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Seven undescribed steroidal alkaloids, including two jervine-type steroidal alkaloids, fritiunibras A-B (1-2), and five cevanine-type steroidal alkaloid glycosides, fritiunibras C-G (3-7), along with six known cevanine-type steroidal alkaloids and their glycosides (8-13) were isolated from the bulbs of Fritillaria unibracteata Hsiao et K. C. Hsia. Their structures were determined by interpretation of comprehensive spectroscopic and single-crystal X-ray diffraction analysis. The absolute configurations of sugar moieties were determined by HPLC analysis and compared with standards after hydrolysis and derivatization. Furthermore, their inhibitory effects on NO production and cytotoxic activities were evaluated.

Ischemic stroke remains one of the leading causes of death worldwide, thereby highlighting the urgent necessary to identify new therapeutic targets. Deoxyhypusine hydroxylase (DOHH) is a fundamental enzyme catalyzing a unique posttranslational hypusination modification of eukaryotic translation initiation factor 5A (eIF5A) and is highly involved in the progression of several human diseases, including HIV-1 infection, cancer, malaria, and diabetes. However, the potential therapeutic role of pharmacological regulation of DOHH in ischemic stroke is still poorly understood. Our study first discovered a natural small-molecule brazilin (BZ) with an obvious neuroprotective effect against oxygen-glucose deprivation/reperfusion insult. Then, DOHH was identified as a crucial cellular target of BZ using HuProt™ human proteome microarray. By selectively binding to the Cys232 residue, BZ induced a previously undisclosed allosteric effect to significantly increase DOHH catalytic activity. Furthermore, BZ-mediated DOHH activation amplified mitophagy for mitochondrial function and morphology maintenance via DOHH/eIF5A hypusination signaling pathway, thereby protecting against ischemic neuronal injury in vitro and in vivo. Collectively, our study first identified DOHH as a previously unreported therapeutic target for ischemic stroke, and provided a future drug design direction for DOHH allosteric activators using BZ as a novel molecular template.

Two couples of pinene-containing N^C*N and C*N^N-coordinated Pt(II) complexes featuring a fused five-six-membered metallacycle have been developed, and their structures were confirmed by NMR, MS and single crystal X-ray crystallography. Cyclometalated complex (−)-2 has two polymorphs involving yellow-orange form (−)-2·CH3COCH3 and orange form (−)-2·CH3SOCH3, revealing different conformations and intermolecular π−π interactions. Complexes (−)-1 and (−)-2 display prominent aggregation-induced emission (AIE) in THF-water solution system with emission quantum yield (Φem) strengthening from 0.2% to 37%. Despite the structural similarity of complexes (−)-1 and (−)-2, different mechanochromic luminescent phenomena have been distinguished. No detectable change in color and luminescence of yellow solids (−)-1 can be found during the grinding process, whereas yellow solids of complex (−)-2 show a reversible mechanochormic luminescent behavior and a simultaneous crystal-to-amorphous transformation. It is speculated that dimeric structures containing weak π−π interactions are formed under the mechanical force, and simultaneously the molecular conformation becomes more planar, improving the conjugation, inducing the emissive state variance with more 3MLCT/3ILCT character. Moreover, anti-counterfeiting application based on complex (−)-2 has been explored. This research provides a new design strategy for exploring AIE-active Pt(II) complexes with high-contrast mechanochromic luminescence.

Trimethyltin chloride (TMT) is an organotin heat stabilizer that is widely used in the production of plastics, and has strong toxicity. Here, the effect of trimethyltin chloride on mouse kidneys and its related mechanism were studied by taking TMT mouse with drinking water as a model. Histological examination and TUNEL results showed that the trimethyltin chloride group had typical apoptosis and necroptosis characteristics. Therefore, the level of oxidative stress was detected,and the expression of related genes was verified by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot methods. The results showed that oxidative stress was activated (MDA,SOD,CAT,T-AOC), released ROS, activated NF-κB pathway,activated inflammasome (NLRP3,Caspase-1,ASC), and inflammasome-secreted inflammatory factors (IL-1β). The expression of apoptosis (BCL-2, BAX, Caspase-3, Caspase-9) and necroptosis (RIPK1, RIPK33, MLKL, Caspase-8) increased.In addition, HEK293T human embryonic kidney cells were treated with trimethyltin chloride, and the results were similar to the tissue. In conclusion, TMT can induce oxidative stress, activate NF-κB pathway, and induce apoptosis and necroptosis through inflammasomes.

Electrospun blended nanofibrous scaffolds were fabricated from an synthetic biodegradable polymer (poly(ethylene carbonate-ɛ-caprolactone) (poly(EC-CL)) and vascular endothelial growth factor with different weight ratios. Results showed that the diameter of blended scaffolds was 440 ± 55 nm. VEGF on the surface of the blended scaffolds was identified by immunofluorescence. In vitro cell proliferation, viability assay results showed that human umbilical vein endothelial cells (HUVECs) had a good growth and spread morphology on the blended scaffolds. Scaffolds electrospun from this polymer contained VEGF had a good application in tissue engineering.

Two heterometallic coordination polymers, {KBa(ptc)(H2O)2}n(1) and {KCaEr(ptc)2(H2O)}n(2) (H3ptc = pyridine-2,4,6-tricarboxylic acid) have been synthesized under hydrothermal conditions and characterized by elemental analysis, IR and single crystal X-ray diffraction. 1 and 2 exhibit two novel three-dimensional (3D) frameworks, and the luminescence properties of 1, 2 were investigated.

Electrospun blended nanofibrous scaffolds were fabricated from an synthetic biodegradable polymer (poly( l -lactide-co-ɛ-caprolactone): PLCL; 8% solution) and a natural protein (fibrinogen; 100 mg/ml solution) with different volume ratios. Results showed that the blended scaffolds consisted of nanoscale fibers with mean diameters ranging from 224 to 450 nm. The deposition of the fibrinogen amino groups on the surfaces of the blended scaffolds was confirmed by XPS. The hydrophilicity of the blended scaffolds were improved with the fibrinogen content increasing in the blended system. Cell viability assay and SEM results showed that human umbilical vein endothelial cells (HUVECs) had progressive growth and well spread morphology on the blended scaffolds. This study demonstrated that electrospun PLCL/fibrinogen blended scaffolds have potential application in tissue engineering.

Background Stent graft-induced new entry (SINE), defined as the new tear caused by the stent graft and excluding those arising from natural disease progression or iatrogenic injury from the endovascular manipulation, has been increasingly observed after thoracic endovascular aortic repair (TEVAR) for Stanford type B dissection in our center. SINE appears to be remarkably life threatening. We investigated the incidence, mortality, causes, and preventions of SINE after TEVAR for Stanford type B dissection. Methods Data for 22 patients with SINE were retrospectively collected and analyzed from 650 patients undergoing TEVAR for type B dissection from August 2000 to June 2008. An additional patient was referred to our center 14 months after TEVAR was performed in another hospital. The potential associations of SINE with Marfan syndrome, location of SINE and endograft placement, and the oversizing rate were analyzed by Fisher exact probability test or t test. Results We found 24 SINE tears in 23 patients, including SINE at the proximal end of the endograft in 15, at the distal end in 7, and at both ends in 1. Six patients died. SINE incidence and mortality reached 3.4% and 26.1%, respectively. Two SINE patients were diagnosed with Marfan syndrome, whereas there were only 6 Marfan patients among the 651 patients. The 16 proximal SINEs were evidenced at the greater curve of the arch and caused retrograde type A dissection. The eight distal SINEs occurred at the dissected flap, and five caused enlarging aneurysm whereas three remained stable. The endograft was placed across the distal aortic arch during the primary TEVAR in all 23 patients. The incidence of SINE was 33.33% among Marfan patients vs 3.26% among non-Marfan patients ( P = .016). There was no significant difference in mortality between proximal and distal SINE (25% vs 28.6%, P > .99), incidence of SINE between endograft placement across the arch and at the straight portion of descending thoracic aorta (23 of 613 vs 0 of 38, P = .39), and the oversizing rate between SINE and non-SINE patients (13% ± 4.5% vs 16% ± 6.5%, P = .98). Conclusions SINE appears not to be rare after TEVAR for type B dissection and is associated with substantial mortality. The stress yielded by the endograft seems to play a predominant role in its occurrence. It is important to take this stress-induced injury into account during both design and placement of the endograft.

Huanong AVM is a novel nematicide, which was synthesized from avermectin by selective oxidization of the hydroxyl group at C-4, followed by the reaction with glacial acetic acid. Effects of Huanong AVM on Bursaphelechus xylophilus are reported in this paper. Huanong AVM had strong nematicidal activity against B. xylophilus , with LC 50 values of 14.84 μg/mL, 12.49 μg/mL and 11.05 μg/mL, respectively, at 48 h, 72 h and 96 h after treatment. The proteins that responded to Huanong AVM were identified by proteomic analysis. 2-DE analysis revealed eighteen differentially accumulated protein spots. Five spots were successfully identified by MS analysis, and three Huanong AVM induced proteins were annotated in the database as LEVamisole resistant family member (lev-11), ACTin family member (act-4) and Hypothetical protein Y52B11A.10. Two Huanong AVM-up-regulated proteins were assigned as PIP Kinase family member (ppk-3) and Hypothetical protein B0432.6. These proteins are involved in signal transduction, maintaining cytoskeletal structure and LEVamisole resistance. These results point to pathways that are important for the mode of the action of Huanong AVM on B. xylophilus .

Introduction Hirudin is a direct thrombin inhibitor that has potential mechanistic advantages over indirect inhibitors. Peptides containing the RGD motif competitively inhibit binding of fibrinogen to glycoprotein IIb/IIIa on platelets, thus inhibiting platelet aggregation. A novel hirudin derivative, recombinant RGD-hirudin (r-RGD-hirudin), was engineered by fusing the tripeptide RGD sequence to the native hirudin. We tested the antithrombotic effect of r-RGD-hirudin using a carotid artery reconstruction model in rabbits. Materials and methods A fusion gene encoding r-RGD-hirudin was constructed and expressed at high levels in Pichia pastoris. Following traumatic injury and anastomosis, 42 New Zealand White rabbits were randomized to receive normal saline, abciximab, wild-type hirudin, or r-RGD-hirudin. Fibrinogen concentration, aPTT, TT, PT, and PAGm were measured prior to and following the operation. Carotid angiography and pathological examination of the anastomotic site were performed to compare patency rates among the groups. Results The r-RGD-hirudin significantly prolonged aPTT, TT, PT and inhibited PAGm following carotid anastomosis in rabbits. The median dose of r-RGD-hirudin (0.5 mg/kg) had a therapeutic effect equal to that of wild-type hirudin (1.0 mg/kg) and higher than that of abciximab (0.2 mg/kg) with regard to patency rates. Conclusions Compared to wild-type hirudin or antiplatelet agent, the novel anticoagulant, r-RGD-hirudin was capable of inhibiting both thrombin activity and platelet aggregation, and was demonstrated to be effective in the prevention of thrombosis.

To evaluate the potential role of external beam radiation therapy (EBRT) in the treatment of patients with hepatocellular carcinoma (HCC) who have portal vein (PV) and/or inferior vena cava (IVC) tumor thrombi.One hundred fifty-eight patients with HCC who had PV and/or IVC tumor thrombus were reviewed and analyzed by Kaplan-Meier and Cox regression analysis. Forty-four patients with HCC who received local limited EBRT (in addition to other treatment modalities) were classified as the EBRT group. The total radiation dose was 36-60 Gy (median, 50 Gy) and was focused on the tumor thrombi. One hundred fourteen patients with HCC who did not receive EBRT were selected from hospitalized patients with HCC who had PV and/or IVC thrombi during the same period; these were classified as the non-EBRT group, and their intrahepatic tumors were treated with transarterial chemoembolization or resection, on the basis of the patients' status. Parameters observed included survival rates and the tumor thrombus response to EBRT as seen on CT scan or MRI.Of the 44 patients who received EBRT, 15 (34.1%) showed complete disappearance of tumor thrombi, 5 (11.4%) were in partial remission, 23 (52.3%) were stable in their tumor thrombi, and 1 (2.3%) showed disease progression at the end of the study period. The median survival was 8 months, and the 1-year survival rate was 34.8% in the EBRT group. In the non-EBRT group, the median survival and 1-year survival rates were 4 months and 11.4%, respectively. In stepwise multivariate analysis, EBRT showed a strongly protective value (relative risk = 0.324, p0.001). Survival was not related to intrahepatic tumor status in the non-EBRT patients. However, in the EBRT group, poorer prognosis was significantly related to intrahepatic multifocal or diffusion lesions, and the most common reason for death was liver failure caused by uncontrolled intrahepatic disease.Although EBRT is palliative in intent, it is preferred for prolonging survival in the treatment of tumor thrombi.

A new method for growing a GaN initial layer on a GaAs(0 0 1) substrate is reported. The experiments show that the optimized growth condition for a smooth GaN initial layer is to grow a two monolayer thick layer at 600°C under As pressure. The pure cubic GaN films of 500 nm has been obtained on such an initial layer, the X-ray diffraction and photoluminescence show that the C–GaN film has a very high quality. There is no yellow or DA band emission of PL spectrum and the FWHM of the X-ray rocking curve is only 10 min.

Introduction Complications of Takayasu's arteritis are usually ischemia of certain organs caused by progressive arterial narrowing, while dilative lesions or formation of aneurysms are relatively uncommon. Report A 43-year-old man with the chief compliant of abdominal discomfort underwent an enhanced computed tomography scan which showed a 30 mm × 23 mm superior mesenteric artery aneurysm. Because of the acute downward angulation of the superior mesenteric artery and inappropriateness for larger sheath placement brachial arteries, the aneurysm was excluded with a stent-graft via the common carotid artery approach. Discussion Stent-graft implantation through the common carotid artery is a feasible approach for the endovascular treatment of superior mesenteric artery aneurysms when unfavorable anatomic limits exist.

BackgroundThis study investigated the feasibility, safety, and efficacy of the intramuscular injection of CD34+ cells isolated from peripheral blood mononuclear cells (PB-MNCs) mobilized by granulocyte colony-stimulating factor (G-CSF) for the management of patients with critical limb ischemia (CLI) who were considered unlikely to have successful long-term revascularization with open bypass or endovascular methods. Cell therapy represents a new treatment modality for this subgroup of patients with CLI. To date, bone marrow or PB-MNCs have usually been used for transplantation. The current pilot study investigated whether the transplantation of purified CD34+ cells only would be competent in ischemia relief and limb salvage.MethodsFrom May 2009 to July 2011, 25 patients (mean age, 44 ± 12 years) were enrolled, and 25 lower extremities and three upper extremities were treated. After subcutaneous administration of G-CSF for 5 days at a dose of 5 to 10 μg/kg, apheresis and immunomagnetic separation were performed to acquire the isolated CD34+ cells, which were then intramuscularly injected into the ischemic sites. The patients were divided into three groups: low-dose, 105/kg; medium-dose, 5 × 105/kg; and high-dose, 106/kg. The overall outcomes among all patients and the comparison among the groups were evaluated.ResultsDuring the follow-up of 6 to 33 months, the overall outcomes showed that the Wong-Baker FACES pain rating scale score (WFPRSS) decreased from 7 ± 2 to 3 ± 3 (P < .001) and 1 ± 2 (P < .001) at 1 and 2 months, respectively; at 3 and 6 months, respectively, the peak pain-free walking time increased from 4 ± 3 to 13 ± 7 (P < .001) and 18 ± 6 minutes (P < .001), the ankle-brachial index increased from 0.46 ± 0.21 to 0.60 ± 0.17 (P = .003) and 0.67 ± 0.15 (P = .001), and the transcutaneous partial oxygen pressure increased from 27 ± 10 to 41 ± 11 (P < .001) and 55 ± 12 mm Hg (P < .001). Ulcers were healed in 10 of the 14 patients; four patients required above-knee or below-knee amputation ≤ 3 months. The Kaplan-Meier estimate of the rate of freedom from major amputation at 6 months was 84% (95% confidence interval, 63%-94%). The comparison among the three groups (low-dose, 5; medium-dose, 11; high-dose, 9) revealed no significant difference, except that the WFPRSS improvement at 1 month from baseline in the high-dose group (6.3 ± 1.7) was significantly superior to that in the low-dose (3.2 ± 3.3; P = .0487) and medium-dose (3.7 ± 2.8; P = .0352) groups.ConclusionsTransplantation of CD34+ cells isolated from G-CSF-mobilized PB-MNCs appears to be feasible and safe, showing encouraging outcomes in the treatment of CLI patients who appear to have compromised options for long-term revascularization.

The loss of microRNA-122 (miR-122) expression correlates to many characteristic properties of hepatocellular carcinoma (HCC) cells, including clonogenic survival, anchorage-independent growth, migration, invasion, epithelial-mesenchymal transition, and tumorigenesis. However, all of these findings do not sufficiently explain the oncogenic potential of miR-122. In the current study, we used two-dimensional differential in-gel electrophoresis to measure changes in the expression of thousands of proteins in response to the inhibition of miR-122 in human hepatoma cells. Several proteins that were upregulated on miR-122 inhibition were involved in the unfolded protein response (UPR) pathway. The overexpression of miR-122 resulted in the repression of UPR pathway activation. Therefore, miR-122 may act as an inhibitor of the chaperone gene expression and negatively regulate the UPR pathway in HCC. We further showed that the miR-122 inhibitor enhanced the stability of the 26S proteasome non-ATPase regulatory subunit 10 (PSMD10) through the up-regulation of its target gene cyclin-dependent kinase 4 (CDK4). This process may activate the UPR pathway to prevent chemotherapy-mediated tumor cell apoptosis. The current study suggests that miR-122 negatively regulates the UPR through the CDK4-PSMD10 pathway. The down-regulation of miR-122 activated the CDK4-PSMD10-UPR pathway to decrease tumor cell anticancer drug-mediated apoptosis. We identified a new HCC therapeutic target and proclaimed the potential risk of the therapeutic use of miR-122 silencing.

Effects of circumferential stretch vs. deep injury on the in-stent neointimal formation in the atherosclerotic iliac rabbit arteries Jianing Yue , Takamitsu Nakamura, Yuqi Wang , Weiguo Fu, Dongming Guo , Nicolas Chronos c Vascular Surgery Department of Zhongshan Hospital Fudan University, Shanghai, China Department of Internal Medicine II, University of Yamanashi, Chuo, Japan Saint Joseph's Translational Research Institute, Atlanta, GA, USA

Background: Transcatheter delivery of thrombolytic therapy is an effective tool in the treatment of acute deep venous thrombosis (DVT). We sought to determine an effective and safe thrombolytic regimen with tPA in the treatment of severe DVT when used in conjunction with percutaneous endovenous intervention (PEVI). Methods: Eighty consecutive patients with acute symptomatic DVT were randomized to receive four different doses of tPA. They had all undergone PEVI from 0.5 to 18 h following presentation to the hospital. PEVI consisted of any or a combination of the following: Trellis, Angiojet, or manual suction thrombectomy, balloon venoplasty, or stenting. Following initial PEVI, if N50% thrombus remained, tPA was given via an infusion catheter for 16–20 h. Patients were randomized to receive tPA at 0.5, 1, 2, or 4 mg/h and were assigned to Groups I–IV, respectively, with 20 in each group. Warfarin was continued, and during tPA administration heparin dose was reduced to 12 U/kg per hour. The end points evaluated were venous patency post-tPA (b5% residual thrombus), bleeding, and length of hospital stay. Results: The results are demonstrated in the Table 1. Venous patency rate was similar in Groups II–IV. Bleeding was seen more in Group IV, lengthening hospital stay. Venous patency was low in Group I. Conclusions: We conclude that transcatheter endovenous administration of tPA following suboptimal PEVI at 1 mg/h for 16–20 h is highly safe and effective in the treatment of DVT allowing for high patency rate, no complications, and early discharge.