Extract from Periostracum cicadae

Periostracum cicadae is widely used for the treatment of skin diseases such as eczema, pruritus, and itching. The current study sought to evaluate the effect of P. cicadae extract on ultraviolet B (UVB) irradiation and identify the mechanisms involved. Photodamage-protective activity of P. cicadae extracts against oxidative challenge was screened using HaCaT keratinocytes. P. cicadae extracts did not affect cell viability but decreased reactive oxygen species (ROS) production. The extract attenuates the expression of interleukin-6 (IL-6), matrix metalloproteinase-2 (MMP-2), and MMP-9 in UVB-treated HaCaT cells. Also, P. cicadae abrogated UVB-induced activation of NF-κB, p53, and activator protein-1 (AP-1). The downmodulation of IL-6 by P. cicadae was inhibited by the p38 inhibitor (SB203580) or JNK inhibitor (SP600125). Moreover, the extract attenuated the expression of NF-κB and induced thrombomodulin in keratinocytes and thereby effectively downregulated inflammatory responses in the skin. The nuclear accumulation and expression of NF-E2-related factor (Nrf2) were increased by P. cicadae treatment. Furthermore, treatment with P. cicadae remarkably ameliorated the skin’s structural damage induced by irradiation. This study demonstrates that P. cicadae may protect skin cells against oxidative insult by modulating ROS concentration, IL-6, MMPs generation, antioxidant enzymes activity, and cell signaling pathways

Transgenic Expression of Decoy Receptor 3 Protects Islets from Spontaneous and Chemical-induced Autoimmune Destruction in Nonobese Diabetic Mice

Decoy receptor 3 (DCR3) halts both Fas ligand– and LIGHT-induced cell deaths, which are required for pancreatic β cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in β cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants

Exploring the Mechanism Responsible for Cellulase Thermostability by Structure-Guided Recombination

Cellulases from Bacillus and Geobacillus bacteria are potentially useful in the biofuel and animal feed industries. One of the unique characteristics of these enzymes is that they are usually quite thermostable. We previously identified a cellulase, GsCelA, from thermophilic Geobacillus sp. 70PC53, which is much more thermostable than its Bacillus homolog, BsCel5A. Thus, these two cellulases provide a pair of structures ideal for investigating the mechanism regarding how these cellulases can retain activity at high temperature. In the present study, we applied the SCHEMA non-contiguous recombination algorithm as a novel tool, which assigns protein sequences into blocks for domain swapping in a way that lessens structural disruption, to generate a set of chimeric proteins derived from the recombination of GsCelA and BsCel5A. Analyzing the activity and thermostability of this designed library set, which requires only a limited number of chimeras by SCHEMA calculations, revealed that one of the blocks may contribute to the higher thermostability of GsCelA. When tested against swollen Avicel, the highly thermostable chimeric cellulase C10 containing this block showed significantly higher activity (22%-43%) and higher thermostability compared to the parental enzymes. With further structural determinations and mutagenesis analyses, a 3_(10) helix was identified as being responsible for the improved thermostability of this block. Furthermore, in the presence of ionic calcium and crown ether (CR), the chimeric C10 was found to retain 40% residual activity even after heat treatment at 90°C. Combining crystal structure determinations and structure-guided SCHEMA recombination, we have determined the mechanism responsible for the high thermostability of GsCelA, and generated a novel recombinant enzyme with significantly higher activity

Urinary levels of organophosphate flame retardants metabolites in a young population from Southern Taiwan and potential health effects

BackgroundOrganophosphate flame retardants (OPFRs) are widely distributed in the environment and their metabolites are observed in urine, but little is known regarding OPFRs in a broad-spectrum young population from newborns to those aged 18 years.ObjectivesInvestigate urinary levels of OPFRs and OPFR metabolites in Taiwanese infants, young children, schoolchildren, and adolescents within the general population.MethodsDifferent age groups of subjects (n=136) were recruited from southern Taiwan to detect 10 OPFR metabolites in urine samples. Associations between urinary OPFRs and their corresponding metabolites and potential health status were also examined.ResultsThe mean level of urinary Σ10 OPFR in this broad-spectrum young population is 2.25 μg/L (standard deviation (SD) of 1.91 μg/L). Σ10 OPFR metabolites in urine are 3.25 ± 2.84, 3.06 ± 2.21, 1.75 ± 1.10, and 2.32 ± 2.29 μg/L in the age groups comprising of newborns, 1-5 year-olds, 6-10 year-olds, and 11-18 year-olds, respectively, and borderline significant differences were found in the different age groups (p=0.125). The OPFR metabolites of TCEP, BCEP, DPHP, TBEP, DBEP, and BDCPP predominate in urine and comprise more than 90% of the total. TBEP was highly correlated with DBEP in this population (r=0.845, p<0.001). The estimated daily intake (EDI) of Σ5OPFRs (TDCPP, TCEP, TBEP, TNBP, and TPHP) was 2,230, 461, 130, and 184 ng/kg bw/day for newborns, 1-5 yr children, 6-10 yr children, and 11-17 yr adolescents, respectively. The EDI of Σ5OPFRs for newborns was 4.83-17.2 times higher than the other age groups. Urinary OPFR metabolites are significantly correlated with birth length and chest circumference in newborns.ConclusionTo our knowledge, this is the first investigation of urinary OPFR metabolite levels in a broad-spectrum young population. There tended to be higher exposure rates in both newborns and pre-schoolers, though little is known about their exposure levels or factors leading to exposure in the young population. Further studies should clarify the exposure levels and factor relationships

Selective predisposition to bacterial infections in IRAK-4–deficient children: IRAK-4–dependent TLRs are otherwise redundant in protective immunity

Human interleukin (IL) 1 receptor–associated kinase 4 (IRAK-4) deficiency is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3– and TLR4–interferon (IFN)-a/b pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells [MDDCs], myeloid DCs [MDCs], and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK-4–dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4–dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria

Defining the mechanism of action of intravesical therapy in patients with superficial transitional cell carcinoma of the bladder (a role for interferons and interferon stimulated genes in the innate immune response to BCG)

La BCG thérapie, basée sur des instillations intravésicales de Bacille de Calmette Guérin vivant, est utilisée depuis 1976 pour traiter le cancer superficiel de la vessie. Ce traitement est désormais reconnu comme le plus efficace parmi les thérapies prophylatiques pour prévenir les récidives et réduire le risque de progression de ce type de cancer (70% de réponse clinique). Malgré cela, le mécanisme d'action du BCG n'est toujours pas totalement défini. Comprendre l'action précise du BCG nous permettrait d identifier les relations entre le système immunitaire et le cancer afin d adapter la thérapie. Dans cette étude, nous avons réalisé un criblage multi-protéique et cytométrique pour décrire de façon systématique le profil moléculaire et cellulaire dans la vessie après instillation de BCG. Nous avons montré que seize molécules impliquées dans la réponse immune sont secrétées localement par les cellules urothéliales ou les cellules hématopoiétiques infiltrées dans la vessie. Parmi ces molécules, l IFN- induced protein-10 (IP10 or CXCL10) se distingue. En effet sa quantité est multipliée par 100 dans l urine de tous les patients alors que les molécules capables d'induire l'IP10 (IFN , IFN , TNF ) ne sont pas détectables. Afin de définir le méchanisme de production de l'IP10 en réponse au BCG, nous avons développé un modèle in vitro basé sur la stimulation de cellules primaires de carcinome transitionnel. Nous avons montré que le BCG induit faiblement l'IFN de type I. Cette faible production est cependant suffisante pour agir en synergie avec l activation des TLR par le BCG et induire la production d IP10. Par ailleurs nous avons démontré que les facteurs transcriptionels NF B p65, IFR3, IRF7 et IRF9 sont activés par le BCG, ce qui met en avant le rôle critique des IRFs pour la production d IP10. Ces données constituent la première démonstration de l activation par une bactérie des IRF3 et IRF7. Enfin, l activation d IRF3 ainsi que la production d interféron sont abolies en presence de BCG inactivé par la chaleur alors que la voie NF B est conservée. Sachant que seule l utilisation de BCG vivant est efficace dans le traitement du cancer superficiel de la vessie, nos observations mettent en évidence le rôle de l'IFN et des genes stimulés par l interféron tel que l IP10 dans ce contrôle. En conclusion, ce travail suggère que le BCG a la capacité de sensibiliser le microenvironnnement de la vessie pour stimuler une réponse immunitaire innée, et permet de mieux comprendre les mécanismes moléculaires et cellulaires qui y contribuent.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Microbial Etiology of Acute Gastroenteritis in Hospitalized Children in Taiwan

Viral infections are the most common causes of acute infectious diarrhea in the pedi-atric population. To explore any possible microbial etiologies of acute gastroenteritis in children, we detected stool viral antigen including rotavirus, adenovirus, norovirus and astrovirus. We also studied the possible precipitating factors. Methods: During a period of 1 year (from October 2003 to September 2004), children from birth to 15 years old admitted to the pediatric ward were prospectively surveyed. Stool specimens were collected within 48 hours after admission and then frozen at −40°C until analysis. Enzyme immunoassay was used to detect rotavirus, astrovirus, norovirus and adenovirus. Bacterial culture was performed at the same time. Results: During the study period, 82 stool samples were collected due to acute gastroenteritis and fit the definition of a diarrhea episode. Forty-two (51.2%) patients with viral infection, 11 (13.4%) with bacterial infection, and six (7.3%) with mixed viral and bacterial infection were detected. The most prevalent virus was rotavirus (35.4%), followed by norovirus (29.3%). The most prevalent cause of bacterial infection was Salmonella (19.5%). With regard to clinical severity, rotavirus resulted in longer hospital stay, higher rate of vomiting, stool occult blood, leukocytosis, lower rate in stool pus cell, and C-reactive protein elevation more than 5 mg/dL as compared with norovirus. Only the difference in hospital stay reached significant statistical difference. Conclusion: Norovirus is an important cause of acute gastroenteritis in children, although rotavirus is still the leading cause of pediatric acute gastroenteritis

Predictors of HIV testing among youth aged 15-24 years in The Gambia.

BackgroundWorldwide, an estimated 38.0 million people lived with the human immunodeficiency virus in 2019, and 3.4 million young people aged 15~24 years were living with HIV. Sub-Saharan Africa carries a significant HIV burden with West and Central Africa most affected with HIV. Among the young people living with HIV in West and Central Africa, an estimated 810,000 were aged 15~24 years. This study aimed to assess predictors that influence the uptake of HIV testing among youth aged 15~24 years in The Gambia.MethodsThe 2013 Gambia Demographic and Health Survey data for youth aged 15~24 years was used. The Andersen behavioral model of health service use guided this study. A cross-sectional study design was used on 6194 subjects, among which 4730 were female. The analysis employed Chi-squared tests and hierarchical logistic regression.ResultsLess than one-quarter of the youth 1404 (22.6%) had ever been tested for HIV. Young people aged 20~24 years (adjusted odds ratio (aOR): 1.98), who were females (aOR: 1.13), married youth (aOR: 3.89), with a primary (aOR: 1.23), secondary or higher education (aOR: 1.46), and who were from the Jola/Karoninka ethnic group (aOR: 1.81), had higher odds of having been tested for HIV. Those with adequate HIV knowledge and those who were sexually active and had aged at first sex ≥15 years (aOR: 3.99) and those <15 years (aOR: 3.96) were more likely to have been tested for HIV compared to those who never had sex.ConclusionThis study underscores the low level of model testing on HIV testing among youth (15~24 years) in The Gambia. Using Anderson's Model of Health Service Utilization, the predisposing factors (socio-demographic and HIV knowledge) and the need-for-care factors (sexual risk behaviors) predict healthcare utilization services (HIV testing) in our study; however, only socio-demographic model explained most of the variance in HIV testing. The low effect of model testing could be related to the limited number of major variables selected for HIV knowledge and sexual risk behavior models. Thus, consideration for more variables is required for future studies

Entecavir Treatment in Children and Adolescents with Chronic Hepatitis B Virus Infection

The aim of this study was to investigate the treatment response of entecavir (ETV) in children and adolescents with chronic hepatitis B (CHB) who acquired infection perinatally or during early childhood. Methods: A total of nine treatment-naïve patients [median aged 12.2 years (range: 2.6–18.0); five girls and four boys], with hepatitis B e antigen (HBeAg) seropositive > 6 months, alanine aminotransferase (ALT) > 2 times of upper limit of normal value (30 IU/L), were enrolled for ETV therapy. They received ETV therapy with a dose of 0.015 mg/kg/d, with a maximal dose of 0.5 mg daily for at least 52 weeks. Another 27 untreated CHB patients matched for age, sex, ALT levels, and HBeAg status were recruited as the control group. A complete response at 48–52 weeks was defined as follows: (1) normalization of ALT; (2) undetectable hepatitis B virus DNA; and (3) HBeAg/anti-HBe seroconversion. All 36 patients were retrospectively reviewed for their biochemical, serological, and virologic responses. Results: ETV-treated patients achieved rapid ALT normalization (all before 8 months of treatment) compared with the control group (p < 0.001) and they had a greater chance of achieving undetectable HBV DNA levels at Week 52 after treatment (55.6% vs. 11.1%, p = 0.013). The cumulative incidence rates of HBeAg seroconversion were similarly high in both groups (ETV group 44% at 1 year 78% at 2 years; control group 37% at 1 year 63% at 2 years, respectively). The ETV group also had a trend of better complete response than the control group (22.2% vs. 0%, p = 0.057). None of the ETV-treated patients reported significant adverse effects. Conclusion: Entecavir for pediatric CHB treatment is safe and shows clinical benefits in short-term biochemical and virologic responses. Further studies to determine long-term remission and drug resistance are required