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Hypoxia-inducible factor-1α is the therapeutic target od the SGLT2 inhibitor for diabetic nephropathy （低酸素誘導因子はSGLT2阻害薬による糖尿病腎症治療標的である）
Get PDFPrevious studies have demonstrated intrarenal hypoxia in patients with diabetes. Hypoxia-inducible factor (HIF)-1 plays an important role in hypoxia-induced tubulointerstitial fibrosis. Recent clinical trials have confirmed the renoprotective action of SGLT2 inhibitors in diabetic nephropathy. We explored the effects of an SGLT2 inhibitor, luseogliflozin on HIF-1α expression in human renal proximal tubular epithelial cells (HRPTECs). Luseogliflozin significantly inhibited hypoxia-induced HIF-1α protein expression in HRPTECs. In addition, luseogliflozin inhibited hypoxia-induced the expression of the HIF-1α target genes PAI-1, VEGF, GLUT1, HK2 and PKM. Although luseogliflozin increased phosphorylated-AMP-activated protein kinase α (p-AMPKα) levels, the AMPK activator AICAR did not changed hypoxia-induced HIF-1α expression. Luseogliflozin suppressed the oxygen consumption rate in HRPTECs, and subsequently decreased hypoxia-sensitive dye, pimonidazole staining under hypoxia, suggesting that luseogliflozin promoted the degradation of HIF-1α protein by redistribution of intracellular oxygen. To confirm the inhibitory effect of luseogliflozin on hypoxia-induced HIF-1α protein in vivo, we treated male diabetic db/db mice with luseogliflozin for 8 to 16 weeks. Luseogliflozin attenuated cortical tubular HIF-1α expression, tubular injury and interstitial fibronectin in db/db mice. Together, luseogliflozin inhibits hypoxia-induced HIF-1α accumulation by suppressing mitochondrial oxygen consumption. The SGLT2 inhibitors may protect diabetic kidneys by therapeutically targeting HIF-1α protein.博士（医学）旭川医科大
Hypothermia-induced activation of the splenic platelet pool as a risk factor for thrombotic disease in a mouse model. （マウス低体温症モデルにおける脾臓内血小板活性化は血栓症の危険因子となる）
Get PDFBackground: Hypothermia, either therapeutically induced or accidental (ie, an involuntary decrease in core body temperature to <35°C), results in hemostatic disorders. However, it remains unclear whether hypothermia enhances or inhibits coagulation, especially in severe hypothermia. The present study evaluated the thrombocytic and hemostatic changes in hypothermic mice.
Methods: C57Bl/6 mice were placed at an ambient temperature of -20°C under general anesthesia. When the rectal temperature decreased to 15°C, 10 mice were immediately euthanized, while another 10 mice were rewarmed, kept in normal conditions for 24 hours, and then euthanized. These treatments were also performed in 20 splenectomized mice.
Results: The hypothermic mice had adhesion of CD62P-positive platelets with high expression of von Willebrand factor (vWF) in their spleens, while the status of the peripheral platelets was unchanged. Furthermore, the plasma levels of platelet factor 4 (PF4) and pro-platelet basic protein (PPBP), which are biomarkers for platelet degranulation, were significantly higher in hypothermic mice than in control mice, indicating that hypothermia activated the platelets in the splenic pool. Thus, we analyzed these biomarkers in asplenic mice. There was no increase in either PF4 or PPBP in splenectomized hypothermic mice. Additionally, the plasma D-dimer elevation and microthrombosis were caused in rewarmed mice, but not in asplenic rewarmed mice.
Conclusions: Our results indicate that hypothermia leads to platelet activation in the spleen via the upregulation of vWF, and this activation causes hypercoagulability after rewarming.博士（医学）旭川医科大
Monomerization of ALK Fusion Proteins as a Therapeutic Strategy in ALK-Rearranged Non-Small Cell Lung Cancers （ALK陽性非小細胞肺癌におけるEML4-ALK融合蛋白の単量体化による治療戦略）
Get PDFObjective: Oncogenic echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) (EML4-ALK) fusion proteins found in non-small cell lung cancers (NSCLC) are constitutively phosphorylated and activated by dimerization via the coiled-coil domain (cc) within EML4. Here, we investigated whether disruption of ALK fusion protein oligomerization via competitive cc mimetic compounds could be a therapeutic strategy for EML4-ALK NSCLC. Methods: A Ba/F3 cell model was created that expressed an ALK intracellular domain in which the dimer/monomer state is ligand-regulated. This novel cell model was used to investigate the effect of disrupting ALK fusion protein oligomerization on tumor cell growth in vitro and in vivo using nude mice. Subsequently, the antiproliferative effects of endogenous cc domain co-expression and mimetic cc peptides were assayed in EML4-ALK cancer cell lines. Results: Cells induced to express monomeric ALK in vitro did not survive. When transplanted into mice, induction of monomers abrogated tumor formation. Using a fluorescent protein system to quantify protein-protein interactions of EML4-ALK and EML4cc, we demonstrated that co-expression of EML4cc suppressed EML4-ALK assembly concomitant with decreasing the rate of tumor growth in vitro and in vivo. In EML4-ALK cancer cell lines, administration of synthetic EML4cc peptide elicited a decrease of phosphorylation of ALK leading to reduction in tumor cell growth. Conclusions: Our findings support the monomerization of ALK fusion proteins using EML4cc peptides for competitive inhibition of dimerization as a promising therapeutic strategy for EML4-ALK NSCLC. Further studies are warranted to explore the use of specific cc peptide as a therapeutic option for other lung cancers harboring driver fusion genes containing a cc or oligomerization domain within the fusion partner.博士（医学）旭川医科大
Heterogenous nuclear ribonucleoprotein H1 promotes colorectal cancer progression through the stabilization of mRNA of sphingosine-1- phosphate Lyase 1 （Heterogenous nuclear ribonucleoprotein H1はsphingosine-1- phosphate lyase 1 mRNAの安定化を介して大腸癌の発育を促進する）
Get PDFThe oncogenic properties of heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) have been reported, although the tumor-promoting mechanism remains unclear. We herein report the mechanism underlying colorectal cancer cell progression mediated by hnRNP H1. The growth of colorectal cancer cells was suppressed by hnRNP H1 downregulation. A terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed the anti-apoptotic effect of hnRNP H1 in colorectal cancer cells. An RNA immunoprecipitation assay revealed that hnRNP H1 bound to sphingosine-1-phosphate lyase 1 (SGPL1). Reverse transcription-polymerase chain reaction revealed the high expression of hnRNP H1 mRNA in colorectal cancer cells and Spearman's rank correlation coefficient showed a strong positive correlation between hnRNP H1 mRNA and SGPL1 mRNA. An siRNA of hnRNP H1 decreased SGPL1 mRNA expression in colorectal cancer cells, but not in non-tumorous cells. These findings suggested that hnRNP H1 increased SGPL1 mRNA expression specifically in cancer cells through direct binding. Targeted knockdown of hnRNP H1 or SGPL1 with siRNAs upregulated p53 phosphorylation and p53-associated molecules, resulting in cell growth inhibition, while hnRNP H1 upregulated the mRNA of SGPL1 and inhibited p53 activation, thereby promoting tumor cell growth. This is a novel mechanism underlying colorectal cancer cell progression mediated by hnRNP H1-SGPL1 mRNA stabilization
かぐらおか 第176号
Get PDF平成31年度入学生への学長挨拶 2/ 第17代図書館長に就任して 13/ 教授就任の挨拶 14/ 教授就任の挨拶 15/ 教授就任の挨拶 16/ 旭川医科大学に入学して 18/ 旭川医科大学に入学して 18/ 旭川医科大学での学び 19/ 旭川医科大学に入学して 19/ 旭川医科大学に入学して 20/ 旭川医科大学に入学して 20/ 旭川医科大学に入学して 21/ 旭川医科大学に入学して 21/ 旭川医科大学に入学して 22/ 旭川医科大学に入学して 22/ 旭川医科大学に入学して 23/ 旭川医科大学に入学して 23/ 旭川医科大学に入学して 24/ 平成31年度入学式を挙行しました 25/ 平成31年度医学部医学科・看護学科新入生合同研修会が実施されました 26/ 健康セミナー「わたしのみんなのげんき種in緑が丘」を開催 27/ 医大祭2019「医進月歩」を終えて 28/ 地域学生枠とメンター教員との交流会を開催 30/ 難病の方々から体験談を聴く 31/ 教員の異動 32/ 今後のスケジュール 32/ 訃報 3