Nesfatin-1 suppresses peripheral arterial remodeling without elevating blood pressure in mice

Nesfatin-1 is a novel anorexic peptide hormone that also exerts cardiovascular protective effects in rodent models. However, nesfatin-1 treatment at high doses also exerts vasopressor effects, which potentially limits its therapeutic application. Here, we evaluated the vasoprotective and vasopressor effects of nesfatin -1 at different doses in mouse models. Wild-type mice and those with the transgene nucleobindin-2, a precursor of nesfatin-1, were employed. Wild-type mice were randomly assigned to treatment with vehicle or nesfatin-1 at 0.2, 2.0 or 10 μg/kg/day (Nes-0.2, Nes-2, Nes-10, respectively). Subsequently, mice underwent femoral artery wire injury to induce arterial remodeling. After 4 weeks, injured arteries were collected for morphometric analysis. Compared with vehicle, nesfatin-1 treatments at 2.0 and 10 μg/kg/day decreased body weights and elevated plasma nesfatin-1 levels with no changes in systolic blood pressure. Furthermore, these treatments reduced neointimal hyperplasia without inducing undesirable remodeling in injured arteries. However, nesfatin-1 treatment at 0.2 μg/kg/day was insufficient to elevate plasma nesfatin-1 levels and showed no vascular effects. In nucleobindin-2- transgenic mice, blood pressure was slightly higher but neointimal area was lower than those observed in littermate controls. In cultured human vascular endothelial cells, nesfatin-1 concentration-dependently increased nitric oxide production. Additionally, nesfatin-1 increased AMP-activated protein kinase phosphorylation, which was abolished by inhibiting liver kinase B1. We thus demonstrated that nesfatin-1 treatment at appropriate doses suppressed arterial remodeling without affecting blood pressure. Our findings indicate that nesfatin-1 can be a therapeutic target for improved treatment of peripheral artery disease

Combination Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor and a Dipeptidyl Peptidase-4 Inhibitor Additively Suppresses Macrophage Foam Cell Formation and Atherosclerosis in Diabetic Mice

Dipeptidyl peptidase-4 inhibitors (DPP-4is), in addition to their antihyperglycemic roles, have antiatherosclerotic effects. We reported that sodium-glucose cotransporter 2 inhibitors (SGLT2is) suppress atherosclerosis in a glucose-dependent manner in diabetic mice. Here, we investigated the effects of combination therapy with SGLT2i and DPP-4i on atherosclerosis in diabetic mice. SGLT2i (ipragliflozin, 1.0 mg/kg/day) and DPP-4i (alogliptin, 8.0 mg/kg/day), either alone or in combination, were administered to db/db mice or streptozotocin-induced diabetic apolipoprotein E-null (Apoe−/−) mice. Ipragliflozin and alogliptin monotherapies improved glucose intolerance; however, combination therapy did not show further improvement. The foam cell formation of peritoneal macrophages was suppressed by both the ipragliflozin and alogliptin monotherapies and was further enhanced by combination therapy. Although foam cell formation was closely associated with HbA1c levels in all groups, DPP-4i alone or the combination group showed further suppression of foam cell formation compared with the control or SGLT2i group at corresponding HbA1c levels. Both ipragliflozin and alogliptin monotherapies decreased scavenger receptors and increased cholesterol efflux regulatory genes in peritoneal macrophages, and combination therapy showed additive changes. In diabetic Apoe−/− mice, combination therapy showed the greatest suppression of plaque volume in the aortic root. In conclusion, combination therapy with SGLT2i and DPP4i synergistically suppresses macrophage foam cell formation and atherosclerosis in diabetic mice

Involvement of Vascular Endothelial Cells in the Anti-atherogenic Effects of Liraglutide in Diabetic Apolipoprotein E-null Mice

Glucagon-like peptide 1 receptor agonists （GLP-1RAs） have been shown to exert anti-atherosclerotic effects via multiple mechanisms on different types of cells. However, it is unclear which of these mechanisms are crucial. We investigated the role of vascular endothelial cells （VECs） in the anti-atherogenic effects of the GLP-1RA liraglutide in a mouse model of atherosclerosis. Streptozotocin-induced diabetic apolipoprotein E-null mice were randomly assigned to treatment with either vehicle （saline） or liraglutide （107nmol/kg/day）, and were subjected to femoral artery wire injury to remove VECs. After 4 weeks, vessel samples were collected for analysis. Streptozotocin-injected mice had fasting plasma glucose levels of ＞300mg/dl and hemoglobin A1c levels of ＞9％, indicating that the injections had induced severe hyperglycemia. However, there were no differences in metabolic characteristics such as levels of hemoglobin A1c, fasting plasma glucose, total cholesterol, and triglycerides between the vehicle and liraglutide groups. Analysis of atherosclerotic plaque formation revealed that liraglutide treatment significantly suppressed plaque formation in the aorta. In addition, liraglutide treatment reduced plaque volume and intra-plaque macrophage accumulation at the aortic sinus. Furthermore, liraglutide treatment suppressed vascular expression of pro-inflammatory cytokines. In uninjured femoral arteries, no plaques were observed; however, severe plaque formation occurred in femoral arteries that had been injured by wire insertion to remove VECs. Unlike in the uninjured aorta, liraglutide treatment did not affect plaque volume or arterial remodeling （intimal and medial thinning, and arterial dilation） in wire-injured femoral arteries. Of the various cells that liraglutide affects, VECs play a central role in liraglutide’s anti-atherogenic effects in diabetic mice

Associations of Glucose and Blood Pressure Variability with Cardiac Diastolic Function in Patients with Type 2 Diabetes Mellitus and Hypertension: A Retrospective Observational Study

We evaluated the effects of glucose metabolism and blood pressure（BP） variability on cardiac diastolic function in patients with type 2 diabetes mellitus（T2DM） and hypertension. A total of 23 inpatients with T2DM underwent ambulatory BP monitoring（ABPM） and echocardiography. BP variability was assessed by measuring the mean BP and the standard deviation（SD） of systolic and diastolic BP over 24 hours, as well as daytime and nighttime ABPM. Cardiac diastolic function was assessed using the echocardiography E/e′ ratio. Participants had a mean age of 69.0±10.6 years, disease duration of 11.0±10.5 years, glycated hemoglobin（HbA1c） of 8.2％±1.3％, and glycated albumin（GA） of 22.0％±4.2％. Univariate analysis showed that the nighttime systolic BP, nighttime SDs of systolic and diastolic BP, urinary albumin, estimated glomerular filtration rate, and GA/HbA1c ratio were all significantly correlated with the E/e′ ratio. Moreover, stepwise multiple regression analysis identified nighttime SD of diastolic BP, urinary albumin, and GA/HbA1c ratio as independent contributors to the E/e′ ratio. In patients with T2DM and hypertension, cardiac diastolic function was associated with nighttime diastolic BP variability and the GA/HbA1c ratio

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

Pheochromocytoma presenting with severe hyperglycemia and metabolic acidosis following intra-articular glucocorticoid administration: a case report

Abstract Background There are several reports of pheochromocytoma crisis triggered by systemic glucocorticoid administration. However, pheochromocytoma crisis after intra-articular glucocorticoid administration has been rarely reported. Case presentation A 45-year-old Japanese man presented to our hospital with a sudden, severe headache. He had no history of diabetes. He had received an intra-articular injection of betamethasone (2 mg) for joint pain, 2 days prior to his admission. On examination, his blood pressure was 240/126 mmHg and pulse was 120 beats/minute. The possibility of cerebrovascular events was ruled out by imaging studies and lumbar puncture. Blood tests revealed severe hyperglycemia (523 mg/dL) and metabolic acidosis (pH 7.21, anion gap 26.2 mEq/L, lactate 11.75 mmol/L) with a glycosylated hemoglobin level of 5.7%. Although a urine sample could not be obtained, fulminant type 1 diabetes mellitus and diabetic ketoacidosis were suspected based on these findings. However, after the initial treatment for diabetic ketoacidosis, his insulin secretion was found to be normal and the plasma levels of ketones were not elevated. This excluded the possibility of fulminant type 1 diabetes mellitus and diabetic ketoacidosis. Subsequently, a left adrenal gland tumor and elevated levels of serum catecholamine and urinary catecholamine metabolites were detected, while his other hormone levels were normal. Serum catecholamine levels did not decrease following the clonidine test, and a functional scintigraphy using iodine-131 metaiodobenzylguanidine showed strong uptake in the region of the left adrenal gland. Although no signs of pheochromocytoma crisis, such as paroxysmal hyperglycemia and hypertension, had been observed since admission, a pheochromocytoma was diagnosed based on the investigations. After controlling his blood pressure, a left adrenalectomy was performed. Conclusions This case illustrates that intra-articular glucocorticoid administration can induce a pheochromocytoma crisis and an increase in hyperglycemia, and that pheochromocytoma crisis can resemble the clinical picture of fulminant type 1 diabetes mellitus owing to severe hyperglycemia with metabolic acidosis and normal glycosylated hemoglobin levels, especially under the influence of glucocorticoid

Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice.

Direct associations between hyperglycemia and atherosclerosis remain unclear. We investigated the association between the amelioration of glycemia by sodium-glucose cotransporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe-/-) mice, streptozotocin-induced diabetic Apoe-/- mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macrophages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in diabetic Apoe-/- mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macrophage infiltration in the aortic root increased in diabetic Apoe-/- mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclerosis or plasma parameters in non-diabetic Apoe-/- mice. In db/db mice, foam cell formation increased by 4-fold compared with C57/BL6 mice, whereas ipragliflozin decreased it by 31%. Foam cell formation exhibited a strong correlation with HbA1c. Gene expression of lectin-like ox-LDL receptor-1 and acyl-coenzyme A:cholesterol acyltransferase 1 was upregulated, whereas that of ATP-binding cassette transporter A1 was downregulated in the peritoneal macrophages of both types of diabetic mice. SGLT2i normalized these gene expressions. Our study is the first to demonstrate that SGLT2i exerts anti-atherogenic effects by pure glucose lowering independent of insulin action in diabetic mice through suppressing macrophage foam cell formation, suggesting that foam cell formation is highly sensitive to glycemia ex vivo

A Dipeptidyl Peptidase-4 Inhibitor Suppresses Macrophage Foam Cell Formation in Diabetic db/db Mice and Type 2 Diabetes Patients

Dipeptidyl peptidase-4 (DPP-4) inhibitors could have antiatherosclerotic action, in addition to antihyperglycemic roles. Because macrophage foam cells are key components of atherosclerosis, we investigated the effect of the DPP-4 inhibitor teneligliptin on foam cell formation and its related gene expression levels in macrophages extracted from diabetic db/db (C57BLKS/J Iar -+Leprdb/+Leprdb) mice and type 2 diabetes (T2D) patients ex vivo. We incubated mouse peritoneal macrophages and human monocyte-derived macrophages differentiated by 7-day culture with oxidized low-density lipoprotein in the presence/absence of teneligliptin (10 nmol/L) for 18 hours. We observed remarkable suppression of foam cell formation by teneligliptin treatment ex vivo in macrophages isolated from diabetic db/db mice (32%) and T2D patients (38%); this effect was accompanied by a reduction of CD36 (db/db mice, 43%; T2D patients, 46%) and acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) gene expression levels (db/db mice, 47%; T2D patients, 45%). Molecular mechanisms underlying this effect are associated with downregulation of CD36 and ACAT-1 by teneligliptin. The suppressive effect of a DPP-4 inhibitor on foam cell formation in T2D is conserved across species and is worth studying to elucidate its potential as an intervention for antiatherogenesis in T2D patients

Ton-scale metal–carbon nanotube composite: The mechanism of strengthening while retaining tensile ductility

One-dimensional carbon nanotubes (CNT), which are mechanically strong and flexible, enhance strength of the host metal matrix. However, the reduction of ductility is often a serious drawback. Here, we report significantly enhanced plastic flow strength, while preventing tensile ductility reduction, by uniformly dispersing CNTs in Al matrix. Nanoscale plasticity and rupturing processes near CNTs were observed by in-situ mechanical tests inside Transmission Electron Microscope (TEM). CNTs act like forest dislocations and have comparable density (∼1014/m2), and such 1D nano-dispersion hardening is studied in detail by in situ TEM and molecular dynamics simulations. Rupture-front blunting and branching are seen with in situ TEM, which corroborates the result from macro-scale tension tests that our Al + CNT nanocomposite is quite damage- and fault-tolerant. We propose a modified shear-lag model called ‘‘Taylor-dispersion’’ hardening model to highlight the dual roles of CNTs as load-bearing fillers and ‘‘forest dislocations’’ equivalent that harden the metal matrix, for the plastic strength of metal + CNT nanocomposite. © 2016 Elsevier Ltd.