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Molecular bases of pathogenic enhancement of Ca2+ release channel activities in RYR1 carrying disease-associated mutations at the N-terminal region were studied. Functional studies and MD simulation revealed that the interactions between domains have a strong correlation with channel activity., Type 1 ryanodine receptor (RYR1) is a Ca2+ release channel in the sarcoplasmic reticulum in skeletal muscle and plays an important role in excitation–contraction coupling. Mutations in the RYR1 gene cause severe muscle diseases such as malignant hyperthermia (MH), which is a disorder of CICR via RYR1. Thus far, >300 mutations in RYR1 have been reported in patients with MH. However, owing to a lack of comprehensive analysis of the structure–function relationship of mutant RYR1, the mechanism remains largely unknown. Here, we combined functional studies and molecular dynamics (MD) simulations of RYR1 bearing disease-associated mutations at the N-terminal region. When expressed in HEK293 cells, the mutant RYR1 caused abnormalities in Ca2+ homeostasis. MD simulations of WT and mutant RYR1s were performed using crystal structure of the N-terminal domain (NTD) monomer, consisting of A, B, and C domains. We found that the mutations located around the interdomain region differentially affected hydrogen bonds/salt bridges. Particularly, mutations at R402, which increase the open probability of the channel, cause clockwise rotation of BC domains with respect to the A domain by alteration of the interdomain interactions. Similar results were also obtained with artificial mutations that mimic alteration of the interactions. Our results reveal the importance of interdomain interactions within the NTD in the regulation of the RYR1 channel and provide insights into the mechanism of MH caused by the mutations at the NTD.

Dexmedetomidine is a potent and highly selective α2-adrenoceptor agonist with sedative, analgesic, and sympatholytic properties, though it also exhibits some affinity for imidazoline binding sites. In addition to its sedative effects, dexmedetomidine exerts neuroprotective effects under ischemic conditions. Invasive incidents such as ischemia or hypoxia induce dysfunctions in energy production or depletion of ATP as well as accumulation and aggregation of abnormal proteins in the endoplasmic reticulum (ER), leading to an ER-stress response. In the present study, we examined whether dexmedetomidine exerts inhibitory effects on apoptosis mediated by thapsigargin-induced ER-stress in SH-SY5Y cells, and proposed a possible underlying mechanism for its neuroprotective effects. We used thapsigargin (TG) to generate an ER-stress response in SH-SY5Y cells. SH-SY5Y cells were pretreated with Dex (1–1000 nM) or receptor antagonists (atipamezole, efaroxan, BU99006, and 2’,5’-dideoxyadenosine) for 1 hour before co-treatment with 1 mM TG for 20 hours. Co-incubation with dexmedetomidine suppressed thapsigargin-induced increases in cytosolic Ca2+, caspase-4 and -3 activity, eIF2α phosphorylation, and expression of ER-stress biomarkers. Dexmedetomidine treatment also decreased cAMP levels. In the presence of atipamezole or efaroxan, but not BU99006, inhibition of eIF2α phosphorylation and CHOP expression significantly increased following treatment with dexmedetomidine in thapsigargin-treated cells. However, pretreatment with BU99006 enhanced the increase in mitochondrial membrane potential associated with dexmedetomidine treatment. The results of the present study demonstrate that dexmedetomidine at clinically relevant concentrations suppresses ER-stress-induced apoptosis in SH-SY5Y cells. Some neuroprotective effects of dexmedetomidine may be mediated by α2-adrenoceptor and I1- and I2-receptors.

Background/aim We have previously reported the protection of doxorubicin-induced keratinocyte toxicity by alkaline extract of the leaves of Sasa senanensis Rehder (SE). In order to extend the generality of the cell protective effect of SE, we investigated whether it also protects rat PC12 and human SH-SY5Y neuron model cells from amyloid β-peptide (Aβ)-induced injury. Materials and methods Viability of cells was determined by the MTT method. Cytotoxicity was evaluated by the concentration that reduces the cell viability by 50% (CC50). Protection from Aβ-induced cytotoxicity was evaluated by the concentration that reversed the Aβ-induced reduction of viability by 50% (EC50). The selectivity index (SI) of neuroprotective activity was defined as the ratio of EC50 to CC50 Aβ1-42 aggregation was assayed using Aβ1-42 ammonium hydroxide. Results SE showed hormetic growth stimulation at lower concentrations in both neuron precursors and differentiated cells. SE reproducibly inhibited Aβ-induced cytotoxicity against both undifferentiated and differentiated neuron cells. Both the extent of differentiation induction and viability depended on the cell density, suggesting the release of growth and differentiation stimulation substances into culture supernatant. Higher concentrations of SE partially reduced the Aβ1-42 aggregation. Conclusion Hormetic growth stimulation and inhibition of aggregation may be involved in the neuroprotective activity of SE.

Triple-negative breast cancer (TNBC), which does not show hormone sensitivity, is a poor prognosis disease without an established targeted treatment, so that establishing a therapeutic target for each subtype is desired. In addition, microRNA (miRNA), a non-cording RNA 19-25 nucleotide-longs in length, is known to be involved in regulating gene expression. We examined miRNA expression after exposure to eribulin, MDA-MB-231 cells, non-basal-like type of TNBC cell lines, and HCC1143 cells, basal-like type of TNBC cell lines. The activity of caspase-3 significantly increased compared to the control in MDA-MB-231, whereas no significant difference was observed in HCC1143. The expression level of 20-miRNAs significantly increased compared to the control in MDA-MB-231 after exposure to eribulin. The expression level of 6-miRNAs also significantly increased compared to the control in HCC1143. In these 2 cell types, miR-125b-1 and miR-195 were commonly expressed. While the expression level of miR-125b-1 decreased in both cells, the expression level of miR-195 increased in MDA-MB-231 and decreased in HCC1143. The expression level of miR-195 targeting Wnt3a significantly decreased compared to the control in MDA-MB-231, whereas it significantly increased in HCC1143. These results showed that exposure to eribulin highly increased the expression of miR-195 while it decreased the expression of Wnt3a in non-basal-like type of TNBC. Some miRNAs are known to regulate other signaling pathways involved in human pathogenesis by regulating the Wnt signaling pathway, and miRNA can act as a tumor-suppressing gene; therefore, miR-195 may serve as a therapeutic target in non-basal-like type of TNBC.

Denosumab, a fully human monoclonal antibody that neutralizes receptor activator of nuclear factor-κB ligand (RANKL) and blocks osteoclast differentiation, has received approval in Japan for use as an anti-resorptive drug for osteoporosis and skeletal-related events (SREs) in patients with solid cancer. Denosumab is contraindicated during pregnancy, though the effects of blocking RANKL activity on pregnant mothers and their newborns are unclear. We used mice to investigate the effects of an anti-RANKL antibody on maternal and newborn health. Mothers injected with the anti-RANKL antibody had increased bone mass as compared with the controls, while osteoclast number and the level of tartrate-resistant acid phosphatase (TRAP) in serum were increased at the end of pregnancy. Newborn mice exposed to the antibody in utero were normally born, but showed increased bone mass and died within 48 h after birth. None of the newborns were found to have milk in their stomachs, suggesting that they died due to a maternal defect in lactation. Consistent with this, anti-RANKL antibody-injected mothers displayed impaired mammary gland development. However, fostering by healthy surrogate mothers rescued only 33% of the antibody-exposed newborns, suggesting that neonatal mortality was due, at least in part, to an intrinsic defect in the newborns. Our findings show that anti-RANKL antibody administration during pregnancy results in not only an undesirable increase in bone mass, but also has harmful effects on newborn survival.

Anesthetic treatment has been associated with widespread apoptotic neurodegeneration in the neonatal rodent brain. It has recently been suggested that propofol, a short-acting intravenous anesthetic agent, may have a potential as a neuroprotective agent. An apoptotic pathway mediated through endoplasmic reticulum (ER) stress has been attracting attention. ER stress is associated with accumulation of unfolded or misfolded proteins in ER, and ER stress-induced apoptosis is implicated in a wide range of diseases, including ischemia/reperfusion injury, neurodegeneration, and diabetes. We investigated whether thapsigargin-induced ER stress is prevented by propofol in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were pretreated with various concentrations of propofol (1-10 μM) for 3h before co-treatment with 0.5 μM thapsigargin and propofol for 20 h. Levels of ssDNA, specific evidence of apoptosis, and biomarkers of ER stress (mRNA expression of Chop and sXbp-1) were determined. We also assayed calpain and caspase-4 activities and intracellular Ca(2+) ([Ca(2+)]i) levels. Thapsigargin-induced increases in ssDNA levels, expressions of ER stress biomarkers, activities of caspase-4 and calpain, and level of [Ca(2+)]i were suppressed by co-incubation with propofol. Our data indicate the possibility that propofol inhibits the Ca(2+) release from ER at clinically employed dose levels. These results demonstrate that propofol suppresses the ER stress-induced apoptosis in this cell system, and may have the neuroprotective potency. It may also be a promising agent for preventing damage from cerebral ischemia or edema.

Inflammation and glycemic control are important prognosis-related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti-inflammatory effects of monotherapy with linagliptin-a dipeptidase-4 inhibitor-in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin-6 (IL-6), high-sensitivity C-reactive protein, GA, blood glucose, and active glucagon-like peptide-1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low-density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL-6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 ± 50 ng/mL to 26 ± 5 ng/mL; IL-6 levels, from 1.5 ± 0.4 pg/mL to 0.6 ± 0.1 pg/mL; and GA levels, from 21.3% ± 0.6% to 18.0% ± 0.6%. Glucagon-like peptide-1 levels increased 2.5-fold during the treatment. Over the 6-month treatment period, body weight and levels of high-sensitivity C-reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti-inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes.

Aims In recent years, there has been an increase in patients with arteriosclerosis and the risk of lifestyle-related diseases. However, the pathogenesis and medication of atherosclerosis have not been elucidated. We developed a rat model of lifestyle-related diseases by feeding a high-fat diet and 30% sucrose solution (HFDS) to spontaneously hypertensive hyperlipidemic rats (SHHR) and reported that this model is a useful model of early atherosclerosis. In order to elucidate the pathogenesis of early atherosclerosis, we searched for atherosclerosis-related genes by microarray analysis using the aortic arch rat model of lifestyle-related diseases. Main methods Four-month-old male Sprague–Dawley rats and SHHR were each divided into two normal diet (ND) groups and two HFDS groups. After a four-month treatment, the expression of mRNA in the aortic arch was detected using the oligo DNA microarray one-color method and quantified using real-time PCR. Key findings In this study, we detected 39 genes in microarray analysis. Esm1, Retnlb Mkks, and Grem2 showed particularly marked changes in gene expression in the SHHR-HFDS group. Compared with the SD-ND group, the SHHR-HFDS group had an increase in Mkks gene expression of about 26-fold and an approximately 22-fold increase in the expression of Grem2. Similarly, the expression of Esm1 increased by about 12-fold and that of Retnlg by about 10-fold as shown by quantitative real-time PCR. Significance This study suggested that these four genes might be important in early atherosclerosis development.

Aim: To evaluate the long-term efficacy of monotherapy with the dipeptidase-4 inhibitor alogliptin benzoate in hemodialysis (HD) patients with type 2 diabetes. Methods: Sixteen diabetic HD patients with inadequate glycemic control (hemoglobin A1c (HbA1c) level >6.5% and glycated albumin (GA) level >20%) on diet and exercise participated in the study. No patients were taking other oral antidiabetic drugs or receiving insulin therapy. Alogliptin 6.25 mg was administered to patients once daily. HbA1c, GA levels were obtained before and after 2 years of treatment. Body weight and active glucagon-like peptide-1, blood glucose, insulin, C-peptide immunoreactivity, glucagon, albumin, hemoglobin, and total cholesterol levels were also examined before and after treatment. Results: Both HbA1c and GA levels decreased after starting alogliptin administration. As compared to the pretreatment levels, HbA1c and GA levels significantly decreased at 3 and 18 months, respectively, after starting alogliptin administration. HbA1c and GA levels decreased from 7.1 ± 0.2 to 5.8 ± 1.6% and from 22.5 ± 0.7 to 19.6 ± 0.6%, respectively, 24 months after beginning treatment. Glucagon-like peptide-1 levels (8.9 ± 5.7 pmol/l before treatment) doubled after treatment. Body weight and blood glucose, insulin, C-peptide immunoreactivity, glucagon, albumin, hemoglobin, and total cholesterol levels did not change with treatment. Only one significant adverse effect, a drug-related rash, was seen in 1 patient. Conclusion: Long-term (2-year) effects of alogliptin benzoate monotherapy suggest its efficacy as a new treatment strategy in diabetic HD patients.

Glioblastoma is the most malignant central nervous system tumor. Patients with glioblastoma are treated with a combination of surgery, radiotherapy and chemotherapy; however, this effect is not satisfactory with regard to the prognosis. It is reported that the tumor stem cells affect recurrence, and radio- and chemotherapy resistance of the tumor, and that these cells play an important role in tumorigenesis and tumor progression. Using human glioblastoma cell lines (T98G and A172), irradiated (0, 30, 60 Gy) glioblastoma cells were prepared under the same conditions as clinical therapy. We analyzed cell proliferation rate, side population analysis by fluorescence-activated cell sorting and isolation of CD133⁺ cells, and performed genetic analysis (human stem cells) on these cells. We also investigated the difference in gene expression in the cells after radiation. The stem cell-related genes were highly expressed in the CD133⁺ cells compared with the CD133⁻ cells, suggesting that the cancer stem cells may be located in these CD133⁺ cells. In the T98G cell line, the cell proliferation rate of 30-Gy irradiated cells was higher than those of non-irradiated cells and 60-Gy irradiated cells. Stem cell-related genes were highly expressed in 30-Gy irradiated CD133⁺ T98G cells. In conclusion, we suggest that CD133⁺ cells may strongly affect tumor proliferation and the resistance against radiation therapy.

A 71-year-old man with a right lower abdominal quadrant epithelial tumor developed gradually worsening lumbago and dysbasia. He became comatose and was admitted to our hospital. He had swelling of the left axillary lymph nodes and necrosis of the 4.0-cm diameter abdominal tumor, which infiltrated the subcutaneous tissues. He was hypercalcemic (16.7 mg / dl) , and had elevated levels of soluble interleukin-2 receptor (24,090 U / ml) and parathyroid hormone- related protein (5.4 pmol / l) . Computerized tomography (CT) showed left axillary lymphadenopathy, splenomegaly, and a right abdominal-wall mass that was described as anaplastic large cell lymphoma upon pathology. Brain radiography and CT revealed multiple lesions infiltrating the cranium. Magnetic resonance imaging showed diffuse low signal intensity throughout the vertebral spine. The patient was diagnosed with anaplastic lymphoma kinase (ALK) -negative anaplastic large cell lymphoma with hypercalcemia. Fluid replacement and drug therapies including calcitonin had no effect on the hypercalcemia or the coma. The patients serum calcium concentration decreased after hemodialysis (calcium dialysate concentra- tion, 5 mg / dl) and subsequent zoledronic acid hydrate therapy. His consciousness improved by thefth day of treatment. This rare case of hypercalcemia in ALK- negative anaplastic large cell lymphoma improved with combined medical and hemodialysis therapy.

Silencing of gene expression by RNA interference(RNAi)has become a widely used tool for assessing gene function in a fast and easy manner. An important advance in the RNAield was the discovery that plasmid-based short hairpin RNA transcription can substitute for synthetic small interference RNAs both in vitro and in vivo. The constitutive knockdown of gene expression by RNAi can limit the scope of experiments, especially if the inhibition of genes leads to cell lethality, which prevents in vivo functional analysis. We have generated double-conditional short hairpin RNA from a single vector that can regulate its own transcription by a combination of tetracycline-inducible and Cre-loxP systems. This vector will be useful for the control of short hairpin RNA expression in a spatially-regulated manner by Cre recombinase as well as a temporally-regulated manner by tetracycline induction. These control features provide for the specic silencing of genes to facilitate functional genetic analysis in mammals in vivo.

Our study aimed to clarify speci c oxidative stress and glucose metabolic disorders in hemodialysis patients, by examining hydrogen peroxide (H2O2)and high glucose-induced oxidative stress, glucose transport and the failure of glycolysis. As an in vitro blood cell model of end-stage renal disease (ESRD) in patients with diabetes, human monocytic U937 cells of malignant lymphoma origin were exposed to high glucose (28.9 mM) for 6 days, with 5 mM H2O2 added on the last day. The generation of intracellular reactive oxygen species (ROS), glucose levels, lactate levels, AMP-activated protein kinase (AMPK) activity and Glut4 levels were examined. Exposure of U937 cells to H2O2 resulted in a signi cant increase in intracellular ROS generation and glucose levels. Under high glucose conditions, treatment with H2O2 signi cantly promoted these actions. In H2O2-induced U937 cells, AMPK activity and Glut4 levels were signi cantly increased, but lactate and pyruvate levels were signi cantly decreased. Thus, exposure of U937 cells to H2O2 and a high glucose load promoted an increase in intracellular ROS, and exposure to H2O2 induced increased glucose transport and high intracellular glucose due to reduced glycolytic metabolism. This suggests that reduced glycolytic metabolism might be induced in states of high oxidative stress in hemodialysis patients with diabetes.

Sitagliptin Inhibits the Lipopolysaccharide-Induced Inflammation Abstract Objective: Sitagliptin is an anti-diabetic Dipeptidyl peptidase-4 (DPP-4) inhibitor; used worldwide with a well-established evidence base as an effective anti-diabetic therapy and the lowest cost of all DPP-4 inhibitors. Atherosclerosis and inflammation are more common in diabetic patients than in nondiabetic patients, and progression of atherosclerosis contributes to this inflammation. Therefore, anti-inflammatory therapy is important for the prognosis of diabetic patients. Although several reports have investigated the anti-inflammatory mechanisms of sitagliptin in vitro, none of these studies has described its effects on mitogenactivated protein kinase (MAPK) in human umbilical vein endothelial cells (HUVECs) stimulated with lipopolysaccharide (LPS). We assessed the MAPK-dependent anti-inflammatory effects of sitagliptin in HUVECs. Methods: HUVECs (1–2 × 105 cell/mL) were either pretreated with different doses of sitagliptin for 1 h or left untreated. Subsequently, HUVECs were either incubated with lipopolysaccharide (LPS) together with sitagliptin (after treatment) or left untreated. Five hours post incubation, the culture medium was sampled for interleukin (IL)-6. Additionally, intranuclear p65 levels were measured 5 h after simultaneous treatment with LPS and sitagliptin. p38 MAPK levels and PKC activity were measured in the cytosolic fractions 30 min after simultaneous treatment with LPS and sitagliptin. Results: Treatment with LPS alone induced significant IL-6 production compared with untreated control cells. Pretreatment of cells with sitagliptin at all concentrations tested significantly reduced LPS-stimulated IL-6 production. However, after treatment of cells with sitagliptin at any concentration did not inhibit LPS-stimulated IL-6 production. Compared to untreated cells, treatment with 5 nM sitagliptin significantly inhibited LPS-stimulated intranuclear p65 expression, and p38 MAPK phosphorylation. There was no significant difference in PKC activity with LPS or sitagliptin. Conclusion: In HUVECs, sitagliptin elicits its anti-inflammatory effects through MAPK-dependent mechanisms.

Matrix metalloproteinases (MMPs) play an important role in degeneration of the matrix associated with bone and cartilage. Regulation of osteoclast activity is essential in the treatment of bone disease, including osteoporosis and rheumatoid arthritis. Polyphenols in green tea, particularly epigallocatechin-3-gallate (EGCG), inhibit MMPs expression and activity. However, the effects of the black tea polyphenol, theaflavin-3,3′-digallate (TFDG), on osteoclast and MMP activity are unknown. Therefore, we examined whether TFDG and EGCG affect MMP activity and osteoclast formation and differentiation in vitro. TFDG or EGCG (10 and 100 μM) was added to cultures of rat osteoclast precursors cells and mature osteoclasts. Numbers of multinucleated osteoclasts and actin rings decreased in polyphenol-treated cultures relative to control cultures. MMP-2 and MMP-9 activities were lower in TFDG- and EGCG-treated rat osteoclast precursor cells than in control cultures. MMP-9 mRNA levels declined significantly in TFDG-treated osteoclasts in comparison to control osteoclasts. TFDG and EGCG inhibited the formation and differentiation of osteoclasts via inhibition of MMPs. TFDG may suppress actin ring formation more effectively than EGCG. Thus, TFDG and EGCG may be suitable agents or lead compounds for the treatment of bone resorption diseases. Keywords:: theaflavin-3,3′-digallate (TFDG), epigallocatechin-3-gallate (EGCG), rat osteoclast, rat osteoclast precursor cell, matrix metalloproteinase (MMP)-9

Background: Previously, we reported an increase in expressions of mRNA of Cu/Zn-superoxide dismutase (SOD) in leukocytes of hemodialysis (HD) patients, and speculated that the increase is associated with oxidative stress on the leukocyte membrane due to the HD process. Methods: Expressions of Cu/Zn-SOD mRNA in leukocytes, contents of plasma SOD, and malondialdehyde (MDA) in leukocyte and erythrocyte membranes, respectively, were examined in 25 HD patients and 14 healthy volunteers. These were also determined after using a vitamin E-coated dialyzer (VE dialyzer) for 4 weeks. Results: All values were significantly higher in HD patients. A significant correlation was found between leukocyte Cu/Zn-SOD mRNA expression and membrane MDA. After using the VE dialyzer, all values were significantly lowered, showing a significant correlation between changing rate of leukocyte Cu/Zn-SOD mRNA expression and membrane MDA. Conclusion: In HD patients, oxidative stress is generated on the leukocyte membrane, and the level of Cu/Zn-SOD mRNA in leukocytes can be a useful oxidative stress marker.

Migraine is a multifactorial disease with various factors, such as genetic polymorphisms and personality traits, but the contribution of those factors is not clear. To clarify the pathogenesis of migraine, the contributions of genetic polymorphisms and personality traits were simultaneously investigated using multivariate analysis. Ninety-one migraine patients and 119 non-headache healthy volunteers were enrolled. The 12 gene polymorphisms analysis and NEO-FFI personality test were performed. At first, the univariate analysis was performed to extract the contributing factors to pathogenesis of migraine. We then extracted the factors that independently contributed to the pathogenesis of migraine using multivariate stepwise logistic regression analysis. Using the multivariate analysis, three gene polymorphisms including monoamine oxidase A (MAOA) T941G, methylenetetrahydrofolate reductase (MTHFR) C677T, and tumor necrosis factor beta (TNF-β) G252Α, and the neuroticism and conscientiousness scores in NEO-FFI were selected as significant factors that independently contributed to the pathogenesis of migraine. Their odds ratios were 1.099 (per point of neuroticism score), 1.080 (per point of conscientiousness score), 2.272 (T and T/T or T/G vs G and G/G genotype of MAOA), 1.939 (C/T or T/T vs C/C genotype of MTHFR), and 2.748 (G/A or A/A vs G/G genotype of TNF-β), respectively. We suggested that multiple factors, such as gene polymorphisms and personality traits, contribute to the pathogenesis of migraine. The contribution of polymorphisms, such as MAOA T941G, MTHFR C677T, and TNF-β G252A, were more important than personality traits in the pathogenesis of migraine, a multifactorial disorder.

Mobilization of intracellular Ca2+ stores regulates a multitude of cellular functions, but the role of intracellular Ca2+ release via the ryanodine receptor (RyR) in the brain remains incompletely understood. We found that nitric oxide (NO) directly activates RyRs, which induce Ca2+ release from intracellular stores of central neurons, and thereby promote prolonged Ca2+ signalling in the brain. Reversible S-nitrosylation of type 1 RyR (RyR1) triggers this Ca2+ release. NO-induced Ca2+ release (NICR) is evoked by type 1 NO synthase-dependent NO production during neural firing, and is essential for cerebellar synaptic plasticity. NO production has also been implicated in pathological conditions including ischaemic brain injury, and our results suggest that NICR is involved in NO-induced neuronal cell death. These findings suggest that NICR via RyR1 plays a regulatory role in the physiological and pathophysiological functions of the brain.

糖尿病合併血液透析患者におけるアログリプチン安息香酸塩（以下アログリプチン）の効果を検討した．対象は2010年9月に埼友草加病院で血液透析治療をしている患者381例中，ヘモグロビンA1c（以下HbA1c）≧6.1％かつグリコアルブミン（以下GA)≧20％で，食事療法や運動療法では血糖コントロールが不良な2型糖尿病患者16名を対象とした．インスリン注射や経口糖尿病薬の内服をしている患者はすべて除外された．年齢は62.5±9.2歳で，男性は13名，女性は3名だった．アログリプチンは1日1回6.25mgを内服とした．アログリプチンの投薬前後のHbA1c，GA，血糖値，インスリン値，C-peptide immunoreactivity値，グルカゴン値，活性型グルカゴン様ペプチド-1（以下GLP-1）値を測定した．採血はすべて透析開始前に行われた．検査値はWilcoxon signed-rank testを用いて解析された．HbA1cおよびGAは，投薬開始8週以降で投薬開始前とくらべて有意に低下した（p＜0.05）．HbA1cは投薬開始前が6.7±0.2％（平均±標準誤差）で，投薬開始後40週で5.6±0.2％に低下した．GAは投薬開始前が22.5±0.7％で，投薬開始後40週で19.7±0.5％に低下した．40週の観察期間で，16名中13名（81.3％）の患者がHbA1c＜6.1％かつGA＜20％を達成した．アログリプチン投薬前の活性型GLP-1値は8.9±5.7pmol/Lで，アログリプチン投薬前後で約2倍上昇した（p＜0.05）．アログリプチン内服による有害事象は，薬疹が1名だったが低血糖はいなかった．本研究では，糖尿病治療の選択肢が少ない血液透析患者において，新規治療戦略の一つとして期待されるアログリプチン（DPP-4阻害薬）の有効性を示唆することができた．

The novel T helper subset, Th17, plays a critical role in the pathogenesis of a variety of chronic inflammatory disorders such as rheumatoid arthritis, Crohn's disease, and others. Although inflammatory dendritic cells (DCs), such as DCs producing TNFα and iNOS, have been suggested to act as an inducer of Th17-immunity both in humans and mice in vivo; it is unclear how DCs elicit Th17-immunity. Recently, some Th17-differentiation pathways, both TGF-β-dependent and -independent pathways, have been identified in mice. However, the DC biology to evoke Th17-immunity in chronic inflammation or autoimmunity has not yet been clarified, in particular, in human cells. This review summarizes and discusses the induction of Th17 cells by DCs.