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2017  Vol. 48  No. 3

Abstract:
Arterial thrombosis(AT)is a common disease which usually causes acute myocardial infarction, ischemic stroke and other ischemic cardiovascular and cerebrovascular diseases, which shows high rates of morbidity and mortality, and has become a serious problem to human health. It is increasingly clear that the interactions among platelets, the endothelium and leukocytes are important throughout all stages of the atherothrombotic process. It is of great significance to search for therapeutic targets in the process of AT and developing the therapeutic drugs based on those newly discovered targets. This article reviews the research advances in the discovery of antithrombotic targets and the current situation of drug development based on those antithrombotic targets found in the recent 5 years, in order to provide some references or clues for the development of innovative drugs to prevent and treat AT.
Abstract:
Glucose-sensitive materials have attracted much interest due to their potential application in diabetes treatment in recent years. Phenylboronic acid-based glucose-responsive polymers, which possess continuous glucose sensitivity and good stability, have been most widely used in self-regulated insulin delivery. This review covers the recent advances in PBA-functionalized nanogels(microgels), micelles, vesicles and nanoparticles. Synthesis and application of these nanomaterials are discussed. With the development of PBA-regulated polymers, these nanomaterials will migrate from laboratory to clinical use in the near future.
Abstract:
Polyethylene glycol(PEG)with good hydrophilicity and flexibility can improve pharmacokinetic and pharmacodynamic properties of the nano-preparation, so PEG modification in the surface of nano-preparation can increase the in vivo residence time and concentration of drugs. At present, the targeted nano-preparation with PEG modification has become a research hotspot in the field of pharmaceutics. In this paper, the physical and chemical methods of PEG modification in targeted nano-preparation was summarized, which includes physically inserting PEG-lipid derivatives in nanostructure of targeted nano-preparation or modifying PEG with targeted nano-preparation. In addition, the influence of PEG parameters(molecular mass, modified density and spatial conformation)on properties of targeted nano-preparation was also discussed, which is important to preferably structure PEGylated targeted nano-preparation.
Abstract:
5-(4-Hydroxyphenyl)-3H-1, 2-dithiole-3-thione(ADT-OH)is a slowly releasing H2S donor with some neuroprotective effect. In order to study the structure-activity relationships, seventeen compounds( Y1 - Y17 )were synthesized by modification of ADT-OH at the aromatic ring position, and their structures were confirmed by 1H NMR, 13C NMR and HR-MS. Among them, 6 compounds( Y4, Y13 - Y17 )were novel compounds. Their effects had been evaluated on HT-22 hippocampal neuron cells damaged by glutamate with MTT method. The pharmacological results demonstrated that all the Y compounds had potent neuroprotection at most of the tested concentrations(1-100 μmol/L). Compounds Y1 - Y9 and Y11 significantly improved the survival rates of the damaged cells at 1-100 μmol/L(P<0. 01). Specially, compounds Y1, Y4, Y6 - Y9, Y11 are more potent than their parent compound ADT-OH at concentration of 1-10 μmol/L, which is worthy of further study.
Abstract:
The purpose of this study was to synthesize and evaluate the necrosis target of MRI contrast agent based on rhein. The novel ligand 10-{[6-(1, 8-dihydroxyanthraquinone-3-carboxamido)hexyl]amino}acetyl-1, 4, 7, 10-tetraazacyclododecan-1, 4, 7-triacetic acid(DO3A-rhein)was synthesized by two-step acylation and two-step deprotection. The paramagnetic contrast agent gadolinium 10-{[6-(1, 8-dihydroxyanthraquinone-3-carboxamido)hexyl]amino} acetyl-1, 4, 7, 10-tetraazacyclododecan-1, 4, 7-triacetate(Gd-DO3A-rhein)was obtained by coordination of Gd3+ with the synthesized ligand. Its necrosis affinity was evaluated by liver infarction and muscular necrosis on rat models. The MRI was performed before administration of Gd-DO3A-rhein and during 0 h to 12 h after administration of Gd-DO3A-rhein(0. 1 mmol/kg), respectively, and Gd-DOTA was used as control. After MRI scanning, rats were sacrificed and necrotic tissues were stained using triphenyltetrazolium chloride(TTC)and hematoxylin-eosin(HE). MRI images of liver infarction and muscular necrosis on rat models showed significantly enhanced signal intensity compared with normal tissues. The contrast ratios of necrotic liver/normal liver were 1. 61±0. 14 and 2. 36±0. 20 at 3 h and 12 h postinjection of Gd-DO3A-rhein(0. 1 mmol/kg)respectively, demonstrating a significant difference compared with pre-administration of Gd-DO3A-rhein(1. 16±0. 10; P<0. 05). The same results were obtained from necrotic muscles. These findings suggested that Gd-DO3A-rhein possessed the necrosis target and imaging capability of necrotic tissues.
Abstract:
The aim of this study was to synthesize 1-(5-(hydroxymethyl)-4-methyl-3-oxo-3, 4-dihydro-pyrazin-2-yl)guanidine(mucunaguanide), a pyrazinone alkaloid compound extracted from the seed of Stizotobium cochinchinensis. Starting from benzyloxy acetaldehyde, following four steps in reaction including condensation, cyclization, substitution and hydrogenation reaction, mucunaguanide was synthesized with total yield of 27. 9%, and purity of more than 97. 5%. Structures of all the intermediates and target compound were confirmed by IR, 1H NMR and MS. This synthetic process was characterized with raw materials available, simple in operation with much milder reaction conditions, and was an ideal method of synthesis of this compound.
Abstract:
A five-step synthetic method of ambrisentan starting from benzophenone was developed. The reaction methods of resolution and substitution were optimized. A stable, facilitating method of detection and efficient resolution reagent, L-phenylglycinamide, was used and helped to obtain highly optical pure intermediates. In the substitution reaction, NaOH was chosen as the base, which is safe and suitable for the industry. This method was mild, easily operated with a total yield up to 31. 0%, and may have a good application prospect.
Abstract:
The aim of the present study was to increase distribution of yuanhuacine in the lungs and achieve the purpose of reducing toxicity and increasing efficiency. Therefore, yuanhuacine was designed to be dry powder inhalers innovatively and directly delivered to the lungs. Accordingly, inhaled lactose was used as a carrier to adsorb yuanhuacine on the surface of lactose. Fine particle fraction(FPF)was utilized as evaluation index to filtrate the optimal prescription for pulmonary administration. Besides, an UHPLC-MS/MS method was established for the analysis of heart, liver, spleen, lung, kidney, brain and reproductive system of rats. Intravenous injection was taken as reference to investigate the distribution of yuanhuacine and calculate relevant targeting parameters. The experimental result indicated that the prescription(rough lactose ∶fine lactose=10 ∶1)has the highest FPF, which can be chosen as the most suitable prescription for pulmonary administration of yuanhuacine. Moreover, by comparing the distribution of yuanhuacine through pulmonary administration and intravenous injection, it was found that the concentration of yuanhuacine in the lung tissue was greatly increased by pulmonary administration, which decreased the distribution in heart, liver, spleen, kidney, brain and reproductive system, thus sequentially reducing the toxicity in other tissues and increased the efficiency.
Abstract:
In order to construct a novel multifunctional targeting nano-carrier based on pH-redox characteristics of tumor microenvironment, ketone bonds and disulfide bonds were bonded to the oligomeric hyaluronic acid(oHA)being sensitive to pH and the reduction environment. The chemical structure of oligomeric hyaluronic acid-8-mercaptomenthone 1, 2-glycerolketal(oHMST)was characterized by 1H NMR, IR and ESI-MS. Curcumin-loaded micelles were prepared by dialysis. The single factor investigation was carried out on the dosage form. Some properties, including particle size zeta potential, the morphology of micelles, and pH-sensitivity were studied. The materials were synthesized successfully. The micelles were spheric with a diameter of about 100 nm. The Zeta potential of the micelles was -(21. 97±1. 08)mV. The in vitro test showed that oHMST carriers have good pH-sensitivity and redox-sensitivity.
Abstract:
The water-soluble 3-mercaptopropionic acid(MPA)-stabilized CdTe(MPA-CdTe)quantum dots(QDs)were synthesized by aqueous suspension. The study showed that the fluorescence quenching process of Cu2+ to MPA-CdTe QDs, whose largest emission peak was 599 nm, could be described well by the theory of fluorescence quenching in competitive absorption systems and its modification of Stern-Volmer equations. By fittings, the results showed a good polynomial relationship between the fluorescence intensity F0/F and the concentration of Cu2+, when the concentration was in the range of 2. 28×10-6-18. 24×10-6 mol/L and 4. 8×10-7-12×10-7mol/L, and two polynomial equations were respectively elucidated based on dynamic and static quenching in competitive-absorption systems: F0/F=7. 999-2. 470c +0. 339 c2, F0/F=3. 154-0. 160 c+0. 049 c2 and degree of fitting are 0. 991 and 0. 993, respectively. The detection limit was 1. 326×10-7.
Abstract:
An RP-HPLC method was established to separate the related substances of benzyl hydroxybenzoate. The separation was carried out on a Agilent ZORBAX Eclipse Plus Phenyl-Hexyl column. The mobile phase was methonal-0. 1% glacial acetic acid, using linear gradient elution, and the detection wavelength was 254 nm. There was a good linear relationship between 0. 051-101. 88 μg/mL(r=1. 00)and 0. 050-99. 48 μg/mL(r=0. 999 8)for benzyl hydroxybenzoate and p-hydroxybenzoic acid, repectively. The average recovery of p-hydroxybenzoic acid was 100. 3% and the RSD was 0. 95%. The LOQ of p-hydroxybenzoic acid was 0. 24 ng. The detected impurities were also identified by UPLC-Q-TOF. The established method is accurate and reproducible, and could be used for the quality control of benzyl hydroxybenzoate.
Abstract:
To establish an HPLC method to determine osimertinib mesylate, Agilent ZORBAX Eclipse Plus C18 column(4. 6 mm × 250 mm, 5 μm)was used with a mobile phase consisting of methanol-buffer solution(20 mmol/L NaH2PO4, pH 3. 0 adjusted with 85% H3PO4)(50 ∶50)at the flow rate of 1. 0 mL/min. The detection wavelength was 210 nm, and the column temperature was kept at 35 ℃. The calibration curve was liner over the range from 50% to 150% of determination concentration(0. 201 1- 0. 603 2 mg/mL, r=0. 999 9). The limit of quantitation(LOQ)and limit of detection(LOD)were 0. 32 μg/mL and 0. 08 μg/mL, respectively. The contents of osimertinib mesylate in samples were 100. 1%, 99. 5% and 99. 7%. Good chromatographic separation of osimertinib mesylate and its related substances, including synthetic impurities and degradation products, were obtained. The established HPLC method is specific, accurate, simple and durable, and could be used for the determination of osimertinib mesylate.
Abstract:
The effect of realgar nanoparticles(NPs)on endogenous small molecules in rat kidney was analyzed by mass spectrometry-based metabolomics. The relationship between the changes of metabolites and the nephrotoxicity of realgar NPs was also discussed to provide a basis for the further toxicity study and the clinical application of realgar NPs. SD rats were randomly divided into seven groups, including control group, three doses(40, 200, 1 000 mg/kg)of relegar and realgar NPs groups, respectly. After 28 days of continuous intragastric administration, all rats were sacrificed and their serum and kidney samples were collected. The toxic effect of realgar NPs on kidney tissues were examined by biochemical analysis and histopathologic examination, which revealed a dose-dependent nephrotoxicity induced by realgar NPs. The LC-MS and GC-MS analysis were performed for the subsequent metabolomics study. A series of 32 metabolites were found to be altered significantly in the kindey of realgar NPs treated rats, and might serve as potential nephrotoxicity biomarkers. The results of metabolic pathway analysis indicated that the nephrotoxicity of realgar NPs might be associated with the disorders of the amino acids and phosphatidic acid metabolism.
Abstract:
To investigate the protective effect of the seed oil of Abelmoschus esculentus on gastric ulcer, two acute gastric ulcer mice models were established by intragastric administration of aspirin or absolute ethanol, respectively. Clinical index of ulcer area, ulcer index, gastric volume, gastric pH value, free acidity, total acidity, and histopathological assessment were measured to evaluate the injuries of gastric ulcer and the protective effect of okra seed oil. In order to comprehensively uncover the possible underlying mechanism, a series of biochemical assays were also performed, including serum TNF-α, IL-6, IL-10 and Tbil, NO, MPO and SOD in the stomach included. Moreover, the ALT, AST and ALP in the liver of mice were also tested to evaluate the possible hepatic toxicity of the seed oil. The results indicated that the seed oil of A. esculentus exerted protective effect in ethanol-induced gastric ulcer mice by reducing the ulcer area and ulcer index, declining the free and total acidity, and increasing the pH value of gastric content. Histopathological observation showed the gastric mucosa of the acute gastric ulcer mice induced by alcohol was incomplete and severely damaged, with submucosal edema and nuclear pyknosis, as well as glandular structure disappearing, compared with that of normal mice. What′s more, a number of inflammatory cell infiltration occured in the gastric mucosa of alcohol-model mice, with messes of neutrophils, lymphocytes, eosinophils and plasma cells. Okra seed oil could improve the damaged structure of the gastric mucosa and gland caused by ethanol, but could not ameliorate the condensation of nucleus and infiltration of inflammatory cells. Biochemical analysis revealed that the seed oil of A. esculentus could counteract the damage induced by ethanol via decreasing Tbil and TNF-α in serum, decreasing NO and myeloperoxidase, and increasing SOD in stomach. Meanwhile, okra seed oil exhibited protective effect in aspirin-induced gastric ulcer mice by increasing the gastric content pH, and reducing free and total acidity. Compared with the control group, the gastric mucosa of aspirin-model group showed multifocal coagulation necrosis, sheet edema and infiltration of inflammatory cells by histopathological assessment. Compared with the aspirin-model group, the soybean oil group and okra seed oil group could ameliorate the inflammatory cell infiltration. Biochemical analysis revealed that okra seed oil could counteract the injury induced by aspirin via decreasing TNF-α and IL-6, and increasing IL-10 in serum, decreasing NO and MPO and increasing SOD in stomach. In a word, the okra seed oil exerted protective effect on acute gastric ulcer by anti-inflammation, anti-oxidation and hepatocyte protection. The okra seed oil deserves further development and utilization.
Abstract:
The aim of the present study was to investigate the effects and mechanisms of quercetin on plantar incision-induced matrix metalloproteinase(MMP)-9 and MMP-2 activity, microglia activation and the analgesic effect of quercetin on plantar incision surgery-treated mice. Postoperative pain model was mediated by plantar incision surgery and Von Frey Hairs was used to test the mechanical pain threshold. The activity of MMP-9 and MMP-2 in spinal cord was evaluated by gelatin zymography. The marker of microglia ionized calcium binding adapter molecule 1(IBA-1), phosphorylated p38 mitogen-activated protein kinase(p-p38 MAPK)was detected by Western blot. Results showed that quercetin(20, 40, 80 mg/kg, ip)significantly inhibited plantar incision-induced mechanical allodynia and suppressed the activity of MMP-9 and MMP-2 in the spinal cord. Moreover, quercetin also markedly inhibited plantar incision-induced up-regulation of IBA-1 and p-p38 in spinal cord. In conclusion, quercetin may alleviate postoperative pain by suppressing MMP-9 and MMP-2 activity in microglia.
Abstract:
To study the effect of antioxidants R-(+)-lipoic acid(R-LA)on cells growth, proliferation and related mechanisms in human HepG2 cells lines. MTT was used to measure cells growth and proliferation. Reactive oxygen species(ROS)kit was used to analyze ROS level. Cell apoptosis and cell morphological changes were observed by flow cytometry and Hoechst 33258 test. Protein expression levels of apoptosis, autophagy and related pathway were analyzed through Western blot, including Bax, Bcl-2, caspase 3, PARP, ATG5, ATG7, LC3, Beclin1, mTOR, P70S6K, P38, P53, ERK and Akt etc. Results showed that cell growth and proliferation were inhibited in a dose- and time-dependent manner after being treated by lipoic acid. R-LA could increase ROS production, pro-apoptosis proteins Bax levels, activated caspase family and PARP. Meanwhile, R-LA could up-regulate the levels of autophagy-related proteins including ATG5, ATG7, Beclin1 and LC3, and down-regulate phospho-mTOR and P70S6K levels. Signal pathway results showed that R-LA could up-regulate phospho-P38 and phospho-JNK levels, and decrease phospho-Akt and phospho-ERK. When adding 3-methyladenine, autophagy was inhibited. Thus, R-LA might activate autophagy and induce apoptosis by P38/AMPK-JNK, PI3K/AKT and Ras/Raf/MEK/ERK pathways.
Abstract:
In order to solve the difficucties of renaturation and immunogenicity of new bifunctional fusion protein GAD, inclusion bodies of GAD were modified by PEG-maleimide. Conformational changes of the modified GAD were compared by circular dichroism and tryptophan fluorescence spectroscopy. The biological activity was verified by oral glucose tolerance test and lipid scavenging. The results showed that PEG-maleimide completed the specific-point modification of GAD, and improved its refolding efficiency. The secondary and tertiary structures of mPEGylated GAD were consistent with that of GAD. PEG-GAD has significant hypoglycemic and lipid-lowering effects(P<0. 001)with longer half life in vivo and lower immunogenicity(P<0. 01). This study provides effective strategies for the development of strongly hydrophobic peptide drugs.
Abstract:
Indoleamine 2, 3-dioxygenase 1(IDO1)is the rate-limiting enzyme which catalyses the metabolism of L-tryptophan(L-Trp)in the kynurenine pathway. It is overexpressed in many tumor cells and antigen presenting cells. This enzyme inhibits local immune response and supports tumor cells to evade immune surveillance by depleting L-Trp and producing kynurenine metabolites, thus, it is an important target for cancer immunotherapy. There are several IDO1 inhibitors with different scarfold under investigation, three of which have already entered clinical stage. The role of IDO1 in tumor immune tolerance and the research progress on IDO1 inhibitors in recent years are summarized in this paper.
Abstract:
Long non-coding RNA(lncRNA)is a newly identified non-coding RNA subfamily with various regulatory functions. Recent evidence has shown the fundamental role of long noncoding RNAs in affecting the development of diseases at different levels, from gene modification, transcriptional regulation to protein translation. The study on lncRNA has made great progress in the studies of genomic imprinting, cancer diseases and neurodegenerative disorders, while the research relevant to autoimmune diseases has just started recently. However, many lncRNAs have been identified to involve in immune cells proliferation, differentiation and maturation, acting as the key regulators in immune homeostasis and autoimmune diseases. This review is focused on the advances of lncRNA in immune cells and autoimmune diseases.