I-Kappa-B-Zeta Regulates Interleukin-17A/Tumor Necrosis Factor-Alpha Mediated Synergistic Induction of Interleukin-19 and Interleukin-20 in Humane Keratinocytes

BackgroundInterleukin (IL)-19 and IL-20 are important members of the IL-10 cytokine family, which are known to play a role in inflammatory processes. Both anti-IL-19 and -IL-20 targeting drugs have been suggested in the treatment of inflammatory diseases such as psoriasis and rheumatoid arthritis. Recently, we presented I-kappa-B-zeta (IκBζ) as a key player in psoriasis by identifying IκBζ as a regulator of IL-17/tumor necrosis factor (TNF)α-inducible psoriasis-associated genes and proteins. Some of these genes were synergistically regulated by IL-17/TNFα.ObjectiveThe purpose of this study was to explore the role of IκBζ in the regulation of IL-17A/TNFα-mediated induction of IL-19 and IL-20 expression in human keratinocytes.MethodsIn vitro experiments with cultured primary humane keratinocytes were conducted and investigated by quantitative polymerase chain reaction (qPCR), Western blotting, ELISA and EMSA. For statistics, a one- or two- way repeated-measures analysis of variance (RM ANOVA) or the Friedman test (a nonparametric equivalent to the RM ANOVA) were conducted.ResultsWe demonstrated that IL-19 and IL-20 mRNA and protein expressions were synergistically induced by IL-17A and TNFα, whereas IL-17A and TNFα alone had only a minor effect on the IL-19 and IL-20 expression. Moreover, we demonstrated IκBζ to be a regulator of this synergistic induction of IL-19 and IL-20. Finally, the IL-17A/TNFα-induced synergistic induction of IL-19 and IL-20 expression was found to be mediated by a p38 MAPK-, NF-κB- and JNK1/2-dependent mechanism.ConclusionThis study demonstrates that IκBζ plays a role in the IL-17A/TNFα-mediated synergistic induction of IL-19 and IL-20 in humane keratinocytes.     

Bioavailability and efficacy of antisense morpholino oligomers targeted to c-myc and cytochrome P-450 3A2 following oral administration in rats

Antisense phosphorodiamidate Morpholino oligomers (PMO) are resistant to degradation by cellular hydrolases, DNases, RNases, and phosphodiesterases, but remain sensitive to prolonged exposure to low pH. The present studies evaluate the oral fractional bioavailability, stability, and efficacy of two distinct PMO sequences targeted to c-myc and cytochrome P-450 (CYP) 3A2. The c-myc antisense 20-mer, AVI-4126 (5'-ACGTTGAGGGGCATCGTCGC-3'), slowed the regenerative process in the rat liver after a 70% partial hepatectomy (PH). Rats were administered 3.0 mg/kg AVI-4126 in 0.1 mL saline via a bolus intravenous injection or in 0.5 mL sterile phosphate-buffered saline via gavage immediately following PH. The areas under the plasma concentration versus time curves revealed a fractional oral availability of 78.8% over a period of 10 min through 24 h. Immunoblot analysis of liver tissue from rats treated orally with AVI-4126 demonstrated a sequence-specific reduction in the target protein c-Myc, as well as secondary proliferation markers: proliferating cell nuclear antigen (PCNA), cyclin D1, and p53. The CYP3A2 antisense 22-mer AVI-4472 (5'-GAGCTGAAAGCAGGTCCATCCC-3') caused a sequence-dependent reduction of approximately five-fold in the rat liver CYP3A2 protein levels and erythromycin demethylation activity in 24 h following oral administration at a dose of 2 mg/kg. It is concluded that oral administration of PMOs can inhibit c-myc and CYP3A2 gene expression in rat liver by an antisense-based mechanism of action. These studies highlight the potential for development of PMOs as orally administered therapeutic agents.     

Enhancement of methylnitrosourea skin carcinogenesis by inhibiting cell proliferation with hydroxyurea or skin extracts

To study the relationship between epidermal DNA synthesis andcarcinogenesis, groups of hairless mice were given a singleskin application of 2 mg N-methyl-N-nitrosourea (MNU) in acetone.One group received no pretreatment, another group was injectedi.p. with 5 mg hydroxyurea (HU) 30 min before MNU, and a furthergroup with 0.5 mg Colcemid^® 3 h before MNU. Other groupswere injected i.p. 14 and 4 h before MNU with either saline,5 mg crude aqueous skin extract, 2 mg dialysed skin extractsof two types, or 2 mg dialysed extracts of liver or heart muscle,respectively. All substances were dissolved in 0.5 ml distilledwater. Cell kinetic studies showed that the three skin extractsinhibited epidermal DNA synthesis and mitosis. HU inhibitedDNA synthesis and increased the mitotic rate. The other pretreatmentshad no effect on epidermal DNA synthesis. There was a significantenhancement of the production of skin tumors in the groups pretreatedwith epidermal extracts or HU. MNU is a short-acting carcinogenwith a half-life in the cell of 30 min. Hence, the results showthat when DNA synthesis is inhibited at the time of MNU application,more tumors are produced in the skin. A possible explanationof the enhancement is that a compensatory wave of proliferationa short time after carcinogen binding may fix a DNA injury beforerepair can take place.     

Longitudinal change in cardiac structure and function following acute coronary syndrome according to culprit coronary artery lesion

The International Journal of Cardiovascular Imaging - Acute coronary syndrome (ACS) may lead to adverse remodelling and impaired cardiac function. Limited data exists on the effect of culprit...     

Tibial avulsion fracture of the posterior root of the medial meniscus in children

Few reports have described avulsion fractures of the posterior root of the medial meniscus in skeletally immature patients. This lesion should not be overlooked as it damages the load absorptive (distributive) function of the meniscus, increasing the risk of cartilage degeneration. Two cases of displaced avulsion fractures of the posterior root of the medial meniscus in children are presented along with a concise report of the literature regarding avulsion fractures of the posterior root of the medial meniscus. Both avulsions were reattached arthroscopically by trans-tibial pull-out sutures with a good clinical result at 2-years follow-up, and in one case, the avulsion was found at re-arthroscopy after 6 weeks to have healed. Level of evidence IV.     

Housing Instability among People Who Inject Drugs: Results from the Australian Needle and Syringe Program Survey

High rates of substance dependence are consistently documented among homeless people, and are associated with a broad range of negative outcomes among this population. Investigations of homelessness among drug users are less readily available. This study examined the prevalence and correlates of housing instability among clients of needle syringe programs (NSPs) via the Australian NSP Survey, annual cross-sectional seroprevalence studies among NSP attendees. Following self-completion of a brief, anonymous survey and provision of a capillary blood sample by 2,396 NSP clients, multivariate logistic regressions identified the variables independently associated with housing instability. Nineteen percent of ANSPS participants reported current unstable housing, with primary (‘sleeping rough’; 5 %), secondary (staying with friends/relatives or in specialist homelessness services; 8 %), and tertiary (residential arrangements involving neither secure lease nor private facilities; 6 %) homelessness all evident. Extensive histories of housing instability were apparent among the sample: 66 % reported at least one period of sleeping rough, while 77 % had shifted between friends/relatives (73 %) and/or resided in crisis accommodation (52 %). Participants with a history of homelessness had cycled in and out of homelessness over an average of 10 years; and one third reported first being homeless before age 15. Compared to their stably housed counterparts, unstably housed participants were younger, more likely to be male, of Indigenous Australian descent, and to report previous incarceration; they also reported higher rates of key risk behaviors including public injecting and receptive sharing of injecting equipment. The high prevalence of both historical and current housing instability among this group, particularly when considered in the light of other research documenting the many adverse outcomes associated with this particular form of disadvantage, highlights the need for increased supply of secure, affordable public housing in locations removed from established drug markets and serviced by health, social, and welfare support agencies.