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Guizhou Province, as an inland province of China without borders and seas, has relatively backward economic development, but its economic growth is fast and its development potential is great. Studying its import and export trade is important to improve residents ' income and accelerate internationalization. This paper analyzes and establishes the indicator system of regional import and export influencing factors through literature analysis, and then uses ( radial basis function ) RBF neural network to analyze the influencing factors of import and export in Guizhou Province. Taking the economic data of Guizhou Province from 2001 to 2020 as samples, RBF neural network is used as a tool to analyze the relationship between various influencing factors and total import and export volume. The results show that when the number of hidden layer neurons is 14 or more, the RBF neural network model accuracy is the highest, R2 is 0.7005, and MAPE is 0.0834. Among the first-level indicators affecting import and export, the importance of the regional internal economic level is the highest. Among the second-level indicators, the importance of scientific and technological progress is the highest, followed by GDP.

The consumer price index (CPI) is a statistical indicator to measure the macroeconomic development of a region. Studying the influencing factors of regional CPI is helpful to deeply explore the mechanism of CPI change, and then help to measure inflation, national economic accounting, and contract indexation adjustment. In this paper, the coefficient of variation method (CVM) and analytic hierarchy process (AHP) is used to determine the subjective and objective weights of the evaluation factors, and the coupling weights are calculated based on the Lagrange multiplier method. Shanghai, China, is selected for empirical analysis to evaluate the suitability of CPI influencing factors in the study area. The results show that regional CPI is closely related to population size, population density, the proportion of the elderly population, urban resident population, GDP, per capita disposable income, PPI, and fixed asset investment. Among them, GDP, per capita disposable income, and fixed asset investment have the most prominent impact on CPI. The proportion of the elderly population and PPI have a more obvious impact, and the impact of population size, population density, and urban resident population is not obvious. The research on the influencing factors of regional CPI in this paper is of great practical significance to explore the causes of China's inflation and formulate reasonable macroeconomic policies.

Polypropylene-fiber-reinforced foamed concrete (PPFRFC) is often used to reduce building structure weight and develop engineering material arresting systems (EMASs). This paper investigates the dynamic mechanical properties of PPFRFC with densities of 0.27 g/cm3, 0.38 g/cm3, and 0.46 g/cm3 at high temperatures and proposes a prediction model to characterize its behavior. To conduct the tests on the specimens over a wide range of strain rates (500~1300 s−1) and temperatures (25~600 °C), the conventional split-Hopkinson pressure bar (SHPB) apparatus was modified. The test results show that the temperature has a substantial effect on the strain rate sensitivity and density dependency of the PPFRFC. Additionally, the analysis of failure models demonstrates that with the melting of polypropylene fibers, the level of damage in PPFRFC under dynamic loading increases, resulting in the generation of a greater number of fragments.

Apertures generally exist in the sandwich structures attributing to mechanical connection and lightweight, which might induce failure of such structures. Thus, it is required to realize the impact of aperture on mechanical behaviors of sandwich structures. If transverse shear deformations are unable to be described accurately, the reasonable prediction of dynamic behaviors of the form-core sandwich plates with apertures will meet severe challenges due to a large difference of transverse shear modulus at the adjacent layers. Thereby, such issue is less studied by using the efficient models and experimental testing, so an alternative sinusoidal-type finite element formulation is to be proposed to precisely predict dynamic response of the form-core sandwich structures with apertures. The proposed finite element formulation can meet beforehand compatible conditions of transverse shear stresses at the interfaces of adjacent laminates. In order to appraise strictly capability of the proposed model, experimental tests on natural frequencies of three groups of specimens with different apertures have been carried out. Moreover, four specimens in each group are tested to reduce the testing errors, which is less reported in the published literature. In addition, three-dimensional Finite Element Method (3-D FEM) is also selected to account for the good performance of the present model. Finally, the impact of aperture diameter on the natural frequencies of the sandwich structures is both experimentally and numerically investigated, which can serve as a reference for other researchers.

Cell death is involved in numerous pathological conditions such as cardiovascular disorders, ischemic stroke and organ transplant rejection, and plays a critical role in the treatment of cancer. Cell death imaging can serve as a noninvasive means to detect the severity of tissue damage, monitor the progression of diseases, and evaluate the effectiveness of treatments, which help to provide prognostic information and guide the formulation of individualized treatment plans. The high abundance of phosphatidylethanolamine (PE), which is predominantly confined to the inner leaflet of the lipid bilayer membrane in healthy mammalian cells, becomes exposed on the cell surface in the early stages of apoptosis or accessible to the extracellular milieu when the cell suffers from necrosis, thus representing an attractive target for cell death imaging. Duramycin is a tetracyclic polypeptide that contains 19 amino acids and can bind to PE with excellent affinity and specificity. Additionally, this peptide has several favorable structural traits including relatively low molecular weight, stability to enzymatic hydrolysis, and ease of conjugation and labeling. All these highlight the potential of duramycin as a candidate ligand for developing PE-specific molecular probes. By far, a couple of duramycin-based molecular probes such as Tc-99 m-, F-18-, or Ga-68-labeled duramycin have been developed to target exposed PE for in vivo noninvasive imaging of cell death in different animal models. In this review article, we describe the state of the art with respect to in vivo imaging of cell death using duramycin-based molecular probes, as validated by immunohistopathology.

Necrosis is an important biomarker, which only occurs in pathological situations. Tracking of necrosis avid agents is of crucial importance toward understanding their mechanisms. Herein, we developed a modular probe strategy based on bioorthogonal copper-free click chemistry. Structural modification of rhein with transcyclooctene (TCO) led to the identification of rhein-TCO2 as the most active probe with specific necrosis affinity. In a systematic evaluation, the colocalization of rhein-TCO2 in the nucleus (exposed DNA and rRNA) of necrotic cells was observed. This work provides a foundation for the development of target-identified of rhein compounds, and binding to exposed DNA and rRNA may be an important target of rhein compounds in necrotic cells.

Autophagy plays a critical role in cancer, since it can either suppress tumorigenesis by inhibiting cancer cell survival, or facilitate tumorigenesis by promoting cancer cell proliferation and tumor growth. However, the role of genetic variants of autophagy-regulated key genes for bladder cancer risk remained unclear. Here, we aimed to explore the association of bladder cancer with genetic variants on genes involved in autophagy pathway. Gene-based analysis was performed with multi-marker analysis of genomic annotation (MAGMA) in 580 bladder cancer cases and 1101 controls. The logistic regression model was used to calculate the SNP effects on bladder cancer susceptibility. Expression quantitative trait loci (eQTL) analysis was conducted by the genotype-tissue expression (GTEx) project. Gene expression was evaluated based on the Cancer Genome Atlas (TCGA) database. Three potentially functional SNPs RPS6KB1 rs1292038, PIK3R1 rs34303, and rs56352616 were demonstrated to be associated with risk of bladder cancer (OR = 0.71, 95% CI = 0.61–0.82, P = 7.88 × 10−6 for rs1292038; OR = 1.25, 95% CI = 1.09–1.45, P = 2.11 × 10−3 for rs34303; OR = 0.74, 95% CI = 0.62–0.90, P = 2.47 × 10−3 for rs56352616). An increasing number of risk genotypes of these three SNPs were associated with a higher risk of developing bladder cancer. Besides, rs1292038 exhibited an eQTL effect for RPS6KB1 in whole blood (P = 3.90 × 10−7). Furthermore, the higher expression of RPS6KB1 and lower expression of PIK3R1 were both significantly associated with bladder cancer risk. Our findings indicated that genetic variants in autophagy pathway genes RPS6KB1 and PIK3R1 confer bladder cancer susceptibility.

The precise detection of polyester filament yarn (PFY) tension in the spinning process is critical to ensure product quality. The laser Doppler vibrometer (LDV) method is proposed to achieve non-contact detection of PFY tension in this paper. By employing the Hamilton principle, the transverse dynamics differential equations of PFY are derived, which are discretized and solved by the Galerkin method and Runge–Kutta method, respectively. In the equations, the PFY between two adjacent rollers is simplified as an axially moving string to verify the generality of calculating natural frequencies. The calculated natural frequencies from the axially moving string model are compared with solved results from the transverse dynamics differential equations. It is shown that the approximation of natural frequencies can be obtained from the axially moving string model. This study attempts to establish an approximate generic model among the PFY tension, the spinning speed and the first natural frequency based on axially moving string model, from which the PFY tension can be calculated efficiently by employing the measured natural frequencies. The LDV method is used to measure the natural frequencies. A major advantage of the proposed method is to realize non-contact detection of PFY tension. The method is more useful under high-speed spinning conditions where contact tension detectors are not available. An experimental analysis is carried out to verify the effectiveness and accuracy of the proposed method. Therefore, it is believed that the non-contact detection of PFY tension in the spinning process by the LDV method is feasible.

Dietary fiber is the basic therapeutic method to relieve the symptoms of chronic constipation. The aim of this study was to compare the laxative effect of konjac glucomannan (KGM) and konjac oligosaccharides (KOS) on constipated rats. KGM and KOS were administered to loperamide-induced constipated rats at dosages of 100 mg per kg bw and 400 mg per kg bw for 15 days. Feces were collected to evaluate the defecation function. X-ray imaging and an electrophysiological system were used to determine gastrointestinal (GI) motility. Immunohistochemistry and western blotting were used to measure the protein levels. Magnetic resonance imaging (MRI) was performed to assess flatulence. Our results demonstrated that low-dose KOS (L-KOS) exerted the best laxative effect. Compared to the normal control (NC) group, the fecal number in the L-KOS group increased by 39.4%, and the fecal weight significantly increased by 31.9% which was higher than those in the low-dose KGM (L-KGM) and high-dose KGM (H-KGM) groups. The fecal moisture content and transit scores were significantly increased only in the L-KOS group. Meanwhile, less GI gas was produced by KOS. Additionally, further investigations suggested that KOS could upregulate the protein expression of stem cell factors (SCF)/c-kit, and significantly promoted the secretion of mucus. In conclusion, compared to KGM, KOS had a conspicuous laxative effect especially at a low dosage. The potential laxative mechanisms of KOS probably are regulating the SCF/c-kit signalling pathway and increasing mucus secretion. These findings indicated that as a kind of functional oligosaccharide, KOS is more conducive to alleviating constipation compared to polysaccharides.

Objectives Combretastatin A4 phosphate (CA4P), a vascular disrupting agent (VDA), can cause rapid tumour vessel occlusion. Subsequently, extensive necrosis is discovered in the tumour center, which induces widespread hypoxia and the rise of the α subunit of hypoxia-inducible factor-1 (HIF-1α). The aim of this study was to evaluate the inhibition of hepatocellular carcinoma growth by combining CA4P with HIF-1 α inhibitor and investigate the mechanism of this combination. Methods Ginsenoside Rd (Rd) was used in combination with CA4P to estimate the inhibition effect in HepG2 cells and HepG2 xenograft mouse model. The efficacy of anti-tumour was evaluated by tumour growth curve. The protein expression of HIF-1α and PI3K/AKT/mTOR signalling pathway were analysed by western blot. Key findings Combination of CA4P and Rd inhibited HepG2 cell proliferation and induced apoptosis in vivo and in vitro. It also increased the necrotic area of the tumour and delayed the tumour growth. Moreover, Rd down-regulated HIF-1α protein expression by inhibiting PI3K/AKT/mTOR signalling pathway. Conclusions Combination of CA4P and Rd had synergistic anti-tumour effects. The mechanism may be related to the inhibition of HIF-1α by PI3K/AKT/mTOR signalling pathway. This strategy provides a new thought for the combinative therapy of VDAs.

Necrosis-avid agents possess exploitable theragnostic utilities including evaluation of tissue viability, monitoring of therapeutic efficacy as well as diagnosis and treatment of necrosis-related disorders. Rhein (4,5-dihydroxyl-2-carboxylic-9,10-dihydrodiketoanthracene), a naturally occurring monomeric anthraquinone compound extensively found in medicinal herbs, was recently demonstrated to have a newly discovered necrosis-avid trait and to show promising application in necrosis imaging. In this overview, we present the discovering process of rhein as a new necrosis-avid agent as well as its potential imaging applications in visualisation of myocardial necrosis and early evaluation of tumour response to therapy. Moreover, the molecular mechanism exploration of necrosis avidity behind rhein are also presented. The discovery of necrosis avidity with rhein and the development of rhein-based molecular probes may further expand the scope of necrosis-avid compounds and highlight the potential utility of necrosis-avid molecular probes in necrosis imaging. ispartof: JOURNAL OF DRUG TARGETING vol:28 issue:9 pages:904-912 ispartof: location:England status: published

Cell death plays a prominent role in the treatment of cancer, because most anticancer therapies act by the induction of cell death including apoptosis, necrosis, and other pathways of cell death. Imaging cell death helps to identify treatment responders from nonresponders and thus enables patient-tailored therapy, which will increase the likelihood of treatment response and ultimately lead to improved patient survival. By taking advantage of molecular probes that specifically target the biomarkers/biochemical processes of cell death, cell death imaging can be successfully achieved. In recent years, with the increased understanding of the molecular mechanism of cell death, a variety of well-defined biomarkers/biochemical processes of cell death have been identified. By targeting these established cell death biomarkers/biochemical processes, a set of molecular imaging probes have been developed and evaluated for early monitoring treatment response in tumors. In this review, we mainly present the recent advances in identifying useful biomarkers/biochemical processes for both apoptosis and necrosis imaging and in developing molecular imaging probes targeting these biomarkers/biochemical processes, with a focus on their application in early evaluation of tumor response to therapy.

Acute myocardial infarction (AMI) remains the most severe and common cardiac emergency among various ischaemic heart diseases. Both unregulated (necrosis) and regulated (apoptosis, autophagy and necroptosis et al.) forms of cell death can occur during AMI. Non-invasive imaging of cardiomyocyte death represents an attractive approach to acquire insights into the pathophysiology of AMI, track the temporal and spatial evolution of MI, guide therapeutic decision-making, evaluate response to therapeutic intervention and predict prognosis. Although several forms of cell death have been identified during AMI, to date, only apoptosis- and necrosis-detecting probes compatible with currently available tomographic imaging modalities have been successfully developed for non-invasive visualisation of cardiomyocyte death. Myocardial apoptosis imaging has gained more attention because of its potential controllability while less attention has been paid to myocardial necrosis imaging. In our opinion, although cardiomyocyte necrosis is unsalvageable, imaging necrosis can play an important role in early diagnosis, risk stratification, prognostic prediction and guidance in therapeutic decision-making of AMI. In this mini-review, we summarise the updated advances achieved by us and others and discuss the challenges in the development of molecular imaging probes for visualisation of myocardial necrosis.

A [3 + 2] annulation/C-arylation of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 with in situ generated arynes has been established for the synthesis of 3,3-disubstituted oxindole scaffolds. These highly functionalized scaffolds were assembled in moderate yields (up to 85% yield). The novel spirooxindole scaffolds displayed moderate antitumor activities, which represented promising lead compounds for antitumor drug discovery.

A one-pot, two-step protocol for the synthesis of libraries of remarkable functionalized sulfone analogues of 9b,10,10a,10b-tetrahydro-1H-cyclopropa[c][1,4]thiazino[4,3-a]quinolines is described. A class of various functionalized molecular skeletons was obtained by cyclopropanation of quinolinium zwitterionic thiolates. The reaction pathway involves the formation of a [2 + 1] cycloaddition intermediate followed by a [5 + 1] cycloaddition.

Abnormal enhancement of hepatic gluconeogenesis is a vital mechanism of the pathogenesis of Type 2 diabetes mellitus (T2DM); thus, its suppression may present an efficient therapeutic strategy for T2DM. Cyclocarya paliurus (CP), a plant species native to China, has been reported to have anti-hyperglycemia activity. Our previous studies have revealed that Cyclocarya paliurus triterpenic acids (CPT) exert the favorable glucose-lowering activity, but the regulatory effect of CPT on hepatic gluconeogenesis is still unclarified.This study aimed to investigate the potential role and mechanism of CPT in gluconeogenesis.In this study, the ameliorative effect and underlying mechanism of CPT on gluconeogenesis were investigated: high-fat diet and streptozotocin-induced T2DM mice and glucagon-challenged mouse primary hepatocytes.T2DM model mice with or without oral administration of CPT for 4 weeks were monitored for body weight, glucose and lipid metabolism. Hematoxylin and eosin staining was used to observe liver lipid deposition. Real-time PCR assays were performed to examine the mRNA expression of glucose-6-phosphate (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes involved in liver gluconeogenesis. Western blotting was used to determine AMP-dependent protein kinase (AMPK) expression and induction of the glucagon signaling pathway. The possible mechanism of CPT on liver gluconeogenesis was further explored in glucagon-induced mouse primary hepatocytes.In vivo and in vitro experiments revealed that CPT treatment significantly reduced fasting blood glucose, total cholesterol and triglyceride levels, and improved insulin resistance. Furthermore, CPT could obviously decreased the mRNA and protein expression of G6Pase and PEPCK, the cyclic AMP content, the phosphorylation level of protein kinase A and cyclic AMP response element-binding protein. But CPT promoted the phosphorylation of AMP-dependent protein kinase (AMPK) and activation of phosphodiesterase 4B. Mechanistically, intervention with Compound C (an AMPK inhibitor) partially blocked the suppressive effect of CPT on hepatic gluconeogenesis.These findings suggested that CPT may inhibit hepatic gluconeogenesis against T2DM by activating AMPK.

PURPOSE: Early evaluation of tumor response to thermal ablation therapy can help identify untreated tumor cells and then perform repeated treatment as soon as possible. The purpose of this work was to explore the potential of rhein-based necrosis-avid contrast agents (NACAs) for early evaluation of tumor response to microwave ablation (MWA). METHODS: 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay was performed to test the cytotoxicity of rhein-based NACAs against HepG2 cells. Rat models of liver MWA were used for investigating the effectiveness of rhein-based NACAs in imaging the MWA lesion, the optimal time period for post-MWA MRI examination, and the metabolic behaviors of 68 Ga-labeled rhein-based NACAs. Rat models of orthotopic liver W256 tumor MWA were used for investigating the time window of rhein-based NACAs for imaging the MWA lesion, the effectiveness of these NACAs in distinguishing the residual tumor and the MWA lesion, and their feasibility in early evaluating the tumor response to MWA. RESULTS: Gadolinium 2,2',2''-(10-(2-((4-(4,5-Dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamido)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (GdL2 ) showed low cytotoxicity and high quality in imaging the MWA region. The optimal time period for post-MWA MRI examination using GdL2 was 2 to 24 h after the treatment. During 2.5 to 3.5 h postinjection, GdL2 can better visualize the MWA lesion in comparison with gadolinium 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetic acid (Gd-DOTA), and the residual tumor would not be enhanced. The tumor response to MWA as evaluated by using GdL2 -enhanced MRI was consistent with histological examination. CONCLUSION: GdL2 appears to be a promising NACA for the tumor response assessment after thermal ablation therapies. ispartof: MAGNETIC RESONANCE IN MEDICINE vol:82 issue:6 pages:2212-2224 ispartof: location:United States status: published

This study aimed to synthesize a necrosis-avid agent using rhein as a precursor and labeled with gallium-68 (Ga-68) for positron emission tomography/computed tomography (PET/CT) imaging, to evaluate response to anticancer treatment in a mouse model. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)–conjugated rhein was radiolabeled with Ga-68 to formulate [68Ga]DOTA-rhein. The in vitro stability of [68Ga]DOTA-rhein was assessed by radio-HPLC. Necrosis avidity was evaluated in a mouse model of muscle necrosis by microPET/CT imaging, biodistribution study, histochemical staining, and autoradiography studies. Murine tumor models with the subcutaneous implantation of S180 cell lines were generated for the evaluation of therapeutic effect. Tumor necrosis was induced by the treatment of combretastatin A4 disodium phosphate (CA4P), and microPET/CT imaging was performed at 1 h post tracer injection. DNA binding studies were conducted to explore the necrosis avidity mechanism of the tracer. [68Ga]DOTA-rhein exhibited a satisfactory yield, a radiochemical purity over 97 %, and a good serum stability. The uptakes of [68Ga]DOTA-rhein in necrotic muscles and tumors were significantly higher than those in normal muscles and tumors (P

Cell death plays important roles in living organisms and is a hallmark of numerous disorders such as cardiovascular diseases, sepsis and acute pancreatitis. Moreover, cell death also plays a pivotal role in the treatment of certain diseases, for example, cancer. Noninvasive visualization of cell death contributes to gained insight into diseases, development of individualized treatment plans, evaluation of treatment responses, and prediction of patient prognosis. On the other hand, cell death can also be targeted for the treatment of diseases. Although there are many ways for a cell to die, only apoptosis and necrosis have been extensively studied in terms of cell death related theranostics. This review mainly focuses on molecular imaging and therapeutic strategies directed against necrosis. Necrosis shares common morphological characteristics including the rupture of cell membrane integrity and release of cellular contents, which provide potential biomarkers for visualization of necrosis and necrosis targeted therapy. In the present review, we summarize the updated joint efforts to develop molecular imaging probes and therapeutic strategies targeting the biomarkers exposed by necrotic cells. Moreover, we also discuss the challenges in developing necrosis imaging probes and propose several biomarkers of necrosis that deserve to be explored in future imaging and therapy research. KEY WORDS: Necrosis avid agents, Exposed DNA, Molecular imaging, Targeted therapy, Solid tumor, Myocardial infarction

Tracking of necrosis avid agents is of crucial importance toward understanding their mechanisms. We explored the cellular localisation of rhein by synthesising a clickable derivative (compound 3) and labelling it in situ with an Alexa-fluor 488 click partner. Binding to exposed DNA may be an important mechanism of targeting of rhein compounds to necrotic cells.

This study aimed to seek necrosis avid agents with high safety from DNA binding agents. The interaction of 5-hydroxytryptophan (5-HTP) with DNA was investigated by a series of spectroscopic studies. Then, 5-HTP was labeled with iodine-131 ([131I]5-HTP) and the necrosis avidity of [131I]5-HTP was evaluated by in vitro cell binding assays, in vivo biodistribution experiments and blocking experiment. Finally, the potential of [131I]5-HTP to image necrotic myocardium was explored in rat models with myocardial infarction by SPECT/CT imaging. Results showed that 5-HTP bound to DNA in groove binding mode and the binding constant was 1.69 × 104 L/mol. [131I]5-HTP showed specific affinity to necrotic A549 cells, which might be related to cell nucleus. Biodistribution and autoradiography results showed preferential accumulation of [131I]5-HTP in necrotic muscle (necrotic/viable muscle ratio: 6.95 ± 0.68 at 3 h post-injection (p.i.)), which could be blocked by 5-HTP with 66.7% decline, indicating that [131I]5-HTP might share the same necrotic targets with 5-HTP. On SPECT/CT images, a hotspot was clearly observed at 3 h p.i. in the necrotic myocardium while not in the control myocardium. In conclusion, [131I]5-HTP is a novel necrosis avid agent and can rapidly visualize necrotic myocardium at 3 h p.i. The necrosis avidity mechanism of [131I]5-HTP may be attributed to its interactions with exposed DNA in the necrotic tissues.

Bladder cancer is a malignant tumor characterized by high recurrence and persistence due to the limited therapies that are currently available. Hirudin exerts a strong anticancer effect on several tumors. Thus, it is urgent to explore the biological function of hirudin in bladder cancer and the role of bladder cancer-derived exosomes in tumor inhibition.First, a network pharmacology analysis was performed to explore the relationships among hirudin, bladder cancer, and exosomes. Then, the effects of hirudin were examined by CCK-8 assay, flow cytometry, Transwell assay, and tumorigenic ability experiments in vitro. Exosomes derived from cells were identified with transmission electron microscopy, fluorescence labeling, and Western blotting and collected for further microarray analysis. Only CDC6 expression and mRNA abundance in hirudin-treated cells and exosomes was subjected to further validation using quantitative PCR and Western blotting.Through network analysis, we found that hirudin affected bladder cancer, and this effect was related to exosomes. Our studies verified the effects of hirudin by revealing that hirudin inhibits malignant processes of bladder cancer cells in vitro, such as invasion, metastasis, and apoptosis. Similarly, the oncogenic effects of bladder cancer-derived exosomes were successfully isolated and identified. Via microarray assessment of the exosomes, we identified 600 differential mRNAs, of which the expression of the core target CDC6 was found to be significantly different in both The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. We further confirmed that hirudin suppresses CDC6 expression mRNA abundance in both cells and exosomes.Hirudin was able to decrease the expression of CDC6 in bladder cancer cells and exosomes, which effectively repressed the malignant processes of bladder cancer cells.

Ethnopharmacological relevance Aloe vera (L.) Burm. f. (Aloe vera) is a medicinal herb that used in Traditional Chinese Medicine (TCM) practice for the treatment of gastrointestinal diseases such as constipation and colitis. Recent studies also reported its beneficial effect in mitigating ulcerative colitis (UC). Nevertheless, the underlying mechanisms of Aloe vera against UC remain largely unknown. Aim of the study This study aimed to explore a relation between the therapeutical effects of Aloe vera in UC and colonic mucus secretion, and further investigate the underlying pathways through which Aloe vera regulates colon mucus as well as preliminarily studied the main active constitute of Aloe vera to alleviate UC. Materials and methods UPLC-MS/MS were employed to analyze the Aloe vera extract. The rat models of UC were induced by free subjected to fresh 3% dextran sulfate sodium (DSS) solution for 8 days and then accessed to tap water for 2 days. Aloe vera extract (18 mg/kg and 72 mg/kg) or 5-ASA (400 mg/kg) was administered orally from day 1–10. At the end of experiment, rats were sacrificed and the colon tissues were harvested for analysis. UC symptoms was evaluated by disease activity index (DAI), colon length and H&E staining. The Alcian blue stain were determined colon mucus layer. Myeloperoxidase (MPO) activity, mucin and inflammatory cytokines in colon tissues were determined by ELISA. The expression of related proteins on PI3K/AKT and PKC/ERK signaling pathway was analyzed by Western blot. We then evaluated the effects of three main components of Aloe vera (Aloe-emodin, aloin A and B) on mucin secretion and cytokine expression in vitro by ELISA. Results Oral supplement with Aloe vera extract resulted in a significantly decreased DSS-induced UC symptoms, including decreased DAI, prevention of the colon length shortening, and alleviation of the pathological changes occurring in colon. The expression of colonic pro-inflammatory mediators, including IL-6, IL-1β and TNF-α were suppressed, yet the expression of IL-10 was up-regulated by Aloe vera treatment. Moreover, Aloe vera significantly up-regulated the expressions of mucin proteins (e.g., MUC2 and MUC5AC) and increased the thickness of mucus layer in the colon. Further, we revealed that Aloe vera significantly upregulated p-PKC and p-ERK expression and downregulated p-PI3K and p-AKT expression. Finally, we discovered that treat with aloin A markedly decreased IL-6 levels and increased MUC2 expression in LPS-stimulated LS174T cell. Conclusion These results support that Aloe vera improved UC by enhancing colon mucus barrier functions in addition to reducing inflammation. Moreover, aloin A might be a main active components of Aloe vera to ameliorate UC.

Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors, especially liver cancer. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR4 inhibitors. Currently, several selective irreversible inhibitors containing pyrrolo[2,3-b]pyridine-3-one and pyrrolo[2,3-d]pyrimidin-2-amine skeletons were designed and synthesized as FGFR4 inhibitors. Among the screened compounds, derivative 25 showed excellent enzymatic inhibitory activity (IC50, 51.6 nM) and antiproliferative potency of 0.1397 μM against Hep3B cell lines. Compound 25 exhibited good in vitro human liver microsomal stability with the half-life of 62.0 min, which was more stable than BLU9931 (46.7 min). But the in vivo pharmacokinetic results showed that the oral bioavailability was only 6.65%, which needs to be improved in the next work. These results showed that compound 25 might be an effective lead compound for further investigation to treat the hepatocellular carcinoma.

Glucarate, a physiologic end-product of the D-glucuronic acid pathway in mammals, is a six-carbon dicarboxylic acid with a wide range of uses. Glucarate-based molecular imaging probes including [99mTc]glucarate and [18F]glucarate have been developed and demonstrated to have infarct/necrosis-avid and/or tumor-seeking properties, showing potential applications in early detection of myocardial infarction, evaluation of tissue viability, monitoring of therapeutic effectiveness, and noninvasive imaging of certain tumors including drug-resistant ones. The mechanism by which [99mTc]glucarate localizes in acute necrotic tissues has been demonstrated to be largely attributable to its binding to the positively charged histones, which become accessible after the disruption of the cell and nuclear membranes as a result of irreversible damage, while the tumor-seeking mechanism of [99mTc]glucarate has been found to be closely related to glucose transporter 5 expression. Moreover, the recently developed [18F]glucarate provides a new alternative probe for positron emission tomography imaging and may have potential advantages over [99mTc]glucarate. In this review, we present the untiring pursuit for glucarate-based molecular imaging probes as infarct/necrosis-avid agent and/or tumor-seeking agent. Moreover, the limitations and the prospects for future research of glucarate-based molecular probes are also discussed.

Visualization of tumor necrosis can determine tumor response to therapy. Our previous study showed that the rhein-based magnetic resonance imaging (MRI) contrast agent with alkane linker (GdL2) could clearly image tumor necrosis. However, its water solubility and cell safety needed to be improved. Herein, three rhein-based MRI agents with ether or lysine linkers were designed. Three rhein-based MRI agents were synthesized with a tetracarbon ether (GdP1), a hexacarbon ether (GdP2), and a lysine (GdP3) linker, respectively. Their octanol-water partition coefficients (log P) and cytotoxicity were determined. Necrosis avidity of the leading agent was explored on HepG2 cells and ischemia reperfusion-induced liver necrosis (IRLN) rats by MRI. The effect of visualization of tumor necrosis was tested on nude mice with W256 tumor treated by combretastatin-A4 phosphate (CA4P). DNA binding assays were applied to evaluate the possible necrosis-avidity mechanism of the leading agent. The log P of three agents (− 1.66 ± 0.09, − 1.74 ± 0.01, − 1.95 ± 0.01) decreased when compared with GdL2, indicating higher water solubility. GdP1 not only presented lower cytotoxicity and good necrotic affinity in vitro and in vivo, but also can be fast excreted by renal. According to MRI results of tumor, distinct visualization of tumor necrosis can be discernible from 3 to 4.5 h post-injection of GdP1. In DNA-binding assays, the fluorescence quenching constant KSV (1.00 × 104 M−1) and the ultraviolet binding constant Kb (1.11 × 104 M−1) suggested that GdP1 may bind to DNA through intercalation. GdP1 may serve as a potential candidate for early evaluation of tumor response to CA4P treatment.

Precise measurement of Polyester Filament Yarn (PFY) tension in the spinning process is critical to ensure good uniformity of product quality. A newly proposed real-time method is used to estimate the tension based on the natural frequencies extraction of the PFY. The theoretical relationship is established among the PFY tension, the spinning speed, and the first natural frequency based on the characteristics of the transverse dynamic vibration of the PFY in the spinning process. Then, an improved wavelet threshold denoising model has been applied to denoising the vibration signals, and the gravity center frequency of the denoised amplitude spectrum is used to extract the natural frequency of the PFY, and then the PFY tension can be estimated efficiently by employing the extracted natural frequencies. To monitor the uniformity of product quality, a new real-time evaluation index, namely the PFY tension fluctuation rate, is proposed to evaluate the overall fluctuation of PFY tension, which can be used for quantitative analysis and comparison of PFY tension. Additionally, the measurement data is of great significance to the evaluation and optimization of the performance of high-speed spinning equipment. The research intends to serve as a basis for the design of the spinning technology as well as its reliable operation.

Noninvasive imaging of treatment-induced necrosis is important to distinguish early responders from patients resistant to the treatment plan, enabling the tailored-made therapeutic intervention. The purpose of this study was to explore the feasibility of [99mTc]EDDA-HYNIC-2C-rhein for early assessment of tumor response to treatment. In vitro necrosis avidity of [99mTc]EDDA-HYNIC-2C-rhein was evaluated in human lung cancer A549 cells treated with hyperthermia. Single photon emission–computed tomography/X-ray-computed tomography (SPECT/CT) imaging was performed in rats bearing subcutaneous W256 tumor treated with combretastatin A-4 disodium phosphate (CA4P) and rats bearing orthotopic liver W256 tumor treated with a single microwave ablation. All rats were euthanized immediately after the imaging session for biodistribution and histology studies. The mechanism of necrosis avidity for the tracer was further explored by in vivo blocking experiment and in vitro histochemistry and fluorescence staining. The uptake of [99mTc]EDDA-HYNIC-2C-rhein in necrotic cells was significantly higher than that in viable cells (p

This study aimed to explore the use of 131I-Hoechst 33258 (131I-H33258) for early prediction of tumor response to vascular-disrupting agents (VDAs) with combretastatin-A4 phosphate (CA4P) as a representative. Necrosis avidity of 131I-H33258 was evaluated in mouse models with muscle necrosis and blocking was used to confirm the tracer specificity. Therapy response was evaluated by 131I-H33258 SPECT/CT imaging 24 h after CA4P therapy in W256 tumor-bearing rats. Radiotracer uptake in tumors was validated ex vivo using γ-counting, autoradiography, and histopathological staining. Results showed that 131I-H33258 had predominant necrosis avidity and could specifically bind to necrotic tissue. SPECT/CT imaging demonstrated that an obvious “hot spot” could be observed in the CA4P-treated tumor. Ex vivo γ-counting revealed 131I-H33258 uptake in tumors was increased 2.8-fold in rats treated with CA4P relative to rats treated with vehicle. Autoradiography and corresponding H&E staining suggested that 131I-H33258 was mainly localized in necrotic tumor area and the higher overall uptake in the treated tumors was attributed to the increased necrosis. These results suggest that 131I-H33258 can be used to image induction of cell necrosis 24 h after CA4P therapy, which support further molecular design of probes based on scaffold H33258 for monitoring of tumor response to VDAs treatment.

Identifying necrotic myocardium in ischemic regions is of great importance for risk stratification and clinical decision-making. However, rapid noninvasive imaging of necrotic myocardium is still challenging. This study sought to evaluate the potential of 1,4-naphthoquinones to rapidly visualize necrotic myocardium and the possible mechanisms of necrosis avidity. Six 1,4-naphthoquinones were radiolabeled with iodine-131 and the necrosis avidity was estimated in mouse models with muscular necrosis by gamma counting and autoradiography. The necrotic myocardium imaging property and biodistribution of [131I]naphthazarin (6) were determined in rat models with re-perfused myocardial infarction. A possible mechanism of necrosis avidity was explored by in vitro DNA-binding and in vivo blocking experiments. The radiochemical purities of the six radiotracers were greater than 95 %. The uptakes in necrotic muscles of all six radiotracers were higher than those in viable muscles, and [131I]naphthazarin (6) showed the highest necrotic-to-viable ratio and necrosis-to-blood ratio at all tested time points. The necrotic myocardium could be clearly visualized by single-photon emission computed tomography/x-ray computed tomography (SPECT/CT) using [131I]naphthazarin (6) as early as 3 h post-injection. Post-mortem biodistribution showed the uptake of [131I]naphthazarin (6) in necrotic myocardium was 11.67-fold higher than that in viable myocardium. Absorption spectra and emission spectra suggested naphthazarin (6) could bind to DNA through intercalation. The uptake of [131I]naphthazarin (6) in necrotic muscle could be significantly blocked by excessive ethidium bromide (a typical DNA intercalator) and cold naphthazarin (6) with 63.49 and 71.96 % decline at 3 h post-injection in vivo, respectively. 1,4-Naphthoquinones retained necrosis avidity and [131I]naphthazarin (6) rapidly visualized necrotic myocardium. The necrosis avidity mechanism of [131I]naphthazarin (6) may be attributed to its binding with exposed DNA in necrotic tissues.

A facile and efficient cyclization of N-alkoxy α-halogenoacetamides with N-(2-chloromethyl)aryl amides has been achieved for rapid access to 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one derivatives (up to 95% yield). The intriguing features of this intermolecular cyclization include its mild reaction conditions and easy handling for scalable synthesis.

Noninvasive imaging of cell necrosis can provide an early evaluation of tumor response to treatments. Here, we aimed to design and synthesize a novel diindole-based magnetic resonance imaging (MRI) contrast agent (Gd-bis-DOTA-diindolylmethane, Gd-DIM) for assessment of tumor response to therapy at an early stage.The oil-water partition coefficient (Log P) and relaxivity of Gd-DIM were determined in vitro. Then, its necrosis avidity was examined in necrotic cells in vitro and in rat models with microwave ablation-induced muscle necrosis (MAMN) and ischemia reperfusion-induced liver necrosis (IRLN) by MRI. Visualization of tumor necrosis induced by combretastatin A-4 disodium phosphate (CA4P) was evaluated in rats bearing W256 orthotopic liver tumor by MRI. Finally, DNA binding assay was performed to explore the possible necrosis-avidity mechanism of Gd-DIM.The Log P value and T1 relaxivity of Gd-DIM is - 2.15 ± 0.01 and 6.61 mMGd-DIM may serve as a promising necrosis-avid MRI contrast agent for early assessment of tumor response to therapy.

This study aimed to synthesize a necrosis-avid agent using rhein as a precursor and labeled with gallium-68 (Ga-68) for positron emission tomography/computed tomography (PET/CT) imaging, to evaluate response to anticancer treatment in a mouse model.1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated rhein was radiolabeled with Ga-68 to formulate [[Our results demonstrated that [

Nanomedicines can generally only reach cancer cells at the edges of tumors, leaving most tumor cells in the central regions untreated. Previous studies showed that treatment with the vascular disrupting agent combretastatin-A4-phosphate (CA4P) can disrupt tumor vasculature, causing vascular shutdown and leading to massive necrosis in the tumor core. In this research, we explored the effect of co-administration of CA4P on the antitumor activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in Walker 256 tumor-bearing rats. The iodine 131 isotope was used for tracing and biodistribution analysis of nab-paclitaxel uptake. Liquid chromatography coupled with tandem mass spectrometry was performed to detect the intratumoral concentration of paclitaxel. Magnetic resonance imaging (MRI) was used to evaluate the effect of tumor treatment. Biodistribution results demonstrated that the tumor accumulations of both nab-paclitaxel and paclitaxel in the 131I-nab-paclitaxel + CA4P group were much higher than those in the 131I-nab-paclitaxel group. Nab-paclitaxel in combination with CA4P inhibited tumor growth significantly more potently compared with the CA4P group, nab-paclitaxel group and PBS group. Our results demonstrate that co-administration of CA4P increased the intratumoral accumulation of nab-paclitaxel and improved its therapeutic effect compared with single treatments.

// Meng Gao 1, 2 , Dongjian Zhang 1, 2 , Qiaomei Jin 1, 2 , Cuihua Jiang 1, 2 , Cong Wang 3 , Jindian Li 3 , Fei Peng 1, 2 , Dejian Huang 1, 2 , Jian Zhang 1, 2 , Shaoli Song 4 1 Laboratory of Translational Medicine, Jiangsu Province Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R.China 2 Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R.China 3 Department of Natural Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu Province, P.R. China 4 Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200127, P.R. China Correspondence to: Jian Zhang, email: zjwonderful@hotmail.com Shaoli Song, email: shaoli-song@163.com Keywords: combretastatin-A-4 phosphate, interstitial fluid pressure, albumin-bound paclitaxel, tissue distribution, combination therapy Received: February 15, 2016 Accepted: July 27, 2016 Published: August 12, 2016 ABSTRACT Nanomedicine holds great promise for fighting against malignant tumors. However, tumor elevated interstitial fluid pressure (IFP) seriously hinders convective transvascular and interstitial transport of nanomedicines and thus damages its antitumor efficacy. In this study, combretastatin-A4 phosphate (CA4P) was utilized to reduce tumor IFP, and thereby to improve the intratumoral distribution and antitumor efficacy of nanoparticle albumin-bound paclitaxel (nab-paclitaxel). IFP was measured using the wick-in-needle method in tumors growing subcutaneously pretreatment and posttreatment with a single intravenous injection of CA4P. The tracing method of iodine 131 isotope was used for biodistribution analysis of nab-paclitaxel. Liquid chromatography coupled with tandem mass spectrometry was used to detect the intratumoral concentration of paclitaxel. Magnetic resonance imaging was applied to monitor tumor volume and ratios of necrosis. The tumor IFP continued to decline gradually over time following CA4P treatment, reaching approximately 31% of the pretreatment value by 1 h posttreatment. Biodistribution data indicated that both 131 I-nab-paclitaxel and paclitaxel exhibited higher tumor uptake in CA4P + 131 I-nab-paclitaxel group compared with I 131 -nab-paclitaxel group. Nab-paclitaxel combined with CA4Pshowed significant tumor growth inhibition and higher tumor necrosis ratio relative to PBS, CA4P and nab-paclitaxel group, respectively. In conclusion, CA4P improved the intratumoral distribution and antitumor efficacy of nab-paclitaxel in W256 tumor-bearing rats.

Early and accurate assessment of therapeutic response to anticancer therapy plays an important role in determining treatment planning and patient management in clinic. Magnetic rseonance imaging (MRI) of necrosis that occurs after cancer therapies provides chances for that. Here, we reported three novel MRI contrast agents, GdL1, GdL2, and GdL3, by conjugating rhein with gadolinium 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetic acid (Gd-DOTA) through different linkers. The T1 relaxivities of three probes (7.28, 7.35, and 8.03 mM-1 s-1) were found to be higher than that of Gd-DOTA (4.28 mM-1 s-1). Necrosis avidity of GdL1 was evaluated on the rat models of reperfused liver infarction (RLI) by MRI, which showed an increase of T1-weighted contrast between necrotic and normal liver during 0.5-12 h. Besides, L1 was also labeled with 64Cu to assess its necrosis avidity on rat models of RLI and muscle necrosis (MN) by a γ-counter. The uptakes of 64CuL1 in necrotic liver and muscle were higher than those in normal liver and muscle ( P < 0.05). Then, the ability of GdL1 to assess therapeutic response was tested on rats bearing Walker 256 breast carcinoma injected with a vascular disrupting agent CA4P by MR imaging. The signal intensity of tumoral necrosis was strongly enhanced, and the contrast ratio between necrotic and viable tumor was 1.63 ± 0.11 at 3 h after administration of GdL1. Besides, exposed DNA in necrosis cells may be an important mechanism of three probes targeting to necrosis cells. In summary, GdL1 may serve as a promising MRI contrast agent for accurate assessment of treatment response.

A base-mediated [2 + 4] annulation of in situ formed azaoxyallyl cations with in situ generated aza-oQMs has been realized. This one-pot cycloaddition process assembled the corresponding 1,4-dihydro-2H-benzo[d][1,3]oxazines in moderate to good yields (up to 99% yield).

A [3 + 4] annulation of isatin N, N'-cyclic azomethine imine 1,3-dipole 1 with in situ-generated aza-oQMs has been established for the synthesis of spirooxindole seven-membered scaffolds. These highly functionalized scaffolds were assembled in moderate to good yields (up to 96% yield). The novel spirooxindole scaffolds displayed moderate antitumor activities, which represented promising lead compounds for antitumor drug discovery.

PURPOSE: Rapid noninvasive delineation of necrotic myocardium in ischemic regions is very critical for risk stratification and clinical decision-making but still challenging. This study aimed to evaluate the necrosis avidity of radioiodinated hypocrellins and its potential for rapidly imaging necrotic myocardium. PROCEDURES: The aggregation constants of four natural hypocrellins were analyzed by UV/vis spectroscopy. Then, they were radiolabeled with iodine-131 by iodogen oxidation method. Necrosis avidity of iodine-131-labeled hypocrellins was evaluated in rat models with reperfused liver infarction and muscular necrosis by gamma counting, autoradiography, and histopathology. Their pharmacokinetic properties were examined in normal rats. The potential of iodine-131-labeled hypomycin A ([131I]HD) for early imaging of necrotic myocardium was explored in rat models with reperfused myocardial infarction. Finally, the possible mechanism of necrosis avidity was investigated by in vitro DNA binding and in vivo blocking experiments. RESULTS: The aggregation constants of four hypocrellins were all much smaller than that of hypericin, a most studied necrosis avid agent. The radiochemical purities of the four radiotracers after purification were all greater than 95 %, and more than 90 % of tracers remained intact after incubation in rat serum for 24 h. Among the four tracers, [131I]HD exhibited the highest necrotic to viable tissue uptake ratio and the fastest blood clearance. The necrotic myocardium could be clearly visualized 4 h after injection of [131I]HD by single-photon emission computed tomography/X-ray computed tomography (SPECT/CT). DNA binding studies suggested that HD could bind to DNA through intercalation. Blocking studies demonstrated that uptake of [131I]HD in necrotic muscle could be significantly blocked by excess unlabeled HD and ethidium bromide with 67 and 60 % decline at 6 h after coinjection, respectively. CONCLUSIONS: [131I]HD can be used to rapidly visualize necrotic myocardium. The necrosis avidity mechanism of [131I]HD may be attributed to its binding to the exposed DNA in necrotic tissues. ispartof: Molecular Imaging and Biology vol:20 issue:4 pages:551-561 ispartof: location:United States status: published