Taurine resumed neuronal differentiation in arsenite-treated N2a cells through reducing oxidative stress,endoplasmic reticulum stress,and mitochondrial dysfunction

The goal of the study is to investigate the preventive effect of taurine against arsenite-induced arrest of neuronal differentiation in N2a cells. Our results revealed that taurine reinstated the neurite outgrowth in arsenite-treated N2a cells. Meanwhile, arsenite-induced oxidative stress and mitochondrial dysfunction as well as degradation of mitochondria DNA (mtDNA) were also inhibited by co-treatment of taurine. Since oxidative stress and mitochondrial dysfunction is closely associated with endoplasmic reticulum (ER) stress, we further examined indicators of ER stress, 78 kDa glucose-regulated protein (GRP78), and C/EBP-homologous protein (CHOP) protein expression. The results demonstrated that taurine significantly reduced arsenite-induced ER stress in N2a cells. In the parallel experiment, arsenite-induced disruption of intracellular calcium homeostasis was also ameliorated by taurine. The proven bio-function of taurine preserved a preventive effect against deleteriously cross-talking between oxidative stress, mitochondria, and ER. Overall, the results of the study suggested that taurine reinstated neuronal differentiation by inhibiting oxidative stress, ER stress, and mitochondrial dysfunction in arsenite-treated N2a cells.     

Mapping the Fitness Landscape of Gene Expression Uncovers the Cause of Antagonism and Sign Epistasis between Adaptive Mutations

How do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? Here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of Methylobacterium extorquens to uncover the fitness landscape defined by gene expression levels. We found strong antagonism and sign epistasis between these beneficial mutations. Mutations with the largest individual benefit interacted the most antagonistically with other mutations, a trend we also uncovered through analyses of datasets from other model systems. However, these beneficial mutations interacted multiplicatively (i.e., no epistasis) at the level of enzyme expression. By generating a model that predicts fitness from enzyme levels we could explain the observed sign epistasis as a result of overshooting the optimum defined by a balance between enzyme catalysis benefits and fitness costs. Knowledge of the phenotypic landscape also illuminated that, although the fitness peak was phenotypically far from the ancestral state, it was not genetically distant. Single beneficial mutations jumped straight toward the global optimum rather than being constrained to change the expression phenotypes in the correlated fashion expected by the genetic architecture. Given that adaptation in nature often results from optimizing gene expression, these conclusions can be widely applicable to other organisms and selective conditions. Poor interactions between individually beneficial alleles affecting gene expression may thus compromise the benefit of sex during adaptation and promote genetic differentiation.     

The effects of patchouli alcohol and combination with cisplatin on proliferation,apoptosis and migration in B16F10 melanoma cells

Melanoma is a highly metastatic cancer with a low incidence rate, but a high mortality rate. Patchouli alcohol (PA), a tricyclic sesquiterpene, is considered the main active component in Pogostemon cablin Benth, which improves wound healing and has anti-tumorigenic activity. However, the pharmacological action of PA on anti-melanoma remains unclear. Thus, the present study aimed to investigate the role of PA in the proliferation, cell cycle, apoptosis and migration of melanoma cells. These results indicated that PA selectively inhibited the proliferation of B16F10 cells in a dose- and time-dependent manner. It induced cell cycle arrest at the G₀/G₁ phase and typical morphological changes in apoptosis, such as chromatin condensation, DNA fragmentation and apoptotic bodies. In addition, PA reduced the migratory ability of B16F10 cells by upregulating E-cadherin and downregulating p-Smad2/3, vimentin, MMP-2 and MMP-9 expression. PA was also found to strongly suppress tumour growth in vivo. Furthermore, PA combined with cisplatin synergistically inhibited colony formation and migration of B16F10 cells and attenuated the development of resistance to treatment. Therefore, the results of this study indicate that PA may play a pivotal role in inducing apoptosis and reducing the migration of melanoma cells, and may thus be a potential candidate for melanoma treatment.     

Identification of low-frequency modes in protein molecules.

It is demonstrated that the observed low-frequency motions with wave numbers of 22 cm-1 and 25 cm-1 for insulin and lysozyme respectively originate from the accordion-like motions of the principal helices therein. The calculated results based on such a model are in good agreement with the observed values. During calculations the role of the internal microenvironment upon the low-frequency motion is naturally revealed, so as to elucidate as well why this kind of low-frequency motion is so sensitive to the conformations of proteins observed.     

Zinc deficiency-induced iron accumulation, a consequence of alterations in iron regulatory protein-binding activity, iron transporters, and iron storage proteins

One consequence of zinc deficiency is an elevation in cell and tissue iron concentrations. To examine the mechanism(s) underlying this phenomenon, Swiss 3T3 cells were cultured in zinc-deficient (D, 0.5 microM zinc), zinc-supplemented (S, 50 microM zinc), or control (C, 4 microM zinc) media. After 24 h of culture, cells in the D group were characterized by a 50% decrease in intracellular zinc and a 35% increase in intracellular iron relative to cells in the S and C groups. The increase in cellular iron was associated with increased transferrin receptor 1 protein and mRNA levels and increased ferritin light chain expression. The divalent metal transporter 1(+)iron-responsive element isoform mRNA was decreased during zinc deficiency-induced iron accumulation. Examination of zinc-deficient cells revealed increased binding of iron regulatory protein 2 (IRP2) and decreased binding of IRP1 to a consensus iron-responsive element. The increased IRP2-binding activity in zinc-deficient cells coincided with an increased level of IRP2 protein. The accumulation of IRP2 protein was independent of zinc deficiency-induced intracellular nitric oxide production but was attenuated by the addition of the antioxidant N-acetylcysteine or ascorbate to the D medium. These data support the concept that zinc deficiency can result in alterations in iron transporter, storage, and regulatory proteins, which facilitate iron accumulation.     

Two non-homologous brain diseases-related genes, <Emphasis Type="Italic">SERPINI1</Emphasis> and <Emphasis Type="Italic">PDCD10</Emphasis>, are tightly linked by an asymmetric bidirectional promoter in an evolutionarily conserved manner

Background  

Despite of the fact that mammalian genomes are far more spacious than prokaryotic genomes, recent nucleotide sequencing data have revealed that many mammalian genes are arranged in a head-to-head orientation and separated by a small intergenic sequence. Extensive studies on some of these neighboring genes, in particular homologous gene pairs, have shown that these genes are often co-expressed in a symmetric manner and regulated by a shared promoter region. Here we report the identification of two non-homologous brain disease-related genes, with one coding for a serine protease inhibitor (SERPINI1) and the other for a programmed cell death-related gene (PDCD10), being tightly linked together by an asymmetric bidirectional promoter in an evolutionarily conserved fashion. This asymmetric bidirectional promoter, in cooperation with some cis-acting elements, is responsible for the co-regulation of the gene expression pattern as well as the tissue specificity of SERPINI1 and PDCD10.     

Predictions of bone remodeling around dental implant systems

This study presents the implementation of a mathematical bone remodeling algorithm to bone adaptation in the premolar area of the mandible around various dental implant systems, and thus sheds a new perspective to the complex interactions in dental implant mechanics. A two-dimensional, plane strain model of the bone was built from a CT-scan. The effect of implant contour on internal bone remodeling was investigated by considering four dental implant systems with contours similar to commercially available ones and another four with cylindrical and conical cross-sections. The remodeling algorithm predicts non-homogeneous density/elastic modulus distribution; and, implant contour has some effect on how this is distributed. Bone density is predicted to increase on the tips of the threads of the implants, but to decrease inside the grooves. Threadless implants favor to develop a softer bone around their periphery, compared to implant systems that have threads. The overall contour (dimensions and the shape) of an implant affect the bone density redistribution, but the differences between different implant systems are relatively small.     

Utility of a Histone Deacetylase Inhibitor (PXD101) for Thyroid Cancer Treatment

Background

We evaluated the therapeutic effects of the histone deacetylase inhibitor PXD101 alone and in combination with conventional chemotherapy in treating thyroid cancer.

Methodology/Principal Findings

We studied eight cell lines from four types of thyroid cancer (papillary, follicular, anaplastic and medullary). The cytotoxicity of PXD101 alone and in combination with three conventional chemotherapeutic agents (doxorubicin, paclitaxel and docetaxel) was measured using LDH assay. Western blot assessed expression of acetylation of histone H3, histone H4 and tubulin, proteins associated with apoptosis, RAS/RAF/ERK and PI3K/AKT/mTOR signaling pathways, DNA damage and repair. Apoptosis and intracellular reactive oxygen species (ROS) were measured by flow cytometry. Mice bearing flank anaplastic thyroid cancers (ATC) were daily treated with intraperitoneal injection of PXD101 for 5 days per week. PXD101 effectively inhibited thyroid cancer cell proliferation in a dose-dependent manner. PXD101 induced ROS accumulation and inhibited RAS/RAF/ERK and PI3K/mTOR pathways in sensitive cells. Double-stranded DNA damage and apoptosis were induced by PXD101 in both sensitive and resistant cell lines. PXD101 retarded growth of 8505C ATC xenograft tumors with promising safety. Combination therapy of PXD101with doxorubicin and paclitaxel demonstrated synergistic effects against four ATC lines in vitro.

Conclusions

PXD101 represses thyroid cancer proliferation and has synergistic effects in combination with doxorubicin and paclitaxel in treating ATC. These findings support clinical trials using PXD101 for patients with this dismal disease.     

A Two-Level Computation Model Based on Deep Learning Algorithm for Identification of piRNA and Their Functions via Chou’s 5-Steps Rule

International Journal of Peptide Research and Therapeutics - Piwi interacting RNA (piRNA) molecules belong to a largest class of small non coding RNA molecules which are originally discovered in...