RNA-binding proteins (RBPs) are key regulators of posttranscriptional gene expression and control many important biological processes including cell proliferation, development, and differentiation. RBPs bind specific motifs in their target mRNAs and regulate mRNA fate at many steps. The AU-rich element (ARE) is one of the major cis-regulatory elements in the 3′ untranslated region (UTR) of labile mRNAs. Many of these encode factors requiring very tight regulation, such as inflammatory cytokines and growth factors. Disruption in the control of these factors’ expression can cause autoimmune diseases, developmental disorders, or cancers. Therefore, these mRNAs are strictly regulated by various RBPs, particularly ARE-binding proteins (ARE-BPs). To regulate mRNA metabolism, ARE-BPs bind target mRNAs and affect some factors on mRNAs directly, or recruit effectors, such as mRNA decay machinery and protein kinases to target mRNAs. Importantly, some ARE-BPs have stabilizing roles, whereas others are destabilizing, and ARE-BPs appear to compete with each other when binding to target mRNAs. The function of specific ARE-BPs is modulated by posttranslational modifications (PTMs) including methylation and phosphorylation, thereby providing a means for cellular signaling pathways to regulate stability of specific target mRNAs. In this review, we summarize recent studies which have revealed detailed molecular mechanisms of ARE-BP-mediated regulation of gene expression and also report on the importance of ARE-BP function in specific physiological contexts and how this relates to disease. We also propose an mRNP regulatory network based on competition between stabilizing ARE-BPs and destabilizing ARE-BPs.

ABSTRACT-To clarify the relationship between SART (specific alternation of rhythm in temperature) stress (repeated cold stress) and anxiety, the effects of various types of stress on the behavior of mice were studied in elevated plus-maze tests and then the effects of anxiolytics were evaluated. The percentage of time spent in the open arms of the plus-maze apparatus decreased in mice subjected to SART stress without change in the total number of arm entries. No change was noted in mice subjected to other stresses, such as 1-h, 2-day and 5-day cold stress and 1-h, 15-h and 5´15-h restraint stress. The reduction in the percentage of time spent in the open arms caused by SART stress was inhibited by single and repeated administrations of diazepam and alprazolam and by a single administration of buspirone, which have no influence on the percentage of time spent in the open arms in nonstressed mice, but not by flumazenil, WAY-100635 and chronic treatment with buspirone. The effects of diazepam and buspirone were antagonized by flumazenil and WAY-100635, respectively. The behavior of SART-stressed mice in the plus-maze would thus appear to arise from anxiety, to which benzodiazepine and serotonin receptors are related, but the diazepam binding inhibitor, an endogenous anxiogenic protein, is not. Thus SART-stressed animals may be useful for investigating the psychopharmacological and neuropharmacological basis of anxiety.Keywords: Elevated plus-maze, Stress, SART stress, Anxiety, Repeated cold stressThe relationship between anxiety and stress is a point of much interest. Chronic stress induces mood disorder-like behavior in mammals including humans, and it may be a main factor in the development of anxiety (1, 2). Exposure to various types of stress results in anxiogenic behavior in tests for anxiety in animals. Social stress (3, 4), inescapable electric foot-shocks (5), immersion in water (6) and exposure to unpleasant smells such as cat odor (7) reduce the exploration of open spaces in an elevated plus-maze and cause reduction in social interactions in mice (7, 8).The behavioral characteristics of animals exposed to SART (specific alternation of rhythm in temperature) stress (9 -13) were studied. SART stress (14) is stimulation by repeated and sudden changes in environmental temperature from room temperature to cold temperature, an event that may be encountered by humans in daily life such as in early spring or autumn or when leaving an air-conditioned room in summer or a heated room in winter. Animals exposed to SART stress are a model of autonomic imbalance (15) and show adverse biological events (16 -19) and physiological abnormalities (14, 20 -23). Abnormal behavior is shown in open-field (9), step-down (11) and forced swimming tests (12, 13). This abnormal behavior is normalized by antianxiety agents (9, 12, 13). Changes in neurotransmitters related to abnormal behavior have been noted (24 -26). Certain aspects of these abnormalities are thought to be related to anxiety.To clarify the relationship between SART ...

It was reported that cilostazol (CLZ) suppressed disruption of the microvasculature in ischemic areas. In this study, we have designed novel injection formulations containing CLZ nanoparticles using 0.5% methylcellulose, 0.2% docusate sodium salt, and mill methods (CLZnano dispersion; particle size 81 ± 59 nm, mean ± S.D.), and investigated their toxicity and usefulness in a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The pharmacokinetics of injections of CLZnano dispersions is similar to that of CLZ solutions prepared with 2-hydroxypropyl-β-cyclodextrin, and no changes in the rate of hemolysis of rabbit red blood cells, a model of cell injury, were observed with CLZnano dispersions. In addition, the intravenous injection of 0.6 mg/kg CLZnano dispersions does not affect the blood pressure and blood flow, and the 0.6 mg/kg CLZnano dispersions ameliorate neurological deficits and ischemic stroke in MCAO/reperfusion mice. It is possible that the CLZnano dispersions will provide effective therapy for ischemic stroke patients, and that injection preparations of lipophilic drugs containing drug nanoparticles expand their therapeutic usage.

Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose-limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin-induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin-induced neuropathy via the PKC/ extracellular signal-regulated kinase (ERK)/c-Fos pathway in lumbar spinal cords (lumbar segments 4-6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells-implanted mice. Moreover, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin-induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin-induced neuropathy is associated with PKC/ERK/c-Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin-induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin-induced neuropathy and could aid in combination antitumor pharmacotherapy.Oxaliplatin, a third-generation organoplatinum compound, has become the principal chemotherapy agent used in combination with 5-fluorouracil and leucovorin against colorectal cancer in both adjuvant and palliative therapy.1 However, neuropathy associated with oxaliplatin use is the predominant reason for dose modification, treatment schedule extension and termination of therapy.2 Oxaliplatin induces two different forms of neuropathy.3 A dose-limiting sensory neuropathy occurs at a cumulative dose above 540-850 mg/m 2 and may develop gradually following oxaliplatin treatment. 4A transient, acute syndrome consisting of cold-induced paraesthesia, dysesthesia or pain in the hands, feet, face and perioral regions appears in 80% of patients during the first or second cycle. 4 Current therapeutic options for alleviating neuropathy are mainly limited to drugs approved for other pain conditions, and none of the current agents proven to provide relief. 5 As chemotherapy becomes more effective, the number of cancer survivors is likely to increase, and neuropathy will become an important factor affecting their quality of life. Thus, it is of critical importance to elucidate the mechanism of oxaliplatin-induced neuropathy and consequently develop effective treatment strategies for this debilitating syndrome.Temperature-activated transient receptor potential (TRP) ion channels play important roles in pain sensation. Two particular TRP channels, TRPM8 and TRPA1, have been linked to the sensation of cold. Recently, i...

Anxiety is one of the most prominent psychiatric disorder related to a common stress. The success of pharmacological treatments for this disorder has been dampened by various factors, including resistance to treatment and adverse effects of the drugs used. Although the themes of stress and anxiety have long been a topic of investigation, current anxiolytic drugs are only based on pharmacological interactions with classic neurotransmitters. Accordingly, we investigated possible alternative mechanisms that might lead to development of new classes of anxiolytic drugs using SART-stressed animals.Corticotropin-releasing factor (CRF), a hypothalamic peptide consisting of 41 amino acids, is a key mediator of mammalian endocrine, behavioral, autonomic, and immune responses to stress. 1,2) Within the hypothalamic-pituitaryadrenal (HPA) axis, CRF is the principal regulator of pituitary adrenocorticotropic hormone (ACTH) and adrenal glucocorticoid secretion in responses to stressful stimuli. Basic research studies indicate that elevated central CRF levels are involved in the etiology of stress-related psychiatric, physiological and behavioral disorders.3) Central administration of CRF exerts potent anxiogenic effects in experimental animals.4) Clinical studies also demonstrate that CRF is implicated in anxiety. 5,6) We have investigated the effects of stress on physiological conditions and on emotions using SART (specific alternation of rhythm in temperature) stress, 7) which is known as a model of autonomic imbalance.8) The stressful situation is created by repeated and sudden changes in environmental temperature from room temperature to cold temperature, an event that may be encountered by humans in daily life such as in early spring or autumn, or when leaving an air-conditioned room in summer or a heated room in winter to go outdoors. Animals exposed to SART stress show adverse biological events 9-11) and physiological abnormalities. 7,12,13) Furthermore, a series of our behavioral studies using SARTstressed animals demonstrated that environmental stress induces anxiety-like behavior. 14-16) The anxiety-like behaviors caused by SART stress are normalized by anxiolytic agents such as diazepam, alprazolam, benzodiazepine-receptor agonists, and buspirone, a selective 5-HT 1A serotonin-receptor agonist.14-16) This evidence suggests that SART-stressed animals may be in a state of anxiety.As SART stress causes anxiety-like behavior in mice and rats in several tests, we turned our attention to the possibility that CRF may be involved in the stress and anxiety of SARTstressed mice. In the present study, we determined whether inhibition of CRF receptor function using a-helical CRF as a specific CRF receptor antagonist could normalize anxietylike behavior caused by SART stress using forced swimming (FS) test and elevated plus-maze (EPM) test.The FS test is a well-known screening model for antidepressants developed by Porsolt et al. 17,18) At first, they suggested that the characteristic immobility observed in the FS test reflect...