A novel prenylated C6–C3 compound with estrogen-like activity from the fruits of Illicium arborescens

A novel C₆–C₃ prenylated compound, illicarborene A (1), together with illioliganfunone D (2), 1-allyl-3,5-dimethoxy-4-(3-methylbut-2-enyloxy)benzene (3), (?)-illicinone A (4), (?)-illicinone B (5) and (?)-illicinone A derivative (6) was isolated and characterized from the fruits of Illicium arborescens Hayata. Compound 1 possesses a new class of tricyclic 6/6/5 ring system. The structure of 1 was determined by spectroscopic analysis such as ¹H–¹H COSY, HMQC, HMBC, and NOESY, and confirmed by chemical reaction to yield 7. Compounds 1–5 were found to increase proliferative activity in primary cell culture of osteoblast cells.     

Formalin-Inactivated EV71 Vaccine Candidate Induced Cross-Neutralizing Antibody against Subgenotypes B1, B4, B5 and C4A in Adult Volunteers

Background

Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia. No effective EV71 vaccine is available. A randomized and open-label phase I clinical study registered with ClinicalTrials.gov #NCT01268787, aims to evaluate the safety, reactogenicity and immunogenicity of a formalin-inactivated EV71 vaccine candidate (EV71vac) at 5- and 10-µg doses. In this study we report the cross-neutralizing antibody responses from each volunteer against different subgenotypes of EV71 and CVA16.

Methods

Sixty eligible healthy adults were recruited and vaccinated. Blood samples were obtained on day 0, 21 and 42 and tested against B1, B4, B5, C2, C4A, C4B and CVA16 for cross-neutralizing antibody responses.

Results

The immunogenicity of both 5- and 10- µg doses were found to be very similar. Approximately 45% of the participants had <8 pre-vaccination neutralization titers (Nt) against the B4 vaccine strain. After the first EV71vac immunization, 95% of vaccinees have >4-fold increase in Nt, but there was no further increase in Nt after the second dose. EV71vac induced very strong cross-neutralizing antibody responses in >85% of volunteers without pre-existing Nt against subgenotype B1, B5 and C4A. EV71vac elicited weak cross-neutralizing antibody responses (∼20% of participants) against a C4B and Coxsackie virus A16. Over 90% of vaccinated volunteers did not develop cross-neutralizing antibody responses (Nt<8) against a C2 strain. EV71vac can boost and significantly enhance the neutralizing antibody responses in volunteers who already had pre-vaccination antibodies against EV71 and/or CVA16.

Conclusion

EV71vac is efficient in eliciting cross-neutralizing antibody responses against EV71 subgenotypes B1, B4, B5, and C4A, and provides the rationale for its evaluation in phase II clinical trials.

Trial Registration

ClinicalTrials.gov __NCT01268787     

Hyperthyroidism and Risk for Bipolar Disorders: A Nationwide Population-Based Study

Background

Thyroid disorders have long been associated with psychiatric illness, often with symptoms suggestive of mood disorders. The most common clinical features associated with hyperthyroidism are anxiety and depression. The risk of bipolar disorders, especially bipolar mania, among patients with thyroid disorders has not been well characterized.

Objective

We explored the relationship of hyperthyroidism and the subsequent development of bipolar disorders, and examined the risk factors for bipolar disorders in patients with hyperthyroidism.

Methods

We identified patients who were diagnosed with hyperthyroidism between 2000 and 2010 in the Taiwan National Health Insurance Research Database. A comparison cohort without hyperthyroidism was matched based on age, sex, and comorbidities. The occurrence of bipolar disorders was evaluated in both cohorts based on diagnosis and the use of mood stabilizer drugs.

Results

The hyperthyroidism cohort consisted of 21, 574 patients, and the comparison cohort consisted of 21, 574 matched control patients without hyperthyroidism. The incidence of bipolar disorders (incidence rate ratio [IRR], 2.31, 95% CI 1.80–2.99, P<.001) was higher for the hyperthyroidism patients than the control patients. Multivariate, matched regression models showed that women (HR 2.02, 95% CI 1.34–3.05, P = .001), patients with alcohol use disorders (HR 3.03, 95% CI 1.58–5.79, P = .001), and those with asthma (HR 1.70, 95% CI 1.18–2.43, P = .004) were independent risk factors for the development of bipolar disorders in hyperthyroidism patients.

Conclusions

Although a possibility that the diagnosis of bipolar disorders in this study actually includes "bipolar disorders due to hyperthyroidism" cannot be excluded, this study suggests that hyperthyroidism may increase the risk of developing bipolar disorders.     

Celecoxib-Induced Cytotoxic Effect Is Potentiated by Inhibition of Autophagy in Human Urothelial Carcinoma Cells

Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, can elicit anti-tumor effects in various malignancies. Here, we sought to clarify the role of autophagy in celecoxib-induced cytotoxicity in human urothelial carcinoma (UC) cells. The results shows celecoxib induced cellular stress response such as endoplasmic reticulum (ER) stress, phosopho-SAPK/JNK, and phosopho-c-Jun as well as autophagosome formation in UC cells. Inhibition of autophagy by 3-methyladenine (3-MA), bafilomycin A1 or ATG7 knockdown potentiated celecoxib-induced apoptosis. Up-regulation of autophagy by rapamycin or GFP-LC3B-transfection alleviated celecoxib-induced cytotoxicity in UC cells. Taken together, the inhibition of autophagy enhances therapeutic efficacy of celecoxib in UC cells, suggesting a novel therapeutic strategy against UC.     

Combining a bio-based polymer and a natural antifoulant into an eco-friendly antifouling coating

Abstract

Biodegradable polymers are promising binders and carriers for natural antifoulants. In the present study, an antifouling (AF) coating was developed by adding a non-toxic AF compound (butenolide) to a bio-based and biodegradable poly(lactic acid)-based polyurethane. Mass loss measurement showed that the polymer degraded in seawater at a rate of 0.013?mg cm^?2?day^?1. Measurements showed that butenolide was released from the coatings into seawater over a period of at least three months. Both the concentration of butenolide in the coatings and the ambient temperature determined the release rate of butenolide. The results further demonstrate that incorporating rosin into the coatings increase the self-renewal rate of the polymer and facilitated the long-term release of butenolide from the coating. The results show that poly(lactic acid)-based polyurethane is a suitable polymer for butenolide-based AF coatings.     

The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current I_Na and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on I_Na. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca²⁺ and Na⁺ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.     

PRASA: An integrated web server that analyzes protein interaction types

This work presents the Protein Association Analyzer (PRASA) (http://zoro.ee.ncku.edu.tw/prasa/) that predicts protein interactions as well as interaction types. Protein interactions are essential to most biological functions. The existence of diverse interaction types, such as physically contacted or functionally related interactions, makes protein interactions complex. Different interaction types are distinct and should not be confused. However, most existing tools focus on a specific interaction type or mix different interaction types. This work collected 7234058 associations with experimentally verified interaction types from five databases and compiled individual probabilistic models for different interaction types. The PRASA result page shows predicted associations and their related references by interaction type. Experimental results demonstrate the performance difference when distinguishing between different interaction types. The PRASA provides a centralized and organized platform for easy browsing, downloading and comparing of interaction types, which helps reveal insights into the complex roles that proteins play in organisms.     

Shining light on nanotechnology to help repair and regeneration

Phototherapy can be used in two completely different but complementary therapeutic applications. While low level laser (or light) therapy (LLLT) uses red or near-infrared light alone to reduce inflammation, pain and stimulate tissue repair and regeneration, photodynamic therapy (PDT) uses the combination of light plus non-toxic dyes (called photosensitizers) to produce reactive oxygen species that can kill infectious microorganisms and cancer cells or destroy unwanted tissue (neo-vascularization in the choroid, atherosclerotic plaques in the arteries). The recent development of nanotechnology applied to medicine (nanomedicine) has opened a new front of advancement in the field of phototherapy and has provided hope for the development of nanoscale drug delivery platforms for effective killing of pathological cells and to promote repair and regeneration. Despite the well-known beneficial effects of phototherapy and nanomaterials in producing the killing of unwanted cells and promoting repair and regeneration, there are few reports that combine all three elements i.e. phototherapy, nanotechnology and, tissue repair and regeneration. However, these areas in all possible binary combinations have been addressed by many workers. The present review aims at highlighting the combined multi-model applications of phototherapy, nanotechnology and, reparative and regeneration medicine and outlines current strategies, future applications and limitations of nanoscale-assisted phototherapy for the management of cancers, microbial infections and other diseases, and to promote tissue repair and regeneration.