Age-dependent expression of ion channel genes in rat

Ion channels regulate a large number of cellular functions and their functional role in many diseases makes them potential therapeutic targets. Given their diverse distribution across multiple organs, the roles of ion channels, particularly in age-associated transcriptomic changes in specific organs, are yet to be fully revealed.Using RNA-seq data, we investigated the rat transcriptomic profiles of ion channel genes across 11 organs/tissues and 4 developmental stages in both sexes of Fischer 344 rats and identify tissue-specific and age-dependent changes in ion channel gene expression. Organ-enriched ion channel genes were identified. In particular, the brain showed higher tissue-specificity of ion channel genes, including Gabrd, Gabra6, Gabrg2, Grin2a, and Grin2b. Notably, age-dependent changes in ion channel gene expression were prominently observed in the thymus, including in Aqp1, Clcn4, Hvcn1, Itpr1, Kcng2, Kcnj11, Kcnn3, and Trpm2. Our comprehensive study of ion channel gene expression will serve as a primary resource for biological studies of aging-related diseases caused by abnormal ion channel functions.

Nobiletin Exhibits Neuroprotective Effects against Mitochondrial Complex I Inhibition via Regulating Apoptotic Signaling

Nobiletin, a polymethoxylated flavonoid found in citrus, has been studied because of its modulatory functions in cellular signaling cascades, and effects to prevent mitochondrial calcium overload and neuronal cell death. Particularly, we previously reported that nobiletin induced changes in the mitochondrial membrane potential through K + channel regulation, suggesting that nobiletin might exert neuroprotective effects via regulating mitochondrial functions associated with the electron transport chain (ETC) system. This study investigated whether nobiletin regulated mitochondrial dysfunction mediated by ETC system downregulation by inhibiting complex I (CI) and complex III (CIII) in pure mitochondria and the cortical neurons of rats. The results showed that nobiletin significantly reduced mitochondrial reactive oxygen species (ROS) production, inhibited apoptotic signaling, enhanced ATP production and then restored neuronal viability under conditions of CI inhibition, but not CIII inhibition.These effects were attributed to the downregulation of translocation of apoptosis-induced factor (AIF), and the upregulation of CI activity and the expression of antioxidant enzymes such as Nrf2 and HO-1. Together with our previous study, these results indicate that the neuroprotective effects of nobiletin under mitochondrial dysfunction may be associated with its function to activate antioxidant signaling cascades. Our findings suggest the possibility that nobiletin has therapeutic potential in treating oxidative neurological and neurodegenerative diseases mediated by mitochondrial dysfunction.

Prenatal Exposure to High Cortisol Induces ADHD-like Behaviors with Delay in Spatial Cognitive Functions during the Post-weaning Period in Rats

High levels of cortisol in blood are frequently observed in patients with major depressive disorders and increased cortisol level induces depressivelike symptoms in animal models. However, it is still unclear whether maternal cortisol level during pregnancy is a critical factor resulting in neuropsychiatric disorders in offspring. In this study, we increased cortisol level in rats by repetitively injecting corticosterone subcutaneously (Corti.Mom, 20 mg/kg/day) during pregnancy and evaluated the behavioral patterns of their pups (Corti.Pups) via forced swimming (FS), open field (OF), elevated plus maze (EPM) and Morris water maze (MWM) tests during the immediate post-weaning period (postnatal day 21 to 25). In results, corticosterone significantly increased plasma cortisol levels in both Corti.Moms and Corti.Pups. Unlike depressive animal models, Corti.Pups showed higher hyperactive behaviors in the FS and OF tests than normal pups (Nor.Pups) born from rats (Nor.Moms) treated with saline. Furthermore, Corti.Pups spent more time and traveled longer distance in the open arms of EPM test, exhibiting higher extremity. These patterns were consistent with behavioral symptoms observed in animal models of attention deficit hyperactivity disorder (ADHD), which is characterized by hyperactivity, impulsivity, and inattention. Additionally, Corti.Pups swam longer and farther to escape in MWM test, showing cognitive declines associated with attention deficit. Our findings provide evidence that maternal cortisol level during pregnancy may affect the neuroendocrine regulation and the brain development of offspring, resulting in heterogeneous developmental brain disorders such as ADHD.

Expression of potassium channel genes predicts clinical outcome in lung cancer

Lung cancer is the most common cause of cancer deaths worldwide and several molecular signatures have been developed to predict survival in lung cancer. Increasing evidence suggests that proliferation and migration to promote tumor growth are associated with dysregulated ion channel expression. In this study, by analyzing high-throughput gene expression data, we identify the differentially expressed K⁺ channel genes in lung cancer. In total, we prioritize ten dysregulated K⁺ channel genes (5 up-regulated and 5 down-regulated genes, which were designated as K-10) in lung tumor tissue compared with normal tissue. A risk scoring system combined with the K-10 signature accurately predicts clinical outcome in lung cancer, which is independent of standard clinical and pathological prognostic factors including patient age, lymph node involvement, tumor size, and tumor grade. We further indicate that the K-10 potentially predicts clinical outcome in breast and colon cancers. Molecular signature discovered through K⁺ gene expression profiling may serve as a novel biomarker to assess the risk in lung cancer.

Prediction of itching diagnostic marker through RNA sequencing of contact hypersensitivity and skin scratching stimulation mice models

Pruritus (itching) is classically defined as an unpleasant cutaneous sensation that leads to scratching behavior. Although the scientific criteria of classification for pruritic diseases are not clear, it can be divided as acute or chronic by duration of symptoms. In this study, we investigated whether skin injury caused by chemical (contact hypersensitivity, CHS) or physical (skin-scratching stimulation, SSS) stimuli causes initial pruritus and analyzed gene expression profiles systemically to determine how changes in skin gene expression in the affected area are related to itching. In both CHS and SSS, we ranked the Gene Ontology Biological Process terms that are generally associated with changes. The factors associated with upregulation were keratinization, inflammatory response and neutrophil chemotaxis. The Kyoto Encyclopedia of Genes and Genomes pathway shows the difference of immune system, cell growth and death, signaling molecules and interactions, and signal transduction pathways. Il1a , Il1b and Il22 were upregulated in the CHS, and Tnf, Tnfrsf1b, Il1b, Il1r1 and Il6 were upregulated in the SSS. Trpc1 channel genes were observed in representative itching-related candidate genes. By comparing and analyzing RNA-sequencing data obtained from the skin tissue of each animal model in these characteristic stages, it is possible to find useful diagnostic markers for the treatment of itching, to diagnose itching causes and to apply customized treatment.

SPORTS1.0: A Tool for Annotating and Profiling Non-coding RNAs Optimized for rRNA- and tRNA-derived Small RNAs / 基因组蛋白质组与生物信息学报·英文版

High-throughput RNA-seq has revolutionized the process of small RNA (sRNA) discovery, leading to a rapid expansion of sRNA categories. In addition to the previously well-characterized sRNAs such as microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and small nucleolar RNA (snoRNAs), recent emerging studies have spotlighted on tRNA-derived sRNAs (tsRNAs) and rRNA-derived sRNAs (rsRNAs) as new categories of sRNAs that bear versatile functions. Since existing software and pipelines for sRNA annotation are mostly focused on analyzing miRNAs or piRNAs, here we developed the sRNA annotation pipelineoptimized for rRNA- and tRNA-derived sRNAs (SPORTS1.0). SPORTS1.0 is optimized for analyzing tsRNAs and rsRNAs from sRNA-seq data, in addition to its capacity to annotate canonical sRNAs such as miRNAs and piRNAs. Moreover, SPORTS1.0 can predict potential RNA modification sites based on nucleotide mismatches within sRNAs. SPORTS1.0 is precompiled to annotate sRNAs for a wide range of 68 species across bacteria, yeast, plant, and animal kingdoms, while additional species for analyses could be readily expanded upon end users' input. For demonstration, by analyzing sRNA datasets using SPORTS1.0, we reveal that distinct signatures are present in tsRNAs and rsRNAs from different mouse cell types. We also find that compared to other sRNA species, tsRNAs bear the highest mismatch rate, which is consistent with their highly modified nature. SPORTS1.0 is an open-source software and can be publically accessed at https://github.com/junchaoshi/sports1.0.

A Carbohydrate Fraction, AIP1, from Artemisia Iwayomogi Reduces the Action Potential Duration by Activation of Rapidly Activating Delayed Rectifier K+ Channels in Rabbit Ventricular Myocytes

We investigated the effects of a hot-water extract of Artemisia iwayomogi, a plant belonging to family Compositae, on cardiac ventricular delayed rectifier K+ current (I(K)) using the patch clamp technique. The carbohydrate fraction AIP1 dose-dependently increased the heart rate with an apparent EC(50) value of 56.1+/-5.5 microgram/ml. Application of AIP1 reduced the action potential duration (APD) in concentration-dependent fashion by activating I(K) without significantly altering the resting membrane potential (IC(50) value of APD(50): 54.80+/-2.24, IC(50) value of APD(90): 57.45+/-3.47 microgram/ml). Based on the results, all experiments were performed with 50 microgram/ml of AIP1. Pre-treatment with the rapidly activating delayed rectifier K+ current (I(Kr)) inhibitor, E-4031 prolonged APD. However, additional application of AIP1 did not reduce APD. The inhibition of slowly activating delayed rectifier K+ current (I(Ks)) by chromanol 293B did not change the effect of AIP1. AIP1 did not significantly affect coronary arterial tone or ion channels, even at the highest concentration of AIP1. In summary, AIP1 reduces APD by activating I(Kr) but not I(Ks). These results suggest that the natural product AIP1 may provide an adjunctive therapy of long QT syndrome.