RNAapt3D: RNA aptamer 3D-structural modeling database.

RNA aptamers are oligonucleotides with high binding affinity and specificity for target molecules and are expected to be a new generation of therapeutic molecules and targeted delivery materials. The tertiary structure of RNA molecules and RNA-protein interaction sites are increasingly important as potential targets for new drugs. The pathological mechanisms of diseases must be understood in detail to guide drug design. In developing RNA aptamers as drugs, information about the interaction mechanisms and structures of RNA aptamer-target protein complexes are useful. We constructed a database, RNA aptamer 3D-structural modeling (RNAapt3D), consisting of RNA aptamer data that are potential drug candidates. The database includes RNA sequences and computationally predicted RNA tertiary structures based on secondary structures and implements methods that can be used to predict unknown structures of RNA aptamer-target molecule complexes. RNAapt3D should enable the design of RNA aptamers for target molecules and improve the efficiency and productivity of candidate drug selection. RNAapt3D can be accessed at https://rnaapt3d.medals.jp.

Estimation of autistic children by metallomics analysis.

Clarification of the pathogenesis and treatment of autism spectrum disorders is one of the challenges today. In this study, we examine scalp hair concentrations of 26 trace elements for 1,967 children with autistic disorders (1,553 males and 414 females). Five-hundred and eighty-four (29.7%), 347 (17.6%) and 114 (5.8%) subjects was found deficient in zinc, magnesium and calcium, respectively, and 2.0% or less in the other essential metals. The incidence rate of mineral deficiency was highly observed in infants aged 0-3 year-old. In contrast, 339 (17.2%), 168 (8.5%) and 94 (4.8%) individuals was found suffering from high burden of aluminium, cadmium and lead, and 2.8% or less from mercury and arsenic burden. These findings suggest that infantile zinc- and magnesium-deficiency and/or toxic metal burdens may epigenetically play principal roles as environmental factors in autistic disorders and that metallomics approach may lead to early screening and prevention of the neurodevelopment disorders.

Two age-related accumulation profiles of toxic metals.

In order to investigate the body burden levels of toxic metals in Japanese, five toxic metal concentrations in scalp hair samples from 28,424 subjects from infant to elderly were determined with inductively coupled plasma mass spectrometry (ICP-MS). The geometric mean of hair mercury concentrations showed a high-significant age-correlated increase (r = 0.341, p < 0.0001) with a peak at the 6th decade of life and then decreased with further aging in both sexes. The mean mercury concentrations in male adults were significantly higher than those in female (p < 0.001), indicating the gender difference (male > female) in mercury accumulation. Arsenic also showed a similar accumulation profile with age dependency and gender difference in adult subjects. In contrast, cadmium, lead and aluminium exhibited another type of accumulation profile: the highest burden level was observed in infants aged 0-3 years old for every element in both sexes. In addition, cadmium was found to have a character accumulating in aged females, with significant age-dependency (r = 0.134, p < 0.0001) and gender difference (female > male). These findings suggest that toxic metals are classified into two families on the basis of their accumulation profiles, and that the three elements of mercury, arsenic and cadmium which accumulate age-dependently in adults, may play a role in aging process and higher burden with them may lead to acceleration of aging.

Infantile zinc deficiency: association with autism spectrum disorders.

Elucidation of the pathogenesis and effective treatment of autism spectrum disorders is one of the challenges today. In this study, we examine hair zinc concentrations for 1,967 children with autistic disorders (1,553 males and 414 females), and show considerable association with zinc deficiency. Histogram of hair zinc concentration was non-symmetric with tailing in lower range, and 584 subjects were found to have lower zinc concentrations than -2 standard deviation level of its reference range (86.3-193 ppm). The incidence rate of zinc deficiency in infant group aged 0-3 year-old was estimated 43.5 % in male and 52.5 % in female. The lowest zinc concentration of 10.7 ppm was detected in a 2-year-old boy, corresponding to about 1/12 of the control mean level. These findings suggest that infantile zinc deficiency may epigenetically contribute to the pathogenesis of autism and nutritional approach may yield a novel hope for its treatment and prevention.

Metallomics study using hair mineral analysis and multiple logistic regression analysis: relationship between cancer and minerals.

OBJECTIVES: The objective of this metallomics study is to investigate comprehensively some relationships between cancer risk and minerals, including essential and toxic metals. METHODS: Twenty-four minerals including essential and toxic metals in scalp hair samples from 124 solid-cancer patients and 86 control subjects were measured with inductively coupled plasma mass spectrometry (ICP-MS), and the association of cancer with minerals was statistically analyzed with multiple logistic regression analysis. RESULTS: Multiple logistic regression analysis demonstrated that several minerals are significantly correlated to cancer, positively or inversely. The most cancer-correlated mineral was iodine (I) with the highest correlation coefficient of r = 0.301, followed by arsenic (As; r = 0.267), zinc (Zn; r = 0.261), and sodium (Na; r = 0.190), with p < 0.01 for each case. In contrast, selenium (Se) was inversely correlated to cancer (r = -0.161, p < 0.05), followed by vanadium (V) (r = -0.128). Multiple linear regression value was highly significantly correlated with probability of cancer (R (2) = 0.437, p < 0.0001), and the area under the receiver-operating characteristic (ROC) curve was calculated to be 0.918. In addition, using contingency table analysis and the chi-square test, the precision of discrimination for cancer was estimated to be 0.871 (chi-square = 99.1, p < 0.0001). CONCLUSIONS: These findings suggest that some minerals such as arsenic, selenium, and probably iodine, zinc, sodium, and vanadium contribute to regulation of cancer and also that metallomics study using multiple logistic regression analysis is a useful tool for estimating cancer risk.

Monomeric A beta and metals reduce their cytotoxicities to each other.

The present study has examined the effect of metals, such as iron and copper on the cytotoxicity of amyloid beta protein 1-40 (Abeta40). First, we showed that monomeric Abeta40 has stronger cytotoxicity than various type of aggregated Abeta40. Next we showed the addition of metals into the monomeric Abeta40 reduced the cytotoxicity of either monomeric Abeta40 or metals (iron and copper) although the addition of metals into monomeric Abeta40 resulted in a marked increase of aggregated form of Abeta40, which composed of beta-sheeted Abeta40 and Abeta40 aggregation not characterized by beta-sheet fibrils (coagrated Abeta40). Taken together, the metals and monomeric Abeta40 affect on each other and cause the reduction of their cell toxicity.

RGMa inhibition promotes axonal growth and recovery after spinal cord injury.

Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We report RGMa as a potent inhibitor of axon regeneration in the adult central nervous system (CNS). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the RhoA-Rho kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is induced around the injury site after spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration.

Metals accelerate production of the aberrant splicing isoform of the presenilin-2.

Oxidative stress is a major risk factor for Alzheimer's disease (AD) and other neurodegenerative disorders. Metals are known to be one of the factors that contribute to oxidative stress. Recently, we reported that the aberrant splicing isoform (PS2V) generated by skipping exon5 of the presenilin-2 (PS2) gene is a diagnostic feature of sporadic AD (SAD). PS2V is inducible by exposure of human neuroblastoma to hypoxia. We examined whether this aberrant splicing was caused by metal-induced oxidative stress, such as exposure to aluminum. As a result, we demonstrated that exposure to aluminum accelerated PS2V production induced by hypoxia. This acceleration of the production of PS2V to hypoxia was caused by chronic aluminum exposure, but was not related to the intracellular content of aluminum. HMGA1a is a mediator of PS2V production, and it was induced by aluminum as well as by hypoxia. Induction of HMGA1a was increased by chronic exposure to aluminum, and a nuclear extract containing HMGA1a bound to a specific sequence on exon5 of PS2 pre-mRNA, as reported previously. Finally, the acceleration of PS2V production induced by aluminum under hypoxic conditions reflected, but has not yet been directly shown to cause, vulnerability to endoplasmic reticulum stress. These results suggest that exposure to some metals can accelerate and enhance PS2V generation, and that hypoxia plus chronic exposure to metals may promote the development of AD.