Iron suppresses erythropoietin expression via oxidative stress-dependent hypoxia-inducible factor-2 alpha inactivation.

Renal anemia is a major complication in chronic kidney disease (CKD). Iron supplementation, as well as erythropoiesis-stimulating agents, are widely used for treatment of renal anemia. However, excess iron causes oxidative stress via the Fenton reaction, and iron supplementation might damage remnant renal function including erythropoietin (EPO) production in CKD. EPO gene expression was suppressed in mice following direct iron treatment. Hypoxia-inducible factor-2 alpha (HIF-2α), a positive regulator of the EPO gene, was also diminished in the kidney of mice following iron treatment. Anemia-induced increase in renal EPO and HIF-2α expression was inhibited by iron treatment. In in vitro experiments using EPO-producing HepG2 cells, iron stimulation reduced the expression of the EPO gene, as well as HIF-2α. Moreover, iron treatment augmented oxidative stress, and iron-induced reduction of EPO and HIF-2α expression was restored by tempol, an antioxidant compound. HIF-2α interaction with the Epo promoter was inhibited by iron treatment, and was restored by tempol. These findings suggested that iron supplementation reduced EPO gene expression via an oxidative stress-HIF-2α-dependent signaling pathway.

Palliative Radiofrequency Ablation Therapy for Intractable Cancer-Related Pain Due to Malignant Psoas Syndrome: Case Report.

Uncontrollable cancer pain is a highly feared and debilitating symptom. The effectiveness of radiofrequency ablation (RFA) for osseous metastases with intractable cancer-related pain refractory to pharmacological therapy has been reported previously. This case report is the first to demonstrate the use of RFA to achieve pain relief in a patient suffering severe pain caused by para-aortic lymph node metastasis. A 55-year-old male complained of intractable pain in the left groin and perineum due to malignant psoas syndrome caused by metastatic para-aortic lymph nodes. The pain was refractory to medications including opioids and nerve blocks. Considering the dermatome indicating referred pain and the imaging findings, RFA of the area of invasion was performed at the L3 level. The severe pain was relieved within 24 hours without any complications. Opioids were tapered at each postoperative outpatient visit. We discuss the use of RFA for control of intractable cancer-related pain refractory to medication, including opioids.

Intraprocedural Plaque Protrusion during Carotid Artery Stenting with a CASPER Stent: A Case Report.

Objective: Plaque protrusion (PP) during carotid artery stenting (CAS) is considered to be associated with periprocedural ischemic stroke. A new double-layer micromesh stent, the CASPER stent (CS), was approved for use in Japan in 2020. The expectation is that this micromesh stent system will reduce the risk of PP, but we report a case of PP during CAS despite the use of a CS. Case Presentation: An 87-year-old man presented with left hemiparesis. MRI showed right brain infarction and angiography showed right internal carotid artery stenosis with thrombus. Follow-up angiography after medical treatment showed that thrombus disappeared. We therefore performed CAS for right internal carotid artery stenosis with unstable plaque. CAS was performed under local anesthesia with Mo.Ma Ultra and FilterWire EZ protection using a CS placed to sufficiently cover the stenotic region. Conservative post-dilatation was then performed. Intravascular ultrasonography (IVUS) after post-dilatation showed the presence of PP. A second CS was then added using the stent-in-stent technique. No postoperative neurological abnormalities were found and the patient was discharged without postoperative complications. No stroke or restenosis has been observed as of 16 months after CAS. Conclusion: PP can occur even when CAS is performed using the CS for carotid artery stenosis with unstable plaque. The importance of checking for PP using IVUS is suggested.

Transarterial Chemoembolization with Irinotecan-loaded Beads Followed by Arterial Infusion of 5-Fluorouracil for Metastatic Liver Tumors Refractory to Standard Systemic Chemotherapy.

We report two cases of liver metastases from colorectal and anal cancers after the failure of systemic chemotherapies that were successfully treated with a combination therapy of transarterial chemoembolization using irinotecan-loaded drug-eluting beads and hepatic arterial infusion chemotherapy. In both cases, hepatic arterial infusion chemotherapy was performed as maintenance therapy after irinotecan-loaded drug-eluting beads. Irinotecan at a dose of 120 mg was loaded on drug delivery beads for irinotecan-loaded drug-eluting bead-transarterial chemoembolization. A weekly high-dose 5-fluorouracil regimen (1000 mg/m2/5 h) was used for hepatic arterial infusion chemotherapy. The liver metastases shrank remarkably in both cases, and progression-free survivals of 13 and 9 months, respectively, were obtained without any severe adverse events.

Percutaneous Trans-jejunum Pancreatojejunostomy Reconstruction for Intractable Pancreatic Fistula after Pancreatoduodenectomy.

We present an interventional radiology technique for percutaneous trans-jejunal pancreatojejunostomy reconstruction for intractable pancreatic fistula. A 70-year-old man with pancreatic cancer who had undergone pancreatoduodenectomy underwent percutaneous drainage for leakage from the anastomosis of the pancreatic duct to the jejunum. The leakage continued and the hole at the anastomosis site in the jejunum closed completely after 5 months. We performed percutaneous jejunostomy; the previously placed drainage catheter was then replaced with a balloon catheter, which was punctured by a 19-gauge needle from inside the jejunum through the percutaneous jejunostomy tube. The seeking catheter was inserted into the pancreatic duct. Finally, a side-holed 6-Fr straight catheter was successfully placed in the pancreatic duct through the percutaneous jejunostomy route.

Symptomatic Intracranial Hemorrhage after Mechanical Thrombectomy - the Difference between Iso-Osmolar and Low-Osmolar Contrast Media.

Objective: Symptomatic intracranial hemorrhage (SICH) after mechanical thrombectomy (MT) is generally considered a critical complication. Hemorrhagic transformation after ischemic stroke has also been associated with contrast media administration. The objective of our study was to evaluate correlations between contrast media type and incidence of SICH after MT. Methods: Ninety-three consecutive patients (41 men; mean age, 80.2 years; range, 44-98 years) underwent MT reperfusion (expanded thrombolysis in cerebral infarction score, 2a-3) for acute large-vessel occlusion ischemic stroke within 8 h after symptom onset between April 2020 and July 2023 were retrospectively reviewed. Correlations between contrast media type (iso-osmolar or low-osmolar medium) and incidence of SICH were assessed. Results: Contrast media were iso-osmolar in 60 cases or low-osmolar in 33 cases. The overall incidence of SICH was 5.5%. The frequency of SICH was significantly lower in the iso-osmolar group (1.7%) than in the low-osmolar group (12.1%; P = 0.033). Conclusion: Iso-osmolar contrast media was associated with a lower incidence of SICH compared with low-osmolar contrast media in patients after MT.

Thermostability of Hybrid Thermoelectric Materials Consisting of Poly(Ni-ethenetetrathiolate), Polyimide and Carbon Nanotubes.

Three-component organic/inorganic hybrid films were fabricated by drop-casting the mixed dispersion of nanodispersed-poly(nickel 1,1,2,2-ethenetetrathiolate) (nano-PETT), polyimide (PI) and super growth carbon nanotubes (SG-CNTs) in N-methylpyrrolidone (NMP) at the designed ratio on a substrate. The dried nano-PETT/PI/SG-CNT hybrid films were prepared by the stepwise cleaning of NMP and methanol, and were dried once more. The thermoelectric properties of Seebeck coefficient S and electrical conductivity σ were measured by a thin-film thermoelectric measurement system ADVANCE RIKO ZEM-3M8 at 330-380 K. The electrical conductivity of nano-PETT/PI/SG-CNT hybrid films increased by 1.9 times for solvent treatment by clearing insulated of polymer. In addition, the density of nano-PETT/PI/SG-CNT hybrid films decreased 1.31 to 0.85 g·cm-3 with a decrease in thermal conductivity from 0.18 to 0.12 W·m-1·K-1. To evaluate the thermostability of nano-PETT/PI/SG-CNT hybrid films, the samples were kept at high temperature and the temporal change of thermoelectric properties was measured. The nano-PETT/PI/SG-CNT hybrid films were rather stable at 353 K and kept their power factor even after 4 weeks.

Maxizymes and small hairpin-type RNAs that are driven by a tRNA promoter specifically cleave a chimeric gene associated with leukemia in vitro and in vivo.

Many leukemias result from chromosomal translocations that lead to the generation of chimeric oncoproteins. Chimeric gene for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) is the hallmark of acute promyelocytic leukemia. Specific gene silencing of an oncogene is desirable for the treatment of these diseases. We have previously constructed an allosterically controllable ribozyme (designated maxizyme) targeted for bcr-abl chimeric mRNA, whose cleavage activity is induced only in the presence of a specific RNA sequence of interest. It has been demonstrated recently that RNA interference induced by short hairpin-type RNAs provides a powerful method for sequence-specific gene silencing. Here we report that DNA vector-based maxizymes and short hairpin-type RNAs driven by the promoter of a human gene for tRNA(Val) specifically inhibit the expression of the chimeric gene for PML-RAR alpha both in vitro and in vivo. Our findings confirm the potential utility of maxizymes and shRNAs as therapeutic agents.

Novel hybrid organic thermoelectric materials:three-component hybrid films consisting of a nanoparticle polymer complex, carbon nanotubes, and vinyl polymer.

A novel class of hybrid organic thermoelectric materials is demonstrated for the first time for constructing flexible thermoelectric devices on polyimide substrates with high output power by using nanotechnology instead of conducting polymers such as poly(3,4-ethylenedioxythiophene). The hybrid organic thermoelectric materials are composed of nanoparticles of a polymer complex, carbon nanotubes, and poly(vinyl chloride), and show high performance (dimensionless thermoelectric figure-of-merit, ZT ≈ 0.3, based on the thermal conductivity through the film).

Evidence that bone morphogenetic protein 4 has multiple biological functions during kidney and urinary tract development.

BACKGROUND: We have suggested that bone morphogenetic protein 4 (BMP4), acting on the Wolffian duct and ureter epithelium, determines the budding site of the ureter by locally antagonizing ubiquitous inductive signal(s) from the metanephric mesenchyme. In the present study, we examine the effect of BMP4 on the development of metanephric and periureteral mesenchymal cells, which express the BMP type I receptor gene, Bmpr1a (Alk3). METHODS: Urogenital tissues obtained from Bmp4 heterozygous null mutant (Bmp4+/-) embryos at different stages, and metanephric and ureteral tissue explants cultured in the presence of recombinant BMP4 were subjected to morphologic, immunohistochemical and in situ hybridization analyses. To examine the chemotactic activity of BMP4 for periureteral mesenchymal cells, a modified Boyden chamber assay was performed. RESULTS: Many of the kidneys of newborn Bmp4+/- mice contained multicystic dysplastic regions. This morphology was preceded by abnormally high apoptotic activity in the metanephric mesenchyme of mutant embryos at E14.5. In whole metanephric explants, BMP4 uniformly promoted the expansion of the Pax2-negative and weakly Foxd1 (previously Bf2) -positive peripheral stromal compartment of metanephric mesenchyme in the presence of fibroblast growth factor 2 (FGF2). In addition, in isolated metanephric mesenchyme, BMP4-loaded beads prevented apoptosis locally. Thus, BMP4 prevents cell death and promotes the growth of the metanephric mesenchyme. The effect of BMP4 on periureteral mesenchyme is different from its effect on metanephric mesenchyme. In utero, periureteral mesenchymal cells condense around the ureter epithelium, followed by differentiation into smooth muscle cells at a site where Bmp4 is intensely expressed. Analysis of Bmp4+/- ureters at E15.5 reveals that the alpha-smooth muscle actin (alpha-SMA)-positive cells are low in number. In vitro, BMP4-loaded beads promote the accumulation of periureteral mesenchymal cells to form several cell layers surrounding the beads. In addition, in a Boyden chamber assay, BMP4 increases the migration of periureteral mesenchymal cells through the filter. Thus, BMP4 can serve as a chemoattractant for periureteral mesenchymal cells and induce locally the smooth muscle layer of the ureter at Bmp4-expressing sites. CONCLUSION: Depending on local context, BMP4 has several biological actions on the morphogenesis of different portions of the excretory system, namely, the development of the ureterovesical junction, the ureter, and the kidney.

A functional gene discovery in cell differentiation by hybrid ribozyme and siRNA libraries.

Recently, we developed a gene discovery system that can identify functional genes using a randomized hybrid ribozyme library. In this system, inhibition of the expression of a particular gene by active ribozymes was reflected by a change in a particular phenotype, the method allowed the identification of functional genes. In the case of identification of functional genes for apoptosis pathways, we identified many pro-apoptotic genes in TNF-alpha and Fas-mediated apoptosis pathways. In this study, we tried to identify the functional genes that are necessary for the retinoic acid (RA)-induced cell differentiation using randomized ribozyme and siRNA libraries. We succeeded to identify the several differentiation factors. Therefore, our gene discovery system based on randomized ribozyme and siRNA libraries are high potential to identify the differentiation and undifferentiation factors in the post genome era.

Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy.

BACKGROUND: Unilateral ureteral obstruction (UUO) is characterized by progressive tubular atrophy and interstitial fibrosis. Rupture of the balance between cell proliferation and apoptosis plays a critical role in renal atrophy. Hepatocyte growth factor (HGF) is a cytokine function on cell survival and tissue regeneration. We studied the effects and possible mechanisms of HGF gene therapy on tubular cell survival and anti-fibrosis in chronic obstructed nephropathy. METHODS: An in vivo transfection procedure of repeatedly transducing skeletal muscles with the HGF gene using liposomes containing the hemagglutinating virus of Japan (HVJ liposome) was tested on UUO rats. Expression of HGF and c-Met were examined by in situ hybridization, ELISA, or immunohistochemical staining. Interstitial fibrosis and macrophage infiltration were evaluated by Masson's Trichrome staining, alpha-smooth muscle actin and ED-1 immunostaining. Cell survival indices including proliferating cell nuclear antigen (PCNA), Bcl-2, Bcl-xL and Bax were measured by immunohistochemistry and Western blots. Apoptosis was determined by the TUNEL method. RESULTS: After HVJ-HGF gene transfer, endogenous HGF and c-Met were up-regulated in UUO kidneys. Renal fibrosis, macrophage infiltration and tubular atrophy were suppressed both at day 14 and 28 after UUO (P < 0.05 or 0.01). Tubular cell proliferation was activated while apoptosis was inhibited, especially at the late stage of UUO. Bcl-2 was enhanced in the HGF-transfected UUO rats, while no changes of Bcl-xL and Bax were found. CONCLUSIONS: In vivo HGF gene transfection retards the progression of chronic obstructed nephropathy and protects tubular cell survival in the long-term UUO model. Bcl-2 rather than Bcl-xL or Bax may contribute to the anti-apoptotic function of HGF.