Search

Background: Defects in DNA damage repair can cause genetic mutations, which in turn can cause different types of cancers. Chromatin remodeling complexes, which help repair damaged DNA, can cause the chromatin structure to change as a result of DNA damage. ARID1A may play a role in the process of DNA damage repair, and arid1a may be related to the occurrence and development of gastric cancer (GC). This study aimed to investigate the mechanism of ARID1A regulating the DNA damage repair of gastric adenocarcinoma cell lines AGS and SGC-7901 and its effect on migration, proliferation and apoptosis., Methods: The expression of ARID1A plasmid was detected by Western blot and real-time polymerase chain reaction (PCR). The effect of etoposide (ETO) on the survival rate of AGS and SGC-7901 gastric adenocarcinoma cell lines was detected by MTT assay. The DNA double-strand break model was established by ETO and then passed through the comet assay and immunofluorescence co-localization to observe DNA damage; western blot method was used to detect the effect of ARID1A on the expression of related proteins in DNA damage repair pathway in gastric adenocarcinoma cells; scratch test and colony formation experiments were used to observe ARID1A migration and proliferation of gastric adenocarcinoma cells. The flow cytometry was used to detect the effect of ARID1A on apoptosis of gastric adenocarcinoma cells., Results: The expression of mRNA and protein was increased after transfection of ARID1A plasmid. ETO was confirmed by MTT assay to inhibit cell survival in a dose-dependent manner. After the DNA double-strand break model was established by ETO, the expression levels of phospho-ataxia telangiectasia mutated (p-ATM) protein increased in the overexpressed ARID1A group. Meanwhile, the overexpressed ARID1A group had a shortened tail moment, and γ-H2AX and ARID1A co-localized in the DNA damage site of the nucleus. The over-expressed ARID1A group had weaker wound healing ability, reduced number of clone formation, and increased apoptosis rate., Conclusions: ARID1A may repair DNA double-strand breaks caused by ETO by p-ATM pathway; ARID1A can inhibit the migration and proliferation of gastric adenocarcinoma cells and promote apoptosis. Our findings indicate that ARID1A could serve as a therapeutic target and biomarker for GC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-283/coif). The authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: There is a lack of sufficient evidence on whether mixed-type differentiated predominant early gastric cancer (MD-EGC) can be treated endoscopically by referring to the criteria for differentiated-type early gastric cancer (EGC). This study aims to evaluate the efficacy of endoscopic submucosal dissection (ESD) in MD-EGC., Methods: Patients with differentiated-type EGC treated with ESD first from January 2015 to June 2021 were reviewed, including MD-EGC and pure differentiated-type EGC (PD-EGC). Clinical data, including the clinicopathological characteristics, resection outcomes of ESD, and recurrence and survival time, were collected, and the difference between MD-EGC and PD-EGC was tested., Results: A total of 48 patients (48 lesions) with MD-EGC and 850 patients (890 lesions) with PD-EGC were included. Compared with PD-EGC, MD-EGC had a higher submucosal invasion rate (37.5% vs. 13.7%, P<0.001) and lymphatic invasion rate (10.4% vs. 0.4%, P<0.001). The rates of complete resection (70.8% vs. 92.5%, P<0.001) and curative resection (54.2% vs. 87.4%, P<0.001) in MD-EGC were lower than those of PD-EGC. Multivariate analysis revealed that MD-EGC (OR 4.26, 95% CI, 2.22-8.17, P<0.001) was an independent risk factor for noncurative resection. However, when curative resection was achieved, there was no significant difference in the rates of recurrence (P=0.424) between the 2 groups, whether local or metachronous recurrence. Similarly, the rates of survival(P=0.168) were no significant difference., Conclusions: Despite the greater malignancy and lower endoscopic curative resection rate of MD-EGC, patients who met curative resection had a favorable long-term prognosis., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and the leading cause of blindness and severe visual impairment in adults. The high levels of glucose trigger multiple intracellular oxidative stress pathways, such as POLDIP2, resulting in excessive reactive oxygen species (ROS) production and increased expression of vascular cell adhesion molecule-1 (VCAM-1), hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF), causing microvascular dysfunction. Dihydromyricetin (DMY) is a natural flavonoid small molecule antioxidant. However, it exhibits poor solubility in physiological environments, has a short half-life in vivo, and has low oral bioavailability. In this study, we present, for the first time, the synthesis of ultra-small Fe-DMY nano-coordinated polymer particles (Fe-DMY NCPs), formed by combining DMY with low-toxicity iron ions. In vitro and in vivo experiments confirm that Fe-DMY NCPs alleviate oxidative stress-induced damage to vascular endothelial cells by high glucose, scavenge excess ROS, and improve pathological features of DR, such as retinal vascular leakage and neovascularization. Mechanistic validation indicates that Fe-DMY NCPs can inhibit the activation of the Poldip2-Nox4-H 2 O 2 signaling pathway and downregulate vital vascular function indicators such as VCAM-1, HIF-1α, and VEGF. These findings suggest that Fe-DMY NCPs could serve as a safe and effective antioxidant and microangio-protective agent, with the potential as a novel multimeric drug for DR therapy., Competing Interests: The authors declare that there are no conflicts of interest., (© 2023 The Author(s).)

Portal hypertension (PT) commonly occurs in cirrhosis. Nitric oxide (NO) imbalance contributes to PT via reduced soluble guanylyl cyclase (sGC) activation and cGMP production, resulting in vasoconstriction, endothelial cell dysfunction, and fibrosis. We assessed the effects of BI 685509, an NO-independent sGC activator, on fibrosis and extrahepatic complications in a thioacetamide (TAA)-induced cirrhosis and PT model. Male Sprague-Dawley rats received TAA twice-weekly for 15 weeks (300-150 mg/kg i.p.). BI 685509 was administered daily for the last 12 weeks (0.3, 1, and 3 mg/kg p.o.; n = 8-11 per group) or the final week only (Acute, 3 mg/kg p.o.; n = 6). Rats were anesthetized to measure portal venous pressure. Pharmacokinetics and hepatic cGMP (target engagement) were measured by mass spectrometry. Hepatic Sirius Red morphometry (SRM) and alpha-smooth muscle actin ( α SMA) were measured by immunohistochemistry; portosystemic shunting was measured using colored microspheres. BI 685509 dose-dependently increased hepatic cGMP at 1 and 3 mg/kg (3.92 ± 0.34 and 5.14 ± 0.44 versus 2.50 ± 0.19 nM in TAA alone; P < 0.05). TAA increased hepatic SRM, α SMA, PT, and portosystemic shunting. Compared with TAA, 3 mg/kg BI 685509 reduced SRM by 38%, α SMA area by 55%, portal venous pressure by 26%, and portosystemic shunting by 10% ( P < 0.05). Acute BI 685509 reduced SRM and PT by 45% and 21%, respectively ( P < 0.05). BI 685509 improved hepatic and extrahepatic cirrhosis pathophysiology in TAA-induced cirrhosis. These data support the clinical investigation of BI 685509 for PT in patients with cirrhosis. SIGNIFICANCE STATEMENT: BI 685509 is an NO-independent sGC activator that was tested in a preclinical rat model of TAA-induced nodular, liver fibrosis, portal hypertension, and portal systemic shunting. BI 685509 reduced liver fibrosis, portal hypertension, and portal-systemic shunting in a dose-dependent manner, supporting its clinical assessment to treat portal hypertension in patients with cirrhosis., (Copyright © 2023 by The Author(s).)

Introduction: No study has investigated the efficacy and safety of vonoprazan-amoxicillin dual therapy compared with bismuth quadruple therapy (B-quadruple). This study aimed to evaluate the efficacy and safety of 10-day vonoprazan-amoxicillin dual therapy as a first-line treatment of Helicobacter pylori infection compared with B-quadruple and to explore the optimal dosage of amoxicillin in the dual therapy., Methods: A total of 375 treatment-naive, H. pylori -infected subjects were randomly assigned in a 1:1:1 ratio into 3 regimen groups including VHA-dual (vonoprazan 20 mg twice/day + amoxicillin 750 mg 4 times/day), VA-dual (vonoprazan 20 mg + amoxicillin 1,000 mg twice/day), and B-quadruple (esomeprazole 20 mg + bismuth 200 mg + amoxicillin 1,000 mg + clarithromycin 500 mg twice/day). Eradication rates, adverse events (AEs), and compliance were compared between 3 groups., Results: The eradication rates of B-quadruple, VHA-dual, and VA-dual were 90.9%, 93.4%, and 85.1%, respectively, by per-protocol analysis; 89.4%, 92.7%, and 84.4%, respectively, by modified intention-to-treat analysis; 88.0%, 91.2%, and 82.4%, respectively, by intention-to-treat analysis. The efficacy of the VHA-dual group was not inferior to the B-quadruple group ( P < 0.001), but VA-dual did not reach a noninferiority margin of -10%. The AEs rates of the B-quadruple group were significantly higher than those of the VHA-dual ( P = 0.012) and VA-dual ( P = 0.001) groups. There was no significant difference in medication compliance among 3 treatment groups ( P = 0.995)., Conclusions: The 10-day VHA-dual therapy provided satisfactory eradication rates of >90%, lower AEs rates, and similar adherence compared with B-quadruple therapy as a first-line therapy for H. pylori infection. However, the efficacy of VA-dual therapy was not acceptable., (Copyright © 2022 by The American College of Gastroenterology.)

Activation of soluble guanylate cyclase (sGC) to restore cyclic guanosine monophosphate (cGMP) and improve functionality of nitric oxide (NO) pathways impaired by oxidative stress is a potential treatment of diabetic and chronic kidney disease. We report the pharmacology of BI 685509, a novel, orally active small molecule sGC activator with disease-modifying potential. BI 685509 and human sGC α 1/ β 1 heterodimer containing a reduced heme group produced concentration-dependent increases in cGMP that were elevated modestly by NO, whereas heme-free sGC and BI 685509 greatly enhanced cGMP with no effect of NO. BI 685509 increased cGMP in human and rat platelet-rich plasma treated with the heme-oxidant ODQ; respective EC 50 values were 467 nM and 304 nM. In conscious telemetry-instrumented rats, BI 685509 did not affect mean arterial pressure (MAP) or heart rate (HR) at 3 and 10 mg/kg (p.o.), whereas 30 mg/kg decreased MAP and increased HR. Ten days of BI 685509 at supratherapeutic doses (60 or 100 mg/kg p.o., daily) attenuated MAP and HR responses to a single 100 mg/kg challenge. In the ZSF1 rat model, BI 685509 (1, 3, 10, and 30 mg/kg per day, daily) coadministered with enalapril (3 mg/kg per day) dose-dependently reduced proteinuria and incidence of glomerular sclerosis; MAP was modestly reduced at the higher doses versus enalapril. In the 7-day rat unilateral ureteral obstruction model, BI 685509 dose-dependently reduced tubulointerstitial fibrosis ( P < 0.05 at 30 mg/kg). In conclusion, BI 685509 is a potent, orally bioavailable sGC activator with clear renal protection and antifibrotic activity in preclinical models of kidney injury and disease. SIGNIFICANCE STATEMENT: BI 685509 is a novel small soluble guanylate cyclase (sGC) molecule activator that exhibits an in vitro profile consistent with that of an sGC activator. BI 685509 reduced proteinuria and glomerulosclerosis in the ZSF1 rat, a model of diabetic kidney disease (DKD), and reduced tubulointerstitial fibrosis in a rat 7-day unilateral ureteral obstruction model. Thus, BI 685509 is a promising new therapeutic agent and is currently in phase II clinical trials for chronic kidney disease and DKD., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Non-alcoholic fatty liver disease (NAFLD) affects about 24% of the world's population. Progression of early stages of NAFLD can lead to the more advanced form non-alcoholic steatohepatitis (NASH), and ultimately to cirrhosis or liver cancer. The current gold standard for diagnosis and assessment of NAFLD/NASH is liver biopsy followed by microscopic analysis by a pathologist. The Kleiner score is frequently used for a semi-quantitative assessment of disease progression. In this scoring system the features of active injury (steatosis, inflammation, and ballooning) and a separated fibrosis score are quantified. The procedure is time consuming for pathologists, scores have limited resolution and are subject to variation. We developed an automated deep learning method that provides full reproducibility and higher resolution. The system was established with 296 human liver biopsies and tested on 171 human liver biopsies with pathologist ground truth scores. The method is inspired by the way pathologist's analyze liver biopsies. First, the biopsies are analyzed microscopically for the relevant histopathological features. Subsequently, histopathological features are aggregated to a per-biopsy score. Scores are in the identical numeric range as the pathologist's ballooning, inflammation, steatosis, and fibrosis scores, but on a continuous scale. Resulting scores followed a pathologist's ground truth (quadratic weighted Cohen's κ on the test set: for steatosis 0.66, for inflammation 0.24, for ballooning 0.43, for fibrosis 0.62, and for the NAFLD activity score (NAS) 0.52. Mean absolute errors on a test set: for steatosis 0.29, for inflammation 0.53, for ballooning 0.61, for fibrosis 0.78, and for the NAS 0.77)., (© 2022. The Author(s).)

Diabetic nephropathy is a leading cause of end-stage renal disease, characterized by endothelial dysfunction and a compromised glomerular permeability barrier. Dysregulation of the angiopoietin 1 (ANGPT1)/angiopoietin 2 (ANGPT2) signaling axis is implicated in disease progression. We recently described the discovery of an IgG 1 antibody, O010, with therapeutic potential to elevate circulating endogenous ANGPT1, a tyrosine kinase with Ig and epidermal growth factor (EGF) homology domains-2 (TIE2) agonist. Studies are described that detail the effect of various ANGPT1-elevating strategies to limit progression of renal dysfunction in diabetic-obese (db/db) mice. Results demonstrate that adeno-associated virus- or DNA minicircle-directed overexpression of ANGPT1 elicits a reduction in albuminuria (56%-73%) and an improvement in histopathology score (18% reduction in glomerulosclerosis). An improved acetylcholine response in isolated aortic rings was also observed indicative of a benefit on vascular function. In separate pharmacokinetic studies, an efficacious dose of the ANGPT1 DNA minicircle increased circulating levels of the protein by >80%, resulting in a concomitant suppression of ANGPT2. At a dose of O010-producing maximal elevation of circulating ANGPT1 achievable with the molecule (60% increase), no suppression of ANGPT2 was observed in db/db mice, suggesting insufficient pathway engagement; no reduction in albuminuria or improvement in histopathological outcomes were observed. To pinpoint the mechanism resulting in lack of efficacy, we demonstrate, using confocal microscopy, an interference with TIE2 translocation to adherens junctions, resulting in a loss of protection against vascular permeability normally conferred by ANGPT1. Results demonstrated the essential importance of ANGPT1 to maintain the glomerular permeability barrier, and, due to interference of O010 with this process, led to the discontinuation of the molecule for clinical development. SIGNIFICANCE STATEMENT: This body of original research demonstrates that elevation of systemic angiopoietin 1 (ANGPT1) is protective against diabetic nephropathy. However, using a novel biotherapeutic approach to elevate systemic ANGPT1 renoprotection was not observed; we demonstrate that protection was lost due to interference of the therapeutic with ANGPT1/ tyrosine kinase with Ig and EGF homology domains-2 translocation to adherens junctions. Thus, the clinical development of the antibody was terminated., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Two new aspidosperma-type monoterpenoid indole alkaloids, 16- O -methylvoafinine ( 1 ) and 14,15- diepi -voafinidine ( 2 ) were isolated from the aerial parts of Ervatamia officinalis . Their structures were established by comprehensive spectroscopic analysis including 1D and 2D NMR, HR-ESI-MS, and electronic circular dichroism calculation. The isolated compounds were evaluated for cytotoxic activities against HepG2, MCF-7, and A549 cell lines by CCK-8 assay.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and it is associated with poor prognosis. Its characteristics of being highly invasive and undergoing heterogeneous genetic mutation, as well as the presence of the blood-brain barrier (BBB), have reduced the efficacy of GBM treatment. The emergence of a novel therapeutic method, namely, sonodynamic therapy (SDT), provides a promising strategy for eradicating tumors via activated sonosensitizers coupled with low-intensity ultrasound. SDT can provide tumor killing effects for deep-seated tumors, such as brain tumors. However, conventional sonosensitizers cannot effectively reach the tumor region and kill additional tumor cells, especially brain tumor cells. Efforts should be made to develop a method to help therapeutic agents pass through the BBB and accumulate in brain tumors. With the development of novel multifunctional nanosensitizers and newly emerging combination strategies, the killing ability and selectivity of SDT have greatly improved and are accompanied with fewer side effects. In this review, we systematically summarize the findings of previous studies on SDT for GBM, with a focus on recent developments and promising directions for future research., (© 2022. The Author(s).)

The biological effects of nanoparticles are of great importance for the in-depth understanding of safety issues in biomedical applications. Induction of autophagy is a cellular response after nanoparticle exposure. Bismuth sulfide nanoparticles (Bi 2 S 3 NPs) are often used as a CT contrast agent because of their excellent photoelectric conversion ability. Yet there has been no previous detailed study other than a cell toxicity assessment. In this study, three types of Bi 2 S 3 NPs with different shapes (Bi 2 S 3 nano rods (BSNR), hollow microsphere Bi 2 S 3 NPs (BSHS) and urchin-like hollow microsphere Bi 2 S 3 NPs (ULBSHS)) were used to evaluatecytotoxicity, autophagy induction, cell migration and invasion in human hepatocellular carcinoma cells (HepG2). Results showed that all three Bi 2 S 3 NPs lead to blockage in autophagic flux, causing p62 protein accumulation. The cell death caused by these Bi 2 S 3 NPs is proved to be autophagy related, rather than related to apoptosis. Moreover, Bi 2 S 3 NPs can reduce the migration and invasion in HepG2 cells in an autophagy-dependent manner. ULBSHS is the most cytotoxic among three Bi 2 S 3 NPs and has the best tumor metastasis suppression. These results demonstrated that, even with relatively low toxicity of Bi 2 S 3 NPs, autophagy blockage may still substantially influence cell fate and thus significantly impact their biomedical applications, and that surface topography is a key factor regulating their biological response.

In this mini-review, we highlighted the recent progresses in the controlled synthesis of metal sulfides hollow nanostructures via hard template technique. After a brief introduction about the formation mechanism of the inorganic hollow nanostructures via hard template technique, the discussions primarily focused on the emerging development of metal sulfides hollow nanostructures. Various synthetic strategies were summarized concerning the use of the hard template engaged strategies to fabricate various metal sulfides hollow nanostructures, such as hydrothermal method, solvothermal method, ion-exchange, sulfidation or calcination etc. Finally, the perspectives and summaries have been presented to demonstrate that a facile synthetic technique would be widely used to fabricate metal sulfides hollow nanostructures with multi-shells and components., (© 2020 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hollow nanostructures of metal sulfides have gained tremendous attention in catalysis, biomedicine, and energy storage and conversion owing to their intriguing structural features and fascinating physicochemical properties. Here, we reported a hard template-engaged cation exchange method to fabricate a family of binary or ternary metal sulfide (CuS, Ag 2 S, Bi 2 S 3 , Cu x Bi 1- x S, Zn x Co 1- x S, Zn x Cd 1- x S, Zn x Ni 1- x S, and Zn x Mn 1- x S) hollow microspheres via adjusting the reaction kinetic parameters including solvent and temperature in the presence of unique ZnS composite microspheres. Particularly, the shell layer thickness of metal sulfide hollow microspheres could be modulated by manipulating the reaction temperature during the cation exchanging procedure. Meanwhile, the desired elementary composition of ternary metal sulfide hollow microspheres could be achieved by varying the mole ratio and species of the metal source. This synthetic strategy could be extended to rationally design and construct other metal sulfide hollow nanostructures and provide a deep insight into the nucleation and growth process of the metal sulfide hollow microspheres with well-controlled composition and microstructures.

Transient receptor potential canonical type 6 (TRPC6) is a nonselective receptor-operated cation channel that regulates reactive fibrosis and growth signaling. Increased TRPC6 activity from enhanced gene expression or gain-of-function mutations contribute to cardiac and/or renal disease. Despite evidence supporting a pathophysiological role, no orally bioavailable selective TRPC6 inhibitor has yet been developed and tested in vivo in disease models. Here, we report an orally bioavailable TRPC6 antagonist (BI 749327; IC 50 13 nM against mouse TRPC6, t 1/2 8.5-13.5 hours) with 85- and 42-fold selectivity over the most closely related channels, TRPC3 and TRPC7. TRPC6 calcium conductance results in the stimulation of nuclear factor of activated T cells (NFAT) that triggers pathological cardiac and renal fibrosis and disease. BI 749327 suppresses NFAT activation in HEK293T cells expressing wild-type or gain-of-function TRPC6 mutants (P112Q, M132T, R175Q, R895C, and R895L) and blocks associated signaling and expression of prohypertrophic genes in isolated myocytes. In vivo, BI 749327 (30 mg/kg/day, yielding unbound trough plasma concentration ∼180 nM) improves left heart function, reduces volume/mass ratio, and blunts expression of profibrotic genes and interstitial fibrosis in mice subjected to sustained pressure overload. Additionally, BI 749327 dose dependently reduces renal fibrosis and associated gene expression in mice with unilateral ureteral obstruction. These results provide in vivo evidence of therapeutic efficacy for a selective pharmacological TRPC6 inhibitor with oral bioavailability and suitable pharmacokinetics to ameliorate cardiac and renal stress-induced disease with fibrosis., Competing Interests: Conflict of interest statement: D.M., J.F.D., L.P., D.W., G.R., S.M.W., S.Z., H.S.Q, J.J.K, A.S., and S.S.P. are full-time employees of Boehringer Ingelheim Pharmaceuticals, Inc. M.M, M.R.N, A.B., and C.S. were full-time employees of Boehringer Ingelheim Pharmaceuticals, Inc. A.B. and M.R.N. are listed as coinventors on a US provisional patent application filed by Boehringer Ingelheim Pharmaceuticals, Inc. relevant to this work. J.F.D., N.Z., D.d.C., X.Z., N.T.B., J.A.C., D.P.H., and M.M.M. were employees of Hydra Biosciences, and received options. This work was supported in part by Boehringer Ingelheim Pharmaceuticals, Inc.

Monodisperse sub-10 nm core-shell nanocrystals have been extensively studied owing to their important applications in catalysis, bioimaging, nanomedicine, and so on. In this work, an amorphous shell component crystallization strategy has been proposed to prepare high quality sub-10 nm NaYF 4 :Yb/Er@NaGdF 4 core-shell nanocrystals successfully via a sequential growth process. The dynamic light scattering technique has been used to investigate the secondary nucleation and growth process forming the core-shell nanocrystals. The size and morphology evolution of the core-shell nanocrystals reveals that the secondary nucleation of the shell component is unavoidable after hot-injecting the shell precursor at high temperatures, which was followed by dissolution and recrystallization (an Ostwald ripening process) to partially produce the core-shell nanocrystals. The present study demonstrates that the size of seed nanocrystals and the injection temperature of the shell component precursor play a vital role in the formation of core-shell nanostructures completely. This work will provide an alternative strategy for precisely controlling the fabrication of sub-10 nm core-shell nanostructures for various applications.

Magnetically recyclable photocatalyst has drawn considerable research interest because of its importance in practical applications. Herein, we demonstrate a facile hydrothermal process to fabricate magnetic core-shell microspheres of Fe 3 O 4 @Zn x Cd 1- x S, successfully using Fe 3 O 4 @ZnS core-shell microspheres as sacrificed templates. The as-prepared magnetically recyclable photocatalysts show efficient photochemical reduction of Cr(VI) under irradiation of visible light. The photochemical reduction mechanism has been studied to illustrate the reduction-oxidation ability of the photogenerated electrons (e - ) and holes (h + ), which play an important role in the reduction of Cr(VI) to Cr(III) and oxidation of organic dyes. The as-prepared Fe 3 O 4 @Zn 0.55 Cd 0.45 S core-shell microspheres show good chemical stability and only a slight decrease in the photocatalytic activity after four recycles. In particular, the as-prepared photocatalysts could be easily recycled and reused by an external magnetic field. Therefore, this work would provide a facile chemical approach for controlled synthesis of magnetic nanostructures combined with alloyed semiconductor photocatalysts for wastewater treatment.

Upconversion core-shell nanoparticles have attracted a large amount of attention due to their multifunctionality and specific applications. In this work, based on a NaGdF 4 sub-10 nm ultrasmall nanocore, a series of core-shell upconversion nanoparticles with uniform size doped with Yb 3+ , Er 3+ and NaDyF 4 shells with different thicknesses were synthesized by a facile sequential growth process. NaDyF 4 coated upconversion luminescent nanoparticles showed an obvious fluorescence quenching under excitation at 980 nm as a result of energy resonance transfer between Yb 3+ , Er 3+ and Dy 3+ . NaGdF 4 :Yb,Er@NaDyF 4 core-shell nanoparticles with ultrathin layer shells exhibited a better T 1 -weighted MR contrast., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Synergistic photodynamic and photothermal therapy of cancer cells is of considerable scientific and technological interest. In this work, we demonstrate a sacrificial template strategy to fabricate yolk-shell nanoparticles combining upconversion nanoparticles (UCNPs) and CuS nanoparticles. Lanthanide-doped upconversion nanoparticles of NaYF 4 :30% Yb,1% Nd,0.5% Er@NaYF 4 :20% Nd (also denoted as UCNPs) have been prepared as 808 nm light excited remote-controlled nanotransducers for in vitro cancer cell treatment. The upconversion fluorescence of the as-prepared UCNPs@CuS yolk-shell nanoparticles is completely quenched under the excitation of an 808 nm laser, which demonstrates that the energy transfer between the UCNPs and CuS is very efficient. In addition, the as-prepared UCNPs@CuS nanoparticles show higher production ability for hydroxyl radicals (˙OH) and singlet oxygen ( 1 O 2 ) compared to CuS hollow nanospheres of similar size. In particular, the excited shell layer (CuS) showed an enhanced photothermal effect while producing reactive oxygen species (ROS) including singlet oxygen ( 1 O 2 ) and hydroxyl radicals (˙OH) after being exposed to near infrared (NIR) light. Thus, the as-prepared UCNPs@CuS yolk-shell nanoparticles exhibited the synergistic effect of photothermal and photodynamic therapy of cancer cells, which resulted in significant cell death after exposure to an 808 nm laser. The synthetic strategy will provide an alternative method to fabricate other UCNP based core-shell nanoparticles for potential and important applications in bionanotechnology including theranostics, multimodal treatment, magnetic resonance imaging-guided photodynamic therapy, etc.

It is a significant challenge to develop nanoscale magnetic resonance imaging (MRI) contrast agents with high performance of relaxation. In this work, Gd 3+ -doped CaF 2 -based core-shell nanoparticles (CaF 2 :Yb,Er@CaF 2 :Gd) of sub-10 nm size were controllably synthesized by a facile sequential growth method. The as-prepared hydrophilic CaF 2 :Yb,Er@CaF 2 :Gd nanoparticles modified using PEG-PAA di-block copolymer benefited from the presence of Gd only in the outer CaF 2 layer of the nanoparticles, which exhibited r 1 as high as 21.86 mM -1 s -1 under 3.0 T, seven times as high as that of commercially used gadopentetate dimeglumine (Gd-DTPA). Low cytotoxicity, no hemolysis phenomenon and no potential gadolinium ion leakage phenomenon of the hydrophilic CaF 2 :Yb,Er@CaF 2 :Gd nanoparticles have been observed and confirmed. Clear vascular details can be observed in magnetic resonance angiography and obvious MR signal of 4T1 tumor area could be significantly improved by intravenous injection of the hydrophilic CaF 2 :Yb,Er@CaF 2 :Gd nanoparticles at a low dosage in mice. A series of in vivo biological safety evaluations confirmed the good biocompatibility of the hydrophilic CaF 2 :Yb,Er@CaF 2 :Gd nanoparticles, which might be employed in clinical blood pool imaging and tumor diagnosis as a safe and efficient MRI probe.

Upconversional core-shell nanostructures have gained considerable attention due to their distinct enhanced fluorescence efficiency, multifunctionality, and specific applications. Recently, we have developed a sequential growth process to fabricate unique upconversion core-shell nanoparticles. Time evolution of morphology for the NaYF 4 :Yb/Er@NaGdF 4 nanodumbbells has been extensively investigated. An Ostwald ripening growth mechanism has been proposed to illustrate the formation of NaYF 4 :Yb/Er@NaGdF 4 nanodumbbells. The hydrophilic NaYF 4 :Yb/Er@NaGdF 4 core-shell nanodumbbells exhibited strong upconversion fluorescence and showed higher magnetic resonance longitudinal relaxivity (r 1 = 7.81 mM -1 s -1 ) than commercial contrast agents (Gd-DTPA). NaYF 4 :Yb/Er@NaGdF 4 nanodumbbells can serve as good candidates for high efficiency fluorescence and magnetic resonance imaging.

Conjugated polymers containing alternating donor/acceptor units have strong and sharp absorbance peaks in near-infrared (NIR) region, which could be suitable for photothermal therapy. However, these polymers as photothermal transducers are rarely reported because of their water insolubility, which limits their applications for cancer therapy. Herein, we report the donor-acceptor conjugated polymer PBIBDF-BT with alternating isoindigo derivative (BIBDF) and bithiophene (BT) units as a novel photothermal transducer, which exhibited strong near-infrared (NIR) absorbance due to its low band gap (1.52 eV). To stabilize the conjugated polymer physiological environments, we utilized an amphiphilic copolymer, poly(ethylene glycol)-block-poly(hexyl ethylene phosphate) (mPEG-b-PHEP), to stabilize PBIBDF-BT-based nanoparticles (PBIBDF-BT@NPPPE) through a single emulsion method. The obtained nanoparticles PBIBDF-BT@NPPPE showed great stability in physiological environments and excellent photostability. Moreover, the PBIBDF-BT@NPPPE exhibited high photothermal conversion efficiency, reaching 46.7%, which is relatively high compared with those of commonly used materials for photothermal therapy. Accordingly, in vivo and in vitro experiments demonstrated that PBIBDF-BT@NPPPE exhibits efficient photothermal anticancer efficacy. More importantly, PBIBDF-BT@NPPPE could simultaneously encapsulate other types of therapeutic agents though hydrophobic interactions with the PHEP core and achieve NIR-triggered intracellular drug release and a synergistic combination therapy of thermo-chemotherapy for the treatment of cancer.

All-inorganic cesium lead-halide perovskite nanocrystals have emerged as attractive optoelectronic nanomaterials owing to their stabilities and highly efficient photoluminescence. Herein we report a new type of highly luminescent perovskite-related CsPb2 Br5 nanoplatelets synthesized by a facile precipitation reaction. The layered crystal structure of CsPb2 Br5 promoted an anisotropic two-dimensional (2D) crystal growth during the precipitation process, thus enabling the large-scale synthesis of CsPb2 Br5 nanoplatelets. Fast anion exchange has also been demonstrated in as-synthesized CsPb2 Br5 nanoplatelets to extend their photoluminescence spectra to the entire visible spectral region. The large-scale synthesis and optical tunability of CsPb2 Br5 nanoplatelets will be advantageous in future applications of optoelectronic devices., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this work, we demonstrate an electrospinning technique to fabricate TiO2 /upconversion nanoparticles (UCNPs)/CdS nanofibers on large scale. In addition, the as-prepared TiO2 nanofibers are incorporated with a high population of UCNPs and CdS nanospheres; this results in Förster resonance energy-transfer configurations of the UCNPs, TiO2 , and CdS nanospheres that are in close proximity. Hence, strong fluorescent emissions for the Tm(3+) ions including the (1) G4 →(3) H6 transition are efficiently transferred to TiO2 and the CdS nanoparticles through an energy-transfer process. The as-prepared TiO2 /UCNPs/CdS nanofibers exhibit full-spectrum solar-energy absorption and enable the efficient degradation of organic dyes by fluorescence resonance energy transfer between the UCNPs and TiO2 (or CdS). The UCNPs/TiO2 /CdS nanofibers may also have enhanced energy-transfer efficiency for wide applications in solar cells, bioimaging, photodynamics, and chemotherapy., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Renal interstitial fibrosis (IF) is an important pathologic manifestation of disease progression in a variety of chronic kidney diseases (CKD). However, the quantitative and reproducible analysis of IF remains a challenge, especially in experimental animal models of progressive IF. In this study, we compare traditional polarized Sirius Red morphometry (SRM) to novel Second Harmonic Generation (SHG)-based morphometry of unstained tissues for quantitative analysis of IF in the rat 5 day unilateral ureteral obstruction (UUO) model. To validate the specificity of SHG for detecting fibrillar collagen components in IF, co-localization studies for collagens type I, III, and IV were performed using IHC. In addition, we examined the correlation, dynamic range, sensitivity, and ability of polarized SRM and SHG-based morphometry to detect an anti-fibrotic effect of three different treatment regimens. Comparisons were made across three separate studies in which animals were treated with three mechanistically distinct pharmacologic agents: enalapril (ENA, 15, 30, 60 mg/kg), mycophenolate mofetil (MMF, 2, 20 mg/kg) or the connective tissue growth factor (CTGF) neutralizing antibody, EX75606 (1, 3, 10 mg/kg). Our results demonstrate a strong co-localization of the SHG signal with fibrillar collagens I and III but not non-fibrillar collagen IV. Quantitative IF, calculated as percent cortical area of fibrosis, demonstrated similar response profile for both polarized SRM and SHG-based morphometry. The two methodologies exhibited a strong correlation across all three pharmacology studies (r2 = 0.89-0.96). However, compared with polarized SRM, SHG-based morphometry delivered a greater dynamic range and absolute magnitude of reduction of IF after treatment. In summary, we demonstrate that SHG-based morphometry in unstained kidney tissues is comparable to polarized SRM for quantitation of fibrillar collagens, but with an enhanced sensitivity to detect treatment-induced reductions in IF. Thus, performing SHG-based morphometry on unstained kidney tissue is a reliable alternative to traditional polarized SRM for quantitative analysis of IF.

Therapies that restore renal cGMP levels are hypothesized to slow the progression of diabetic nephropathy. We investigated the effect of BI 703704, a soluble guanylate cyclase (sGC) activator, on disease progression in obese ZSF1 rats. BI 703704 was administered at doses of 0.3, 1, 3, and 10 mg/kg/d to male ZSF1 rats for 15 weeks, during which mean arterial pressure (MAP), heart rate (HR), and urinary protein excretion (UPE) were determined. Histologic assessment of glomerular and interstitial lesions was also performed. Renal cGMP levels were quantified as an indicator of target modulation. BI 703704 resulted in sGC activation, as evidenced by dose-dependent increases in renal cGMP levels. After 15 weeks of treatment, sGC activation resulted in dose-dependent decreases in UPE (from 463 ± 58 mg/d in vehicle controls to 328 ± 55, 348 ± 23, 283 ± 45, and 108 ± 23 mg/d in BI 703704-treated rats at 0.3, 1, 3, and 10 mg/kg, respectively). These effects were accompanied by a significant reduction in the incidence of glomerulosclerosis and interstitial lesions. Decreases in MAP and increases in HR were only observed at the high dose of BI 703704. These results are the first demonstration of renal protection with sGC activation in a nephropathy model induced by type 2 diabetes. Importantly, beneficial effects were observed at doses that did not significantly alter MAP and HR., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Multidrug resistance (MDR) has been recognized as a key factor contributing to the failure of chemotherapy for cancer in the clinic, often due to insufficient delivery of anticancer drugs to target cells. For addressing this issue, a redox-responsive polyphosphoester-based micellar nanomedicine, which can be triggered to release transported drugs in tumor cells, has been developed. The micelles are composed of diblock copolymers with a hydrophilic PEG block and a hydrophobic polyphosphoester (PPE) block bearing a disulfide bond in a side group. After incubating the redox-responsive micelles with drug-resistant tumor cells, the intracellular accumulation and retention of DOX were significantly enhanced. Moreover, after internalization by MDR cancer cells, the disulfide bond in the side group was cleaved by the high intracellular glutathione levels, resulting in a hydrophobic to hydrophilic transition of the PPE block and subsequent disassembly of the micelles. Thus, the encapsulated DOX was rapidly released, and abrogation of drug resistance in the cancer cells was observed in vitro. Moreover, the DOX-loaded redox-responsive micelles exhibited significantly enhanced inhibition of tumor growth in nude mice bearing MCF-7/ADR xenograft tumors via tail vein injection, indicating that such micelles have great potential in overcoming MDR for cancer therapy.

The intracellular drug release rate from the hydrophobic core of self-assembled nanoparticles can significantly affect the therapeutic efficacy. Currently, the hydrophobic core of many polymeric nanoparticles which are usually composed of poly(ε-caprolactone) (PCL), polylactide (PLA), or poly(D, L-lactide-co-glycolide) (PLGA) may hinder the diffusion of drug from the core because of their glassy state at room temperature. To investigate the effect of the hydrophobic core state on therapeutic efficacy, we synthesized an amphiphilic diblock copolymers of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic polyphosphoester, which were in a viscous flow state at room temperature. The obtained copolymers self-assembled into core-shell nanoparticles, which efficiently encapsulate doxorubicin (DOX) in the hydrophobic polyphosphoester core (NP(PPE)/DOX). As speculated, compared with the nanoparticles bearing glassy core (hydrophobic PLA core, NP(PLA)/DOX), the encapsulated DOX was more rapidly released from NP(PPE)/DOX with viscous flow core, resulting in significantly increased cytotoxicity. Accordingly, the improved intracellular drug release from viscous flow core enhances the inhibition of tumor growth, suggesting the nanoparticles bearing viscous flow core show great potential in cancer therapy.

Uniform SiO2@CdS mesoporous nanospheres with an average diameter of 300 nm have been synthesized successfully by a facile process. The as-prepared mesoporous composite nanospheres have a BET-specific surface area of 640 m(2) g(-1) and an average pore size of 2.82 nm. The results demonstrated that more than 60% Rhodamine B (RhB) dye in solution (4.8 mg L(-1), 50 mL) could be removed by adsorption in the dark for 30 min using the as-prepared SiO2@CdS mesoporous nanospheres (40 mg). The as-prepared SiO2@CdS mesoporous nanospheres have a mesoporous nanostructure, suggesting a higher specific surface area and resulting in a strong adsorption ability. In addition, the mesoporous silica was decorated with ca. 5 nm CdS nanocrystals, which showed excellent photocatalytic activity under visible light and could rapidly remove most of the RhB molecules from a pollutant solution under visible light irradiation. Furthermore, the mesoporous SiO2@CdS nanospheres synthesized by the present protocol exhibited excellent antibacterial activity.

Since their detection 20 years ago, carbon nanotubes (CNTs) have captured the interest of scientists, because one-dimensional (1D) nanostructures (nanowires, nanotubes, and nanoribbons) have fascinating physical properties and many potential technological applications. These are materials with structural features limited to the range of 1-100 nm in one dimension, and unlimited in the others. When their size goes down to certain characteristic lengths, such as the Bohr radius, the wavelength of incandescent light, and the phonon mean-free path, quantum mechanical effects can occur. This results in novel optical, magnetic, and electronic characteristics. These physical properties, along with unique transport features in the longitudinal direction and large surface-to-volume ratio, make 1D nanostructures attract extensive attention in both fundamental research and engineering applications. From a synthetic point of view, it is highly desirable to develop a simple route for fabricating 1D nanostructures in large scale at low cost. On the other hand, in order to transfer the intrinsic features of individual 1D nanostructures into macroscopic scale and realize practical applications, we need to explore highly efficient and scalable assembly methods to integrate 1D nanostructures into functional macroscopic architectures. In 2006, our group developed a simple hydrothermal method for synthesizing ultrathin Te nanowires (TeNWs) using conventional chemicals. As we found through systematic study over the past several years, we can use the ultrathin TeNWs as a versatile templating material to fabricate a series of high-quality 1D nanostructures by taking the unique advantages of TeNWs, such as large-scale synthesis, high processability, and high reactivity. The obtained 1D products inherit the dimensional (high aspect ratio) and mechanical (high flexibility) features of the original TeNW templates, thus allowing us to construct macroscopic architectures by using them as nanoscale building blocks. In this Account, we describe on our recent developments in the multiplex templating synthesis of 1D nanostructures, their macroscopic assemblies, and applications. We first introduce ultrathin TeNWs and their advantages as a templating material. Through the multiplex templating process, we can prepare a family of 1D nanostructures that covers a wide range of materials, including noble metals, metal oxides, semiconductors, carbon, polymers, and their binary and multiple hybrids. We emphasize the reactivity of templating materials and the versatility of templating processes in this Account. On the basis of the templated 1D products, we then describe a series of macroscopic assemblies of 1D nanostructures, including free-standing membranes, films, hydrogels, and aerogels. These exhibit enormous potential for attractive applications, such as liquid filtration and separation, continuous-flow catalysis, electrocatalysis, polymer-based nanocomposites, and superadsorbents, and elastomeric conductors. We believe that the great versatility of templating synthesis, a scalable assembling process, and large-scale synthesis can significantly enhance the application reliability of the 1D nanostructures.

By applying the theories of ecological suitability and the methods of fuzzy mathematics, this paper established a climatic suitability model for citrus, calculated and evaluated the climatic suitability and its spatiotemporal differences for citrus production in subtropical China, and analyzed the climatic suitability of citrus at its different growth stages and the mean climatic suitability of citrus in different regions of subtropical China. The results showed that the citrus in subtropical China had a lower climatic suitability and a higher risk at its flower bud differentiation stage, budding stage, and fruit maturity stage, but a higher climatic suitability and a lower risk at other growth stages. Cold damage and summer drought were the key issues affecting the citrus production in subtropical China. The citrus temperature suitability represented a latitudinal zonal pattern, i. e., decreased with increasing latitude; its precipitation suitability was high in the line of "Sheyang-Napo", medium in the southeast of the line, low in the northwest of the line, and non in high mountainous area; while the sunlight suitability was in line with the actual duration of sunshine, namely, higher in high-latitude areas than in low-latitude areas, and higher in high-altitude areas than in plain areas. Limited by temperature factor, the climatic suitability was in accordance with temperature suitability, i. e., south parts had a higher suitability than north parts, basically representing latitudinal zonal pattern. From the analysis of the inter-annual changes of citrus climatic suitability, it could be seen that the citrus climatic suitability in subtropical China was decreasing, and had obvious regional differences, suggesting that climate change could bring about the changes in the regions suitable for citrus production and in the key stages of citrus growth.

Near-infrared (NIR)-to-visible up-conversion fluorescent nanoparticles have potential to be used for photodynamic therapy (PDT) in deep tissue because NIR light can penetrate thick tissue due to weak absorption in the optical window. Here a uniform layer of mesoporous silica is coated onto NaYF(4) up-converting nanocrystals, with a large surface area of approximately 770 m(2) g(-1) and an average pore size of 2 nm. A photosensitizer, zinc phthalocyanine, is incorporated into the mesoporous silica. Upon excitation by a NIR laser, the nanocrystals convert NIR light to visible light, which further activates the photosensitizer to release reactive singlet oxygen to kill cancer cells. The photosensitizer encapsulated in mesoporous silica is protected from degradation in the harsh biological environment. It is demonstrated that the photosensitizers loaded into the porous silica shell of the nanoparticles are not released out of the silica while they continuously produce singlet oxygen upon excitation by a NIR laser. The nanoparticles are reusable as the photosensitizers encapsulated in the silica are removed by soaking in ethanol.

Hexagonal-phase core-shell-structured NaYF 4:Yb,Tm@beta-NaYF 4:Yb,Er and beta-NaYF 4:Yb,Tm@beta-NaYF 4:Yb,Er@beta-NaYF 4:Yb,Tm nanocrystals were synthesized by a seeded growth approach. beta-NaYF 4:Yb,Tm nanocrystals with 20 nm diameter were used as seed crystals to induce the growth of beta-NaYF 4:Yb,Er and then beta-NaYF 4:Yb,Tm crystals, resulting in the formation of core-shell-structured nanocrystals with upconverting lanthanide ions Tm and Er doped in the core and shell, respectively.

Vessel wall inflammation and matrix destruction are critical to abdominal aortic aneurysm (AAA) formation and rupture. We have previously shown that urokinase plasminogen activator (uPA) is highly expressed in experimental AAA and is essential for AAA formation and expansion. In this study, we examined the effects of overexpression of a natural inhibitor of uPA, plasminogen activator inhibitor-1 (PAI-1), on the development of angiotensin (Ang) II-induced AAA in ApoE-deficient (ApoE(-/-)) mice. Mice were treated with recombinant adenovirus containing either the human PAI-1 gene (Ad5.CMV.PAI-1) or the luciferase gene (Ad5.CMV.Luc) delivered either locally by intra-adventitial injection or systemically by tail vein injection. Our results show that local delivery of the PAI-1 gene completely prevented AAA formation (0 vs 55.6% in Ad5.CMV.Luc controls, P<0.05). In contrast, systemic delivery of the PAI-1 gene did not affect AAA incidence (78 vs 90% in Ad5.CMV.Luc controls, P=0.125). Local delivery of the PAI-1 gene 2 weeks after Ang II infusion prevented further expansion of small aneurysms, but had no significant effect on the progression of larger aneurysms. These data suggest that local PAI-1 gene transfer could be used to stabilize small AAA and reduce the rate of expansion and risk of rupture.

A method was studied for simultaneous determination of multi-elements in natural colored cotton by microwave digestion and ICP-AES. The contents of Ca, Mg, Fe, Cu, Ba, Zn, Al, Sr, Mn and Si in colored and white cotton were determined by this method. The recovery ratio obtained by standard addition method ranged between 93% and 111%, and the relative standard deviation was below 4% (n = 5). The results showed that the contents of Ca, Cu, Zn, Al, Fe, Sr and Si in green and brown cotton are higher than those in white cotton. The data from the study gives some references for further researches on the colored cotton.

A single plasmid regulated expression vector based upon a mifepristone-inducible two plasmid system, termed pBRES, has been constructed and tested in mice using murine interferon-b (mIFNb) as the transgene. The expression of mIFNb in the circulation was followed by measuring the systemic induction of IP-10, a validated biomarker for mIFNb in mice. Long-term, inducible expression of mIFNb was demonstrated following a single intramuscular (i.m.) injection of the pBRES mIFNb plasmid vector into the hind limb of mice. Induction of mIFNb expression was achieved by administration of the small molecule inducer, mifepristone (MFP). Plasmid DNA and mIFNb mRNA levels in the injected muscles correlated with mIFNb expression as monitored by IP-10 over a 3-month time period. Renewable transgene expression was achieved following repeat administration of the plasmid at 3 months following the first plasmid injection. A dose-dependent increase in expression was demonstrated by varying the amount of injected plasmid or the amount of the inducer administered to the mice. Finally, the pBRES plasmid expressing mIFNb under control of the inducer, MFP, was shown to be efficacious in a murine model of experimental allergic encephalomyelitis, supporting the feasibility of gene-based therapeutic approaches for treating diseases such as multiple sclerosis.

Neutralizing antibodies (nAB) at the time of administration hamper the effectiveness of adeno-associated virus (AAV) as a clinical DNA delivery system. The present study was designed to investigate if AAV re-administration in muscle tissue is dependent on the nAB titer. Recombinant (r)AAV serotype 1, as a promising candidate for targeting skeletal muscle, was used for gene delivery. C57Bl/6 mice were infected intramuscularly with doses between 1 x 10(9) and 5 x 10(10) virus particles (vp) of AAV1-expressing luciferase (AAV1-luc) or human interferon-beta (AAV1-hIFNbeta). Increasing transgene expression was observed over the first 2 months and anti-AAV1 nAB titers peaked between weeks 4 and 8. Six months after the first administration, 5 x 10(10) vp of AAV1-IFNbeta were re-administered. Following re-administration, nAB titers increased but did not significantly affect transgene expression from the AAV vector that had been administered first. In contrast, hIFNbeta expression originating from the second vector administration was significantly diminished and reflected the nAB titer present at the day of re-administration. The present study extends earlier observations that preexisting nAB affects AAV1 re-administration. The level of nAB is proportional to the virus dose used for the first injection and transgene expression following re-administration is dependent on preexisting nAB titer.

We have developed a one-plasmid regulated gene expression system, pBRES, based on a mifepristone (MFP)-inducible two-plasmid system. The various expression elements of the pBRES system (promoters, 5' and 3' untranslated regions (UTRs), introns, target gene, and polyA sequences) are bounded by restriction enzyme sites so that each module can be conveniently replaced by alternate DNA elements in order to tailor the system for particular tissues, organs, or conditions. There are four possible orientations of the two expression units relative to each other, and insertion of a variety of expression elements and target genes into the four different orientations revealed orientation- and gene-dependent effects on induced and uninduced levels of gene expression. Induced target gene expression from the pBRES system was shown to be comparable to the two-plasmid system and higher than the expression from the cytomegalovirus (CMV) promoter in vivo, while maintaining low uninduced levels of expression. Finally, a pBRES expression cassette was transferred to an adeno-associated virus (AAV) vector and shown to be capable of regulated gene expression in vivo for nearly 1 year.

The dispersibility and stabilization of freshly synthesized ultrathin tellurium nanowires with diameters of 4-9 nm using poly(vinyl pyrrolidone) (PVP) as a capping agent can be well controlled through an easy acetone-addition process. Ultrathin Te nanowires synthesized by a hydrothermal method using PVP as a capping agent will aggregate in a water/acetone system, and their aggregation state strongly relies on the volume of water and acetone in this mixed solution. This phenomenon is due to the different solubility of PVP in water and acetone, which has significant influence on the dispersibility and stabilization of the nanowires. The results also demonstrate that the freshly prepared Te nanowires are not stable after being stored for a prolonged time in contact with air, ethanol, and water. Ultrathin Te nanowires can be oxidized easily with various final morphologies, which are core-shell structures in contact with air, amorphous nanoparticles and nanoplatelets in ethanol, and large square flakes in water. The entire conversion process from crystalline Te nanowires to amorphous TeO2 nanoparticles or single-crystal paratellurite (TeO2) at room temperature was carefully studied, implying that tellurium nanowires synthesized by other chemical methods and other nanomaterials after synthesis could also not be stable, and their storage methods require special attention.

Mobilization and recruitment of bone marrow-derived progenitor cells (BMDPCs) play an important role in postischemic tissue repair. Patients with coronary artery disease (CAD) or peripheral vascular disease (PVD) exhibit endothelial dysfunction, and as a result are likely to have a reduced number of progenitor cells mobilized in their peripheral circulation following ischemic injury. Identification of eNOS independent pathways for BMDPC mobilization may have important therapeutic value in this patient population. To identify such mechanisms we investigated the effect of granulocyte-colony stimulating factor (GCSF) and stem cell factor (SCF) in eNOS-KO mice with and without surgical hind-limb ischemia. Our results suggest that BMDPC mobilization can be achieved via activation of NO-independent pathways.

Gene delivery of angiogenic growth factors is a promising approach for the treatment of ischemic cardiovascular diseases. However, success of this new therapeutic principle is hindered by the lack of critical understanding as to how disease pathology affects the efficiency of gene delivery and/or the downstream signaling pathways of angiogenesis. Critical limb ischemia occurs in patients with advanced atherosclerosis often exhibiting deficiency in endothelial nitric oxide production. Similar to these patients, segmental femoral artery resection progresses into severe ischemic necrosis in mice deficient in endothelial nitric oxide synthase (ecNOS-KO) as well as in balb/c mice. We used these models to evaluate the influence of severe ischemia on transfection efficiency and duration of transgene expression in the skeletal muscle following plasmid injection in combination with electroporation. Subsequently, we also explored the potential therapeutic effect of the phosphomimetic mutant of ecNOS gene (NOS1177D) using optimized delivery parameters, and found significant benefit both in ecNOS-KO and balb/c mice. Our results indicate that NOS1177D gene delivery to the ischemic skeletal muscle can be efficient to reverse critical limb ischemia in pathological settings, which are refractory to treatments with a single growth factor, such as vascular endothelial growth factor.

Experimental allergic encephalomyelitis (EAE) is a model of central nervous system (CNS) inflammation that follows immunization with certain CNS antigens. The course and clinical manifestations of EAE are similar to those of multiple sclerosis (MS) in humans; therefore, EAE has become an accepted animal model to study MS. The purpose of this study was to demonstrate that systemic expression of murine interferon-beta (IFN-beta) (MuIFN-beta), following intramuscular (i.m.) delivery of plasmid DNA encoding MuIFN-beta to the hind limb of mice, is effective in reducing the clinical manifestations of disease in a model of EAE. The results of the study demonstrate that gene-based delivery of MuIFN-beta caused significantly decreased clinical scores compared with delivery of the null vector. A single injection of the MuIFN-beta plasmid was as effective in reducing the severity of the disease as an every other day injection of MuIFN-beta protein.

Well-defined silver/cross-linked-poly(vinyl alcohol) (PVA) sub-microcables, which were synthesized from a hydrothermal reaction using AgCl and PVA as precursors, have been used as sacrificial templates to fabricate gold/cross-linked-PVA sub-microcables by etching the silver/cross-linked-PVA sub-microcables with tetrachloroaurate(III). In addition, well-defined cross-linked-PVA sub-microtubes/sub-microfibers can also be produced by the removal of the silver cores of such sub-microcables at ambient temperature. The channel diameter and the shell thickness could be tuned by controlling the diameter of the core sub-microfibers and the shell thickness of the precursor sub-microcables. These cross-linked-PVA-based cables, tubes, and fibers have the potential to be used in future applications such as nanodevices.

Large-scale selective synthesis of uniform single crystalline tellurium nanowires with a diameter of 4-9 nm, and microbelts with a width of 250-800 nm and tens of micrometers in length, can be realized by a poly (vinyl pyrrolidone) (PVP)-assisted hydrothermal process. The formation of tellurium nanowires and nanobelts in the presence of PVP is strongly dependent on the reaction conditions such as temperature, the amount of PVP, and reaction time. The results demonstrated that the keys for selective synthesis of Te nanobelts and nanowires are to modulate the growth rates of (100), (101), and (110) planes in the presence of PVP and to precisely control the reaction kinetics. High-quality luminescent ultrathin t-Te nanowires with a diameter of 4-9 nm display strong luminescent emission in the blue-violet region. This approach provides a facile route for the production of high-quality tellurium nanostructures with an interesting optical property. Furthermore, the synthesized ultrathin nanowires with deep blue color and nanobelts in gray color by this approach can be well dispersed in water or ethanol, making it possible for further engineering of their surfaces to prepare other hybrid core-shell nanostructures.

Morbidity and mortality of peripheral arterial occlusive disease significantly increases with age, often exhibiting more severe disease pathology and decreased treatment effectiveness. Therapeutic angiogenesis with angiogenic growth factors may represent a valuable treatment option for the severely ill, older adult patient population. Aging is considered an independent cardiovascular risk factor, but pathomechanistically it is not well understood. Diminished endothelial nitric oxide (EDNO) production has been considered as a major contributor to the aging process. To investigate the effect of age on postischemic revascularization independent of changes in EDNO, we used endothelial nitric oxide synthase-deficient (ecNOS-KO) mice. We found an age-dependent acceleration in ischemic injury following unilateral femoral artery ligation in these animals compared to C57BL/J6 mice. Postischemic revascularization, quantified by measuring von Willebrand factor expression, was significantly impaired, suggesting that factors other than progressive EDNO deterioration are also involved in the age-dependent severe disease phenotype. Ischemia led to an increase in the expression of vascular endothelial growth factor receptor-2, KDR, in younger ecNOS-KO; however, this increase in KDR expression was absent in the older animals. Lack of increased KDR expression may provide a mechanistic explanation for the severe ischemic injury and perhaps can be used as a clinical marker to identify severe, vascular endothelial growth factor refractory patient population.

A facile green chemistry carbonization method has been discovered for the synthesis of uniform silver@carbon rich composite (carbon and cross-linked polyvinyl alcohol) core-shell sub-microcables in large quantities, where the carbon sources such as glucose-based saccharides have played important roles in the formation of these novel sub-microcables.

The genetic loss of endothelial-derived nitric oxide synthase (eNOS) in mice impairs vascular endothelial growth factor (VEGF) and ischemia-initiated blood flow recovery resulting in critical limb ischemia. This result may occur through impaired arteriogenesis, angiogenesis, or mobilization of stem and progenitor cells. Here, we show that after ischemic challenge, eNOS knockout mice [eNOS (-/-)] have defects in arteriogenesis and functional blood flow reserve after muscle stimulation and pericyte recruitment, but no impairment in endothelial progenitor cell recruitment. More importantly, the defects in blood flow recovery, clinical manifestations of ischemia, ischemic reserve capacity, and pericyte recruitment into the growing neovasculature can be rescued by local intramuscular delivery of an adenovirus encoding a constitutively active allele of eNOS, eNOS S1179D, but not a control virus. Collectively, our data suggest that endogenous eNOS-derived NO exerts direct effects in preserving blood flow, thereby promoting arteriogenesis, angiogenesis, and mural cell recruitment to immature angiogenic sprouts.