Regulation and Roles of Urocortins in the Vascular System

Urocortins (Ucns) are members of the corticotropin-releasing factor (CRF) family of peptides. Ucns would have potent effects on the cardiovascular system via the CRF receptor type 2 (CRF2 receptor). Regulation and roles of each Ucn have been determined in the vascular system. Ucns have more potent vasodilatory effects than CRF. Human umbilical vein endothelial cells (HUVECs) express Ucns1-3 mRNAs, and the receptor, CRF2a receptor mRNA. Ucns1-3 mRNA levels are differentially regulated in HUVECs. Differential regulation of Ucns may suggest differential roles of those in HUVECs. Ucn1 and Ucn2 have strong effects on interleukin (IL)-6 gene expression and secretion in rat aortic smooth muscle A7r5 cells. The increase that we observed in IL-6 levels following Ucn treatment of A7r5 cells suggests that smooth muscle cells may be a source of IL-6 secretion under physiological stress conditions. Ucns are important and unique modulators of vascular smooth muscle cells and act directly or indirectly as autocrine and paracrine factors in the vascular system

The identification and functional implications of human-specific "fixed" amino acid substitutions in the glutamate receptor family

<p>Abstract</p> <p>Background</p> <p>The glutamate receptors (GluRs) play a vital role in the mediation of excitatory synaptic transmission in the central nervous system. To clarify the evolutionary dynamics and mechanisms of the GluR genes in the lineage leading to humans, we determined the complete sequences of the coding regions and splice sites of 26 chimpanzee GluR genes.</p> <p>Results</p> <p>We found that all of the reading frames and splice sites of these genes reported in humans were completely conserved in chimpanzees, suggesting that there were no gross structural changes in humans after their divergence from the human-chimpanzee common ancestor. We observed low <it>K</it>_<it>A</it>/<it>K</it>_{<it>S </it>}ratios in both humans and chimpanzees, and we found no evidence of accelerated evolution. We identified 30 human-specific "fixed" amino acid substitutions in the GluR genes by analyzing 80 human samples of seven different populations worldwide. Grantham's distance analysis showed that <it>GRIN2C </it>and <it>GRIN3A </it>are the most and the second most diverged GluR genes between humans and chimpanzees. However, most of the substitutions are non-radical and are not clustered in any particular region. Protein motif analysis assigned 11 out of these 30 substitutions to functional regions. Two out of these 11 substitutions, D71G in <it>GRIN3A </it>and R727H in <it>GRIN3B</it>, caused differences in the functional assignments of these genes between humans and other apes.</p> <p>Conclusion</p> <p>We conclude that the GluR genes did not undergo drastic changes such as accelerated evolution in the human lineage after the divergence of chimpanzees. However, there remains a possibility that two human-specific "fixed" amino acid substitutions, D71G in <it>GRIN3A </it>and R727H in <it>GRIN3B</it>, are related to human-specific brain function.</p

各班の報告

地域連携企画第4弾「平野をさぐる」（大阪市平野区、2008年10月5日・26日）関連企画「大阪を探検しよう！」（大阪市平野区・平野郷、2008年10月5日）補助事業　文部科学省私立大学学術研究高度化推進事業オープン・リサーチ・センター整備事業（平成17年度～平成21年度）なにわ・大阪文化遺産の総合人文学的研

Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy

The anterior pituitary gland comprises a heterogeneous population of pituitary cells [...

Molecular Mechanisms Underlying Stress Response and Resilience

A variety of stressors induce various physiological responses by modulating sympathetic, neuroendocrine, and behavioral systems [...

柴苓湯が有効であった後腹膜線維症の2例

The conventional approach for management of retroperitoneal fibrosis (RF), an inflammatory process of retroperitoneal fibro-adipose tissue, leading to the compression and obstruction of the ureters and other adjacent organs is ureterolysis with omental wrapping, and an effective alternative to surgery is immunosupressive medication such as oral corticosteroids. Sairei-to (TJ-114) is a traditional herbal medicine used for the treatment of RF in Japan. It has both anti-inflammatory and anti-allergic effects. Here we report two cases of RF successfully treated with Sairei-to. One case was idiopathic and the other was caused by artificial graft-induced vasculitis. Both cases were treated with Sairei-to following the decompression of uremia by precutaneous nephrostomy or indwelling ureteral stents. There was hardly any ureteral obstruction three months after the administration of Sairei-to. They have been doing well for 12 and 26 months. Sairei-to rarely causes side effects such as immunodeficiency, gastro-duodenal ulcer and osteoporosis that often accompany long-term administration of corticosteroids. Sairei-to is a safe and effective medicine for the treatment of RF. We therefore recommend Sairei-to as an alternative for corticosteroid therapy.後腹膜線維症では, 後腹膜における炎症のため線維芽細胞が増殖, 尿管を閉塞させる.以前は尿管剥離術がその治療に行われていたが, 現在はステロイド内服を中心とした保存的方法が主体である.柴苓湯は漢方薬の1つであり, 抗炎症作用と抗アレルギー作用をもつ.そのため後腹膜線維症の治療に柴苓湯は本邦においてしばしば使用される.今回われわれは特発性後腹膜線維症と人工血管による血管周囲炎からくる後腹膜線維症の2例に対し柴苓湯が有効であった症例を報告した.柴苓湯にはステロイドにみられる免疫不全, 胃潰瘍, 骨粗鬆症などの副作用がないため, 後腹膜線維症に対するステロイド内服治療の代替になりうる(著者抄録

Advances in Molecular Pathophysiology and Targeted Therapy for Cushing’s Disease

Cushing’s disease is caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from corticotroph pituitary neuroendocrine tumors. As a result, excess cortisol production leads to the overt manifestation of the clinical features of Cushing’s syndrome. Severe complications have been reported in patients with Cushing’s disease, including hypertension, menstrual disorders, hyperglycemia, osteoporosis, atherosclerosis, infections, and mental disorders. Cushing’s disease presents with a variety of clinical features, ranging from overt to subtle. In this review, we explain recent advances in molecular insights and targeted therapy for Cushing’s disease. The pathophysiological characteristics of hormone production and pituitary tumor cells are also explained. Therapies to treat the tumor growth in the pituitary gland and the autonomous hypersecretion of ACTH are discussed. Drugs that target corticotroph pituitary neuroendocrine tumors have been effective, including cabergoline, a dopamine receptor type 2 agonist, and pasireotide, a multi-receptor-targeted somatostatin analog. Some of the drugs that target adrenal hormones have shown potential therapeutic benefits. Advances in potential novel therapies for Cushing’s disease are also introduced

Hypothalamic Regulation of Corticotropin-Releasing Factor under Stress and Stress Resilience

This review addresses the molecular mechanisms of corticotropin-releasing factor (CRF) regulation in the hypothalamus under stress and stress resilience. CRF in the hypothalamus plays a central role in regulating the stress response. CRF stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates glucocorticoid secretion from the adrenal glands. Glucocorticoids are essential for stress coping, stress resilience, and homeostasis. The activated hypothalamic-pituitary-adrenal axis is suppressed by the negative feedback from glucocorticoids. Glucocorticoid-dependent repression of cAMP-stimulated Crf promoter activity is mediated by both the negative glucocorticoid response element and the serum response element. Conversely, the inducible cAMP-early repressor can suppress the stress response via inhibition of the cAMP-dependent Crf gene, as can the suppressor of cytokine signaling-3 in the hypothalamus. CRF receptor type 1 is mainly involved in a stress response, depression, anorexia, and seizure, while CRF receptor type 2 mediates “stress coping” mechanisms such as anxiolysis in the brain. Differential effects of FK506-binding immunophilins, FKBP4 and FKBP5, contribute to the efficiency of glucocorticoids under stress resilience. Together, a variety of factors contribute to stress resilience. All these factors would have the differential roles under stress resilience

A Case of Thyrotoxicosis due to Simultaneous Occurrence of Subacute Thyroiditis and Graves’ Disease

Subacute thyroiditis is an inflammatory disorder of the thyroid. Graves’ disease is an autoimmune thyroid disease in which thyroid hormones are overproduced. Here we present a rare case of thyrotoxicosis due to the simultaneous occurrence of both diseases. Prompt diagnosis and therapy are required to prevent complications in patients with thyrotoxicosis