Connective Tissue News

The editor welcomes for publication short news items of interest to readers of this journal, and especially details of forthcoming symposia and conferences concerned with subjects pertinent to the field.     

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

The aldo-keto reductase (AKR) superfamily comprises enzymes that catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. Substrates of AKRs include glucose, steroids, glycosylation end-products, lipid peroxidation products, and environmental pollutants. These proteins adopt a (β /α )₈ barrel structural motif interrupted by a number of extraneous loops and helixes that vary between proteins and bring structural identity to individual families. The human AKR family differs from the rodent families. Due to their broad substrate specificity, AKRs play an important role in the phase II detoxification of a large number of pharmaceuticals, drugs, and xenobiotics.     

Development of drug-in-adhesive transdermal patch for α-asarone and in vivo pharmacokinetics and efficacy evaluation

A transdermal drug delivery system has been reported that can increase the bioavailability, reduce the administration duration, and maintain the concentration of drug in blood. In the present study, drug-in-adhesive transdermal patches of α-asarone using Eudragit E100 as pressure-sensitive adhesives and oleic acid plus isopropyl myristate as penetration co-enhancers were developed. In vitro permeation, in vivo pharmacokinetics in rabbits, and efficacy in asthmatic rats were evaluated. The results showed that co-enhancers could induce a synergistic effect on α-asarone permeability. In vivo study suggested that the patch can keep a relatively certain blood level of drug within 10–30?h in rabbits. Furthermore, the patch with the size of 4?cm² containing drug 3?mg/cm² showed a noticeable treating effect on asthmatic rats which is equivalent to the effect of dexamethasone, while avoiding the side-effect induced by the corticorsteroid. This suggests that the drug-in-adhesive transdermal patch is a promising delivery system containing α-asarone to be used for asthma treatment.     

MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth

FGF2 and VEGFA are the two most potent angiogenic factors. Here we report that miR-503 can simultaneously down-regulate FGF2 and VEGFA. The expression of miR-503 is repressed in HCC cells and primary tumors due to a potential epigenetic mechanism. Overexpression of miR-503 reduced tumor angiogenesis in vitro and in vivo. We also found that miR-503 expression was down-regulated by hypoxia through HIF1α. These results identify a miRNA that targets both FGF2 and VEGFA in cancers, demonstrate the anti-angiogenesis role of miR-503 in tumorigenesis, and provide a novel mechanism for hypoxia-induced FGF2 and VEGFA through HIF1α-mediated inhibition of miR-503.     

STEAP4 and HIF-1α gene expressions in visceral and subcutaneous adipose tissue of the morbidly obese patients

Aim and backgroundObesity is a multifactorial disease in which environmental and genetic factors play an integrated role. Determining such target genes will help to elucidate the mechanisms underlying complex diseases such as obesity and diabetes which are usually seen together. Present study investigates the expression levels of STEAP4 and HIF-1α in visceral and subcutaneous adipose tissue.Patients and methods30(6 M) morbidly obese patients undergoing bariatric surgery were included in the study. The patients were grouped according to the BMI as Group I (BMI <50 kg/m²) and Group II (BMI ≥50 kg/m²). Samples from visceral (omentum) and subcutaneous adipose tissues were obtained from each patient and real-time PCR (qPCR) was carried out for STEAP4 and HIF-1α gene expressions. Correlations between expression levels and clinical parameters were analyzed.ResultsMean age of the patients recruited to the study was 37.4 (18–64) years. Mean BMI was 46 (36–60) kg/m². STEAP4 expression in visceral adipose tissue was significantly higher than subcutaneous tissue. Visceral STEAP4 expression was also found to be reduced with increased BMI. It was also lower in patients with HbA₁C over 6. Furthermore, expression of subcutaneous and visceral HIF-1α was significantly higher in Group II. There was a significant correlation between BMI, glycosylated hemoglobin, STEAP4 and HIF-1α gene expression.ConclusionsObesity and related disease are linked with the fact that there is a low grade inflammation in the adipose tissue of the obese individuals. Counter-regulatory processes such as STEAP4 protein family are overwhelmed by the proinflammatory stimuli. HIF-1α expression is increased due to tissue hypoxia and pro-inflammatory stimuli in the obese individuals, which results in increased visceral STEAP4 expressions.     

Autoimmune bone marrow environment severely inhibits B cell development by inducing extensive cell death and inhibiting proliferation

Plasmacytoid dendritic cell (PDC) is a Th2-type dendritic cell precursor. It is an important professional effector cell characterized by its capacities to produce large amount of alpha interferon and to differentiate into dendritic cell. PDCs are scarce in normal condition. They circulate in the blood as veiled cells and enter the lymph node and mucosal site in response to immune stimulation. Besides the recent and wide-open field of the implication of PDCs in inflammatory diseases and in the microenvironment of solid or lymphoid tumours it has also been observed that PDCs can also be tumoral cells. In this paper, the authors present the different tumours thought to be originating from tumoral PDCs. To date, two kinds of tumoral conditions are recognized: the so-called PDCs proliferations in patients with myeloid disorders and the blastic plasmacytoid dendritic cell neoplasm. These two entities are exposed and discussed.     

Devitalisierimg Ron Lebenden Pulpen Durch Diathermic

Zusammenfassung

Die Koagulierung der vitalen Pulpa mittels Diathermie wird, im Vergleich zu der Arsenik-Devitalisation und der Vital-Exstirpation, als günstig hervorgehoben. Die Vorteile sind: Koagulation, Exstirpation und Wurzelfüllung können in einer Sitzung stattfinden. Ausser Zeitgewinn, bedeutet dies eine Verminderung der Infektionsgefahr von aussen. Wir erhalten eine reine, aseptische Wundfläche, welche leicht zu heilen ist. Eest-Pulpitiden und Nachblutungen sind nicht eingetroffen. Klinischrontgenologische Untersuchung von 116 Fällen mit einer Kontrollzeit von 4 bis 40 Monaten, zeigt, dass die Wurzelfüllung in 97% der Falle als gelungen zu betrachten ist. Die Behandlung wurde unter Anästhesie ausgeführt. Die anderweitig vermuteten Nachteile, u. a. die Gefahr fiir Verbrennung, wurden nicht von der Untersuchung bestatigt.     

Local and systemic tolerability of a 2′O-methoxyethyl antisense oligonucleotide targeting interleukin-4 receptor-α delivery by inhalation in mouse and monkey

Abstract

Antisense oligonucleotides (ASOs) bind and facilitate degradation of RNA and inhibit protein expression in pathways not easily targeted with small molecules or antibodies. Interleukin (IL)-4 and IL-13 potentiate signaling through the shared IL-4 receptor-α (IL-4Rα) subunit of their receptors. ASO targeting of IL-4Rα mRNA in a mouse model of asthma led to attenuation of airway hyperactivity, demonstrating potential benefit in asthma patients. This study focused on tolerability of inhaled IL-4Rα-targeting ASOs. Toxicity studies were performed with mouse- (ISIS 23189) and human-specific (ISIS 369645) sequences administered by inhalation. Four week (monkey) or 13 week (mouse) repeat doses at levels of up to 15?mg/kg/exposure (exp) and 50?mg/kg/exp, respectively, demonstrated dose-dependent effects limited to increases in macrophage size and number in lung and tracheobronchial lymph nodes. The changes were largely non-specific, reflecting adaptive responses that occur during active exposure and deposition of ASO and other material in the lung. Reversibility was observed at a rate consistent with the kinetics of tissue clearance of ASO. Systemic bioavailability was minimal, and no systemic toxicity was observed at exposure levels appreciably above pharmacological doses and doses proposed for clinical trials.     

Inhibition of Staphylococcus Aureus Mediated by Extracts from Iranian Plants

In order to find new antibacterial agents effective against Staphylococcus aureus, ethanolic extracts of 10 plants were tested. S. aureus (489 samples) were isolated either from healthy carriers (nose and throat) or clinical samples. Out of 489 isolates tested, 98.6% were sensitive to trimethoprim-sulfamethoxazole which was used as the reference antibiotic. From the plant extracts screened for antibacterial activity, Myrtus communis L. (leaves) had the greatest activity, inhibiting the growth of 99% of the isolates. Glycyrrhiza glabra L., Eucalyptus globolus Labill and Menta viridis L., were also active against the isolates inhibiting the growth of 90, 59.5 and 48.7% of the isolates, respectively. All of these extracts were active against the reference strains of S. aureus tested. Saturia hortensis L., Teucrium polium L., and Achillea santolina L., had very little antibacterial activity, while Trigonella foenum graecum L., Echium amoenum Fisch & Mey (flowers) and Juglans regia L. (leaves), had no antibacterial activity against the bacterial isolates.