroyuki; Hashimoto, Toru; Nakajima, Hiroshi; Amemura-Maekawa, Junko

2017-11-22

Legionella species are important causative pathogens for severe community-acquired pneumonia (CAP). Most cases of Legionella pneumonia are due to Legionella pneumophila serogroup 1, and CAP due to L. pneumophila serogroup 9 is rare. A fourth case of CAP due to L. pneumophila serogroup 9 has been reported, and initial treatment using single-dose oral azithromycin appeared useful. Azithromycin or fluoroquinolone injection is usually recommended for the treatment of Legionella pneumonia, and no previous reports have shown the effectiveness of single-dose oral azithromycin. This case report is therefore valuable from the perspective of possible treatment for mild to moderate Legionella pneumonia using single-dose oral azithromycin.

Suppression of Rotational Twins in Epitaxial B 12P 2 on 4H-SiC

DOE PAGES

Frye, C. D.; Saw, C. K.; Padavala, Balabalaji; ...

2017-12-22

B 12P2 was grown epitaxially on (0001) 4H-SiC using two different substrate miscuts: a standard 4° miscut toward the [more » $$11\\bar{20}$$] and a custom miscut 4° toward the [$$1\\bar{10}0$$]. Epitaxy on substrates miscut to the [$$11\\bar{20}$$] resulted in highly twinned B 12P 2 films with a rotational twin density of approximately 70% twin orientation I and 30% twin orientation II. In contrast, epitaxy on substrates tilted toward the [$$1\\bar{10}0$$] produced films of >99% twin orientation I. A H 2 etch model is used to explain the 4H-SiC surface morphology for each miscut prior to epitaxy and demonstrate how the surface steps influence the nucleation of B 12P 2 twin orientations. Surface steps on substrates miscut to the [$$11\\bar{20}$$] tend to be zig-zagged with steps rotated 60° from one another producing B 12P 2 crystals that nucleate in orientations rotated by 60°, hence forming rotationally twinned films. In conclusion, steps on substrates tilted to the [$$1\\bar{10}0$$] tend to be parallel resulting in crystallographically aligned B 12P 2 nucleation.« less

Suppression of Rotational Twins in Epitaxial B 12P 2 on 4H-SiC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frye, C. D.; Saw, C. K.; Padavala, Balabalaji

B 12P2 was grown epitaxially on (0001) 4H-SiC using two different substrate miscuts: a standard 4° miscut toward the [more » $$11\\bar{20}$$] and a custom miscut 4° toward the [$$1\\bar{10}0$$]. Epitaxy on substrates miscut to the [$$11\\bar{20}$$] resulted in highly twinned B 12P 2 films with a rotational twin density of approximately 70% twin orientation I and 30% twin orientation II. In contrast, epitaxy on substrates tilted toward the [$$1\\bar{10}0$$] produced films of >99% twin orientation I. A H 2 etch model is used to explain the 4H-SiC surface morphology for each miscut prior to epitaxy and demonstrate how the surface steps influence the nucleation of B 12P 2 twin orientations. Surface steps on substrates miscut to the [$$11\\bar{20}$$] tend to be zig-zagged with steps rotated 60° from one another producing B 12P 2 crystals that nucleate in orientations rotated by 60°, hence forming rotationally twinned films. In conclusion, steps on substrates tilted to the [$$1\\bar{10}0$$] tend to be parallel resulting in crystallographically aligned B 12P 2 nucleation.« less

Stimulation of IFN-γ production by garlic lectin in mouse spleen cells: involvement of IL-12 via activation of p38 MAPK and ERK in macrophages.

PubMed

Dong, Qing; Sugiura, Tsutomu; Toyohira, Yumiko; Yoshida, Yasuhiro; Yanagihara, Nobuyuki; Karasaki, Yuji

2011-02-15

Several lectins, present in beans and edible plant products, have immuno-potentiating and anti-tumor activities. We here report the effects of garlic lectin purified from garlic bulbs on the production of cytokines such as interleukin-12 (IL-12) and interferon-γ (IFN-γ) in the mouse. Garlic lectin induced IFN-γ production in spleen cells in a bell-shaped time (24-60 h)- and concentration (0.25-2.0 mg/ml)-dependent manner. The maximal enhancement was observed at 36 h with 0.5 mg/ml of garlic lectin. The stimulatory effect of garlic lectin on IFN-γ production was completely inhibited by both actinomycin D and cycloheximide, an inhibitor of ribosomal protein synthesis and DNA-dependent RNA polymerase, respectively, and was associated with an increase in IFN-γ mRNA level. Garlic lectin also induced IL-12 production in mouse peritoneal macrophages in a concentration (0.25-1.0 mg/ml)- and bell-shaped time (3-24 h)-dependent manner. The lectin increased the phosphorylation of extracellular signal-regulated kinases (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) in macrophages. Furthermore, specific pharmacological inhibitors of ERK kinase (U0126) and p38 MAPK (SB203580) also suppressed the production of IL-12 induced by garlic lectin. The present findings suggest that garlic lectin induces IL-12 production via activation of p38 MAPK and ERK in mouse macrophages, which, in turn, stimulates IFN-γ production through an increase in IFN-γ mRNA in the spleen cells. Copyright © 2010 Elsevier GmbH. All rights reserved.

Synthesis and antibacterial activity of novel 15-membered macrolide derivatives: 4''-carbamate, 11,12-cyclic carbonate-4''-carbamate and 11,4''-di-O-arylcarbamoyl analogs of azithromycin.

PubMed

Ma, Shutao; Ma, Ruixin; Liu, Zhaopeng; Ma, Chenchen; Shen, Xuecui

2009-10-01

4''-Carbamate, 11,12-cyclic carbonate-4''-carbamate and 11,4''-di-O-arylcarbamoyl analogs of azithromycin were designed, synthesized and evaluated. The 4''-carbamate analogs retained excellent activity against erythromycin-susceptible Staphylococcus pneumoniae and showed improved activity against erythromycin-resistant Staphylococcus pneumoniae. Compared with 4''-carbamate analogs, 11,12-cyclic carbonate-4''-carbamate analogs exhibited improved activity against erythromycin-resistant Staphylococcus pneumoniae encoded by the mef gene or the erm and mef genes, and 11,4''-di-O-arylalkylcarbamoyl analogs showed greatly improved activity (0.25-0.5 microg/mL) against erythromycin-resistant Staphylococcus pneumoniae encoded by the erm gene. Among them, the novel series of 11,4''-di-O-arylalkylcarbamoyl analogs 7a-k exhibited potent and balanced activity against susceptible and resistant bacteria. In particular, compounds 7f and 7k were the most effective against susceptible bacteria and resistant bacteria encoded by the erm gene or the mef gene.

10 CFR 40.12 - Carriers.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Carriers. 40.12 Section 40.12 Energy NUCLEAR REGULATORY COMMISSION DOMESTIC LICENSING OF SOURCE MATERIAL Exemptions § 40.12 Carriers. (a) Except as specified in... in section 62 of the Act to the extent that they transport or store source material in the regular...

On the pathway to better birth outcomes? A systematic review of azithromycin and curable sexually transmitted infections.

PubMed

Chico, R Matthew; Hack, Berkin B; Newport, Melanie J; Ngulube, Enesia; Chandramohan, Daniel

2013-12-01

The WHO recommends the administration of sulfadoxine-pyrimethamine (SP) to all pregnant women living in areas of moderate (stable) to high malaria transmission during scheduled antenatal visits, beginning in the second trimester and continuing to delivery. Malaria parasites have lost sensitivity to SP in many endemic areas, prompting the investigation of alternatives that include azithromycin-based combination (ABC) therapies. Use of ABC therapies may also confer protection against curable sexually transmitted infections and reproductive tract infections (STIs/RTIs). The magnitude of protection at the population level would depend on the efficacy of the azithromycin-based regimen used and the underlying prevalence of curable STIs/RTIs among pregnant women who receive preventive treatment. This systematic review summarizes the efficacy data of azithromycin against curable STIs/RTIs.

On the pathway to better birth outcomes? A systematic review of azithromycin and curable sexually transmitted infections

PubMed Central

Chico, R Matthew; Hack, Berkin B; Newport, Melanie J; Ngulube, Enesia; Chandramohan, Daniel

2013-01-01

The WHO recommends the administration of sulfadoxine-pyrimethamine (SP) to all pregnant women living in areas of moderate (stable) to high malaria transmission during scheduled antenatal visits, beginning in the second trimester and continuing to delivery. Malaria parasites have lost sensitivity to SP in many endemic areas, prompting the investigation of alternatives that include azithromycin-based combination (ABC) therapies. Use of ABC therapies may also confer protection against curable sexually transmitted infections and reproductive tract infections (STIs/RTIs). The magnitude of protection at the population level would depend on the efficacy of the azithromycin-based regimen used and the underlying prevalence of curable STIs/RTIs among pregnant women who receive preventive treatment. This systematic review summarizes the efficacy data of azithromycin against curable STIs/RTIs. PMID:24191955

A tumor suppressor locus within 3p14-p12 mediates rapid cell death of renal cell carcinoma in vivo.

PubMed Central

Sanchez, Y; el-Naggar, A; Pathak, S; Killary, A M

1994-01-01

High frequency loss of alleles and cytogenetic aberrations on the short arm of chromosome 3 have been documented in renal cell carcinoma (RCC). Potentially, three distinct regions on 3p could encode tumor suppressor genes involved in the genesis of this cancer. We report that the introduction of a centric fragment of 3p, encompassing 3p14-q11, into a highly malignant RCC cell line resulted in a dramatic suppression of tumor growth in athymic nude mice. Another defined deletion hybrid contained the region 3p12-q24 of the introduced human chromosome and failed to suppress tumorigenicity. These data functionally define a tumor suppressor locus, nonpapillary renal carcinoma-1 (NRC-1), within 3p14-p12, the most proximal region of high frequency allele loss in sporadic RCC as well as the region containing the translocation breakpoint in familial RCC. Furthermore, we provide functional evidence that NRC-1 controls the growth of RCC cells by inducing rapid cell death in vivo. Images PMID:8159756

Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea.

PubMed

Marks, Michael; Mitjà, Oriol; Bottomley, Christian; Kwakye, Cynthia; Houinei, Wendy; Bauri, Mathias; Adwere, Paul; Abdulai, Abdul A; Dua, Fredrick; Boateng, Laud; Wangi, James; Ohene, Sally-Ann; Wangnapi, Regina; Simpson, Shirley V; Miag, Helen; Addo, Kennedy K; Basing, Laud A; Danavall, Damien; Chi, Kai H; Pillay, Allan; Ballard, Ronald; Solomon, Anthony W; Chen, Cheng Y; Bieb, Sibauk V; Adu-Sarkodie, Yaw; Mabey, David C W; Asiedu, Kingsley

2018-04-01

A dose of 30 mg/kg of azithromycin is recommended for treatment of yaws, a disease targeted for global eradication. Treatment with 20 mg/kg of azithromycin is recommended for the elimination of trachoma as a public health problem. In some settings, these diseases are co-endemic. We aimed to determine the efficacy of 20 mg/kg of azithromycin compared with 30 mg/kg azithromycin for the treatment of active and latent yaws. We did a non-inferiority, open-label, randomised controlled trial in children aged 6-15 years who were recruited from schools in Ghana and schools and the community in Papua New Guinea. Participants were enrolled based on the presence of a clinical lesion that was consistent with infectious primary or secondary yaws and a positive rapid diagnostic test for treponemal and non-treponemal antibodies. Participants were randomly assigned (1:1) to receive either standard-dose (30 mg/kg) or low-dose (20 mg/kg) azithromycin by a computer-generated random number sequence. Health-care workers assessing clinical outcomes in the field were not blinded to the patient's treatment, but investigators involved in statistical or laboratory analyses and the participants were blinded to treatment group. We followed up participants at 4 weeks and 6 months. The primary outcome was cure at 6 months, defined as lesion healing at 4 weeks in patients with active yaws and at least a four-fold decrease in rapid plasma reagin titre from baseline to 6 months in patients with active and latent yaws. Active yaws was defined as a skin lesion that was positive for Treponema pallidum ssp pertenue in PCR testing. We used a non-inferiority margin of 10%. This trial was registered with ClinicalTrials.gov, number NCT02344628. Between June 12, 2015, and July 2, 2016, 583 (65·1%) of 895 children screened were enrolled; 292 patients were assigned a low dose of azithromycin and 291 patients were assigned a standard dose of azithromycin. 191 participants had active yaws and 392 had presumed

Liposomal Doxorubicin Plus Interleukin-12 for AIDS-Related Kaposi’s Sarcoma | Center for Cancer Research

Cancer.gov

Kaposi’s sarcoma (KS), a disease characterized by the development of malignant tumors usually in the lower extremities, is a major complication of HIV/AIDS. KS continues to be a problem even with the use of highly active antiretroviral therapy (HAART), today’s standard of care for patients with HIV/AIDS. CCR investigators recently investigated the effects of interleukin-12

Co-expression of interleukin 12 enhances antitumor effects of a novel chimeric promoter-mediated suicide gene therapy in an immunocompetent mouse model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Yu, E-mail: xuyu1001@gmail.com; Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, 169 Donghu Road, Wuhan 430071; Liu, Zhengchun, E-mail: l135027@126.com

Highlights: {yields} A novel chimeric promoter consisting of CArG element and hTERT promoter was developed. {yields} The promoter was characterized with radiation-inducibility and tumor-specificity. {yields} Suicide gene system driven by the promoter showed remarkable cytotoxicity in vitro. {yields} Co-expression of IL12 enhanced the promoter mediated suicide gene therapy in vivo. -- Abstract: The human telomerase reverse transcriptase (hTERT) promoter has been widely used in target gene therapy of cancer. However, low transcriptional activity limited its clinical application. Here, we designed a novel dual radiation-inducible and tumor-specific promoter system consisting of CArG elements and the hTERT promoter, resulting in increased expressionmore » of reporter genes after gamma-irradiation. Therapeutic and side effects of adenovirus-mediated horseradish peroxidase (HRP)/indole-3-acetic (IAA) system downstream of the chimeric promoter were evaluated in mice bearing Lewis lung carcinoma, combining with or without adenovirus-mediated interleukin 12 (IL12) gene driven by the cytomegalovirus promoter. The combination treatment showed more effective suppression of tumor growth than those with single agent alone, being associated with pronounced intratumoral T-lymphocyte infiltration and minor side effects. Our results suggest that the combination treatment with HRP/IAA system driven by the novel chimeric promoter and the co-expression of IL12 might be an effective and safe target gene therapy strategy of cancer.« less

Antipneumococcal activities of two novel macrolides, GW 773546 and GW 708408, compared with those of erythromycin, azithromycin, clarithromycin, clindamycin, and telithromycin.

PubMed

Matic, Vlatka; Kosowska, Klaudia; Bozdogan, Bulent; Kelly, Linda M; Smith, Kathy; Ednie, Lois M; Lin, Gengrong; Credito, Kim L; Clark, Catherine L; McGhee, Pamela; Pankuch, Glenn A; Jacobs, Michael R; Appelbaum, Peter C

2004-11-01

The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were >/=0.5 microg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 microg/ml. Single-step studies showed mutation frequencies <5.0 x 10(-10) to 3.5 x 10(-7) for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 x 10(-7) to >4.3 x 10(-3) for

Antipneumococcal Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Erythromycin, Azithromycin, Clarithromycin, Clindamycin, and Telithromycin

PubMed Central

Matic, Vlatka; Kosowska, Klaudia; Bozdogan, Bulent; Kelly, Linda M.; Smith, Kathy; Ednie, Lois M.; Lin, Gengrong; Credito, Kim L.; Clark, Catherine L.; McGhee, Pamela; Pankuch, Glenn A.; Jacobs, Michael R.; Appelbaum, Peter C.

2004-01-01

The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were ≥0.5 μg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 μg/ml. Single-step studies showed mutation frequencies <5.0 × 10−10 to 3.5 × 10−7 for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 × 10−7 to >4.3 × 10−3 for

Tetramethylpyrazine suppresses transient oxygen-glucose deprivation-induced connexin32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathway in cultured hippocampal neurons.

PubMed

Gong, Gu; Yuan, Libang; Cai, Lin; Ran, Maorong; Zhang, Yulan; Gong, Huaqu; Dai, Xuemei; Wu, Wei; Dong, Hailong

2014-01-01

Tetramethylpyrazine (TMP) has been widely used in China as a drug for the treatment of various diseases. Recent studies have suggested that TMP has a protective effect on ischemic neuronal damage. However, the exact mechanism is still unclear. This study aims to investigate the mechanism of TMP mediated ischemic hippocampal neurons injury induced by oxygen-glucose deprivation (OGD). The effect of TMP on hippocampal neurons viability was detected by MTT assay, LDH release assay and apoptosis rate was measured by flow cytometry. TMP significantly suppressed neuron apoptosis in a concentration-dependent manner. TMP could significantly reduce the elevated levels of connexin32 (Cx32) induced by OGD. Knockdown of Cx32 by siRNA attenuated OGD injury. Moreover, our study showed that viability was increased in siRNA-Cx32-treated-neurons, and neuron apoptosis was suppressed by activating Bcl-2 expression and inhibiting Bax expression. Over expression of Cx32 could decrease neurons viability and increase LDH release. Furthermore, OGD increased phosphorylation of ERK1/2 and p38, whose inhibitors relieved the neuron injury and Cx32 up-regulation. Taken together, TMP can reverse the OGD-induced Cx32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathways.

Impaired NFAT and NFκB activation are involved in suppression of CD40 ligand expression by Δ{sup 9}-tetrahydrocannabinol in human CD4{sup +} T cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ngaotepprutaram, Thitirat; Center for Integrative Toxicology, Michigan State University; Kaplan, Barbara L.F.

We have previously reported that Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), the main psychoactive cannabinoid in marijuana, suppresses CD40 ligand (CD40L) expression by activated mouse CD4{sup +} T cells. CD40L is involved in pathogenesis of many autoimmune and inflammatory diseases. In the present study, we investigated the molecular mechanism of Δ{sup 9}-THC-mediated suppression of CD40L expression using peripheral blood human T cells. Pretreatment with Δ{sup 9}-THC attenuated CD40L expression in human CD4{sup +} T cells activated by anti-CD3/CD28 at both the protein and mRNA level, as determined by flow cytometry and quantitative real-time PCR, respectively. Electrophoretic mobility shift assays revealed that Δ{supmore » 9}-THC suppressed the DNA-binding activity of both NFAT and NFκB to their respective response elements within the CD40L promoter. An assessment of the effect of Δ{sup 9}-THC on proximal T cell-receptor (TCR) signaling induced by anti-CD3/CD28 showed significant impairment in the rise of intracellular calcium, but no significant effect on the phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β. Collectively, these findings identify perturbation of the calcium-NFAT and NFκB signaling cascade as a key mechanistic event by which Δ{sup 9}-THC suppresses human T cell function. - Highlights: • Δ{sup 9}-THC attenuated CD40L expression in activated human CD4+ T cells. • Δ{sup 9}-THC suppressed DNA-binding activity of NFAT and NFκB. • Δ{sup 9}-THC impaired elevation of intracellular Ca2+. • Δ{sup 9}-THC did not affect phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β.« less

Liposomal Doxorubicin Plus Interleukin-12 for AIDS-Related Kaposi’s Sarcoma | Center for Cancer Research

Cancer.gov

Kaposi’s sarcoma (KS), a disease characterized by the development of malignant tumors usually in the lower extremities, is a major complication of HIV/AIDS. KS continues to be a problem even with the use of highly active antiretroviral therapy (HAART), today’s standard of care for patients with HIV/AIDS. CCR investigators recently investigated the effects of interleukin-12 (IL-12) on this malignancy in HIV/AIDS patients when combined with pegylated liposomal doxorubicin, an anthracycline. The findings appear in the September 10, 2007, online edition of Blood.

Prevalence of Active and Latent Yaws in the Solomon Islands 18 Months after Azithromycin Mass Drug Administration for Trachoma

PubMed Central

Sokana, Oliver; Nachamkin, Eli; Puiahi, Elliot; Kilua, Georgina; Pillay, Allan; Bottomley, Christian; Solomon, Anthony W.; Mabey, David C.

2016-01-01

Introduction Both yaws and trachoma are endemic in the Pacific. Mass treatment with azithromycin is the mainstay of the WHO strategy for both the eradication of yaws and the elimination of trachoma as a public health problem, but the dose recommended for trachoma is lower than that for yaws. In countries where both diseases are endemic, there is a potential for synergy between yaws and trachoma control programs if mass treatment with the lower dose of azithromycin was shown to be effective for the treatment of yaws. In an earlier study, we demonstrated a profound reduction in the clinical and serological prevalence of yaws following a single round of mass treatment with azithromycin 20 mg/kg undertaken for the purposes of trachoma elimination. Methods This survey was conducted 18 months following a single round of azithromycin mass treatment in the same communities in which we had conducted our previous six-month follow-up survey. We examined children aged 1–14 years and took blood and lesion samples for yaws diagnosis using the Treponema pallidum particle agglutination assay (TPPA) and the non-treponemal Rapid Plasma Reagin (RPR) test. Results A total of 1,284 children were enrolled in the study. Amongst children aged 5–14 years, 223 had a positive TPPA (27.5%, 95% CI 13.6–47.7%). The TPPA seroprevalence amongst this age group did not differ significantly from either our pre-mass treatment survey or our initial follow-up survey. Thirty-five children had positive TPPA and positive RPR (4.3%, 95% CI 2.1–8.7%), and this did not differ significantly from our initial post-mass drug administration (MDA) follow-up survey (4.3% versus 3.5%, p = 0.43) but remained significantly lower than our initial pre-MDA survey (4.3% vs 21.7%, p <0.0001). Village-level MDA coverage was strongly associated with dual-seropositivity (p = 0.005). Amongst children aged 1–4 years, 16 had a positive TPPA (3.5%, 95% CI 1.6–7.1%). This did not differ significantly from the

Prevalence of Active and Latent Yaws in the Solomon Islands 18 Months after Azithromycin Mass Drug Administration for Trachoma.

PubMed

Marks, Michael; Sokana, Oliver; Nachamkin, Eli; Puiahi, Elliot; Kilua, Georgina; Pillay, Allan; Bottomley, Christian; Solomon, Anthony W; Mabey, David C

2016-08-01

Both yaws and trachoma are endemic in the Pacific. Mass treatment with azithromycin is the mainstay of the WHO strategy for both the eradication of yaws and the elimination of trachoma as a public health problem, but the dose recommended for trachoma is lower than that for yaws. In countries where both diseases are endemic, there is a potential for synergy between yaws and trachoma control programs if mass treatment with the lower dose of azithromycin was shown to be effective for the treatment of yaws. In an earlier study, we demonstrated a profound reduction in the clinical and serological prevalence of yaws following a single round of mass treatment with azithromycin 20 mg/kg undertaken for the purposes of trachoma elimination. This survey was conducted 18 months following a single round of azithromycin mass treatment in the same communities in which we had conducted our previous six-month follow-up survey. We examined children aged 1-14 years and took blood and lesion samples for yaws diagnosis using the Treponema pallidum particle agglutination assay (TPPA) and the non-treponemal Rapid Plasma Reagin (RPR) test. A total of 1,284 children were enrolled in the study. Amongst children aged 5-14 years, 223 had a positive TPPA (27.5%, 95% CI 13.6-47.7%). The TPPA seroprevalence amongst this age group did not differ significantly from either our pre-mass treatment survey or our initial follow-up survey. Thirty-five children had positive TPPA and positive RPR (4.3%, 95% CI 2.1-8.7%), and this did not differ significantly from our initial post-mass drug administration (MDA) follow-up survey (4.3% versus 3.5%, p = 0.43) but remained significantly lower than our initial pre-MDA survey (4.3% vs 21.7%, p <0.0001). Village-level MDA coverage was strongly associated with dual-seropositivity (p = 0.005). Amongst children aged 1-4 years, 16 had a positive TPPA (3.5%, 95% CI 1.6-7.1%). This did not differ significantly from the seroprevalence in this age group that had been

Cephalosporin-3'-Diazeniumdiolate NO Donor Prodrug PYRRO-C3D Enhances Azithromycin Susceptibility of Nontypeable Haemophilus influenzae Biofilms.

PubMed

Collins, Samuel A; Kelso, Michael J; Rineh, Ardeshir; Yepuri, Nageshwar R; Coles, Janice; Jackson, Claire L; Halladay, Georgia D; Walker, Woolf T; Webb, Jeremy S; Hall-Stoodley, Luanne; Connett, Gary J; Feelisch, Martin; Faust, Saul N; Lucas, Jane S A; Allan, Raymond N

2017-02-01

PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO) donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against nontypeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free liquid chromatography-mass spectrometry (LC/MS) proteomic analyses were performed to identify differentially expressed proteins following NO treatment. PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking β-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log fold reduction (10-fold reduction or 1-log-unit reduction) in viability (P < 0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log-unit reduction was observed (P < 0.01). Label-free proteomics showed that NO increased expression of 16 proteins involved in metabolic and transcriptional/translational functions. NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm-associated antibiotic tolerance. Copyright © 2017 American Society for Microbiology.

Stress Hormone Cortisol Enhances Bcl2 Like-12 Expression to Inhibit p53 in Hepatocellular Carcinoma Cells.

PubMed

Wu, Weizhong; Liu, Sanguang; Liang, Yunfei; Zhou, Zegao; Bian, Wei; Liu, Xueqing

2017-12-01

The pathogenesis of hepatocellular carcinoma (HC) is unclear. It is suggested that psychological stress associates with the pathogenesis of liver cancer. Bcl2-like protein 12 (Bcl2L12) suppresses p53 protein. This study tests a hypothesis that the major stress hormone, cortisol, inhibits the expression of p53 in HC cells (HCC) via up regulating the expression of Bcl2L12. Peripheral blood samples were collected from patients with HC to be analyzed for the levels of cortisol. HCC were cultured to assess the role of cortisol in the regulation of the expression of Bcl2L12 and p53 in HCC. We observed that the serum cortisol levels were higher in HC patients. Expression of Bcl2L12 in HCC was correlated with serum cortisol. Cortisol enhanced the Bcl2L12 expression in HCC. Bcl2L12 binding to the TP53 promoter was correlated with p53 expression in HCC. Cortisol increased the Bcl2L12 expression in HCC to inhibit p53 expression. Stress hormone cortisol suppresses p53 in HCC via enhancing Bcl2L12 expression in HCC. The results suggest that cortisol may be a therapeutic target for the treatment of HC.

Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia.

PubMed

Kellum, John A; Song, Mingchen; Venkataraman, Ramesh

2004-03-01

Previous studies have shown that inflammatory mediators can be removed from the circulation with hemofiltration and that adsorption plays an important role. Because adsorptive capacity of hollow-fiber dialyzers is limited, we sought to determine whether hemoadsorption using high surface area beads would result in greater mediator removal and improved survival in experimental sepsis. Randomized controlled laboratory experiment. University laboratory. Sixty-six adult Sprague-Dawley rats. We conducted two ex vivo and two in vivo experiments. For in vivo experiments, we administered Escherichia coli endotoxin (20 mg/kg) by intravenous infusion and then randomized each animal to receive either hemoadsorption or a sham circuit for 4 hrs. Hemoadsorption was performed for 4 hrs using an arterial-venous circuit and a CytoSorb cartridge containing 10 g of polystyrene divinyl benzene copolymer beads with a biocompatible polyvinylpyrrolidone coating. Survival time was measured to a maximum of 12 hrs. In a separate set of experiments, we studied 12 animals using the same protocol except that we killed all animals at 4 hrs and removed standardized sections of liver for analysis of nuclear factor-kappaB DNA binding. Mean survival time among hemoadsorption-treated animals was 629+/-114 vs. 518+/-120 mins for sham-treated animals (p <.01). Overall survival (defined at 12 hrs) was also significantly better in the hemoadsorption group, seven of 20 vs. one of 20 (p <.05). Plasma interleukin-6 and interleukin-10 concentrations and liver nuclear factor-kappaB DNA binding were significantly reduced by hemoadsorption. Ex vivo experiments showed no endotoxin adsorption but strengthened our in vivo observations by showing rapid adsorption of tumor necrosis factor, interleukin-6, and interleukin-10. Hemoadsorption was associated with reduced inflammation and improved survival in this murine model of septic shock.

Rosmarinus officinalis Extract Suppresses Propionibacterium acnes–Induced Inflammatory Responses

PubMed Central

Tsai, Tsung-Hsien; Chuang, Lu-Te; Lien, Tsung-Jung; Liing, Yau-Rong; Chen, Wei-Yu

2013-01-01

Abstract Propionibacterium acnes is a key pathogen involved in the progression of acne inflammation. The development of a new agent possessing antimicrobial and anti-inflammatory activity against P. acnes is therefore of interest. In this study, we investigated the inhibitory effect of rosemary (Rosmarinus officinalis) extract on P. acnes–induced inflammation in vitro and in vivo. The results showed that ethanolic rosemary extract (ERE) significantly suppressed the secretion and mRNA expression of proinflammatory cytokines, including interleukin (IL)-8, IL-1β, and tumor necrosis factor-α in P. acnes–stimulated monocytic THP-1 cells. In an in vivo mouse model, concomitant intradermal injection of ERE attenuated the P. acnes–induced ear swelling and granulomatous inflammation. Since ERE suppressed the P. acnes–induced nuclear factor kappa-B (NF-κB) activation and mRNA expression of Toll-like receptor (TLR) 2, the suppressive effect of ERE might be due, at least partially, to diminished NF-κB activation and TLR2-mediated signaling pathways. Furthermore, three major constituents of ERE, carnosol, carnosic acid, and rosmarinic acid, exerted different immumodulatory activities in vitro. In brief, rosmarinic acid significantly suppressed IL-8 production, while the other two compounds inhibited IL-1β production. Further study is needed to explore the role of bioactive compounds of rosemary in mitigation of P. acnes–induced inflammation. PMID:23514231

Development, in vitro and in vivo evaluation of novel injectable smart gels of azithromycin for chronic periodontitis.

PubMed

Venkatesh, M P; Kumar, T M Pramod; Avinash, B S; Kumar, G Sheela

2013-04-01

Periodontitis is an inflammatory condition affecting teeth resulting in progressive destruction of periodontal ligaments, resorption of alveolar bone and loss of teeth. Treatment of periodontitis includes surgical and non surgical management. Systemic antibiotics are also used for the treatment of periodontitis. The aim of this research was to formulate smart gel system of azithromycin (AZT) and to evaluate in vitro and in vivo for non-surgical treatment of chronic periodontitis. Azithromycin dihydrate, used systemically in the treatment of periodontitis, was formulated into smart gels using biodegradable, thermosensitive polymer Pluronic® F-127 (PF-127) and Hydroxy Ethyl Cellulose (HEC) as copolymer. The prepared smart gels were evaluated for sterility, content uniformity, gelation temperature and time, syringeability, rheological behavior, in vitro diffusion and in vivo efficacy in human patients. The prepared smart gels were clear and transparent, sterile, thermoresponsive and injectable. Viscosity of gels increased with increase in concentration of polymer/co-polymer and also with temperature. They gelled in short response time below the body temperature. In vitro release studies showed controlled drug release which was influenced significantly by the properties and concentration of PF-127 and HEC. In vivo efficacy studies showed a significant improvement (p <0.001) in clinical parameters such as gingival index, probing pocket depth, clinical attachment level, bleeding index and plaque index. The developed azithromycin smart gel system is a novel approach for the treatment of chronic periodontitis since it reduces the dose and side effects, bypasses the usual surgical procedures and improves patient compliance.

Activation and cytokine profile of monocyte derived dendritic cells in leprosy: in vitro stimulation by sonicated Mycobacterium leprae induces decreased level of IL-12p70 in lepromatous leprosy.

PubMed

Braga, André Flores; Moretto, Daniela Ferraz; Gigliotti, Patrícia; Peruchi, Mariela; Vilani-Moreno, Fátima Regina; Campanelli, Ana Paula; Latini, Ana Carla Pereira; Iyer, Anand; Das, Pranab Kumar; Souza, Vânia Nieto Brito de

2015-08-01

Dendritic cells (DCs) play a pivotal role in the connection of innate and adaptive immunity of hosts to mycobacterial infection. Studies on the interaction of monocyte-derived DCs (MO-DCs) using Mycobacterium leprae in leprosy patients are rare. The present study demonstrated that the differentiation of MOs to DCs was similar in all forms of leprosy compared to normal healthy individuals. In vitro stimulation of immature MO-DCs with sonicated M. leprae induced variable degrees of DC maturation as determined by the increased expression of HLA-DR, CD40, CD80 and CD86, but not CD83, in all studied groups. The production of different cytokines by the MO-DCs appeared similar in all of the studied groups under similar conditions. However, the production of interleukin (IL)-12p70 by MO-DCs from lepromatous (LL) leprosy patients after in vitro stimulation with M. leprae was lower than tuberculoid leprosy patients and healthy individuals, even after CD40 ligation with CD40 ligand-transfected cells. The present cumulative findings suggest that the MO-DCs of LL patients are generally a weak producer of IL-12p70 despite the moderate activating properties ofM. leprae. These results may explain the poor M. leprae-specific cell-mediated immunity in the LL type of leprosy.

Transverse momentum and centrality dependence of high-pT nonphotonic electron suppression in Au+Au collisions at sqrt[s NN]=200 GeV.

PubMed

Abelev, B I; Aggarwal, M M; Ahammed, Z; Anderson, B D; Arkhipkin, D; Averichev, G S; Bai, Y; Balewski, J; Barannikova, O; Barnby, L S; Baudot, J; Baumgart, S; Belaga, V V; Bellingeri-Laurikainen, A; Bellwied, R; Benedosso, F; Betts, R R; Bhardwaj, S; Bhasin, A; Bhati, A K; Bichsel, H; Bielcik, J; Bielcikova, J; Bland, L C; Blyth, S-L; Bombara, M; Bonner, B E; Botje, M; Bouchet, J; Brandin, A V; Bravar, A; Burton, T P; Bystersky, M; Cadman, R V; Cai, X Z; Caines, H; Calderón de la Barca Sánchez, M; Callner, J; Catu, O; Cebra, D; Chajecki, Z; Chaloupka, P; Chattopadhyay, S; Chen, H F; Chen, J H; Chen, J Y; Cheng, J; Cherney, M; Chikanian, A; Christie, W; Chung, S U; Coffin, J P; Cormier, T M; Cosentino, M R; Cramer, J G; Crawford, H J; Das, D; Dash, S; Daugherity, M; de Moura, M M; Dedovich, T G; Dephillips, M; Derevschikov, A A; Didenko, L; Dietel, T; Djawotho, P; Dogra, S M; Dong, X; Drachenberg, J L; Draper, J E; Du, F; Dunin, V B; Dunlop, J C; Dutta Mazumdar, M R; Eckardt, V; Edwards, W R; Efimov, L G; Emelianov, V; Engelage, J; Eppley, G; Erazmus, B; Estienne, M; Fachini, P; Fatemi, R; Fedorisin, J; Feng, A; Filip, P; Finch, E; Fine, V; Fisyak, Y; Fu, J; Gagliardi, C A; Gaillard, L; Ganti, M S; Garcia-Solis, E; Ghazikhanian, V; Ghosh, P; Gorbunov, Y G; Gos, H; Grebenyuk, O; Grosnick, D; Guertin, S M; Guimaraes, K S F F; Gupta, N; Haag, B; Hallman, T J; Hamed, A; Harris, J W; He, W; Heinz, M; Henry, T W; Heppelmann, S; Hippolyte, B; Hirsch, A; Hjort, E; Hoffman, A M; Hoffmann, G W; Hofman, D; Hollis, R; Horner, M J; Huang, H Z; Hughes, E W; Humanic, T J; Igo, G; Iordanova, A; Jacobs, P; Jacobs, W W; Jakl, P; Jia, F; Jones, P G; Judd, E G; Kabana, S; Kang, K; Kapitan, J; Kaplan, M; Keane, D; Kechechyan, A; Kettler, D; Khodyrev, V Yu; Kim, B C; Kiryluk, J; Kisiel, A; Kislov, E M; Klein, S R; Knospe, A G; Kocoloski, A; Koetke, D D; Kollegger, T; Kopytine, M; Kotchenda, L; Kouchpil, V; Kowalik, K L; Kravtsov, P; Kravtsov, V I; Krueger, K; Kuhn, C; Kulikov, A I; Kumar, A; Kurnadi, P; Kuznetsov, A A; Lamont, M A C; Landgraf, J M; Lange, S; Lapointe, S; Laue, F; Lauret, J; Lebedev, A; Lednicky, R; Lee, C-H; Lehocka, S; LeVine, M J; Li, C; Li, Q; Li, Y; Lin, G; Lin, X; Lindenbaum, S J; Lisa, M A; Liu, F; Liu, H; Liu, J; Liu, L; Ljubicic, T; Llope, W J; Longacre, R S; Love, W A; Lu, Y; Ludlam, T; Lynn, D; Ma, G L; Ma, J G; Ma, Y G; Magestro, D; Mahapatra, D P; Majka, R; Mangotra, L K; Manweiler, R; Margetis, S; Markert, C; Martin, L; Matis, H S; Matulenko, Yu A; McClain, C J; McShane, T S; Melnick, Yu; Meschanin, A; Millane, J; Miller, M L; Minaev, N G; Mioduszewski, S; Mironov, C; Mischke, A; Mitchell, J; Mohanty, B; Morozov, D A; Munhoz, M G; Nandi, B K; Nattrass, C; Nayak, T K; Nelson, J M; Nepali, N S; Netrakanti, P K; Nogach, L V; Nurushev, S B; Odyniec, G; Ogawa, A; Okorokov, V; Oldenburg, M; Olson, D; Pachr, M; Pal, S K; Panebratsev, Y; Pavlinov, A I; Pawlak, T; Peitzmann, T; Perevoztchikov, V; Perkins, C; Peryt, W; Phatak, S C; Planinic, M; Pluta, J; Poljak, N; Porile, N; Poskanzer, A M; Potekhin, M; Potrebenikova, E; Potukuchi, B V K S; Prindle, D; Pruneau, C; Putschke, J; Qattan, I A; Raniwala, R; Raniwala, S; Ray, R L; Relyea, D; Ridiger, A; Ritter, H G; Roberts, J B; Rogachevskiy, O V; Romero, J L; Rose, A; Roy, C; Ruan, L; Russcher, M J; Sahoo, R; Sakrejda, I; Sakuma, T; Salur, S; Sandweiss, J; Sarsour, M; Sazhin, P S; Schambach, J; Scharenberg, R P; Schmitz, N; Seger, J; Selyuzhenkov, I; Seyboth, P; Shabetai, A; Shahaliev, E; Shao, M; Sharma, M; Shen, W Q; Shimanskiy, S S; Sichtermann, E P; Simon, F; Singaraju, R N; Smirnov, N; Snellings, R; Sorensen, P; Sowinski, J; Speltz, J; Spinka, H M; Srivastava, B; Stadnik, A; Stanislaus, T D S; Staszak, D; Stock, R; Strikhanov, M; Stringfellow, B; Suaide, A A P; Suarez, M C; Subba, N L; Sumbera, M; Sun, X M; Sun, Z; Surrow, B; Symons, T J M; Szanto de Toledo, A; Takahashi, J; Tang, A H; Tarnowsky, T; Thomas, J H; Timmins, A R; Timoshenko, S; Tokarev, M; Trainor, T A; Trentalange, S; Tribble, R E; Tsai, O D; Ulery, J; Ullrich, T; Underwood, D G; Van Buren, G; van der Kolk, N; van Leeuwen, M; Vander Molen, A M; Varma, R; Vasilevski, I M; Vasiliev, A N; Vernet, R; Vigdor, S E; Viyogi, Y P; Vokal, S; Voloshin, S A; Waggoner, W T; Wang, F; Wang, G; Wang, J S; Wang, X L; Wang, Y; Watson, J W; Webb, J C; Westfall, G D; Wetzler, A; Whitten, C; Wieman, H; Wissink, S W; Witt, R; Wu, J; Wu, Y; Xu, N; Xu, Q H; Xu, Z; Yepes, P; Yoo, I-K; Yue, Q; Yurevich, V I; Zhan, W; Zhang, H; Zhang, W M; Zhang, Y; Zhang, Z P; Zhao, Y; Zhong, C; Zhou, J; Zoulkarneev, R; Zoulkarneeva, Y; Zubarev, A N; Zuo, J X

2007-05-11

The STAR collaboration at the BNL Relativistic Heavy-Ion Collider (RHIC) reports measurements of the inclusive yield of nonphotonic electrons, which arise dominantly from semileptonic decays of heavy flavor mesons, over a broad range of transverse momenta (1.2<p(T)<10 GeV/c) in p+p, d+Au, and Au+Au collisions at sqrt[s_{NN}]=200 GeV. The nonphotonic electron yield exhibits an unexpectedly large suppression in central Au+Au collisions at high p(T), suggesting substantial heavy-quark energy loss at RHIC. The centrality and p(T) dependences of the suppression provide constraints on theoretical models of suppression.

Suppression of experimental myasthenia gravis, a B cell-mediated autoimmune disease, by blockade of IL-18.

PubMed

Im, S H; Barchan, D; Maiti, P K; Raveh, L; Souroujon, M C; Fuchs, S

2001-10-01

Interleukin-18 (IL-18) is a pleiotropic proinflammatory cytokine that plays an important role in interferon gamma (IFN-gamma) production and IL-12-driven Th1 phenotype polarization. Increased expression of IL-18 has been observed in several autoimmune diseases. In this study we have analyzed the role of IL-18 in an antibody-mediated autoimmune disease and elucidated the mechanisms involved in disease suppression mediated by blockade of IL-18, using experimental autoimmune myasthenia gravis (EAMG) as a model. EAMG is a T cell-regulated, antibody-mediated autoimmune disease in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1- and Th2-type responses are both implicated in EAMG development. We show that treatment by anti-IL-18 during ongoing EAMG suppresses disease progression. The protective effect can be adoptively transferred to naive recipients and is mediated by increased levels of the immunosuppressive Th3-type cytokine TGF-beta and decreased AChR-specific Th1-type cellular responses. Suppression of EAMG is accompanied by down-regulation of the costimulatory factor CD40L and up-regulation of CTLA-4, a key negative immunomodulator. Our results suggest that IL-18 blockade may potentially be applied for immunointervention in myasthenia gravis.

Regulation of interleukin-1beta and interleukin-8 production by agonists of mu and delta opiate receptors in vitro.

PubMed

Gein, S V; Gorshkova, K G; Tendryakova, S P

2009-07-01

The studies reported here showed that beta-endorphin at concentrations of 10(-7)-10(-11) M increased interleukin-1beta (IL-1beta) production in unfractionated leukocyte suspensions both in the presence of 0.1 microg/ml lipopolysaccharide (LPS) and in cultures not stimulated with LPS. Interleukin-8 (IL-8) production by leukocytes was inhibited by beta-endorphin at concentrations of 10(-7) and 10(-11) M in the presence of LPS. The stimulatory effect of beta-endorphin on IL-1beta production was not blocked by naloxone or naltrindole. Suppression of IL-8 production was blocked by naloxone and naltrindole. In the mononuclear cell and neutrophil fractions, beta-endorphin and the delta agonist DADLE increased IL-1beta synthesis in both the spontaneous and stimulated versions of the test, while beta-endorphin and the delta agonist DADLE inhibited IL-8 production in the mononuclear cell and neutrophil fractions only in LPS-stimulated cultures. The mu agonist DAGO had no effect on IL-1beta production by mononuclear cells or neutrophils, though it suppressed LPS-induced secretion of IL-8 by neutrophils.

Treatment of psoriasis with interleukin-12/23 monoclonal antibody: a systematic review.

PubMed

Wu, Yan; Chen, Jing; Li, Yuan-Hong; Ma, Guo-Zhang; Chen, John Z S; Gao, Xing-Hua; Chen, Hong-Duo

2012-01-01

To systematically review the efficacy and safety of interleukin-12/23 monoclonal antibody (IL-12/23 mAb) on psoriasis. Relevant randomized controlled trials (RCTs) were identified by systematic literature searches in MEDLINE, OVID, EMBASE, Cochrane Library, and the metaRegister of Controlled Trials. The efficacy outcomes and adverse effects of included RCTs were critically assessed. A total of 3365 participants in 5 multicenter RCTs were included. The RRs of most efficacy outcomes showed significant differences between i) IL-12/23 mAb and placebo at week 12/16; ii) IL-12/23 mAb and etanercept at week 12; iii) IL-12/23 mAb in high dose and IL-12/23 mAb in low dose at week 24/28. Increasing treatment times did not obviously provide additional benefit to efficacy improvement. The adverse events of IL-12/23 mAb were similar to those of controls. Antibodies to IL-12/23 mAb were mostly undetected or shown at low titer. Treatment with IL-12/23 mAb did not influence related biochemical markers. IL-12/23 mAb was effective in the treatment of psoriasis on skin lesions, health-related quality of life and psoriatic arthritis in the short-term. The increase in treatment time points was not associated with additional efficacy and dose-dependence was observed with the ongoing treatment up to week 24/28. The adverse effects were minimal and tolerable.

Interleukin-12 up-regulates perforin- and Fas-mediated lymphokine-activated killer activity by intestinal intraepithelial lymphocytes

PubMed Central

EBERT, E C

2004-01-01

Human intraepithelial lymphocytes (IELs) comprise a unique compartment of memory T cell receptor (TCR)-αβ+CD8+ T lymphocytes interspersed between intestinal epithelial cells. They develop potent lymphokine-activated killer (LAK) activity with interleukin (IL)-15, a cytokine that is found in excess in certain mucosal inflammatory states. IL-12, released by activated antigen-presenting cells, is known to potentiate perforin-induced cytotoxicity. This study evaluates the mechanism by which IL-12 up-regulates LAK activity. When IELs were stimulated with IL-15, the CD94+ IEL subset expanded and carried out cytotoxic activity in redirected lysis against P815 cells as well as Fas ligand (FL)- and tumour necrosis factor (TNF)-α-mediated lysis of Jurkat and WEHI cells, respectively. IL-12 enhanced the perforin- and FL-, but not TNF-α-mediated events. In addition, the up-regulated killing of HT-29 cells by IL-12 was reduced by concanamycin (which targets perforin) and antibody neutralizing FL but not by anti-TNF-α antibody. Furthermore, IL-12 augmented IL-15-stimulated release of serine esterases as well as expression of perforin and FL by IELs, but not TNF-α. This study shows that LAK activity, carried out by the CD94+ IELs, involves perforin, FL and TNF-α. IL-12 up-regulates the first two mechanisms of action, showing for the first time its effect on FL production and lytic activity. PMID:15498035

The efficacy of azithromycin and doxycycline for the treatment of rectal chlamydia infection: a systematic review and meta-analysis.

PubMed

Kong, Fabian Yuh Shiong; Tabrizi, Sepehr N; Fairley, Christopher Kincaid; Vodstrcil, Lenka A; Huston, Wilhelmina M; Chen, Marcus; Bradshaw, Catriona; Hocking, Jane S

2015-05-01

There are increasing concerns about treatment failure following treatment for rectal chlamydia with 1 g of azithromycin. A systematic review and meta-analysis was conducted to investigate the efficacy of 1 g of azithromycin as a single dose or 100 mg of doxycycline twice daily for 7 days for the treatment of rectal chlamydia. Medline, Embase, PubMed, Cochrane Controlled Trials Register, Australia New Zealand Clinical Trial Register and ClinicalTrials.gov were searched to the end of April 2014. Studies using 1 g of azithromycin or 7 days of doxycycline for the treatment of rectal chlamydia were eligible. Gender, diagnostic test, serovar, symptomatic status, other sexually transmitted infections, follow-up time, attrition and microbial cure were extracted. Meta-analysis was used to calculate pooled (i) azithromycin and doxycycline efficacy and (ii) efficacy difference. All eight included studies were observational. The random-effects pooled efficacy for azithromycin (based on eight studies) was 82.9% (95% CI 76.0%-89.8%; I(2) = 71.0%; P < 0.01) and for doxycycline (based on five studies) was 99.6% (95% CI 98.6%-100%; I(2) = 0%; P = 0.571), resulting in a random-effects pooled efficacy difference (based on five studies) of 19.9% (95% CI 11.4%-28.3%; I(2) = 48.5%; P = 0.101) in favour of doxycycline. The efficacy of single-dose azithromycin may be considerably lower than 1 week of doxycycline for treating rectal chlamydia. However, the available evidence is very poor. Robust randomized controlled trials are urgently required. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Shigella species epidemiology and antimicrobial susceptibility: the implications of emerging azithromycin resistance for guiding treatment, guidelines and breakpoints.

PubMed

Brown, Jeremy D; Willcox, Simon J; Franklin, Neil; Hazelton, Briony; Howard, Peter; Reinten, Tracie; Sheppeard, Vicky; O'Sullivan, Matthew

2017-11-01

To examine antimicrobial susceptibility patterns and predictors of resistance among Shigella isolates in New South Wales (NSW), Australia during 2013-14 with emphasis on azithromycin. Cross-sectional analysis of all shigellosis cases (160) notified to public health authorities in NSW, Australia was performed. Among 160 Shigella isolates tested, 139 (86.9%) were susceptible to azithromycin, 104 (65.0%) to ciprofloxacin and 38 (23.7%) to co-trimoxazole. Ciprofloxacin resistance was 1.9 times more common in infections acquired in Australia compared with those acquired overseas, while azithromycin resistance was 8.5 times more common in males. We recommend ongoing reconsideration of guidelines for the treatment of shigellosis based on emerging resistance patterns. First-line therapy may need to be reconsidered based on local resistance rates due to common resistance to co-trimoxazole and ciprofloxacin. We recommend culture and susceptibility testing for suspected and proven shigellosis. Azithromycin susceptibility breakpoints for Shigella species may need to be species specific. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.

PubMed

Viscardi, Rose M; Othman, Ahmed A; Hassan, Hazem E; Eddington, Natalie D; Abebe, Elias; Terrin, Michael L; Kaufman, David A; Waites, Ken B

2013-05-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial

Azithromycin To Prevent Bronchopulmonary Dysplasia in Ureaplasma-Infected Preterm Infants: Pharmacokinetics, Safety, Microbial Response, and Clinical Outcomes with a 20-Milligram-per-Kilogram Single Intravenous Dose

PubMed Central

Othman, Ahmed A.; Hassan, Hazem E.; Eddington, Natalie D.; Abebe, Elias; Terrin, Michael L.; Kaufman, David A.; Waites, Ken B.

2013-01-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)0.75 [WT(kg)0.75 indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)0.75; central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance

CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression.

PubMed

Honey, K; Cobbold, S P; Waldmann, H

1999-11-01

The CD40-CD40 ligand (CD40L) interaction is a key event in the initiation of an adaptive immune response, and as such the therapeutic value of CD40L blockade has been studied in many experimental models of tissue transplantation and autoimmune disease. In rodents, transplantation of allogeneic tissues under the cover of anti-CD40L Abs has resulted in prolonged graft survival but not tolerance. In this report, we show that failure to induce tolerance probably results from the inability of anti-CD40L Abs to prevent graft rejection elicited by the CD8+ T cell subset. When the CD8+ T cell population is controlled independently, using anti-CD8 Abs, then tolerance is possible. Transplantation tolerance induced by anti-CD4 mAbs can often be associated with dominant regulation, manifested as infectious tolerance and linked suppression, both of which are mediated by CD4+ T cells. We show here that CD4+ T cells rendered tolerant using anti-CD40L therapy exhibit the same regulatory property of linked suppression, as demonstrated by their ability to accept grafts expressing third party Ags only if they are expressed in conjunction with the tolerated Ags. This observation of linked suppression reveals a hitherto undocumented consequence of CD40L blockade that suggests the tolerant state is maintained by a dominant regulatory mechanism. Our results suggest that, although anti-CD40L Abs are attractive clinical immunotherapeutic agents, additional therapies to control aggressive CD8+ T cell responses may be required.

Suppressive effects of retinoids, carotenoids and antioxidant vitamins on heterocyclic amine-induced umu C gene expression in Salmonella typhimurium (TA 1535/pSK 1002).

PubMed

Okai, Y; Higashi-Okai, K; Nakamura, S; Yano, Y; Otani, S

1996-06-12

Effects of retinoids, carotenoids and antioxidant vitamins were studied by mutagen-induced umu C gene expression system in Salmonella typhimurium (TA 1535/pSK 1002). Retinol (vitamin A), retinol acetate and retinoic acid showed remarkable inhibitory activities, whereas retinol palmitate exhibited significant but weak activity for umu C gene expression in tester bacteria induced by 3-amino-3,4-dimethyl-5H-pyrido[4.3-b]indol (Trp-P-1) in the presence of hepatic metabolizing enzymes (S9 mixture). Carotenoids having provitamin A activity (beta-carotene and canthaxanthin) exhibited moderate suppressive effects on the same experimental system. The ranks of suppressive activities were retinol > retinol acetate > retinoic acid > canthaxanthin > beta-carotene > retinol palmitate and their doses for inhibition by 50% (ID50) were estimated to be 1.2 x 10(-7), 3.0 x 10(-7), 5.4 x 10(-7), 1.5 x 10(-6), 4.0 x 10(-5) and 6.0 x 10(-5) M, respectively. However, they did not cause significant inhibition on umu C gene expression induced by direct-acting mutagen (adriamycin or mitomycin C) in the absence of S9 mixture. Inhibition of umu gene expression appears to be due to inhibition of P450-mediated metabolic activation of the heterocyclic amine Trp-P-1. Ascorbic acid (vitamin C) showed weak but significant suppressive activity at high-dose concentrations (3 x 10(-6) - 10(-4)M). However, alpha-tocopherol did not exhibit significant suppression at all dose concentrations. The significance of the experimental results is discussed from the viewpoint of the chemoprevention against genotoxicity associated with carcinogenesis.

Helicobacter pylori neutrophil-activating protein induces release of histamine and interleukin-6 through G protein-mediated MAPKs and PI3K/Akt pathways in HMC-1 cells.

PubMed

Tsai, Chung-Che; Kuo, Ting-Yu; Hong, Zhi-Wei; Yeh, Ying-Chieh; Shih, Kuo-Shun; Du, Shin-Yi; Fu, Hua-Wen

2015-01-01

Helicobacter pylori neutrophil-activating protein (HP-NAP) activates several innate leukocytes including neutrophils, monocytes, and mast cells. It has been reported that HP-NAP induces degranulation and interleukin-6 (IL-6) secretion of rat peritoneal mast cells. However, the molecular mechanism is not very clear. Here, we show that HP-NAP activates human mast cell line-1 (HMC-1) cells to secrete histamine and IL-6. The secretion depends on pertussis toxin (PTX)-sensitive heterotrimeric G proteins but not on Toll-like receptor 2. Moreover, HP-NAP induces PTX-sensitive G protein-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38 MAPK), and Akt in HMC-1 cells. Inhibition of ERK1/2, p38 MAPK, or phosphatidylinositol 3-kinase (PI3K) suppresses HP-NAP-induced release of histamine and IL-6 from HMC-1 cells. Thus, the activation of HMC-1 cells by HP-NAP is through Gi-linked G protein-coupled receptor-mediated MAPKs and PI3K/Akt pathways.

Moxibustion inhibits interleukin-12 and tumor necrosis factor alpha and modulates intestinal flora in rat with ulcerative colitis

PubMed Central

Wang, Xiao-Mei; Lu, Yuan; Wu, Lu-Yi; Yu, Shu-Guang; Zhao, Bai-Xiao; Hu, Hong-Yi; Wu, Huan-Gan; Bao, Chun-Hui; Liu, Hui-Rong; Wang, Jin-Hai; Yao, Yi; Hua, Xue-Gui; Guo, Hui-Ying; Shen, Li-Rong

2012-01-01

AIM: To investigate the effect of moxibustion on intestinal flora and release of interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α) from the colon in rat with ulcerative colitis (UC). METHODS: A rat model of UC was established by local stimulation of the intestine with supernatant from colonic contents harvested from human UC patients. A total of 40 male Sprague-Dawley rats were randomly divided into the following groups: normal (sham), model (UC), herb-partition moxibustion (HPM-treated), and positive control sulfasalazine (SA-treated). Rats treated with HPM received HPM at acupuncture points ST25 and RN6, once a day for 15 min, for a total of 8 d. Rats in the SA group were perfused with SA twice a day for 8 d. The colonic histopathology was observed by hematoxylin-eosin. The levels of intestinal flora, including Bifidobacterium, Lactobacillus, Escherichia coli (E. coli), and Bacteroides fragilis (B. fragilis), were tested by real-time quantitative polymerase chain reaction to detect bacterial 16S rRNA/DNA in order to determine DNA copy numbers of each specific species. Immunohistochemical assays were used to observe the expression of TNF-α and IL-12 in the rat colons. RESULTS: HPM treatment inhibited immunopathology in colonic tissues of UC rats; the general morphological score and the immunopathological score were significantly decreased in the HPM and SA groups compared with the model group [3.5 (2.0-4.0), 3.0 (1.5-3.5) vs 6.0 (5.5-7.0), P < 0.05 for the general morphological score, and 3.00 (2.00-3.50), 3.00 (2.50-3.50) vs 5.00 (4.50-5.50), P < 0.01 for the immunopathological score]. As measured by DNA copy number, we found that Bifidobacterium and Lactobacillus, which are associated with a healthy colon, were significantly higher in the HPM and SA groups than in the model group (1.395 ± 1.339, 1.461 ± 1.152 vs 0.045 ± 0.036, P < 0.01 for Bifidobacterium, and 0.395 ± 0.325, 0.851 ± 0.651 vs 0.0015 ± 0.0014, P < 0.01 for Lactobacillus). On the

Interleukin-2 therapy reverses some immunosuppressive effects of skeletal unloading

NASA Technical Reports Server (NTRS)

Armstrong, Jason W.; Balch, Signe; Chapes, Stephen K.

1994-01-01

Using antiorthostatic suspension, we characterized hematopoietic changes that may be responsible for the detrimental effect of skeletal unloading on macrophage development. Skeletally unloaded mice had suppressed macrophage development in unloaded and loaded bones, which indicated a systemic effect. Bone marrow cells from unloaded mice secreted less macrophage colony-stimulating factor and interleukin-6 than control mice. Additionally, T-lymphocyte proliferation was reduced after skeletal unloading. We show that polyethylene glycol-interleukin-2 therapy reversed the effects of skeletal unloading on macrophage development and cell proliferation.

Transcutaneous electrical nerve stimulation attenuates postsurgical allodynia and suppresses spinal substance P and proinflammatory cytokine release in rats.

PubMed

Chen, Yu-Wen; Tzeng, Jann-Inn; Lin, Min-Fei; Hung, Ching-Hsia; Wang, Jhi-Joung

2015-01-01

Transcutaneous electrical nerve stimulation (TENS) is often used for management of chronic pain. The purpose of this study was to investigate whether TENS altered postincisional allodynia, substance P, and proinflammatory cytokines in a rat model of skin-muscle incision and retraction (SMIR). This was an experimental study. High-frequency (100-Hz) TENS therapy began on postoperative day 3 and was administered for 20 minutes daily to SMIR-operated rats by self-adhesive electrodes delivered to skin innervated via the ipsilateral dorsal rami of lumbar spinal nerves L1-L6 for the next 27 days. The expressions of substance P, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β) in the spinal cord and mechanical sensitivity to von Frey stimuli (4g and 10g) were evaluated. The SMIR-operated rats displayed a marked hypersensitivity to von Frey stimuli on postoperative day 3. In contrast to the SMIR-operated rats, SMIR-operated rats after TENS administration showed a quick recovery of mechanical hypersensitivity. On postoperative days 3, 16, and 30, SMIR-operated rats exhibited an upregulation of substance P and cytokines (TNF-α, IL-6, and IL-1β) in the spinal cord, whereas SMIR-operated rats after TENS therapy inhibited that upregulation. By contrast, the placebo TENS following SMIR surgery did not alter mechanical hypersensitivity and the levels of spinal substance P, TNF-α, IL-6, and IL-1β. The experimental data are limited to animal models and cannot be generalized to postoperative pain in humans. The results revealed that TENS attenuates prolonged postoperative allodynia following SMIR surgery. Increased levels of spinal substance P and proinflammatory cytokines, activated after SMIR surgery, are important in the processing of persistent postsurgical allodynia. The protective effect of TENS may be related to the suppression of spinal substance P and proinflammatory cytokines in SMIR-operated rats. © 2015 American Physical

28 CFR 12.40 - Public examination.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 28 Judicial Administration 1 2011-07-01 2011-07-01 false Public examination. 12.40 Section 12.40 Judicial Administration DEPARTMENT OF JUSTICE REGISTRATION OF CERTAIN PERSONS HAVING KNOWLEDGE OF FOREIGN ESPIONAGE, COUNTERESPIONAGE, OR SABOTAGE MATTERS UNDER THE ACT OF AUGUST 1, 1956 § 12.40 Public examination...

28 CFR 12.40 - Public examination.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 1 2014-07-01 2014-07-01 false Public examination. 12.40 Section 12.40 Judicial Administration DEPARTMENT OF JUSTICE REGISTRATION OF CERTAIN PERSONS HAVING KNOWLEDGE OF FOREIGN ESPIONAGE, COUNTERESPIONAGE, OR SABOTAGE MATTERS UNDER THE ACT OF AUGUST 1, 1956 § 12.40 Public examination...

28 CFR 12.40 - Public examination.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 1 2012-07-01 2012-07-01 false Public examination. 12.40 Section 12.40 Judicial Administration DEPARTMENT OF JUSTICE REGISTRATION OF CERTAIN PERSONS HAVING KNOWLEDGE OF FOREIGN ESPIONAGE, COUNTERESPIONAGE, OR SABOTAGE MATTERS UNDER THE ACT OF AUGUST 1, 1956 § 12.40 Public examination...

28 CFR 12.40 - Public examination.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 1 2013-07-01 2013-07-01 false Public examination. 12.40 Section 12.40 Judicial Administration DEPARTMENT OF JUSTICE REGISTRATION OF CERTAIN PERSONS HAVING KNOWLEDGE OF FOREIGN ESPIONAGE, COUNTERESPIONAGE, OR SABOTAGE MATTERS UNDER THE ACT OF AUGUST 1, 1956 § 12.40 Public examination...

Impaired NFAT and NFκB activation are involved in suppression of CD40 ligand expression by Δ(9)-tetrahydrocannabinol in human CD4(+) T cells.

PubMed

Ngaotepprutaram, Thitirat; Kaplan, Barbara L F; Kaminski, Norbert E

2013-11-15

We have previously reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the main psychoactive cannabinoid in marijuana, suppresses CD40 ligand (CD40L) expression by activated mouse CD4(+) T cells. CD40L is involved in pathogenesis of many autoimmune and inflammatory diseases. In the present study, we investigated the molecular mechanism of Δ(9)-THC-mediated suppression of CD40L expression using peripheral blood human T cells. Pretreatment with Δ(9)-THC attenuated CD40L expression in human CD4(+) T cells activated by anti-CD3/CD28 at both the protein and mRNA level, as determined by flow cytometry and quantitative real-time PCR, respectively. Electrophoretic mobility shift assays revealed that Δ(9)-THC suppressed the DNA-binding activity of both NFAT and NFκB to their respective response elements within the CD40L promoter. An assessment of the effect of Δ(9)-THC on proximal T cell-receptor (TCR) signaling induced by anti-CD3/CD28 showed significant impairment in the rise of intracellular calcium, but no significant effect on the phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β. Collectively, these findings identify perturbation of the calcium-NFAT and NFκB signaling cascade as a key mechanistic event by which Δ(9)-THC suppresses human T cell function. © 2013.

28 CFR 12.40 - Public examination.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Public examination. 12.40 Section 12.40... ESPIONAGE, COUNTERESPIONAGE, OR SABOTAGE MATTERS UNDER THE ACT OF AUGUST 1, 1956 § 12.40 Public examination. Registration statements shall be available for public examination at the offices of the Registration Unit...

A comparative study on the B12N12, Al12N12, B12P12 and Al12P12 fullerene-like cages.

PubMed

Beheshtian, Javad; Bagheri, Zargham; Kamfiroozi, Mohammad; Ahmadi, Ali

2012-06-01

The stability, geometry and electronic structure of the title nanoclusters were compared by using density functional theory (DFT) calculations. Their electrical property analysis showed that the relative magnitude of the HOMO-LUMO gaps (eV) that are average values from the calculated results with five different DFT functionals is as follows: B12N12(7:02)>Al12N12(4.09)>B12P12(3.80)>Al12P12(3.39). Computing the standard enthalpy and the Gibbs free energy of formation, it was found that the B(12)N(12) structure is thermodynamically stable at 298 K and 1 atmosphere of pressure, while the Al(12)N(12) structure may be stable at low temperatures. Due to positive values of change of enthalpy and entropy of formation for both the B(12)P(12) and Al(12)P(12) clusters, it seems that their formation from the consisting atoms is not spontaneous at any temperature.

Antitumour activity mediated by CD4+ cytotoxic T lymphocytes against MHC class II-negative mouse hepatocellular carcinoma induced by dendritic cell vaccine and interleukin-12.

PubMed

Homma, Sadamu; Komita, Hideo; Sagawa, Yukiko; Ohno, Tsuneya; Toda, Gotaro

2005-08-01

When BALA/c mice with BNL hepatocellular carcinoma (HCC) were treated with dendritic cells fused with BNL cells (DC/BNL) and recombinant murine interleukin (IL)-12, tumour development was significantly suppressed, whereas treatment with either DC/BNL or IL-12 alone did not show a tumour-suppressive effect. Antitumour activity induced by DC/BNL + IL-12 was abrogated by depletion of CD4+ T cells, but not by depletion of CD8+ T cells or natural killer cells. Splenic CD4+ T cells and CD8+ T cells from DC/BNL-treated mice showed cytotoxic activity against BNL cells after 3 days of incubation with DC/BNL, although BNL cells do not express major histocompatibility complex (MHC) class II molecules even after treatment with interferon (INF)-gamma. Furthermore, CD4+ T cells killed syngeneic-irrelevant CT26 cells and even allogeneic Hepa1-6 cells. This cytotoxicity was blocked by concanamycin A, but not by an anti-Fas ligand (FasL) monoclonal antibody, indicating that cytotoxic activity was mediated by perforin. Immunofluorescence microscopy demonstrated that abundant CD4+ T cells and MHC class II-positive macrophages, but not CD8(+) T cells, had infiltrated tumour tissue in mice treated with DC/BNL + IL-12. Flow cytometric analysis of tumour-infiltrating cells in mice treated with DC/BNL + IL-12 showed increases in CD4+ T cells and MHC class II+ CD11b+ cells but not in CD8+ T cells or MHC class I+ CD11b+ cells. Our results suggest that, in BNL-bearing mice treated with DC/BNL + IL-12, tumour macrophages activated by INF-gamma produced by IL-12-stimulated T cells might present BNL tumour antigens and activate DC/BNL-primed CD4+ cytotoxic T lymphocytes (CTLs) in a MHC class II-dependent manner, leading to perforin-mediated bystander killing of neighbouring MHC class II-negative tumour cells.

Antitumour activity mediated by CD4+ cytotoxic T lymphocytes against MHC class II-negative mouse hepatocellular carcinoma induced by dendritic cell vaccine and interleukin-12

PubMed Central

Homma, Sadamu; Komita, Hideo; Sagawa, Yukiko; Ohno, Tsuneya; Toda, Gotaro

2005-01-01

When BALA/c mice with BNL hepatocellular carcinoma (HCC) were treated with dendritic cells fused with BNL cells (DC/BNL) and recombinant murine interleukin (IL)-12, tumour development was significantly suppressed, whereas treatment with either DC/BNL or IL-12 alone did not show a tumour-suppressive effect. Antitumour activity induced by DC/BNL + IL-12 was abrogated by depletion of CD4+ T cells, but not by depletion of CD8+ T cells or natural killer cells. Splenic CD4+ T cells and CD8+ T cells from DC/BNL-treated mice showed cytotoxic activity against BNL cells after 3 days of incubation with DC/BNL, although BNL cells do not express major histocompatibility complex (MHC) class II molecules even after treatment with interferon (INF)-γ. Furthermore, CD4+ T cells killed syngeneic-irrelevant CT26 cells and even allogeneic Hepa1-6 cells. This cytotoxicity was blocked by concanamycin A, but not by an anti-Fas ligand (FasL) monoclonal antibody, indicating that cytotoxic activity was mediated by perforin. Immunofluorescence microscopy demonstrated that abundant CD4+ T cells and MHC class II-positive macrophages, but not CD8+ T cells, had infiltrated tumour tissue in mice treated with DC/BNL + IL-12. Flow cytometric analysis of tumour-infiltrating cells in mice treated with DC/BNL + IL-12 showed increases in CD4+ T cells and MHC class II+ CD11b+ cells but not in CD8+ T cells or MHC class I+ CD11b+ cells. Our results suggest that, in BNL-bearing mice treated with DC/BNL + IL-12, tumour macrophages activated by INF-γ produced by IL-12-stimulated T cells might present BNL tumour antigens and activate DC/BNL-primed CD4+ cytotoxic T lymphocytes (CTLs) in a MHC class II-dependent manner, leading to perforin-mediated bystander killing of neighbouring MHC class II-negative tumour cells. PMID:16011514

Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways.

PubMed

Li, Xuelian; Wang, GuoYuan; QiLi, MuGe; Liang, HaiHai; Li, TianShi; E, XiaoQiang; Feng, Ying; Zhang, Ying; Liu, Xiao; Qian, Ming; Xu, BoZhi; Shen, ZhiHang; Gitau, Samuel Chege; Zhao, DanDan; Shan, HongLi

2018-01-01

Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long-term aspirin administration on pressure overload-induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 10 mg·kg-1·day-1 of aspirin for 4 weeks. Masson staining and a collagen content assay were used to detect the effects of aspirin on cardiac fibrosis in vivo and in vitro. Western blot and qRT-PCR were applied to examine the impact of aspirin on extracellular signal-regulated kinases (Erks), p-Akt/β-catenin, SerpinE2, collagen I, and collagen III levels in the mice heart. Aspirin significantly suppressed the expression of α-smooth muscle actin (α-SMA; 1.19±0.19-fold) and collagen I (0.95±0.09-fold) in TAC mice. Aspirin, at doses of 100 and 1000 µM, also significantly suppressed angiotensin II-induced α-SMA and collagen I in cultured CFs. The enhanced phosphorylation of Erk1/2 caused by TAC (p-Erk1, 1.49±0.19-fold; p-Erk2, 1.96±0.68-fold) was suppressed by aspirin (p-Erk1, 1.04±0.15-fold; p-Erk2, 0.87±0.06-fold). SerpinE2 levels were suppressed via the Erk1/2 signalling pathway following treatment with aspirin (1.36±0.12-fold for TAC; 1.06±0.07-fold for aspirin+TAC). The p-Akt and β-catenin levels were also significantly inhibited in vivo and in vitro. Our study reveals a novel mechanism by which aspirin alleviates pressure overload-induced cardiac interstitial fibrosis in TAC mice by suppressing the p-Erk1/2 and p-Akt/β-catenin signalling pathways. © 2018 The Author(s). Published by S. Karger AG, Basel.

MELATONIN-INDUCED SUPPRESSION OF PC12 CELL GROWTH IS MEDIATED BY ITS GI COUPLED TRANSMEMBRANE RECEPTORS. (R826248)

EPA Science Inventory

<p>The effects of pertussis toxin, an uncoupler of Gi protein from adenylate cyclase, and luzindole, a competitive inhibitor of melatonin receptor binding, were examined for their ability to inhibit melatonin-induced suppression of PC12 cell growth. Both agents inhibited the mela...

40 CFR 721.10366 - Benzene, 4-bromo-1,2-dimethyl-.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Benzene, 4-bromo-1,2-dimethyl-. 721... Substances § 721.10366 Benzene, 4-bromo-1,2-dimethyl-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, 4-bromo-1,2-dimethyl-(PMN P-10-76...

40 CFR 721.10366 - Benzene, 4-bromo-1,2-dimethyl-.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Benzene, 4-bromo-1,2-dimethyl-. 721... Substances § 721.10366 Benzene, 4-bromo-1,2-dimethyl-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, 4-bromo-1,2-dimethyl-(PMN P-10-76...

40 CFR 721.10366 - Benzene, 4-bromo-1,2-dimethyl-.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Benzene, 4-bromo-1,2-dimethyl-. 721... Substances § 721.10366 Benzene, 4-bromo-1,2-dimethyl-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzene, 4-bromo-1,2-dimethyl-(PMN P-10-76...

Synergistic stimulation of interleukin 6 release and gene expression by phorbol esters and interleukin 1 beta in rat cortical astrocytes: role of protein kinase C activation and blockade.

PubMed

Grimaldi, M; Arcone, R; Ciliberto, G; Schettini, G

1995-05-01

The involvement of protein kinase C and its interaction with interleukin 1 beta in the control of interleukin 6 release by cortical astrocytes was studied. The blockade of protein kinase C catalytic domain, by staurosporine, as well as the desensitization of protein kinase C by short-term phorbol 12-myristate 13-acetate pretreatment, increased the basal release of interleukin 6 by rat cortical astrocytes, whereas calphostin C, an antagonist of phorbol ester binding on protein kinase C regulatory domain, did not affect the basal release of the cytokine. The activation of protein kinase C by phorbol 12-myristate 13-acetate enhanced concentration- and time-dependently interleukin 6 release. This stimulatory action of phorbol 12-myristate 13-acetate was significantly reduced by staurosporine, by calphostin C and by the desensitization of protein kinase C. Interleukin 1 beta increased interleukin 6 release in a concentration-related manner. Protein kinase C inhibition, by staurosporine or desensitization, potentiated severalfold, whereas calphostin C reduced interleukin 1 beta stimulation of interleukin 6 release. The treatment of cortical astrocytes with both interleukin 1 beta (3 ng/ml) and phorbol 12-myristate 13-acetate (10 nM) caused a synergistic stimulation of interleukin 6 release and its gene expression, an effect that was not relieved by either 20 nM staurospine or by calphostin C but was slightly affected by protein kinase C desensitization. In conclusion, our data show that in rat cortical astrocytes the basal release of interleukin 6 is under a tonic inhibition exerted by a protein kinase C isoform or isoforms sensitive to blockade by staurosporine and desensitization but insensitive to calphostin C.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross section asymmetry of two-body carbon disintegration 12C (γ , p)11B with polarized photons at energy 40-50 MeV

NASA Astrophysics Data System (ADS)

Burdeinyi, D.; Brudvik, J.; Fissum, K.; Ganenko, V.; Hansen, K.; Isaksson, L.; Livingston, K.; Lundin, M.; Nilsson, B.; Schroder, B.

2017-01-01

The cross section asymmetry of 12C (γ ,p01)11B and 12C (γ ,p2-6)11B reactions has been studied at the energy range 40-55 MeV, using linearly polarized tagged photons of the MAX-lab facility. The asymmetry of the 12C (γ ,p01)11B processes, which assume the one-body mechanism of the reaction, is Σ ≈ 0.82 ± 0.05 for photon energies 45-50 MeV. The asymmetry for the 12C (γ ,p2-6)11B reactions, which produce a maximum at excitation energy ∼ 6 MeV, is Σ ≈ 0.53 ± 0.13 for a photon energy 49 MeV. It is close to the asymmetry of reaction of the free deuteron photodisintegration, and can be resulted from the two-body mechanism of the photon absorption.

Features of Postoperative Immune Suppression Are Reversible With Interferon Gamma and Independent of Interleukin-6 Pathways.

PubMed

Longbottom, E Rebecca; Torrance, Hew D T; Owen, Helen C; Fragkou, Paraskevi C; Hinds, Charles J; Pearse, Rupert M; O'Dwyer, Michael J

2016-08-01

The aim of this study was to evaluate the role of interleukin (IL)-6 pathways in postoperative immune suppression and to assess the reversibility of this phenomenon. The postoperative period is characterized by increased IL-6 production and features of immune suppression. In vitro, IL-6 mediates anti-inflammatory effects through inhibition of interferon gamma (IFN-γ) pathways. The significance of the immunomodulatory effects of IL-6 in the clinical setting of postoperative immune suppression remains unclear. Patients over 45 years old undergoing elective surgery, involving the gastrointestinal tract, were recruited. IL-6 levels were assayed using an enzyme linked immunosorbent assay preoperatively, and at 24 and 48 hours. Peripheral blood mononuclear cells from healthy volunteers were cultured in perioperative serum and CD14Human Leukocyte Antigen-DR (HLA-DR) [monocyte HLA-DR (mHLA-DR)] geometric mean florescent intensity was measured in the presence and absence of IL-6 neutralizing antibody and recombinant IFN-γ. Of the 108 patients, 41 developed a postoperative infection. The IL-6 levels increased 19-fold from the preoperative sample to 24 hours postoperatively (P < 0.0001). Higher IL-6 levels at 24 (P = 0.0002) and 48 hours (P = 0.003) were associated with subsequent postoperative infectious complications. mHLA-DR mean florescent intensity fell when healthy peripheral blood mononuclear cells were cultured with postoperative serum compared with preoperative serum (P = 0.008). This decrease was prevented by the presence of IFN-γ in the culture media, but not by the presence of IL-6-neutralizing antibody. IL-6 levels increase after a major surgery and are associated with an increased susceptibility to postoperative infections. Serum obtained from postoperative patients induces an immunosuppressive response, reflected in reduced mHLA-DR levels, mediated through IL-6 independent pathways and is reversible with IFN-γ. These data may have

Interleukin-6 promotes systemic lupus erythematosus progression with Treg suppression approach in a murine systemic lupus erythematosus model.

PubMed

Mao, Xiaoli; Wu, Yunyun; Diao, Huitian; Hao, Jianlei; Tian, Gaofei; Jia, Zhenghu; Li, Zheng; Xiong, Sidong; Wu, Zhenzhou; Wang, Puyue; Zhao, Liqing; Yin, Zhinan

2014-11-01

Our aim is to reveal the role of interleukin 6 (IL-6) in the pathogenesis of systemic lupus erythematosus (SLE) in a murine model of SLE. Normal female C57BL/6 mice were immunized with syngeneic-activated lymphocyte-derived DNA (ALD-DNA) to induce SLE. Non-immunized mice were used as control. SLE-associated markers, including anti-double-stranded DNA (anti-dsDNA) Abs, urine protein, and kidney histopathology, were assayed to ensure the induction of the disease. Compared with control mice, ALD-DNA immunized mice exhibited high levels of anti-dsDNA Abs, IL-6 expression in vivo and in vitro. We also found that IL-6 knockout (IL-6KO) mice were resistant to ALD-DNA-induced SLE. The activation of CD4(+) T cells in immunized IL-6KO mice was lower than in immunized wild-type (Wt) mice. Intracellular cytokine staining showed that Foxp3 expression in immunized IL-6KO mice was higher than in immunized Wt mice, which might be associated with the disease severity. We further discovered that ALD-DNA-stimulated dendritic cells supernatants could result in higher IL-6 and TNF-α expression and could suppress Foxp3 expression. In addition, blocking IL-6 could up-regulate Foxp3 expression. Therefore, our findings show that IL-6 promotes the progression of SLE via suppressing Treg differentiation.

Effects of Interleukin-12 and Interleukin-15 on Measles-Specific T-Cell Responses in Vaccinated Infants

PubMed Central

YASUKAWA, LINDA L.; ZHANG, CATHRYN Z.; WAKIM, RIMA HANNA; RINKI, MARY; DEHOVITZ, ROSS; ARVIN, ANN M.

2008-01-01

Abstract Understanding the infant host response to measles vaccination is important because of their increased mortality from measles and the need to provide effective protection during the first year of life. Measles-specific T- and B-cell responses are lower in infants after measles vaccination than in adults. To define potential mechanisms, we investigated age-related differences in measles-specific T-cell proliferation, CD40-L expression, and IFN-γ production after measles immunization, and the effects of rhIL-12 and rhIL-15 on these responses. Measles-specific T-cell proliferation and mean IFN-γ release from infant PBMCs were significantly lower when compared with responses of vaccinated children and adults. Infant responses increased to ranges observed in children and adults when both rhIL-12 and rhIL-15 were added to PBMC cultures. Furthermore, a significant rise in T-cell proliferation and IFN-γ release was observed when infant PBMCs were stimulated with measles antigen in the presence of rhIL-12 and rhIL-15 compared to measles antigen alone. CD40-L expression by infant and adult T cells stimulated with measles antigen was comparable, but fewer infant CD40-L+ T cells expressed IFN-γ. These observations suggest that lower measles-specific T-cell immune responses elicited by measles vaccine in infants may be due to diminished levels of key cytokines. PMID:18419254

Xenon triggers pro-inflammatory effects and suppresses the anti-inflammatory response compared to sevoflurane in patients undergoing cardiac surgery.

PubMed

Breuer, Thomas; Emontzpohl, Christoph; Coburn, Mark; Benstoem, Carina; Rossaint, Rolf; Marx, Gernot; Schälte, Gereon; Bernhagen, Juergen; Bruells, Christian S; Goetzenich, Andreas; Stoppe, Christian

2015-10-15

Cardiac surgery encompasses various stimuli that trigger pro-inflammatory mediators, reactive oxygen species and mobilization of leucocytes. The aim of this study was to evaluate the effect of xenon on the inflammatory response during cardiac surgery. This randomized trial enrolled 30 patients who underwent elective on-pump coronary-artery bypass grafting in balanced anaesthesia of either xenon or sevoflurane. For this secondary analysis, blood samples were drawn prior to the operation, intra-operatively and on the first post-operative day to measure the pro- and anti-inflammatory cytokines interleukin-6 (IL-6), interleukin-8/C-X-C motif ligand 8 (IL-8/CXCL8), and interleukin-10 (IL-10). Chemokines such as C-X-C motif ligand 12/ stromal cell-derived factor-1α (CXCL12/SDF-1α) and macrophage migration inhibitory factor (MIF) were measured to characterize xenon's perioperative inflammatory profile and its impact on migration of peripheral blood mononuclear cells (PBMC). Xenon enhanced the postoperative increase of IL-6 compared to sevoflurane (Xenon: 90.7 versus sevoflurane: 33.7 pg/ml; p = 0.035) and attenuated the increase of IL-10 (Xenon: 127.9 versus sevoflurane: 548.3 pg/ml; p = 0.028). Both groups demonstrated a comparable intraoperative increase of oxidative stress (intra-OP: p = 0.29; post-OP: p = 0.65). While both groups showed an intraoperative increase of the cardioprotective mediators MIF and CXCL12/SDF-1α, only MIF levels decreased in the xenon group on the first postoperative day (50.0 ng/ml compared to 23.3 ng/ml; p = 0.012), whereas it remained elevated after sevoflurane anaesthesia (58.3 ng/ml to 53.6 ng/ml). Effects of patients' serum on chemotactic migration of peripheral mononuclear blood cells taken from healthy volunteers indicated a tendency towards enhanced migration after sevoflurane anaesthesia (p = 0.07). Compared to sevoflurane, balanced xenon anaesthesia triggers pro-inflammatory effects and suppresses the anti-inflammatory response in

Coulomb suppression in the low-energy p-p elastic scattering via the Trojan Horse Method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tumino, A.; Universita degli Studi di Enna 'Kore', Enna; Spitaleri, C.

2010-11-24

We present here an important test of the main feature of the Trojan Horse Method (THM), namely the suppression of Coulomb effects in the entrance channel due to off-energy-shell effects. This is done by measuring the THM p-p elastic scattering via the p+d{yields}p+p+n reaction at 4.7 and 5 MeV, corresponding to a p-p relative energy ranging from 80 to 670 keV. In contrast to the on-energy-shell (OES) case, the extracted p-p cross section does not exhibit the Coulomb-nuclear interference minimum due to the suppression of the Coulomb amplitude. This is confirmed by the half-off-energy shell (HOES) calculations and strengthened bymore » the agreement with the calculated OES nuclear cross sections.« less

Inhibitors of p38 suppress cytokine production in rheumatoid arthritis synovial membranes: does variable inhibition of interleukin-6 production limit effectiveness in vivo?

PubMed

Page, Theresa H; Brown, Anthony; Timms, Emma M; Foxwell, Brian M J; Ray, Keith P

2010-11-01

The activity of p38 MAPK regulates lipopolysaccharide (LPS)-stimulated production of key proinflammatory cytokines such as tumor necrosis factor α (TNFα). Consequently, p38 MAPK inhibitors have attracted considerable interest as potential treatments of rheumatoid arthritis (RA), and studies in murine models of arthritis have yielded promising results. However, the performance of several compounds in human clinical trials has been disappointing. At present, the reason for this poor performance is unclear. The aim of this study was to examine the effects of p38 inhibitors on both diseased and normal human tissue and cells, in order to test whether this kinase still plays a critical role in cytokine production under conditions of chronic inflammation. Proinflammatory and antiinflammatory cytokine production was monitored after treatment of primary human monocytes, macrophages, and RA synovial membrane cultures with p38 MAPK inhibitor compounds. The following 3 inhibitors were used in these studies: SB-203580 (inhibits the α and β isoforms), BIRB-796 (inhibits the α, β, γ, and δ isoforms), and a novel, structurally distinct p38 MAPK inhibitor, SB-731445 (inhibits the α and β isoforms). SB-731445 and SB-203580 produced profound inhibition of spontaneous production of proinflammatory cytokines (TNFα and interleukin-1 [IL-1]) in both RA membrane cultures and LPS-stimulated primary human monocytes. However, this and other p38 MAPK inhibitors produced a significant increase in IL-6 production by LPS-stimulated primary human macrophages and a decrease in IL-10 production by all cell types examined. The potentially proinflammatory consequences of these activities (decreased IL-10 production and increased IL-6 production) may offer some explanation for the inability of p38 MAPK inhibitors to provide the therapeutic benefit that had been hoped for in RA. Copyright © 2010 by the American College of Rheumatology.

Localization in human interleukin 2 of the binding site to the alpha chain (p55) of the interleukin 2 receptor.

PubMed Central

Sauvé, K; Nachman, M; Spence, C; Bailon, P; Campbell, E; Tsien, W H; Kondas, J A; Hakimi, J; Ju, G

1991-01-01

Human interleukin 2 (IL-2) analogs with defined amino acid substitutions were used to identify specific residues that interact with the 55-kDa subunit (p55) or alpha chain of the human IL-2 receptor. Analog proteins containing specific substitutions for Lys-35, Arg-38, Phe-42, or Lys-43 were inactive in competitive binding assays for p55. All of these analogs retained substantial competitive binding to the intermediate-affinity p70 subunit (beta chain) of the receptor complex. The analogs varied in ability to interact with the high-affinity p55/p70 receptor. Despite the lack of binding to p55, all analogs exhibited significant biological activity, as assayed on the murine CTLL cell line. The dissociation constants of Arg-38 and Phe-42 analogs for p70 were consistent with intermediate-affinity binding; the Kd values were not significantly affected by the presence of p55 in binding to the high-affinity IL-2 receptor complex. These results confirm the importance of the B alpha-helix in IL-2 as the locus for p55-receptor binding and support a revised model of IL-2-IL-2 receptor interaction. PMID:2052547

Antitumor effects of a tumor cell vaccine expressing a membrane-bound form of the IL-12 p35 subunit.

PubMed

Lim, Ho Yong; Ju, Hee Young; Chung, Hee-Yong; Kim, Young Sang

2010-08-15

We investigated whether expression of the IL-12 p35 subunit in membrane-bound form in tumor cells enhanced their immunogenicity. Since p35 is only secreted when associated with the IL-12 p40 subunit, we generated tumor cells expressing membrane-bound forms of p35 and p40 as chimeras with the transmembrane/cytoplasmic region of TNFα (mbIL-12p35 and mbIL-12p40). The relevant vectors were transfected into MethA fibrosarcoma cells, and mbIL-12p35 or mbIL-12p40-expressing tumor clones were isolated and their ability to induce antitumor immunity studied. Cells of the mbIL-12p35 tumor clone induced CD69 expression and IFNγ production in purified CD8(+) T cells in vitro, and their in vivo tumorigenicity was reduced. Cells of the mbIL-12p40 tumor clone failed to show either of these activities. Mice that had rejected cells of the mbIL-12p35 tumor clone possessed systemic antitumor immunity to wild type tumor cells. The growth rate of mbIL-12p35 tumor cells was greater in CD8(+) T cell-depleted mice than in CD4(+) T-cell- and NK cell-depleted mice or normal mice, suggesting that CD8(+) T cells were mainly responsible for the antitumor immunity. These results indicate that expression of mbIL-12p35 on tumor cells enhances their immunogenicity by increasing their ability to activate CD8(+) T cells, possibly by direct priming.

An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastric acid suppression of rabeprazole extended-release with esomeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers.

PubMed

Morelli, G; Chen, H; Rossiter, G; Rege, B; Lu, Y

2011-04-01

Novel rabeprazole extended-release (ER) formulations were developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. To evaluate the pharmacodynamics and pharmacokinetics of six rabeprazole-ER formulations vs. esomeprazole 40 mg and rabeprazole delayed-release (DR) 20 mg. Helicobacter pylori-negative healthy subjects were randomised to receive one of eight treatments once daily for 5 days. Twenty-four-hour intragastric pH was monitored on days -1, 1 and 5. Rabeprazole plasma concentrations were measured on day 5. A total of 248 subjects (N=31/group) were enrolled in the study. On day 5, rabeprazole-ER groups provided mean durations of 18.5-20.2 h (77.0-84.1% of 24-h) with intragastric pH >4.0 vs. esomeprazole 40 mg (15.9 h/66.1% of 24-h) and rabeprazole-DR 20 mg (15.2 h/63.2% of 24-h). A similar increase was observed on day 1. While percentage of daytime (8 am-10 pm) with intragastric pH >4.0 on day 5 was overall similar across the groups, percentage of night-time (10 pm-8 am) with intragastric pH >4.0 was higher with the rabeprazole-ER groups (57.0-72.4%) vs. esomeprazole 40 mg (32.8%) and rabeprazole-DR 20 mg (34.0%). Rabeprazole-ER once daily for 5 days demonstrated a significantly longer duration of gastric acid suppression in 24 h vs. esomeprazole 40 mg and rabeprazole-DR 20 mg. The increase in acid suppression was predominantly due to prolonged acid suppression during the night-time; this was supported by the extended-release pharmacokinetic characteristics. © 2011 Blackwell Publishing Ltd.

Pro-inflammatory proteins S100A9 and tumor necrosis factor-α suppress erythropoietin elaboration in myelodysplastic syndromes.

PubMed

Cluzeau, Thomas; McGraw, Kathy L; Irvine, Brittany; Masala, Erico; Ades, Lionel; Basiorka, Ashley A; Maciejewski, Jaroslaw; Auberger, Patrick; Wei, Sheng; Fenaux, Pierre; Santini, Valeria; List, Alan

2017-12-01

Accumulating evidence implicates innate immune activation in the pathobiology of myelodysplastic syndromes. A key myeloid-related inflammatory protein, S100A9, serves as a Toll-like receptor ligand regulating tumor necrosis factor-α and interleukin-1β production. The role of myelodysplastic syndrome-related inflammatory proteins in endogenous erythropoietin regulation and response to erythroid-stimulating agents or lenalidomide has not been investigated. The HepG2 hepatoma cell line was used to investigate in vitro erythropoietin elaboration. Serum samples collected from 311 patients with myelodysplastic syndrome were investigated (125 prior to treatment with erythroid-stimulating agents and 186 prior to lenalidomide therapy). Serum concentrations of S100A9, S100A8, tumor necrosis factor-α, interleukin-1β and erythropoietin were analyzed by enzyme-linked immunosorbent assay. Using erythropoietin-producing HepG2 cells, we show that S100A9, tumor necrosis factor-α and interleukin-1β suppress transcription and cellular elaboration of erythropoietin. Pre-incubation with lenalidomide significantly diminished suppression of erythropoietin production by S100A9 or tumor necrosis factor-α. Moreover, in peripheral blood mononuclear cells from patients with myelodysplastic syndromes, lenalidomide significantly reduced steady-state S100A9 generation ( P =0.01) and lipopolysaccharide-induced tumor necrosis factor-α elaboration ( P =0.002). Enzyme-linked immunosorbent assays of serum from 316 patients with non-del(5q) myelodysplastic syndromes demonstrated a significant inverse correlation between tumor necrosis factor-α and erythropoietin concentrations ( P =0.006), and between S100A9 and erythropoietin ( P =0.01). Moreover, baseline serum tumor necrosis factor-α concentration was significantly higher in responders to erythroid-stimulating agents ( P =0.03), whereas lenalidomide responders had significantly lower tumor necrosis factor-α and higher S100A9 serum

Acute Illness Is Associated with Suppression of the Growth Hormone Axis in Zimbabwean Infants

PubMed Central

Jones, Andrew D.; Rukobo, Sandra; Chasekwa, Bernard; Mutasa, Kuda; Ntozini, Robert; Mbuya, Mduduzi N. N.; Stoltzfus, Rebecca J.; Humphrey, Jean H.; Prendergast, Andrew J.

2015-01-01

Frequent infections contribute to childhood stunting in developing countries but the causal pathways are uncertain. We tested the hypothesis that intercurrent illnesses suppress the growth hormone axis through reductions in insulin-like growth factor 1 (IGF-1). In a birth cohort of 202 HIV-unexposed Zimbabwean infants, we analyzed data on 7-day illness recall and measured plasma interleukin-6, C-reactive protein, alpha-1-acid glycoprotein, and IGF-1 by enzyme-linked immunosorbent assay, at age 6 weeks, and then 3, 6, 12, and 18 months. Children with recent acute illness had lower IGF-1 concentrations than healthy children and IGF-1 correlated inversely (P < 0.05) with inflammatory biomarkers at most time points between 3 and 18 months. Using path analysis, we showed that cough and fever had a predominantly indirect effect on suppressing IGF-1, through the acute-phase response, whereas diarrhea had a predominantly direct effect on IGF-1. Acute illness may therefore impact the growth hormone axis through both direct and indirect pathways. PMID:25535308

Suppressive role of hepatic dendritic cells in concanavalin A-induced hepatitis

PubMed Central

Tomiyama, C; Watanabe, H; Izutsu, Y; Watanabe, M; Abo, T

2011-01-01

Concanavalin A (Con A)-induced hepatitis is a mouse model of acute autoimmune hepatitis. The aim of this study was to investigate the role of hepatic dendritic cells (DC) in the immune modulation of tissue damage. Almost all hepatic DC were plasmacytoid DC (CD11c+ I-Alow B220+); however, conventional DC were CD11c+ I-Ahigh B220–. At an early stage (3–6 h) after Con A administration, the number of DC in both the liver and spleen decreased, increasing thereafter (12–24 h) in parallel with hepatic failure. The hepatic CD11c+ DC population contained many CD11b- cells, while the majority of splenic CD11c+ DC were CD11b+. After Con A administration, the proportion of I-A+ and CD11b+ cells within the CD11c+ DC population tended to increase in the liver, but not in the spleen. Similarly, expression of the activation markers CD80, CD86 and CD40 by CD11c+ DC increased in the liver, but not in the spleen. Next, adoptive transfer of DC isolated from the liver and spleen was performed 3 h after Con A administration to examine the immunomodulatory function of DC. Only hepatic DC had the ability to suppress hepatic failure. Analysis of cytokine production and subsequent identification of the effector cells showed that hepatic DC achieved this by suppressing the production of interleukin (IL)-12 and IL-2, rather than modulating effector cell function. PMID:21985372

Azithromycin-Ciprofloxacin-Impregnated Urinary Catheters Avert Bacterial Colonization, Biofilm Formation, and Inflammation in a Murine Model of Foreign-Body-Associated Urinary Tract Infections Caused by Pseudomonas aeruginosa.

PubMed

Saini, Hina; Vadekeetil, Anitha; Chhibber, Sanjay; Harjai, Kusum

2017-03-01

Pseudomonas aeruginosa is a multifaceted pathogen causing a variety of biofilm-mediated infections, including catheter-associated urinary tract infections (CAUTIs). The high prevalence of CAUTIs in hospitals, their clinical manifestations, such as urethritis, cystitis, pyelonephritis, meningitis, urosepsis, and death, and the associated economic challenges underscore the need for management of these infections. Biomaterial modification of urinary catheters with two drugs seems an interesting approach to combat CAUTIs by inhibiting biofilm. Previously, we demonstrated the in vitro efficacy of urinary catheters impregnated with azithromycin (AZM) and ciprofloxacin (CIP) against P. aeruginosa Here, we report how these coated catheters impact the course of CAUTI induced by P. aeruginosa in a murine model. CAUTI was established in female LACA mice with uncoated or AZM-CIP-coated silicone implants in the bladder, followed by transurethral inoculation of 10 8 CFU/ml of biofilm cells of P. aeruginosa PAO1. AZM-CIP-coated implants (i) prevented biofilm formation on the implant's surface ( P ≤ 0.01), (ii) restricted bacterial colonization in the bladder and kidney ( P < 0.0001), (iii) averted bacteriuria ( P < 0.0001), and (iv) exhibited no major histopathological changes for 28 days in comparison to uncoated implants, which showed persistent CAUTI. Antibiotic implants also overcame implant-mediated inflammation, as characterized by trivial levels of inflammatory markers such as malondialdehyde ( P < 0.001), myeloperoxidase ( P < 0.05), reactive oxygen species ( P ≤ 0.001), and reactive nitrogen intermediates ( P < 0.01) in comparison to those in uncoated implants. Further, AZM-CIP-coated implants showed immunomodulation by manipulating the release of inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-10 to the benefit of the host. Overall, the study demonstrates long-term in vivo effectiveness of AZM-CIP-impregnated catheters

Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19.

PubMed

Shimatani, Tomohiko; Inoue, Masaki; Kuroiwa, Tomoko; Xu, Jing; Mieno, Hiroshi; Nakamura, Masuo; Tazuma, Susumu

2006-01-01

To improve clinical outcomes of the initial therapy for gastroesophageal reflux disease, intragastric pH should be above 4.0 for more than 20 hours a day (83.3%) and nocturnal gastric acid breakthrough, defined as 60 continuous minutes of intragastric pH below 4.0 at night, should be inhibited. A "step-down" therapy sometimes fails because of insufficient acid suppression. Therefore we compared the acid-suppressive effects of proton pump inhibitors. This was a prospective, randomized, open-label, 8-way crossover study. In 9 healthy Helicobacter pylori-negative cytochrome P450 (CYP) 2C19 homozygous extensive metabolizers, intragastric pH was measured for 24 hours on day 7 of treatment with rabeprazole, omeprazole, and lansoprazole orally administered once daily at reduced and standard doses. Compared with baseline data (7% [range, 5%-20%]), the median values of the 24-hour percent of time that intragastric pH was above 4.0 significantly increased but did not exceed 83.3% under any of the 7 regimens, which were as follows: 10 mg rabeprazole (51% [range, 28%-78%], P < .01), 20 mg rabeprazole (59% [range, 36%-83%], P < .01), 10 mg omeprazole (26% [range, 4%-33%], P < .05), 20 mg omeprazole (48% [range, 31%-73%], P < .01), 40 mg omeprazole (62% [range, 47%-87%], P < .01), 15 mg lansoprazole (34% [range, 5%-51%], P < .05), and 30 mg lansoprazole (56% [range, 20%-76%], P < .05). Significant differences were observed among 10, 20, and 40 mg omeprazole (10 mg versus 20 mg, P < .01; 10 mg versus 40 mg, P < .01; and 20 mg versus 40 mg, P < .05) and between 15 and 30 mg lansoprazole (P < .01), whereas no significant difference was observed between 10 and 20 mg rabeprazole. Nocturnal gastric acid breakthrough was observed under all regimens. Rabeprazole, omeprazole, and lansoprazole, given once daily at standard doses, cannot be expected to achieve ideal acid suppression for the initial therapy for gastroesophageal reflux disease in Helicobacter-negative CYP2C19 homozygous

Chronic exposure of interleukin-13 suppress the induction of matrix metalloproteinase-1 by tumour necrosis factor α in normal and scleroderma dermal fibroblasts through protein kinase B/Akt.

PubMed

Brown Lobbins, M L; Shivakumar, B R; Postlethwaite, A E; Hasty, K A

2018-01-01

Peripheral blood mononuclear cells taken from patients with scleroderma express increased levels of interleukin (IL)-13. Moreover, the expression of matrix metalloproteinase-1 (MMP-1) from involved scleroderma skin fibroblasts is refractory to stimulation by tumour necrosis factor (TNF)-α. To elucidate the mechanism(s) involved, we examined the effect of IL-13 on TNF-α-induced MMP-1 expression in normal and scleroderma human dermal fibroblast lines and studied the involvement of serine/threonine kinase B/protein kinase B (Akt) in this response. Dermal fibroblast lines were stimulated with TNF-α in the presence of varying concentrations of IL-13. Total Akt and pAkt were quantitated using Western blot analyses. Fibroblasts were treated with or without Akt inhibitor VIII in the presence of IL-13 followed by TNF-α stimulation. MMP-1 expression was analysed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using analysis of variance (anova) or Student's t-test. Upon TNF-α stimulation, normal dermal fibroblasts secrete more MMP-1 than systemic sclerosis (SSc) fibroblasts. This increase in MMP-1 is lost when fibroblasts are co-incubated with IL-13 and TNF-α. IL-13 induced a significant increase in levels of pAkt in dermal fibroblasts, while Akt inhibitor VIII reversed the suppressive effects of IL-13 on the response of cultured fibroblasts to TNF-α, increasing their expression of MMP-1. We show that IL-13 suppresses MMP-1 in TNF-α-stimulated normal and scleroderma dermal fibroblast. Akt inhibitor VIII is able to reverse the suppressive effect of IL-13 on MMP-1 expression and protein synthesis. Our data suggest that IL-13 regulates MMP-1 expression in response to TNF-α through an Akt-mediated pathway and may play a role in fibrotic diseases such as scleroderma. © 2017 British Society for Immunology.

40 CFR 721.10212 - 1,2-Ethanediol, reaction products with epichlorohydrin.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false 1,2-Ethanediol, reaction products with... Specific Chemical Substances § 721.10212 1,2-Ethanediol, reaction products with epichlorohydrin. (a... 1,2-ethanediol, reaction products with epichlorohydrin (PMN P-09-241; CAS No. 705265-31-2) is...

Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis.

PubMed

Ruzicka, Thomas; Hanifin, Jon M; Furue, Masutaka; Pulka, Grazyna; Mlynarczyk, Izabela; Wollenberg, Andreas; Galus, Ryszard; Etoh, Takafumi; Mihara, Ryosuke; Yoshida, Hiroki; Stewart, Jonathan; Kabashima, Kenji

2017-03-02

Interleukin-31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in the treatment of atopic dermatitis. In this phase 2, randomized, double-blind, placebo-controlled, 12-week trial, we assigned adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis. Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P<0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group. In this phase 2 trial, nemolizumab at all monthly doses significantly

Azithromycin Resistance and Decreased Ceftriaxone Susceptibility in Neisseria gonorrhoeae, Hawaii, USA.

PubMed

Papp, John R; Abrams, A Jeanine; Nash, Evelyn; Katz, Alan R; Kirkcaldy, Robert D; O'Connor, Norman P; O'Brien, Pamela S; Harauchi, Derek H; Maningas, Eloisa V; Soge, Olusegun O; Kersh, Ellen N; Komeya, Alan; Tomas, Juval E; Wasserman, Glenn M; Kunimoto, Gail Y; Trees, David L; Whelen, A Christian

2017-05-01

During 2016, eight Neisseria gonorrhoeae isolates from 7 patients in Hawaii were resistant to azithromycin; 5 had decreased in vitro susceptibility to ceftriaxone. Genomic analysis demonstrated a distinct phylogenetic clade when compared with local contemporary strains. Continued evolution and widespread transmission of these strains might challenge the effectiveness of current therapeutic options.

Poly (lactide-co-glycolide)-polymethacrylate nanoparticles for intramuscular delivery of plasmid encoding interleukin-10 to prevent autoimmune diabetes in mice.

PubMed

Basarkar, Ashwin; Singh, Jagdish

2009-01-01

Determine the efficiency of cationic nanoparticles prepared by blending poly (lactide-co-glycolide; PLGA) and methacrylate copolymer (Eudragit(R) E100) to deliver a therapeutic gene encoding mouse interleukin-10, in vitro and in vivo. Nanoparticles prepared with PLGA and E100 were evaluated for delivery of plasmid DNA encoding mouse interleukin-10 in vitro and in vivo in mice upon intramuscular injection. Blood-glucose, serum interferon-gamma levels and histology of pancreas were studied to determine therapeutic efficacy. Histological evaluation of skeletal muscle from the injection site was performed to assess the biocompatibility of nanoparticles. PLGA/E100 nanoparticles showed endosomal escape evidenced by confocal microscopy and buffering ability. Transfecting HEK293 cells with plasmid-loaded PLGA/E100 nanoparticles resulted in significantly (p < 0.05) greater expression of interleukin-10 compared to PLGA nanoparticles. Mice treated with PLGA/E100 nanoparticles displayed higher serum levels of interleukin-10 and lower blood glucose levels compared to those treated with interleukin-10 plasmid alone or PLGA nanoparticles. High expression of interleukin-10 facilitated suppression of interferon-gamma levels and reduced islet infiltration. Histology of muscle showed that nanoparticles were biocompatible and did not cause chronic inflammatory response. Nanoparticles prepared by blending PLGA with methacrylate can efficiently and safely deliver plasmid DNA encoding mouse interleukin-10 leading to prevention of autoimmune diabetes.

Influence of chronic azithromycin treatment on the composition of the oropharyngeal microbial community in patients with severe asthma.

PubMed

Lopes Dos Santos Santiago, Guido; Brusselle, Guy; Dauwe, Kenny; Deschaght, Pieter; Verhofstede, Chris; Vaneechoutte, Dries; Deschepper, Ellen; Jordens, Paul; Joos, Guy; Vaneechoutte, Mario

2017-05-10

This study of the oropharyngeal microbiome complements the previously published AZIthromycin in Severe ASThma (AZISAST) clinical trial, where the use of azithromycin was assessed in subjects with exacerbation-prone severe asthma. Here, we determined the composition of the oropharyngeal microbial community by means of deep sequencing of the amplified 16S rRNA gene in oropharyngeal swabs from patients with exacerbation-prone severe asthma, at baseline and during and after 6 months treatment with azithromycin or placebo. A total of 1429 OTUs were observed, of which only 59 were represented by more than 0.02% of the reads. Firmicutes, Bacteroidetes, Fusobacteria, Proteobacteria and Actinobacteria were the most abundant phyla and Streptococcus and Prevotella were the most abundant genera in all the samples. Thirteen species only accounted for two thirds of the reads and two species only, i.e. Prevotella melaninogenica and Streptococcus mitis/pneumoniae, accounted for one fourth of the reads. We found that the overall composition of the oropharyngeal microbiome in patients with severe asthma is comparable to that of the healthy population, confirming the results of previous studies. Long term treatment (6 months) with azithromycin increased the species Streptococcus salivarius approximately 5-fold and decreased the species Leptotrichia wadei approximately 5-fold. This was confirmed by Boruta feature selection, which also indicated a significant decrease of L. buccalis/L. hofstadtii and of Fusobacterium nucleatum. Four of the 8 treated patients regained their initial microbial composition within one month after cessation of treatment. Despite large diversity of the oropharyngeal microbiome, only a few species predominate. We confirm the absence of significant differences between the oropharyngeal microbiomes of people with and without severe asthma. Possibly, long term azithromycin treatment may have long term effects on the composition of the oropharygeal microbiome in

Correlation between IL-17A/F, IL-23, IL-35 and IL-12/-23 (p40) levels in peripheral blood lymphocyte cultures and disease activity in Behcet's patients.

PubMed

Sonmez, Cemile; Yucel, Aysegul Atak; Yesil, Turan Hilmi; Kucuk, Hamit; Sezgin, Berna; Mercan, Ridvan; Yucel, Ahmet Eftal; Demirel, Gulderen Yanikkaya

2018-03-20

Behcet's disease is a chronic multisystemic disease with remissions and relapses. Several studies have shown that immune mechanisms play an important role in the development of the disease. In order to assess the association of disease activity with IL-17A/F, IL-23, IL-12/23 (p40) and IL-35 expression, we aimed to investigate production of these cytokines in peripheral blood mononuclear cells (PBMCs) from Behcet's patients and normal controls. Furthermore, we included Systemic Lupus Erythematosus (SLE) as disease control to evaluate the specificity of our data for immunopathogenesis of BD. Totally 15 active, 15 inactive Behcet's patients, 12 active and 12 inactive SLE patients and 12 healthy volunteers were enrolled in the study. Peripheral blood mononuclear cells were separated, lymphocyte cultures were performed and IL-17A/F, IL-12/23 p(40), IL-23, IL-35 cytokine levels were measured by ELISA in culture supernatants in the presence or absence of phytohemagglutinin (PHA) on time-dependent manner. IL-17 A/F levels increased parallel to IL-23 levels in Behcet's and SLE patients. Compared to healthy controls, IL-17 A/F levels were higher in active Behcet's and SLE patients; on the contrary, levels of IL-35 were lower. IL-17A/F, IL-12/23 (p40) and IL-23 levels were detectable most frequently in active Behcet's patients followed by active SLE patients. Our results indicate that IL-17 A/F, IL-23 and IL-12/23 (p40) may play role in the immunopathogenesis of BD so as Th17 and Th1 cell responses. Since IL-35 levels were lower in active Behcet's patients compared to inactive patients and healthy controls, there may be a plasticity between Th17 and Treg cells according to the state of disease activity.

miR-24-3p Suppresses Malignant Behavior of Lacrimal Adenoid Cystic Carcinoma by Targeting PRKCH to Regulate p53/p21 Pathway.

PubMed

Zhang, Ming-Xue; Zhang, Jie; Zhang, Hong; Tang, Hua

2016-01-01

MicroRNA (miRNA) may function as an oncogene or a tumor suppressor in tumorigenesis. However, the mechanism of miRNAs in adenoid cystic carcinoma (ACC) is unclear. Here, we provide evidence that miR-24-3p was downreglated and functions as a tumor suppressor in human lacrimal adenoid cystic carcinoma by suppressing proliferation and migration/invasion while promoting apoptosis. miR-24-3p down-regulated protein kinase C eta (PRKCH) by binding to its untranslated region (3'UTR). PRKCH increased the of the cell growth and migration/invasion in ACC cells and suppressed the expression of p53 and p21 in both mRNA and protein level. The overexpression of miR-24-3p decreased its malignant phenotype. Ectopic expression of PRKCH counteracted the suppression of malignancy induced by miR-24-3p, as well as ectopic expression of miR-24-3p rescued the suppression of PRKCH in the p53/p21 pathway. These results suggest that miR-24-3p promotes the p53/p21 pathway by down-regulating PRKCH expression in lacrimal adenoid cystic carcinoma cells.

[Tobacco--a producer of recombinant interleukins].

PubMed

Budzianowski, Jaromir

2012-01-01

Interleukins are cytokines of highly pleiotropic activity and they have high potential for application in the treatment of cancer and autoimmune diseases. Trials of recombinant interleukin production in plants relate almost exclusively to tobacco, where through the transformation of the nuclear genome (agroinfection) monomeric (IL-2, IL-4, IL-13, IL-18), homodimeric (IL-10) and single-chain heterodimeric (IL-12) interleukins have been obtained. The expression of IL-10 as a homodimer in the chloroplast genome could not be reached. Expression of the given interleukin was obtained in the leaves, cell culture and culture of hairy roots of tobacco. Interleukins obtained in tobacco showed similar in vitro biological activity as commercial ILs produced mostly in E. coli. Glycosylated IL-13 obtained in tobacco was much more resistant to proteolytic digestion than commercial non-glycosylated IL-13; therefore in the case of sufficiently large production it could be suitable for oral administration in the treatment of type I diabetes.

The P-T-fO 2 stability of deerite, Fe{12/2+}Fe{6/3+}[Si12O40](OH)10

NASA Astrophysics Data System (ADS)

Lattard, Dominique; Le Breton, Nicole

1994-02-01

New equilibrium experiments have been performed in the 20 27 kbar range to determine the upper thermal stability limit of endmember deerite, Fe{12/2+}Fe{6/3+}[Si12O40](OH)10. In this pressure range, the maximum thermal stability limit is represented by the oxygen-conserving reaction: deerite(De)=9 ferrosilite(Fs)+3 magnetite(Mag)+3 quartz(Qtz)+5 H2O(W) (1). Under the oxygen fugacities of the Ni-NiO buffer the breakdown-reduction reaction: De=12 Fs+2 Mag+5 W+1/2 O2 (10) takes place at lower temperatures (e.g. ΔT=63° at 27 kbar). The experimental brackets can be fitted using thermodynamic data for ferrosilite, magnetite and quartz from Berman (1988) and the following 1 bar, 298 K data for deerite (per gfw): Vo=55.74 J.bar-1, So=1670 J.K-1, ΔH{f/o}=-18334 kJ, α=2.5x10-5K-1, β=-0.18x10-5 bar-1. Using these data in conjunction with literature data on coesite, grunerite, minnesotaite, and greenalite, the P-T stability field of endmember deerite has been calculated for P s= P H 2O. This field is limited by 6 univariant oxygenconserving dehydration curves, from which three have positive d P/d T slopes, the other three negative slopes. The lower pressure end of the stability field of endmember deerite is thus located at an invariant point at 250±70°C and 10+-1.5 kbar. Deerite rich in the endmember can thus appear only in environments with geothermal gradients lower than 10°C/km and at pressures higher than about 10 kbar, which is in agreement with 4 out of 5 independent P-T estimates for known occurrences. The presence of such deerite places good constraints on minimum pressure and maximum temperature conditions. From log f O 2- T diagrams constructed with the same data base at different pressures, it appears that endmember deerite is, at temperatures near those of its upper stability limit, stable only over a narrow range of oxygen fugacities within the magnetite field. With decreasing temperatures, deerite becomes stable towards slightly higher oxygen fugacities

Effects of human interleukin-18 and interleukin-12 treatment on human lymphocyte engraftment in NOD-scid mouse

PubMed Central

Senpuku, Hidenobu; Asano, Toshihiko; Matin, Khairul; Salam, M Abdus; Tsuha, Yuzo; Horibata, Shigeo; Shimazu, Yoshihito; Soeno, Yuichi; Aoba, Takaaki; Sata, Tetsutaro; Hanada, Nobuhiro; Honda, Mitsuo

2002-01-01

NOD/LtSz-prkdcscid/prkdcscid (non-obese diabetic-severe combine immunodeficiency; NOD-scid) mice grafted with human peripheral blood lymphoid cells have been used as an in vivo humanized mouse model in various studies. However, cytotoxic human T cells are induced in this model during immune responses, which gives misleading results. To assist in grafting of human lymphocytes without the induction of cytotoxic human T cells, we investigated the effects of T helper type 1 (Th1) and Th2 cytokines on human lymphocyte grafting and migration, as well as the production of immunoglobulin deposited in glomeruli and human immunodeficiency virus-1 (HIV-1) infection using NOD-scid mice. Administration of interleukin-18 (IL-18) and IL-12 enhanced the grafting of human CD4+ and CD8+ T cells in the mice, whereas co-administration prevented grafting due to interferon-γ-dependent apoptosis. Immunoglobulin A (IgA) deposits were observed in mice treated with IL-18 alone, but not in those given phosphate-buffered saline, IL-12 alone, or IL-18 + IL-12. A high rate of HIV infection was also observed in the IL-18-treated group. Together, these results indicate that IL-18 may be effective for the grafting and migration of CD4+ and CD8+ T cells, except for the induction of apoptosis and regulation of class-switching IgA. IL-18-administered NOD-scid mice provide a useful small humanized model for the study of HIV infection and IgA nephropathy. PMID:12383203

Evaluation of selected interleukins in patients with different gastric neoplasms: a preliminary report.

PubMed

Madej-Michniewicz, Anna; Budkowska, Marta; Sałata, Daria; Dołęgowska, Barbara; Starzyńska, Teresa; Błogowski, Wojciech

2015-10-21

Abnormal interactions between cytokines may be an overlooked mechanism linking the development of different types of gastric neoplasms. In this study a comprehensive analysis of the systemic levels of interleukins (IL-1,IL-6, IL-8,IL-10 and IL-12) was performed in 75 patients with different gastric neoplasms (cancer, gastrointestinal stromal tumors, neuroendocrine neoplasms, lymphomas) and 40 healthy volunteers. Patients with gastric cancer (GC) have significantly higher IL-6 levels, and lower IL-8 and IL-10 concentrations, in comparison to controls and patients with other gastric neoplasms. Analogous results were observed in terms of IL-6/IL-8 and IL-6/IL-10 ratios, whose values were also higher in GC patients. In GC patients no associations were detected between the systemic levels/values of interleukins (ratios) and TNM staging. IL-6, IL-10, IL-6/IL-8 and IL-6/IL-10 ratios appeared to hold diagnostic potential in confirming/excluding the presence of GC. Their sensitivity/specificity in GC detection/exclusion was approximately 54-72%. In conclusion, disturbed systemic biochemical balance in multiple interleukins exists at the earliest stages of and appears to be specific to GC. The interleukin ratios proposed here seem to be more promising indicators of GC in humans than direct systemic levels of interleukins, and probably possess the potential to be applied as a supporting factor for techniques routinely used.

Targeting Phosphoinositide 3-Kinase γ in Airway Smooth Muscle Cells to Suppress Interleukin-13-Induced Mouse Airway Hyperresponsiveness

PubMed Central

Jiang, Haihong; Xie, Yan; Abel, Peter W.; Toews, Myron L.; Townley, Robert G.; Casale, Thomas B.

2012-01-01

We recently reported that phosphoinositide 3-kinase γ (PI3Kγ) directly regulates airway smooth muscle (ASM) contraction by modulating Ca2+ oscillations. Because ASM contraction plays a critical role in airway hyperresponsiveness (AHR) of asthma, the aim of the present study was to determine whether targeting PI3Kγ in ASM cells could suppress AHR in vitro and in vivo. Intranasal administration into mice of interleukin-13 (IL-13; 10 μg per mouse), a key pathophysiologic cytokine in asthma, induced AHR after 48 h, as assessed by invasive tracheostomy. Intranasal administration of a broad-spectrum PI3K inhibitor or a PI3Kγ-specific inhibitor 1 h before AHR assessment attenuated IL-13 effects. Airway responsiveness to bronchoconstrictor agonists was also examined in precision-cut mouse lung slices pretreated without or with IL-13 for 24 h. Acetylcholine and serotonin dose-response curves indicated that IL-13-treated lung slices had a 40 to 50% larger maximal airway constriction compared with controls. Furthermore, acetylcholine induced a larger initial Ca2+ transient and increased Ca2+ oscillations in IL-13-treated primary mouse ASM cells compared with control cells, correlating with increased cell contraction. As expected, PI3Kγ inhibitor treatment attenuated IL-13-augmented airway contractility of lung slices and ASM cell contraction. In both control and IL-13-treated ASM cells, small interfering RNA-mediated knockdown of PI3Kγ by 70% only reduced the initial Ca2+ transient by 20 to 30% but markedly attenuated Ca2+ oscillations and contractility of ASM cells by 50 to 60%. This report is the first to demonstrate that PI3Kγ in ASM cells is important for IL-13-induced AHR and that acute treatment with a PI3Kγ inhibitor can ameliorate AHR in a murine model of asthma. PMID:22543031

40 CFR 721.10007 - Alcohols, C12-14-secondary, ethoxylated propoxylated.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alcohols, C12-14-secondary... New Uses for Specific Chemical Substances § 721.10007 Alcohols, C12-14-secondary, ethoxylated... identified as alcohols, C12-14- secondary, ethoxylated propoxylated (PMN P-00-11; CAS No. 103331-86-8) is...

Neutralization or Absence of the Interleukin-23 Pathway Does Not Compromise Immunity to Mycobacterial Infection▿

PubMed Central

Chackerian, Alissa A.; Chen, Shi-Juan; Brodie, Scott J.; Mattson, Jeanine D.; McClanahan, Terrill K.; Kastelein, Robert A.; Bowman, Edward P.

2006-01-01

Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine that is composed of the p40 subunit of IL-12 plus a unique p19 subunit. IL-23 is critical for autoimmune inflammation, in part due to its stimulation of the proinflammatory cytokine IL-17A. It is less clear, however, if IL-23 is required during the immune response to pathogens. We examined the role of IL-23 during Mycobacterium bovis BCG infection. We found that IL-23 reduces the bacterial burden and promotes granuloma formation when IL-12 is absent. However, IL-23 does not contribute substantially to host resistance when IL-12 is present, as the ability to control bacterial growth and form granulomata is not affected in IL-23p19-deficient mice and mice treated with a specific anti-IL-23p19 antibody. IL-23p19-deficient mice are also able to mount an effective memory response to secondary infection with BCG. While IL-23p19-deficient mice do not produce IL-17A, this cytokine is not necessary for effective control of infection, and antibody blocking of IL-17A in both wild-type and IL-12-deficient mice also has little effect on the bacterial burden. These data suggest that IL-23 by itself does not play an essential role in the protective immune response to BCG infection; however, the presence of IL-23 can partially compensate for the absence of IL-12. Furthermore, neutralization of IL-23 or IL-17A does not increase susceptibility to mycobacterial BCG infection. PMID:16923792

Azithromycin Resistance and Decreased Ceftriaxone Susceptibility in Neisseria gonorrhoeae, Hawaii, USA

PubMed Central

Papp, John R.; Abrams, A. Jeanine; Nash, Evelyn; Katz, Alan R.; Kirkcaldy, Robert D.; O’Connor, Norman P.; O’Brien, Pamela S.; Harauchi, Derek H.; Maningas, Eloisa V.; Soge, Olusegun O.; Kersh, Ellen N.; Komeya, Alan; Tomas, Juval E.; Wasserman, Glenn M.; Kunimoto, Gail Y.; Trees, David L.

2017-01-01

During 2016, eight Neisseria gonorrhoeae isolates from 7 patients in Hawaii were resistant to azithromycin; 5 had decreased in vitro susceptibility to ceftriaxone. Genomic analysis demonstrated a distinct phylogenetic clade when compared with local contemporary strains. Continued evolution and widespread transmission of these strains might challenge the effectiveness of current therapeutic options. PMID:28418303

In vivo suppression of plasma IL-12 levels by acute and chronic stress paradigms: potential mediating mechanisms and sex differences

PubMed Central

Shaashua, L.; Sominsky, L.; Levi, B.; Sorski, L.; Reznick, M.; Page, G.; Ben-Eliyahu, S.

2012-01-01

Interleukin-12 (IL-12) is a major pro-inflammatory cytokine, which promotes cell-mediated immunity and TH1 differentiation. In vitro studies indicated suppression of IL-12 production by several stress-related factors, but no effects of behavioral stress were shown on plasma IL-12 levels. Therefore, in the current study we (i) examined the in vivo effects of various behavioral and pharmacological stress paradigms on baseline plasma IL-12 levels; (ii) compared these in vivo findings to those obtained following in vitro stimulation of leukocytes from the same rats; and (iii) assessed potential sexual dimorphism in these outcomes. The findings indicated that plasma IL-12 levels were significantly reduced by social confrontation, wet-cage exposure, surgery, and the administration of corticosterone, epinephrine, or prostaglandin-E2. Notably, most in vivo impacts on plasma levels were not evident when assessed in vitro. The IL-12-reducing effects of wet-cage exposure, and of corticosterone and epinephrine administration, were significantly greater in males than in females, although females exhibited greater total corticosterone levels following stress. The duration of acute stressors predicted the degree of IL-12 reduction, but more prolonged stressors did not. Furthermore, seven days of alternating behavioral stressors reduced plasma IL-12 levels more than fourteen days. These findings suggest animals’ behavioral habituation to stress conditions, or a specific immune mechanism restricting the duration of IL-12 reduction. Overall, our findings indicate a generic and robust stress-induced reduction in plasma IL-12 levels, and suggest epinephrine, corticosterone, and prostaglandin-E2, as potential mediators that should be scrutinized in vivo in the context of natural physiological stress responses. PMID:22659252

How much surface coating of hydrophobic azithromycin is sufficient to prevent moisture-induced decrease in aerosolisation of hygroscopic colistin powder?

PubMed Central

Zhou, Qi (Tony); Loh, Zhi Hui; Yu, Jiaqi; Sun, Si-ping; Gengenbach, Thomas; Denman, John A.; Li, Jian; Chan, Hak-Kim

2017-01-01

Aerosolisation performance of hygroscopic particles of colistin could be compromised at elevated humidity due to increased capillary forces. Co-spray drying colistin with a hydrophobic drug is known to provide a protective coating on the composite particle surfaces against moisture-induced reduction in aerosolisation performance; however, the effects of component ratio on surface coating quality and powder aerosolisation at elevated relative humidities are unknown. In this study, we have systematically examined the effects of mass ratio of hydrophobic azithromycin on surface coating quality and aerosolisation performance of the co-spray dried composite particles. Four combination formulations with varying drug ratios were prepared by co-spray drying drug solutions. Both of the drugs in each combination formulation had similar in vitro deposition profiles, suggesting that each composite particle comprise two drugs in the designed mass ratio, which is supported by XPS and ToF-SIMS data. XPS and ToF-SIMS measurements also revealed that 50 % by weight (or 35 % by molecular fraction) of azithromycin in the formulation provided a near-complete coating of 96.5 % (molar fraction) on the composite particle surface, which is sufficient to prevent moisture-induced reduction in FPFrecovered and FPFemitted. Higher azithromycin content did not increase coating coverage, while contents of azithromycin lower than 20 %w/w did not totally prevent the negative effects of humidity on aerosolisation performance. This study has highlighted that a critical amount of azithromycin is required to sufficiently coat the colistin particles for short-term protection against moisture. PMID:27255350

40 CFR 721.1500 - 1,2-Benzenediamine, 4-ethoxy, sulfate.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false 1,2-Benzenediamine, 4-ethoxy, sulfate... Substances § 721.1500 1,2-Benzenediamine, 4-ethoxy, sulfate. (a) Chemical substance and significant new use...-benzenediamine, 4-ethoxy, sulfate, PMN P-83-105. (2) The significant new use is: Manufacture, import, or...

40 CFR 721.1500 - 1,2-Benzenediamine, 4-ethoxy, sulfate.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false 1,2-Benzenediamine, 4-ethoxy, sulfate... Substances § 721.1500 1,2-Benzenediamine, 4-ethoxy, sulfate. (a) Chemical substance and significant new use...-benzenediamine, 4-ethoxy, sulfate, PMN P-83-105. (2) The significant new use is: Manufacture, import, or...

40 CFR 721.1500 - 1,2-Benzenediamine, 4-ethoxy, sulfate.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false 1,2-Benzenediamine, 4-ethoxy, sulfate... Substances § 721.1500 1,2-Benzenediamine, 4-ethoxy, sulfate. (a) Chemical substance and significant new use...-benzenediamine, 4-ethoxy, sulfate, PMN P-83-105. (2) The significant new use is: Manufacture, import, or...

40 CFR 721.1500 - 1,2-Benzenediamine, 4-ethoxy, sulfate.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false 1,2-Benzenediamine, 4-ethoxy, sulfate... Substances § 721.1500 1,2-Benzenediamine, 4-ethoxy, sulfate. (a) Chemical substance and significant new use...-benzenediamine, 4-ethoxy, sulfate, PMN P-83-105. (2) The significant new use is: Manufacture, import, or...

40 CFR 721.1500 - 1,2-Benzenediamine, 4-ethoxy, sulfate.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false 1,2-Benzenediamine, 4-ethoxy, sulfate... Substances § 721.1500 1,2-Benzenediamine, 4-ethoxy, sulfate. (a) Chemical substance and significant new use...-benzenediamine, 4-ethoxy, sulfate, PMN P-83-105. (2) The significant new use is: Manufacture, import, or...

Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3K-Akt-GSK3 pathway

PubMed Central

Antoniv, Taras T; Ivashkiv, Lionel B

2011-01-01

Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits inflammatory gene expression. Phosphatidylinositol 3-kinase (PI3K) -mediated signalling regulates inflammatory responses and can induce IL-10 production, but a role for PI3K signalling in cellular responses to IL-10 is not known. In this study we investigated the involvement of the PI3K-Akt-GSK3 signalling pathway in IL-10-induced gene expression and IL-10-mediated suppression of Toll-like receptor-induced gene expression in primary human macrophages. A combination of loss and gain of function approaches using kinase inhibitors, expression of constitutively active Akt, and RNA interference in primary human macrophages showed that expression of a subset of IL-10-inducible genes was dependent on PI3K-Akt signalling. The effects of PI3K-Akt signalling on IL-10 responses were mediated at least in part by glycogen synthase kinase 3 (GSK3). In accordance with a functional role for PI3K pathways in contributing to the suppressive actions of IL-10, PI3K signalling augmented IL-10-mediated inhibition of lipopolysaccharide-induced IL-1, IL-8 and cyclo-oxygenase-2 expression. The PI3K signalling selectively modulated IL-10 responses, as it was not required for inhibition of tumour necrosis factor expression or for induction of certain IL-10-inducible genes such as SOCS3. These findings identify a new mechanism by which PI3K-mediated signalling can suppress inflammation by regulating IL-10-mediated gene induction and anti-inflammatory function. PMID:21255011

Attenuation of Pseudomonas aeruginosa biofilm formation by Vitexin: A combinatorial study with azithromycin and gentamicin

NASA Astrophysics Data System (ADS)

Das, Manash C.; Sandhu, Padmani; Gupta, Priya; Rudrapaul, Prasenjit; de, Utpal C.; Tribedi, Prosun; Akhter, Yusuf; Bhattacharjee, Surajit

2016-03-01

Microbial biofilm are communities of surface-adhered cells enclosed in a matrix of extracellular polymeric substances. Extensive use of antibiotics to treat biofilm associated infections has led to the emergence of multiple drug resistant strains. Pseudomonas aeruginosa is recognised as a model biofilm forming pathogenic bacterium. Vitexin, a polyphenolic group of phytochemical with antimicrobial property, has been studied for its antibiofilm potential against Pseudomonas aeruginosa in combination with azithromycin and gentamicin. Vitexin shows minimum inhibitory concentration (MIC) at 260 μg/ml. It’s antibiofilm activity was evaluated by safranin staining, protein extraction, microscopy methods, quantification of EPS and in vivo models using several sub-MIC doses. Various quorum sensing (QS) mediated phenomenon such as swarming motility, azocasein degrading protease activity, pyoverdin and pyocyanin production, LasA and LasB activity of the bacteria were also evaluated. Results showed marked attenuation in biofilm formation and QS mediated phenotype of Pseudomonas aeruginosa in presence of 110 μg/ml vitexin in combination with azithromycin and gentamicin separately. Molecular docking of vitexin with QS associated LuxR, LasA, LasI and motility related proteins showed high and reasonable binding affinity respectively. The study explores the antibiofilm potential of vitexin against P. aeruginosa which can be used as a new antibiofilm agent against microbial biofilm associated pathogenesis.

Multi-walled carbon nanotubes suppress potassium channel activities in PC12 cells

NASA Astrophysics Data System (ADS)

Xu, Haifei; Bai, Juan; Meng, Jie; Hao, Wei; Xu, Haiyan; Cao, Ji-Min

2009-07-01

The advancement in nanotechnology has produced technological and conceptual breakthroughs but the effects nanomaterials have on organisms at the cellular level are poorly understood. Here we report that carboxyl-terminated multi-walled carbon nanotubes (MWCNTs) act as antagonists of three types of potassium channels as assessed by whole-cell patch clamp electrophysiology on undifferentiated pheochromocytoma (PC12) cells. Our results showed that carboxyl-terminated MWCNTs suppress the current densities of Ito, IK and IK1 in a time-dependent and irreversible manner. The suppressions were most distinct 24 h after incubation with MWCNTs. However, MWCNTs did not significantly change the expression levels of reactive oxygen species (ROS) or intracellular free calcium and also did not alter the mitochondrial membrane potential (ΔΨm) in PC12 cells. These results suggest that oxidative stress was not involved in the MWCNTs suppression of Ito, IK and IK1 current densities. Nonetheless, the suppression of potassium currents by MWCNTs will impact on electrical signaling of excitable cells such as neurons and muscles.

Activities of two novel macrolides, GW 773546 and GW 708408, compared with those of telithromycin, erythromycin, azithromycin, and clarithromycin against Haemophilus influenzae.

PubMed

Kosowska, Klaudia; Credito, Kim; Pankuch, Glenn A; Hoellman, Dianne; Lin, Gengrong; Clark, Catherine; Dewasse, Bonifacio; McGhee, Pamela; Jacobs, Michael R; Appelbaum, Peter C

2004-11-01

The MIC at which 50% of strains are inhibited (MIC(50)) and the MIC(90) of GW 773546, a novel macrolide, were 1.0 and 2.0 microg/ml, respectively, for 223 beta-lactamase-positive, beta-lactamase-negative, and beta-lactamase-negative ampicillin-resistant Haemophilus influenzae strains. The MIC(50)s and MIC(90)s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 microg/ml, respectively, while the MIC(50) and MIC(90) of azithromycin were 1.0 and 2.0 microg/ml, respectively. The MIC(50) and MIC(90) of erythromycin were 4.0 and 8.0 microg/ml, respectively; and those of clarithromycin were 4.0 and 16.0 microg/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 x 10(-9) to 2.2 x 10(-6) with

Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Telithromycin, Erythromycin, Azithromycin, and Clarithromycin against Haemophilus influenzae

PubMed Central

Kosowska, Klaudia; Credito, Kim; Pankuch, Glenn A.; Hoellman, Dianne; Lin, Gengrong; Clark, Catherine; Dewasse, Bonifacio; McGhee, Pamela; Jacobs, Michael R.; Appelbaum, Peter C.

2004-01-01

The MIC at which 50% of strains are inhibited (MIC50) and the MIC90 of GW 773546, a novel macrolide, were 1.0 and 2.0 μg/ml, respectively, for 223 β-lactamase-positive, β-lactamase-negative, and β-lactamase-negative ampicillin-resistant Haemophilus influenzae strains. The MIC50s and MIC90s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 μg/ml, respectively, while the MIC50 and MIC90 of azithromycin were 1.0 and 2.0 μg/ml, respectively. The MIC50 and MIC90 of erythromycin were 4.0 and 8.0 μg/ml, respectively; and those of clarithromycin were 4.0 and 16.0 μg/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 × 10−9 to 2.2 × 10−6 with GW 773546, 1.5 × 10−9 to 6.0 �

Assembly interdependence among the S. cerevisiae bud neck ring proteins Elm1p, Hsl1p and Cdc12p.

PubMed

Thomas, Courtney L; Blacketer, Melissa J; Edgington, Nicholas P; Myers, Alan M

2003-07-15

In Saccharomyces cerevisiae, a complex comprising more than 20 different polypeptides assembles in a ring at the neck between the mother cell and the bud. This complex functions to coordinate cell morphology with cell division. Relatively little is known about this control system, including the physical relationships between the components of the neck ring. This study addressed the assembly interactions of three components of the ring, specifically the protein kinases Elm1p and Hsl1p and the septin Cdc12p. Specific amino acid substitutions in each of these three proteins were identified that either cause or suppress a characteristic phenotype of abnormally elongated cells and delay in the G(2)-M transition. Each protein was fused to green fluorescent protein, and its ability to localize at the neck was monitored in vivo in cells of various genotypes. Localization of Hsl1p to the neck requires Elm1p function. Elm1p localized normally in the absence of Hsl1p, although a specific point mutation in Hsl1p clearly affected Elm1p localization. The cdc12-122 mutation prevented assembly of Elm1p or Hsl1p into the neck ring. Normal assembly of Cdc12p at the neck was dependent upon Elm1p and also, to a smaller extent, on Hsl1p. Ectopic localization of Cdc12p at the bud tip was observed frequently in elm1 mutants and also, to a lesser extent, in hsl1 mutants. Thus, Elm1p is a key factor in the assembly and/or maintenance of Hsl1p, as well as at least one septin, into the bud neck ring. Copyright 2003 John Wiley & Sons, Ltd.