Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions

Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1α protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1α protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation

Soft Magnetic Properties of Electrodeposited Fe-Ni Films Prepared in Citric Acid Based Bath

Electrodeposited Fe-Ni films are widely used in device applications. However, there is a growing awareness of the toxicity of the plating bath containing boric acid. In order to avoid boric acid in the deposition process, we have employed a citric acid based bath for electrodeposition of Fe-Ni films and investigated the effect of the acid content in the bath on the structural and magnetic properties of the deposited films. It is found that the Fe content of the film depends largely on the acid concentration and low coercivity values of less than 30 A/m are realized when the Fe content of the film is around 22 at.%. This magnetic softness is attainable in a wide film thickness range between 20 and 120 μm. Our process exhibits a relatively high cathode efficiency of above 55%. Furthermore, a high deposition rate of 170 μm is obtained without sacrificing the magnetic softness of the film by increasing the current density during the deposition. From these results, we conclude that the citric acid based bath is an environmentally friendlier plating bath ideal for mass-production of magnetically soft Fe-Ni films

miR-200b Precursor Can Ameliorate Renal Tubulointerstitial Fibrosis

Members of the miR-200 family of micro RNAs (miRNAs) have been shown to inhibit epithelial-mesenchymal transition (EMT). EMT of tubular epithelial cells is the mechanism by which renal fibroblasts are generated. Here we show that miR-200 family members inhibit transforming growth factor-beta (TGF-beta)-induced EMT of tubular cells. Unilateral ureter obstruction (UUO) is a common model of EMT of tubular cells and subsequent tubulointerstitial fibrosis. In order to examine the role of miR-200 family members in tubulointerstitial fibrosis, their expression was investigated in the kidneys of UUO mice. The expression of miR-200 family miRNAs was increased in a time-dependent manner, with induction of miR-200b most pronounced. To clarify the effect of miR-200b on tubulointerstitial fibrosis, we injected miR-200b precursor intravenously. A single injection of 0.5 nM miR-200b precursor was sufficient to inhibit the increase of collagen types I, III and fibronectin in obstructed kidneys, and amelioration of fibrosis was confirmed by observation of the kidneys with Azan staining. miR-200 family members have been previously shown to inhibit EMT by reducing the expression of ZEB-1 and ZEB-2 which are known repressors of E-cadherin. We demonstrated that expression of ZEB-1 and ZEB-2 was increased after ureter obstruction and that administration of the miR-200b precursor reversed this effect. In summary, these results indicate that miR-200 family is up-regulated after ureter obstruction, miR-200b being strongly induced, and that miR-200b ameliorates tubulointerstitial fibrosis in obstructed kidneys. We suggest that members of the miR-200 family, and miR-200b specifically, might constitute novel therapeutic targets in kidney disease

Risk factors for an additional port in single-incision laparoscopic cholecystectomy in patients with cholecystitis

Although single-incision laparoscopic cholecystectomy is now widely performed in patients with cholecystitis, some cases require an additional port to complete the procedure. In this study, we focused on risk factor of additional port in this surgery. We performed single-incision cholecystectomy in 75 patients with acute cholecystitis or after cholecystitis between 2010 and 2014 at Gunma University Hospital. Surgical indications followed the TG13 guidelines. Our standard procedure for single-incision cholecystectomy routinely uses two needlescopic devices. We used logistic regression analysis to identify the risk factors associated with use of an additional full-size port (5 or 10 mm). Surgical outcome was acceptable without biliary injury. Nine patients (12.0%) required an additional port, and one patient (1.3%) required conversion to open cholecystectomy because of severe adhesions around the cystic duct and common bile duct. In multivariate analysis, high C-reactive protein (CRP) values (>7.0 mg/dl) during cholecystitis attacks were significantly correlated with the need for an additional port (P = 0.009),with a sensitivity of 55.6%, specificity of 98.5%, and accuracy of 93.3%. This study indicated that the severe inflammation indicated by high CRP values during cholecystitis attacks predicts the need for an additional port

Time-resolved magnetic resonance angiography as a follow-up method for visceral artery aneurysm treated with coil-embolisation

Purpose: The purpose of this study is to assess the feasibility and usefulness of time-resolved magnetic resonance angiography (TR-MRA) for follow-up of visceral artery aneurysms (VAAs) after embolotherapy. Material and methods: Twenty-one VAAs (11 splenic, six renal, three internal iliac, and one superior pancreaticoduodenal artery aneurysms) in 18 patients (median age, 64 years; range, 36-88 years) previously treated by embolisation with platinum coils, were evaluated. The mean size of the aneurysm was 10.5 cm3 (range, 0.3-132 cm3). Among them, 19 lesions were treated by aneurysmal packing with or without distal-to-proximal embolisation. For the remaining two lesions, distal-to-proximal embolization alone was performed. The mean observation period after embolotherapy was 35 weeks (range, 4-216). All patients underwent TR-MRA following an intravenous bolus injection of gadolinium chelate. Recanalisation was diagnosed when any portion of the aneurysmal sac was enhanced in the arterial phase. Results: On TR-MRA, two lesions were diagnosed as recanalised. They were confirmed by transcatheter arteriography and re-treated by embolotherapy. For the remaining 19 lesions, there were no findings of recanalisation on TR-MRA. Conclusions: TR-MRA appears to be a feasible method for follow-up examination of VAAs treated by embolotherapy

Identification of the ultrahigh-risk subgroup in neuroblastoma cases through DNA methylation analysis and its treatment exploiting cancer metabolism

神経芽腫の新たな診断法と治療戦略を創出 --がん細胞の生存戦略「がん代謝」を逆用する--. 京都大学プレスリリース. 2022-11-02.Neuroblastomas require novel therapies that are based on the exploitation of their biological mechanism. To address this need, we analyzed the DNA methylation and expression datasets of neuroblastomas, extracted a candidate gene characterizing the aggressive features, and conducted functional studies. Based on the DNA methylation data, we identified a subgroup of neuroblastoma cases with 11q loss of heterozygosity with extremely poor prognosis. PHGDH, a serine metabolism-related gene, was extracted as a candidate with strong expression and characteristic methylation in this subgroup as well as in cases with MYCN amplification. PHGDH inhibition suppressed neuroblastoma cell proliferation in vitro and in vivo, indicating that the inhibition of serine metabolism by PHGDH inhibitors is a therapeutic alternative for neuroblastoma. Inhibiting the arginine metabolism, which is closely related to serine metabolism using arginine deiminase, had a combination effect both in vitro and in vivo, especially on extracellular arginine-dependent neuroblastoma cells with ASS1 deficiency. Expression and metabolome analyses of post-dose cells confirmed the synergistic effects of treatments targeting serine and arginine indicated that xCT inhibitors that inhibit cystine uptake could be candidates for further combinatorial treatment. Our results highlight the rational therapeutic strategy of targeting serine/arginine metabolism for intractable neuroblastoma