Controlling conjugated polymer morphology by precise oxygen position in single-ether side chains.

Recently, polar side chains have emerged as a functional tool to enhance conjugated polymer doping properties by improving the polymer miscibility with polar chemical dopants and facilitate solvated ion uptake. In this work, we design and investigate a novel family of side chains containing a single ether function, enabling the modulation of the oxygen atom position along the side chain. A meticulous investigation of this new polymer series by differential scanning calorimetry, fast scanning chip calorimetry and X-ray scattering shows that polymers bearing single-ether side chains can show high degree of crystallinity under proper conditions. Importantly, due to a gauche effect allowing the side chain to bend at the oxygen atom, the degree of crystallinity of polymers can be controlled by the position of the oxygen atom along the side chain. The further the oxygen atom is from the conjugated backbone, the more crystalline the polymer becomes. In addition, for all new polymers, high thermomechanical properties are demonstrated, leading to remarkable electrical conductivities and thermoelectric power factors in rub-aligned and sequentially doped thin films. This work confirms the potential of single-ether side chains to be used as polar solubilizing side chains for the design of a next generation of p- and n-type semiconducting polymers with increased affinity to polar dopants while maintaining high molecular order.

Structural impacts on the degradation behaviors of Ir-based electrocatalysts during water oxidation in acid.

Large-scale hydrogen production by electrocatalytic water splitting still remains as a critical challenge due to the severe catalyst degradation during the oxygen evolution reaction (OER) in acidic media. In this study, we investigate the structural impacts on catalyst degradation behaviors using three iridium-based oxides, namely SrIrO3, Sr2IrO4, and Sr4IrO6 as model catalysts. These Ir oxides possess different connection configurations of [IrO6] octahedra units in their structure. Stable OER performance is observed on SrIrO3 and attributed to the edge-linked [IrO6] structure and rapid formation of a continuous IrOx layer on its surface, which functions not only as the "real" catalyst but also a shield preventing continuous cation leaching (with <1.0 at.% of Ir leaching). In comparison, both Sr2IrO4 and Sr4IrO6 catalysts demonstrate quick current fading with structure transformation to rutile IrO2 and formation of inconducive SrSO4 precipitates on surface, blocking the reactive sites. Nevertheless, over 60 at.% of Ir leaching is detected from the Sr4IrO6 catalyst due to its isolated [IrO6] structure configuration. Results of this work highlight the structural impacts on the catalyst stability in acidic OER conditions.

Effect and Safety of Herbal Medicine Foot Baths in Patients with Diabetic Peripheral Neuropathy: A Multicenter Double-Blind Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect and safety of foot baths with Tangbi Waixi Decoction (TW) in treating patients with diabetic peripheral neuropathy (DPN). METHODS: It is a multicenter double-blinded randomized controlled trial. Participants with DPN were recruited between November 18, 2016 and May 30, 2018 from 8 hospitals in China. All patients received basic treatments for glycemic management. Patients received foot baths with TW herbal granules either 66.9 g (intervention group) or 6.69 g (control group) for 30 min once a day for 2 weeks and followed by a 2-week rest, as a therapeutic course. If the Toronto Clinical Scoring System total score (TCSS-TS) ⩾6 points, the patients received a total of 3 therapeutic courses (for 12 weeks) and were followed up for 12 weeks. The primary outcome was change in TCSS-TS score at 12 and 24 weeks. Secondary outcomes included changes in bilateral motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) of the median and common peroneal nerve. Safety was also assessed. RESULTS: Totally 632 patients were enrolled, and 317 and 315 were randomized to the intervention and control groups, respectively. After the 12-week intervention, patients in both groups showed significant declines in TCSSTS scores, and significant increases in MNCV and SNCV of the median and common peroneal nerves compared with pre-treatment (P<0.05). The reduction of TCSS-TS score at 12 weeks and the increase of SNCV of median nerve at 24 weeks in the control group were greater than those in the intervention group (P<0.05). The number of adverse events did not differ significantly between groups (P>0.05), and no serious adverse event was related with treatment. CONCLUSION: Treatment of TW foot baths was safe and significantly benefitted patients with DPN. A low dose of TW appeared to be more effective than a high dose. (Registry No. ChiCTR-IOR-16009331).

Electrochemical Preparation of Crystalline Hydrous Iridium Oxide and Its Use in Oxygen Evolution Catalysis.

Even the most stable Ir-based oxides inevitably encounter a severe degradation problem during the oxygen evolution reaction (OER) in acid, resulting in quick formation of amorphous IrOx layers on the catalyst surface. Unfortunately, there is still a lack of fundamental understanding of such hydrous IrOx layers, including the atomic arrangement, key active structure, compositions, chemical stability, and so on. In this work, we demonstrate an electrochemical strategy to prepare two types of protonated iridium oxides with well-defined crystalline structures: one possesses a 2D layered structure (denoted as α-HxIrO3) and the other consists of 3D interconnected polymorphs (denoted as ß-HxIrO3). Both protonated iridium oxides demonstrate superior electrochemical stabilities with 6 times suppressed Ir dissolution comparing to the initial Li2IrO3 and rutile IrO2. It is hypothesized that the enriched protons and fast diffusions in these two protonated HxIrO3 crystal oxides may promote surface structural stability by suppressing the formation of high-valence Ir species at the solid-liquid interfaces during OER. Overall, the results of this work shed light on the role of proton dynamics toward the OER processes on the catalyst surface in acid media.

Bioinformatics study of the potential therapeutic effects of ginsenoside Rf in reversing nonalcoholic fatty liver disease.

OBJECTIVE: Ginsenoside Rf, a tetracyclic triterpenoid only present in Panax ginseng, has been proven to relieve lipid metabolism and inflammatory reactions, which can be a potential treatment for nonalcoholic fatty liver disease (NAFLD). Therefore, this study aimed to reveal the underlying mechanisms of ginsenoside Rf in the treatment of early-stage NAFLD (NAFL) by using a bioinformatics method and biological experiments. METHODS: Target genes associated with NAFL were screened from the Gene Expression Omnibus (GEO) database, a database repository of high-throughput gene expression data and hybridization arrays, chips, and microarrays. Subsequently, gene set enrichment analysis was performed by using Gene Ontology enrichment analysis tool. Then, the binding capacity between ginsenoside Rf and NAFL-related targets was evaluated by molecular docking. Finally, the FFA-induced HepG2 cell model treated with ginsenoside Rf was adopted to verify the effect of ginsenoside Rf and the related mechanisms. RESULTS: There were 41 common differentially expressed genes in the GEO dataset. Gene Ontology and Reactome pathway enrichment analysis of the differentially expressed genes showed that many pathways could be related to the pathogenesis of NAFL, including those participating in the cytokine-mediated signaling pathway, G protein-coupled receptor signaling pathway, and response to lipopolysaccharide. Finally, the qRT-PCR analysis results indicated that ginsenoside Rf therapy could ameliorate the transcription of ANXA2, BAZ1A, DNMT3L and MMP9. CONCLUSION: Our research discovered the relevant mechanisms and basic pharmacological effects of ginsenoside Rf in the treatment of NAFL. These results might facilitate the development of ginsenoside Rf as an alternative medication for NAFL.

Down Syndrome Candidate Region 1 Isoform 1L regulated tumor growth by targeting both angiogenesis and tumor cells.

Angiogenesis is critical for solid tumor growth beyond its minimal size. Previously, we reported that Down Syndrome Candidate Region 1 isoform 1L (DSCR1-1L) was one of the most up-regulated genes in endothelial cells induced by VEGF and histamine, and regulated endothelial cell proliferation, migration and angiogenesis. However, it was not known whether DSCR1-1L played a role in tumor growth. In this study, we found that DSCR1-1L shRNAs significantly inhibited the growth of transplanted melanoma in mice and its associated tumoral angiogenesis. In the gain of function assay, overexpression of DSCR1-1L cDNA in mouse endothelium is sufficient to significantly increase the tumor initiation induced by carcinogen, the growth of xenografted tumor, and the tumor metastasis in our endothelially-expressed DSCR1-1L transgenic mice, in which angiogenesis was induced. It was the first time to find that DSCR1-1L was also expressed in various tumor cells. DSCR1-1L shRNAs inhibited, but overexpression of DSCR1-1L cDNA increased, the tumor cell proliferation and migration. Most recently, we reported that DSCR1-1L modulated angiogenesis by down-regulation of VE-cadherin expression. Here, we found that DSCR1-1L down-regulated the expression of E-cadherin. Hence, DSCR1-1L is an excellent therapeutic target for cancers by regulation of both the endothelial and tumor cells through down-regulating (V)E-cadherin. DSCR1-1L shRNAs have the potential to be developed for clinical application.

A novel transcriptional complex on the VE-cadherin promoter regulated the downregulation of VE-cadherin in the Down Syndrome Candidate Region 1 isoform 1L-mediated angiogenesis.

Angiogenesis is critical for many diseases. Previously, we reported that Down Syndrome Candidate Region 1 isoform 1L (DSCR1-1L) was one of the most up-regulated genes in endothelial cells induced by VEGF and histamine, and regulated endothelial cell proliferation and Matrigel angiogenesis in mice. However, it was not known whether DSCR1-1L regulated angiogenesis in vivo and what was the molecular mechanism underlying it. In this study, gene knockdown and overexpression models were established to study the role of DSCR1-1L in angiogenesis in vivo. Further, the downstream regulatory target of DSCR1-1L was explored with molecular biological methods in vascular endothelial cells. We found that DSCR1-1L shRNAs significantly inhibited angiogenesis induced by VEGF in mice (p < 0.0001). In the gain-of-function assay, overexpression of DSCR1-1L cDNA in mouse endothelium of EC-FH-DSCR1-1L transgenic mice was sufficient to induce angiogenesis significantly (p < 0.01). DSCR1-1L regulated angiogenesis in the early stage by down-regulation of the VE-cadherin expression through targeting its transcription, but not mRNA stability. Three DSCR1-1L-targeted DNA elements in the VE-cadherin promoter were identified by promoter reporter assays, among which, a novel specific transcriptional complex was found. The DNA sequence (CTTCTG) in the VE-cadherin promoter was identified to directly interact with proteins by Electrophoresis Mobility Shift Assays and DNase I footprint assay. Hence, DSCR1-1L is an excellent therapeutic target for angiogenic diseases through down-regulating the formation of a novel transcriptional complex on the VE-cadherin promoter. DSCR1-1L shRNAs and cDNA have the potential to be developed for clinical application. Our results also contribute significantly to the field of mechanistic studies.

Boosting oxygen reduction activity and enhancing stability through structural transformation of layered lithium manganese oxide.

Structural degradation in manganese oxides leads to unstable electrocatalytic activity during long-term cycles. Herein, we overcome this obstacle by using proton exchange on well-defined layered Li2MnO3 with an O3-type structure to construct protonated Li2-xHxMnO3-n with a P3-type structure. The protonated catalyst exhibits high oxygen reduction reaction activity and excellent stability compared to previously reported cost-effective Mn-based oxides. Configuration interaction and density functional theory calculations indicate that Li2-xHxMnO3-n has fewer unstable O 2p holes with a Mn3.7+ valence state and a reduced interlayer distance, originating from the replacement of Li by H. The former is responsible for the structural stability, while the latter is responsible for the high transport property favorable for boosting activity. The optimization of both charge states to reduce unstable O 2p holes and crystalline structure to reduce the reaction pathway is an effective strategy for the rational design of electrocatalysts, with a likely extension to a broad variety of layered alkali-containing metal oxides.

Non-invasive neuromodulation effects on painful diabetic peripheral neuropathy: a systematic review and meta-analysis.

Diabetic Peripheral Neuropathy (DPN) typically is accompanied by painful symptoms. Several therapeutic agents have been tried for symptomatic relief, but with varying results. The use of non-invasive neuromodulation (NINM) is a potential treatment option for DPN. The objective of our study is to evaluate NINM effects on pain rating and nerve conduction velocity in DPN patients. The search was carried out in seven databases until Aug 30th, 2019. Finally, twenty studies met the inclusion criteria. We found a significant reduction of pain scores by central NINMs (effect size [ES] = - 0.75, 95% CI = - 1.35 to - 0.14), but not by the overall peripheral techniques (electrical and electromagnetic) (ES = - 0.58, 95% CI = - 1.23 to 0.07). However, the subgroup of peripheral electrical NINMs reported a significant higher effect (ES = - 0.84, 95% CI = - 1.57 to - 0.11) compared to electromagnetic techniques (ES = 0.21; 95% CI = - 1.00 to 1.42, I2 = 95.3%) . Other subgroup analysis results show that NINMs effects are higher with intensive protocols and in populations with resistant symptoms or intolerance to analgesic medications. Besides, NINMs can increase motor nerves velocity (ES = 1.82; 95% CI = 1.47 to 2.17), and there were no effects on sensory nerves velocity (ES = 0.01, 95% CI = - 0.79 to 0.80). The results suggest that central and peripheral electrical NINMs could reduce neuropathic pain among DPN patients, without reported adverse events. Well-powered studies are needed to confirm that NINM techniques as an alternative effective and safe treatment option.

Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease.

BACKGROUND: Cardiovascular outcomes in clinical trials with type 2 diabetes mellitus (T2DM) patients have shown that glucagon-like peptide-1 receptor agonist can have a beneficial effect on the kidney. This trial aimed to assess the effects of exenatide on renal outcomes in patients with T2DM and diabetic kidney disease (DKD). METHODS: We performed a randomized parallel study encompassing 4 general hospitals. T2DM patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and macroalbuminuria, defined as 24-h urinary albumin excretion rate (UAER) >0.3 g/24 h were randomized 1:1 to receive exenatide twice daily plus insulin glargine (intervention group) or insulin lispro plus glargine (control group) for 24 weeks. The primary outcome was the UAER percentage change from the baseline after 24 weeks of intervention. The rates of hypoglycemia, adverse events (AEs), and change in eGFR during the follow-up were measured as safety outcomes. RESULTS: Between March 2016 and April 2019, 92 patients were randomized and took at least 1 dose of the study drug. The mean age of the participants was 56 years. At baseline, the median UAER was 1,512.0 mg/24 h and mean eGFR was 70.4 mL/min/1.73 m2. After 24 weeks of treatment, the UAER percentage change was significantly lower in the intervention group than in the control group (p = 0.0255). Moreover, the body weight declined by 1.3 kg in the intervention group (the difference between the 2 groups was 2.7 kg, p = 0.0001). Compared to the control group, a lower frequency of hypoglycemia and more gastrointestinal AEs were observed in the intervention group. CONCLUSION: Exenatide plus insulin glargine treatment for 24 weeks resulted in a reduction of albuminuria in T2DM patients with DKD.

Decreased neural inhibitory state in fibromyalgia pain: A cross-sectional study.

OBJECTIVES: Chronic pain is one of the most common and challenging symptoms in fibromyalgia (FM). Currently, self-reported pain is the main criterion used by clinicians assessing patients with pain. However, it is subjective, and multiple factors can affect pain levels. In this study, we investigated the neural correlates of FM pain using conditioned pain modulation (CPM), electroencephalography (EEG), and transcranial magnetic stimulation (TMS). METHODS: In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 36 patients with fibromyalgia were included. We analyzed CPM, EEG variables and TMS measures and their correlation with pain levels as measured by a visual analog scale. Univariate and multivariate linear regression analyses were performed to identify the predictors of pain severity. RESULTS: We found: (1) no association between pain levels and CPM; (2) an association between reduced alpha and beta power over the central region in resting-EEG and higher pain levels; (3) an association between smaller event-related desynchronization (ERD) responses in theta and delta bands over the central region and higher pain levels; (4) an association between smaller ERD responses in theta and delta bands and smaller intracortical inhibition and higher intracortical facilitation ratios; (5) an association between smaller ERD responses in delta band and reduced CPM. CONCLUSIONS: Our results do not support CPM as a biomarker for pain intensity in FM. However, our specific EEG findings showing the relationship between pain, CPM and TMS measures suggest that FM leads to a disruption of inhibitory neural modulators and thus support CPM as a likely predictive marker of disrupted pain modulation system. These neurophysiological markers need to be further explored in potential future trials as to find novel targets for the treatment of FM.

Exercise-induced pain threshold modulation in healthy subjects: a systematic review and meta-analysis.

BACKGROUND: The use of exercise is a potential treatment option to modulate pain (exercise-induced hypoalgesia). The pain threshold (PT) response is a measure of pain sensitivity that may be a useful marker to assess the effect of physical exercise on pain modulation. AIM: The aim of this systematic review and meta-analysis is to evaluate the PT response to exercise in healthy subjects. METHODS: We searched in MEDLINE, EMBASE, Web of Science, Lilacs, and Scopus using a search strategy with the following search terms: "exercise" OR "physical activity" AND "Pain Threshold" from inception to December 2nd, 2019. As criteria for inclusion of appropriate studies: randomized controlled trials or quasi-experimental studies that enrolled healthy subjects; performed an exercise intervention; assessed PT. Hedge's effect sizes of PT response and their 95% confidence intervals were calculated, and random-effects meta-analyses were performed. RESULTS: For the final analysis, thirty-six studies were included (n=1326). From this we found a significant and homogenous increase in PT in healthy subjects (ES=0.19, 95% CI= 0.11 to 0.27, I2=7.5%). According to subgroup analysis the effect was higher in studies: with women (ES=0.36); performing strength exercise (ES=0.34), and with moderate intensity (ES=0.27), and no differences by age were found. Confirmed by the meta-regression analysis. CONCLUSION: This meta-analysis provides evidence of small to moderate effects of exercise on PT in healthy subjects, being even higher for moderate strength exercise and in women. These results support the idea of modulation of the endogenous pain system due to exercise and highlight the need of clinical translation to chronic pain population.

Orphan nuclear receptor TR3/Nur77 biologics inhibit tumor growth by targeting angiogenesis and tumor cells.

Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 was a critical mediator of angiogenesis to regulate tumor growth, sepsis and skin wound healing. However, none of the TR3/Nur77 targeting molecule has been in clinical trial so far. Here, we designed and generated novel TR3 shRNAs and two minigenes that had therapeutic potential for cancer treatment. In addition to extend our previous findings that tumor growth was inhibited in Nur77 knockout mice, we found that metastasis of colorectal tumor was completely inhibited in Nur77-/- mice. Tumor masses were increased ~70% and decreased ~40% in our transgenic EC-Nur77-S mice and EC-Nur77-DN mice, in which the full-length cDNA and the dominant negative mutant of TR3/Nur77 were inducibly and specifically expressed in mouse endothelium, respectively. TR3 was highly expressed in the vasculature and tumor cells of human melanoma and colorectal cancer tissues, but not in normal tissues. The novel TR3 shRNAs and two minigenes almost completely inhibited the proliferation and migration of HUVECs and human melanoma A375sm cells. Angiogenesis induced by adenoviruses expressing VEGF and melanoma growth in mice were greatly and significantly inhibited by systemically administration of adenoviruses expressing TR3 shRNAs and two minigenes. Tumor angiogenesis and the expressions of genes associated with angiogenesis were greatly regulated in tumor tissues treated with TR3 shRNAs and minigenes. Taken together, these studies demonstrated that TR3/Nur77 was a specific therapeutic target for several human cancers by targeting both tumor cells and tumor microenvironment. These TR3/Nur77 biologics inhibit angiogenesis and tumor growth, and have translational potential.

The novel axis of YAP1, transcription enhancer factor 3 and Down Syndrome Candidate Region 1 isoform 1L is a common signaling pathway downstream of several angiogenic factors.

Angiogenesis is a hallmark of many diseases. Previously, we found that Down Syndrome Candidate Region 1 Isoform 1L (DSCR1-1L) was expressed in human tumor vessels, but was not detectable in normal tissues, and played important roles in angiogenesis induced by vascular endothelial growth factor (VEGF-A165). The expressions of DSCR1-1L mRNA and protein induced by VEGF-A165 were regulated via the direct interaction of transcription enhancer factor 3 (TEF3) with DSCR1-1L promoter. However, the function and the regulation of DSCR1-1L in angiogenesis had not been completely understood. In this study, we found that the expressions of DSCR1-1L mRNA and proteins were upregulated by other angiogenic factors, including VEGF-A121, VEGF-E, histamine, PAF, the endothelial cell (EC) growth medium, and the conditional medium obtained from cancer cells, but not by PlGF, bFGF, PDGF, and serotonin. The EC proliferation, migration and elongation induced by histamine and EC growth medium were inhibited by knocking down the mRNA and protein expressions of DSCR1-1L and TEF3. The TEF3 activation was regulated by its interaction with YAP1, and translocation from cytosol to nuclei, but not by increase of protein expression, after the stimulation of VEGF, histamine and EC growth medium. YAP1 regulated the protein expression of DSCR1-1L, the proliferation, migration and elongation of ECs induced by VEGF, histamine and EC growth medium. Taken together, this study identified a novel axis of YAP1, TEF3 and DSCR1-1L that was a common signaling pathway downstream of several angiogenic factors to regulate angiogenesis, suggesting that this pathway is an excellent therapeutic target for angiogenic diseases and cancers. Our results contribute significantly to the field of mechanistic studies.

DLL4 and Jagged1 are angiogenic targets of orphan nuclear receptor TR3/Nur77.

Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 was a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via regulating the expression of the junctional proteins and integrins. However, the molecular mechanism, by which TR3/Nur77 regulates angiogenesis is not completely understood. Here, we were the first to find that TR3/Nur77, via its various amino acid fragments, regulated the expression of DLL4 and Jagged 1 in cultured endothelial cells. DLL4 and Jagged1 mediated TR3/Nur77-induced angiogenic responses and signaling molecules, but not the expression of integrins. Instead, integrins regulated the expressions of DLL4 and Jagged1 induced by TR3/Nur77. Further, DLL4, Jagged1 and integrins α1, α2, ß3 and ß5 were regulated by TR3/Nur77 in animal sepsis models of lipopolysaccharide (LPS)-induced endotoxemia, and cecal ligation and puncture (CLP), in which, TR3/Nur77 expression was significantly and tranciently increased. Mouse survival rates were greatly increased in Nur77 knockout mice bearing both CLP and LPS models. The results elucidated a novel axis of VEGF/histamine ➔ TR3/Nur77 ➔ integrins ➔ DLL4/Jagged1 in angiogenesis, and demonstrated that TR3/Nur77 was an excellent target for sepsis. These studies supported our previous findings that TR3/Nur77 was an excellent therapeutic target, and further our understanding of the molecular mechanism, by which TR3/Nur77 regulated angiogenesis.

Effect of Alkyl Side Chain Length on Doping Kinetics, Thermopower, and Charge Transport Properties in Highly Oriented F4TCNQ-Doped PBTTT Films.

Doping of polymer semiconductors such as poly(2,5-bis(3-alkylthiophen-2-yl)thieno[3,2- b]thiophene) (PBTTT) with acceptor molecules such as 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) is widely used to tune the charge transport and thermoelectric (TE) properties in thin films. However, the mechanism of dopant insertion in the polymer matrix, insertion kinetics, and the ultimate doping levels reached have been investigated only marginally. This contribution addresses the effect of alkyl side chain length on the doping mechanism of a series of PBTTTs with linear side chains ranging from n-octyl to n-octyldecyl. The study focuses on thin films oriented by high-temperature rubbing and sequentially doped in F4TCNQ solution. Structure-property correlations are established as a function of side chain length by a combination of transmission electron microscopy, polarized UV-vis-NIR spectroscopy, and charge transport/thermopower measurements. Intercalation of F4TCNQ into the layers of side chains results in the expansion of the lattice along the side chains and the contraction along the π-stacking direction for all polymers. The extent of lattice expansion decreases with the increasing side chain length. UV-vis-NIR spectroscopy demonstrates integer charge transfer for all investigated PBTTTs. The doping kinetics and the final doping level depend on both the side chain length and packing. Highly disordered n-octyl and crystalline n-octyldecyl side chain layers tend to hamper dopant diffusion in the side chain layers contrary to n-dodecyl side chains that can host the highest proportion of dopants. Consequently, the best TE properties are observed for C12-PBTTT films. Alignment of the polymers significantly enhances the TE performance by increasing the charge conductivity and the thermopower along the rubbing direction. Aligned films of C12-PBTTT show charge conductivities of 193 S cm-1 along the rubbing direction and power factors of approximately 100 µW m-1 K-2 versus a few µW m-1 K-2 for nonoriented films.

Orphan nuclear receptor TR3/Nur77 differentially regulates the expression of integrins in angiogenesis.

Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 (human homolog, Nur77, mouse homolog) is a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via down-regulating the expression of the junctional proteins and integrin ß4. However, the molecular mechanism, by which TR3/Nur77 regulated angiogenesis, was still not completely understood. In this report by analyzing the integrin expression profile in endothelial cells, we found that the TR3/Nur77 expression highly increased the expression of integrins α1 and ß5, decreased the expression of integrins α2 and ß3, but had some or no effect on the expression of integrins αv, α3, α4, α5, α6, ß1 and ß7. In the angiogenic responses mediated by TR3/Nur77, integrin α1 regulated endothelial cell proliferation and adhesion, but not migration. Integrin ß5 shRNA inhibited cell migration, but increased proliferation and adhesion. Integrin α2 regulated all of the endothelial cell proliferation, migration and adhesion. However, integrin ß3 did not play any role in endothelial cell proliferation, migration and adhesion. TR3/Nur77 regulated the transcription of integrins α1, α2, ß3 and ß5, via various amino acid fragments within its transactivation domain and DNA binding domain. Furthermore, TR3/Nur77 regulated the integrin α1 promoter activity by directly interacting with a novel DNA element within the integrin α1 promoter. These studies furthered our understanding of the molecular mechanism by which TR3/Nur77 regulated angiogenesis, and supported our previous finding that TR3/Nur77 was an excellent therapeutic target for pathological angiogenesis. Therefore, targeting TR3/Nur77 inhibits several signaling pathways that are activated by various angiogenic factors.

Expressions of Orphan Nuclear Receptor TR3/Nur77 in Chronic Hepatopathy and Its Clinical Significance.

OBJECTIVE: Although great success has been achieved in cancer treatment, current cancer therapies, including anti-tumorigenesis and anti-angiogenesis, still face the problems of insufficient efficacy, resistance and intrinsic refractoriness, in addition to their toxic side effects. There is a demand to identify additional targets that can be blocked to turn off the downstream effects of most, if not all, pathways. Our studies suggest that orphan nuclear receptor TR3 (human)/Nur77 (mouse) is such a target. Most recently, we reported that TR3/Nur77 expression in human hepatic cancer tissues correlates well with tumor progress, suggesting that TR3 is a specific therapeutic target for hepatic cancers. However, the correlation of TR3/Nur77 expression in hepatocellular carcinoma (HCC) with chronic hepatitis has not been studied. METHODS: The expression of TR3/Nur77 was analyzed in human primary hepatic cancer specimens from patients that have complete medical records with Immunohistochemically staining. The statistical analysis was used to access the significance of TR3 expression in tumor tissues, cirrhosis tissues and chronic hepatitis tissues with and without hepatitis B virus infection (HBV(+) and HBV(-)), which were obtained from para-tumor tissues. RESULTS: The positive rates of TR3/Nur77 expression in hepatocellular carcinoma, cancerous liver cirrhosis and chronic hepatitis are 66.67%, 30%, and 20%, respectively, which are statistic significant (p<0.05). The positive rates of TR3/Nur77 expression in hepatocellular carcinoma are statistic significant (p<0.05) with 81.25% and 20% in HBV (+) or HBV (-), respectively. CONCLUSION: The positive expression rate of TR3/Nur77 in hepatocellular carcinoma is higher than that in chronic hepatitis and cirrhosis. The positive rate of TR3/Nur77 expression in hepatocellular carcinoma is higher with HBV infection than that without infection. Our results suggest that TR3/Nur77 plays an important role in the progression of chronic hepatitis, and the occurrence and development of HCC.

Orphan Nuclear Receptor TR3/Nur77 is a Specific Therapeutic Target for Hepatic Cancers.

OBJECTIVE: Although great success has been achieved in cancer treatment, current cancer therapies, including anti-tumorigenesis and anti-angiogenesis, still face the problems of insufficient efficacy, resistance and intrinsic refractoriness, in addition to their toxic side effects. There is a demand to identify additional targets that can be blocked to turn off the downstream effects of most, if not all, pathways. Our previous studies suggest that orphan nuclear receptor TR3 (human) / Nur77 (mouse) is such a target. However, the correlation of TR3 expression and clinical tumor progression has not been studied. METHODS: The expression of TR3 was analysed in human primary hepatic cancer specimens from patients that have complete medical records with Immunohistochemical staining. The statistical analysis was used to assess the significance of TR3 expression in tumor tissues, paratumor tissues and normal tissues, and to investigate the correlation of TR3 expression and clincopathologic characteristics. RESULTS: TR3 is highly expressed in human hepatic cancer tissues, but not in normal liver tissues. The positive expression yields of TR3 are 67.67% (14/21), 19.05% (4/21) and 0% (0/10) in cancer tissues, para cancer tissues, and normal liver tissue, respectively, which are statistic significant (χ2=17.07, p<0.005). The expression of TR3 is significantly higher in cancer tissues than in para cancer tissues χ2=9.722, p<0.005) and in normal tissues (p<0.0005). The levels of TR3 expression in human hepatic cancer tissues correlates well with tumors that are at low/middle degree of tumor differentiation and have portal vein thrombosis, metastasis and recurrence, but not with age, gender, tumor number and Alpha-fetal protein (AFP) volume. CONCLUSION: The results indicate that TR3 is a specific therapeutic target for hepatic cancers.

AP-1 transcription factor mediates VEGF-induced endothelial cell migration and proliferation.

VEGF, upon binding to its endothelial cell specific receptors VEGF-R1 and VEGF-R2, can induce endothelial cell migration, proliferation and angiogenesis. However, the molecular mechanism of these effects still remains unclear. In this study, we investigated whether VEGF promotes human umbilical vascular endothelial cell (HUVEC) migration and proliferation through activator protein-1 transcription factor (AP-1) family. We first showed that VEGF induces immediate-early genes AP-1 family gene expression differentially with the profound induction of JunB (both mRNA and protein) under various conditions (PBS, DMSO or control adenoviruses). The increase in AP-1 mRNA expression occurs primarily at the transcriptional level. Inhibition of AP-1 DNA binding activity by adenovirus expressing a potent dominant negative form of c-Fos (Afos) significantly attenuated VEGF-induced HUVEC migration and proliferation and cyclin D1 expression. Knockdown of JunB with adenovirus expressing JunB shRNA reduces VEGF-induced JunB expression and attenuated HUVEC migration. However the shJunB-expressing virus has no effect on VEGF-induced cyclin D1 protein expression and proliferation. These results suggest that VEGF-induced endothelial migration is mediated primarily by induction of JunB whereas the promotion of endothelial proliferation by VEGF is mediated by JunB-independent AP-1 family members.