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Androgen-deprivation therapy (ADT) via targeting androgens/androgen receptor (AR) signals may suppress cell proliferation in both prostate cancer (PCa) and bladder cancer (BCa), yet its impact on the cell invasion of these two urological cancers remains unclear. Here we found targeting androgens/AR with either the recently developed antiandrogen Enzalutamide (Enz) or AR-shRNAs led to increase PCa cell invasion, yet decrease BCa cell invasion. Mechanistic dissection revealed that suppressing androgens/AR signals could result in differential alterations of the selective circular RNAs (circRNAs) as a result of differential endogenous AR transcription. A negative autoregulation in PCa, yet a positive autoregulation in BCa, as a result of differential binding of AR to different androgen-response elements (AREs) and a discriminating histone H3K4 methylation, likely contributes to this outcome between these two urological tumors. Further mechanistic studies indicated that AR-encoded circRNA-ARC1 might sponge/alter the availability of the miRNAs miR-125b-2-3p and/or miR-4736, to impact the metastasis-related PPARγ/MMP-9 signals to alter the PCa vs. BCa cell invasion. The preclinical study using the in vivo mouse model confirms in vitro cell lines data, showing that Enz treatment could increase PCa metastasis, which can be suppressed after suppressing circRNA-ARC1 with sh-circRNA-ARC1. Together, these in vitro/in vivo results demonstrate that antiandrogen therapy with Enz via targeting AR may lead to either increase PCa cell invasion or decrease BCa cell invasion. Targeting these newly identified AR/circRNA-ARC1/miR-125b-2-3p and/or miR-4736/PPARγ/MMP-9 signals may help in the development of new therapies to better suppress the Enz-altered PCa vs. BCa metastasis.

Objective The purpose of the present study is to investigate whether angiopoietin-like 4 (ANGPTL4) can promote angiogenesis and neurogenesis following stroke, as well as to explore the potential underlying mechanisms. Methods ANGPTL4 (40 μg/kg) or a vehicle was administered via tail vein beginning 5 min prior to electrocoagulation-induced stroke in male C57/B6 J mice. Infarct volume was measured via Nissl staining at day 3 post-stroke. Angiogenesis, neurogenesis and activation of microglia were evaluated by immunofluorescence co-labelling bromodeoxyuridine (BrdU) with von Willebrand factor (vWF), doublecortin (DCX), neuronal nuclei (NeuN) and Iba1 at day 7 post-stroke. The levels of p-AKT, T-AKT, VEGF, MPO, Fas and FasL in the ipsilesional brain were detected by Western blot analysis at day 1 post-stroke. Results Compared with the Vehicle group, ANGPTL4 reduced infarct volume significantly at day 3 post-stroke. ANGPTL4 significantly increased the number of BrdU+, BrdU+/vWF+and BrdU+/DCX+ cells in the peri-infarct zone, subventricular zone and subgranular zone and inhibited BrdU+/Iba1+ cells in the peri-infarct zone at day 7 post-stroke. The level of p-AKT and the ratio of phospho-AKT to total-AKT in the ipsilesional brain were significantly elevated, the levels of MPO, Fas and FasL were significantly declined; however, there was no significant difference at day 1 post-stroke between the VEGF and total-AKT levels in both groups. Conclusions ANGPTL4 enhances angiogenesis and neurogenesis post-stroke by upregulating the phosphorylation of AKT, reduces neuronal death and inhibits inflammatory response, which resultes from the inhibition of FasL/Fas expression and its downstream pathway.

Light is an important variable affecting the plant growth. In present study, the effects of different color light-emitting diodes (mixed colors, red, blue, and orange light) on plant growth, gas exchange, and oxidative stress were investigated in Boehmeria nivea L., by means of measuring growth, photosynthesis, chlorophyll (Chl) content, reactive oxygen species (ROS), and activity of antioxidant enzymes under controlled conditions. Comparing to the mixed colors light, red light significantly increased shoot and leaf biomass, plant height, number of leaves per plant, and stem diameter by increasing the Chl content and therefore promoting the highest photosynthetic capacity. This might partially be explained by the decrease of malondialdehyde and proline contents as well as the activities of superoxide dismutase and peroxidase under red light, to keep a better internal environment of the cell. However, blue and orange light decreased plant growth, and increased the activities of antioxidant enzymes which suggest an environmental stress on plants. These results suggest that red light can enhance B. nivea growth by activating photosynthesis and reducing ROS accumulation.

Background: The paper aimed to determine whether Tripchlorolide can exert anti-fibrotic effects by up-regulating Sufu to influence the Hedgehog signaling pathway, and to promote the application of Tripchlorolide in diseases associated with the Hedgehog signaling pathway. Material and Methods: In vivo experiment, bronchoalveolar lavage was performed on the 7th day after intratracheal instillation of bleomycin. The number of inflammatory cells and IL-6 levels were analyzed to observe the anti-inflammatory effect of Tripchlorolide. The lung tissues were obtained on the 14th day. The lung tissue injury was observed, and the expressions of a-SMA, collagen I, TGF-β i, Gli 1 and Sufu were determined. In vitro experiments, mouse lung was transfected with lentivirus to make fibroblasts. The Sufii was overexpressed, the changes in Gli 1 and Gli 2 levels were observed. The effects of the overexpressed Sufti of on the phenotype transformed a-SMA and collagen I levels in TGF-β 1 induced mouse lung fibroblasts were observed. Results: After administration with bleomycin, IL-6 level, total number of cells, neutrophils and macrophages in BALF of the Tripchlorolide group mice were reduced. The lung injury score, the expressions of lung tissue TGF-βl, a-SMA and Collagen I were low. The expression of Sufu was high, while the expression of Gli 1 was low. Compared with the groups in which cells were not transfected with lentivirus, the expression of Sufu in the transfected cells increased, and the expressions of Gli 1 and Gli 2 decreased. After stimulation with TGF-β Sufu decreased. Conclusion: Tripchlorolide can inhibit Hedgehog signaling pathway by up-regulating Sufu to exert an anti-fibrotic effect.

Through its impact on morphogenesis, light is the key environmental factor that alters plant structural development; however, the understanding how light controls plant growth and developmental processes is still poor and needs further research. For this purpose, a Petri dish and pot experiment was conducted to investigate the effects of different LEDs, i.e., white light (WL), red light (RL), blue light (BL), and orange light (OL) on morphology, gas-exchange parameters, and antioxidant capacity of Brassica napus. Compared with WL, RL significantly promoted plant growth and biomass, contents of photosynthetic pigments, and gas-exchange parameters in comparison to BL and OL. However, RL also helped decline malondialdehyde and proline contents and superoxide anion and peroxide production rate. In contrast, BL and OL significantly reduced plant growth and biomass, gas-exchange attributes and increased the activities of superoxide dismutase and peroxidase in Petri dish as well as in pot experiment. These results suggest that red light could improve plant growth in B. napus plants through activating gas-exchange attributes, reduce reactive oxygen species accumulation, and promote antioxidant capacity.

Gynura japonica (also named Tusanqi in Chinese) is used as a folk herbal medicine for treating blood stasis or traumatic injury. However, hundreds of hepatic sinusoidal obstruction syndrome (HSOS) cases have been reported after consumption of preparations made from G. japonica because it contains large amounts of hepatotoxic pyrrolizidine alkaloids (PAs). To date, blood pyrrole-protein adducts (PPAs) are suggested as biomarkers for the diagnosis of PA-induced HSOS in clinics. However, the concentration of PPAs in the blood is greatly affected by several factors including the amount of PA exposure, herb intake period, and blood sampling time after the last exposure. In present study, the kinetic characters of PPAs in serum and liver as well as other potential target organs were studied systematically and comprehensively following multiple exposures of PAs in G. japonica extract (GJE). As results, PPAs content reached to a plateau both in serum and liver after the mice were treated with GJE for 2 weeks on daily basis. PPAs cleared significantly slower in liver (T1/2ke∼184.6 h, ∼7.7 days) than in serum (T1/2ke∼95.8 h, ∼4.0 days). Although more than 90 % PPAs were removed 2 weeks after the last dosing, PPAs still persisted in the liver until the end of the experiment, i.e. 8 weeks after the last dosing. The results would be of great help for understanding the importance of PPAs for PA-induced toxicity and its detoxification.

Breast cancer is the most common type of cancer in women. About 12% of all women in the United States will be diagnosed with breast cancer over their lifetimes. At the same time, incidences of brain metastases (BMs) are increasing and represent an emerging health threat. However, there is no effective chemotherapy for breast cancer brain metastases (BCBMs), which is largely due to lack of efficient delivery of antitumor drugs or drug combinations to the brain. In this study, oleanolic acid (OA), a natural pentacyclic triterpenoid compound with excellent antitumor activity, was found to form nanoparticles (NPs) and efficiently penetrate the brain for BCBMs treatment. On the basis of these findings, we developed a synergistic combinatorial chemotherapeutic regimen by formulating paclitaxel (PTX) into OA NPs and demonstrated that the resulting PTX-OA NPs effectively inhibited primary breast cancer and BCBMs in mouse xenografts. Collectively, this study introduces a new direction to treat primary breast cancer and BCBMs through noninvasive combination chemotherapy.

Hemp is a multipurpose crop that is cultivated worldwide for fiber, oil, and cannabinoids. Nitrogen (N) is a key factor for getting a higher production of hemp, but its application is often excessive and results in considerable losses in the soil–plant–water continuum. Therefore, a rational N supply is important for increasing N efficiency and crop productivity. The main objective of this paper was to determine the responses of four hemp cultivars to different levels of exogenous-N supply as nutrient solution during the vegetative growing period. The experiment was conducted at Yunnan University in Kunming, China. Yunma 1, Yunma 7, Bamahuoma, and Wanma 1 were used as the experimental materials, and five N supplying levels (1.5, 3.0, 6.0, 12.0, and 24.0 mmol/L NO3-N in the nutrient solution) were set by using pot culture and adding nutrient solution. The root, stem, and leaf of the plant were sampled for the determination of growth indexes, dry matter and N accumulation and distribution, and physiological indicators. The plant height, stem diameter, plant dry weight, and plant N accumulation of four hemp cultivars were significantly increased with the increase in exogenous-N supply. Root/shoot dry weight ratios, stem mass density, and N use efficiency decreased significantly with the increase in exogenous-N supply. Nitrogen accumulation, chlorophyll content, soluble protein content, and nitrate reductase activity in leaves were increased with the increase in exogenous-N supply. Among the four indexes, the increase in N accumulation was more than the increase in NR activity. The activities of superoxide dismutase and peroxidase in leaves were increased first and then decreased with the increase in exogenous-N supply, with the maximum value at N 6.0 mmol/L, while the content of malondialdehyde in leaves increased significantly when the level of exogenous-N supply exceeded 6.0 mmol/L. These results revealed that increasing the exogenous-N supply could improve the plant growth, dry matter accumulation, and N accumulation in hemp during the vegetative growth period, but N supply should not exceed 6.0 mmol/L. Among four hemp cultivars, Wanma 1 performed well at 6.0 mmol/L N application.

Background: Several β-carboline alkaloids (βCBs), harmine, harmaline, harmane, and nor-harmane, are effective for Alzheimer’s disease (AD) model mice. They were discovered in some plants, common foodstuffs, and in blank plasma of various mammals. However, whether these compounds in mammals are exogenous or endogenous remained unclear. The exposure levels of these βCBs in plasma and tissues of pup rats, aging rats and volunteer were detected by UPLC-MS/MS.Result: Results showed that harmine was the main compound found in rats, mice, human, and even in newborn rats without consumption. The changes of harmine concentration showed a high dependence with growth (aging), gender and race. And the concentration of harmine in rat plasma showed a decreasing trend during the growth period of 18 months. Conclusion: These results revealed that harmine may be relevant to AD. The exposure level of harmine in plasma indicate that in addition to exogenous ingestion, spontaneous synthesis might be another important source of harmine in mammals.

The goal of this study was to explore the regulatory mechanisms of phenyllactic acid (PLA) overaccumulation in Lactobacillus plantarum. The dynamics of PLA production revealed that 24 h was a suitable fermentation time, at which one of the largest differences in PLA content between strains S1 and YM-4-3 was 22.42 mg/L. Additionally, an optimization experiment showed that PLA production under the optimal condition (sample YM-4-3y) was up to 400.74 mg/L, 7.61-13.26 times as those of YM-4-3 and S1. Subsequently, an integrated analysis of genomic, transcriptomic and metabolomic data revealed that, YM-4-3 and YM-4-3y, compared with S1, although lacking a complete de novo biosynthetic pathway, increased PLA production by strengthening the core pathway and central carbon metabolism, and weakening the biosynthesis pathway of amino acids and their derivatives. These changes can provide sufficient precursors and compensate for or balance the energy consumed by the reinforced core pathway.

Context Fruit of Avicennia marina (Forsk.) Vierh. (Acanthaceae) is used as a Chinese herb. Studies have found that it contains marinoid J, a novel phenylethanoid glycoside (PG) compound, but its neuroprotective functions are largely unknown. Objective This study evaluated the effects of marinoid J on vascular dementia (VD) and determined its potential mechanisms of action. Materials and methods The VD model was established by the ligation of the bilateral common carotid artery in Sprague–Dawley rats, who received daily intragastrically administration of saline, marinoid J (125 or 500 mg/kg body weight/d), or oxiracetam (250 mg/kg body weight/d) for 14 days (20 rats in each group). The Morris water maze (MWM) was used to evaluate cognitive performance. The hippocampus was subjected to histological and proteomic analyses. Results Marinoid J shortened the escape latency of VD rats (31.07 ± 3.74 s, p

Background Icariin is a major component isolated from Epimedium brevicornum Maxim and has been reported to exhibit anti-tumor activity. However, whether icariin could reverse the acquired drug resistance in breast cancer remains largely unclear. Therefore, this study was designed to explore the antitumor effects of icariin and its underlying mechanisms in a tamoxifen-resistant breast cancer cell line MCF-7/TAM. Methods 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Lactate dehydrogenase (LDH) assay were performed to determine the effects of icariin on cell viability and cell death. Cell cycle progression and apoptosis were detected by flow cytometry analysis. Transmission electron microscopy (TEM) assay was utilized to observe cell autophagy. The downstream protein levels were measured using western blotting. Results Here, we observed that icariin treatment not only inhibited the growth of MCF-7 but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Moreover, icariin significantly induced cell cycle G0/G1 phase arrest and apoptosis, as well as suppressed autophagy. At molecular levels, icariin treatment remarkably down-regulated the expression levels of CDK2, CDK4, Cyclin D1, Bcl-2, LC3-1, LC3-II, AGT5, Beclin-1, but upregulated the expression levels of caspase-3, PARP and p62. Most importantly, we found inhibition of autophagy via 3-MA treatment could significantly enhance the effects of icariin on cell viability and apoptosis. Enhanced autophagy via autophagy related 5 (ATG5) overexpression could partially reverse the effects of icariin on cell viability and apoptosis. Conclusion These results revealed that icariin might potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen through suppression of autophagy in vitro and provide insight into the therapeutic potential of icariin for the treatment of chemo-resistant breast cancer.

Ethnopharmacological relevance Aerial parts of Peganum harmala Linn are a Uighur traditional medicinal herb in China used to treat amnesia, bronchial asthma, and cough. Deoxyvasicine (DVAS), a potent cholinesterase inhibitor exhibiting anti-senile dementia activity, is one of the chief active ingredients in aerial parts of P. harmala and plays a key role in mediating the pharmacological effects of P. harmala. However, the metabolic profiling and in vivo pharmacokinetic characteristics of DVAS still remain unknown. Aim of the study The aim of this present study was to investigate the metabolism and pharmacokinetic properties of DVAS in rats by using ultra-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-QTOF-MS) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS) method. Materials and methods The metabolic profiling of DVAS was evaluated in vitro and in vivo by rat liver microsomes (RLMs) incubation and by rat bio-specimens, such as urine, feces, plasma, and bile, after the oral administration of 45 mg/kg DVAS. An efficient and sensitive UPLC-ESI-MS/MS method was developed and validated to simultaneously determine DVAS and its major four metabolites, namely, vasicine, deoxyvasicinone, vasicinone, and 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-3-β-D-glucuronide in rat plasma. For pharmacokinetic studies, 32 Sprague-Dawley rats were randomly divided into four groups, namely, intravenous dosage group (2 mg/kg DVAS) and three oral dosage groups (5, 15, and 45 mg/kg DVAS). In addition, the activity of the components in plasma after intravenous administration of DVAS was evaluated by in vitro anti-butyrylcholinesterase (BChE) assays. Results A total of 23 metabolites were found in RLMs, plasma, urine, feces, and bile by UPLC-ESI-QTOF-MS. The metabolic pathway of DVAS in vivo and in vitro mainly involved hydroxylation, dehydrogenation, acetylation, methylation, glucuronidation, and O-sulphate conjugation, and the C-3 and C-9 sites were the main metabolic soft spots. All 23 metabolites were detected in the urine sample, and 13, 8, 22, and 6 metabolites were identified from rat feces, plasma, bile, and RLMs, respectively. The standard curves of DVAS and four metabolites in rat plasma showed good linearity in the concentration range of 0.82–524.00 ng/mL with acceptable selectivity, precision, accuracy, recovery, and stability. DVAS exhibited linear dose-proportional pharmacokinetics at doses of 5, 15, and 45 mg/kg after oral administration, and the average oral absolute bioavailability of DVAS was 47.46%. The in vitro anti-BChE assays implied that the inhibitive activities were mainly due to the different concentrations of prototype DVAS. Conclusions DVAS can be rapidly absorbed and excreted by blood, and it is also extensively metabolized in vivo, and the anti-BChE activity in blood is mainly attributed to DVAS. These findings can lay a foundation for new drug development for DVAS.

High-performance adsorbents are central to the effective removal of heavy metal ions from aqueous media by adsorption. In this study, novel carboxylate-functionalized hollow polymer nanoparticles (HPPs-COO-) were used to remove Cu(II) from aqueous media. The FT-IR, XPS and EDS results demonstrated that the complexation of Cu(II) with the carboxylate group was in a bidentate bridging form. The optimal pH for adsorption was 5.0, and the adsorption behavior could be described by the Langmuir isotherm and pseudo-second-order kinetics model. HPPs-COO- had a comparable adsorption capacity (145.14 mg/g) with other reported polymeric adsorbents. In addition, the adsorption equilibrium of Cu(II) onto HPPs-COO- could be achieved within 1 min. The superfast adsorption rate allowed the quick removal of Cu (II) from the wastewater, and definitely reduced the operating cost. The application of HPPs-COO- in the treatment of real wastewater showed that not only the main contaminant Cu(II), but other toxic heavy metal ions Ni(II) and Pb(II) in the wastewater could be effectively removed. Additionally, HPPs-COO- exhibited a good reusability in the treatment of the wastewater. The above results revealed that HPPs-COO- had a bright prospect in the application of the wastewater treatment.

CO2-expanded ethanol (CXE) has been proposed as an ideal green medium for performing natural products extractions and chemical reactions. However, its systematic complexity concerning vapor-liquid equilibrium (VLE) in extractions is not favorable to the industrial application. In this study, the isothermal binary system was theoretically split into three phase regions in consideration of the state of CO2 as well as the phasic behaviors. In different phase regions, the lipid extractions from microalgae were investigated, showing that subcritical CO2-expanded ethanol in one phase region exhibited higher solubility of lipids, with the maximum recovery approaching 25.0%(w/w), basically equivalent to the complete extraction with organic solvent. Meanwhile, subcritical CXE extracted 15.6 mg of lipids per milliliter of ethanol, significantly higher than 3–6 mg lipids per milliliter of other organic solvent, suggesting more efficient process than other methods. Compared with the conventional products, CXE extracts presented the higher DHA content, 41.92%(w/w) as well as the larger antioxidant capacity (IC50 of 2.49 mg/mL). This study revealed the necessity of the consideration of key factors such as phase equilibrium during employing CXE for the extraction of oxidizable or thermolabile products.

Hemp (Cannabis sativa L.) cultivars Yunma 5 (YM5, fiber-type) and Bamahuoma (BM, seed-type) were seriously affected by salt-alkali stress during germination, while the knowledge about the salt tolerance during seedling stage is deficient. Here, responses of hemp (Cannabis sativa L.) seedlings of the cultivars YM5 and BM to the stress of different concentrations of NaCl and Na2CO3 were investigated to explore the salt tolerance of hemp. Results showed that the plant height, dry weight and root length of YM5 and BM seedlings gradually decreased as the concentration of NaCl or Na2CO3 increased. Although physiological indices such as EC (Electrical conductivity), SOD (Superoxide dismutase) and Pro (Proline) increased as the salt concentration increased, the increase extent was significantly greater in YM5 than in BM. Under the conditions of 100 and 200 mM NaCl, BM had greater dry weight and root length, and lower Pro content than YM5. However, under the stress of 100 and 200 mM Na2CO3, the opposite results were recorded, with the exception for lower chlorophyll content and higher SOD activity in BM than in YM5. These findings indicated that BM had a stronger NaCl tolerance than YM5. Moreover, morphological indices of the two cultivars under Na2CO3 stress were stunted more than under NaCl stress, and the seedlings died when Na2CO3 concentration increased up to 300 mM. Some up-regulation of salt-tolerant genes were observed in the two hemp cultivars, a higher expression under NaCl stress than under Na2CO3 stress, and a higher expression in YM5 than in BM were recorded. Findings from the study indicated that hemp seedling is more sensitive to Na2CO3 stress, and the tolerance of hemp to salt stress varies with salt type and salt concentration, although both cultivars can withstand moderate doses of NaCl and Na2CO3.

Purpose To construct the albumin-bilirubin (ALBI) grade and the Child-Turcotte-Pugh (CTP) score based on nomograms, as well as to develop an artificial neural network (ANN) to compare the prognostic performance of the 2 scores for hepatocellular carcinoma (HCC) that has undergone transarterial chemoembolization. Materials and Methods This multicentric retrospective study included patients with HCC who underwent transarterial chemoembolization monotherapy as an initial treatment at 4 institutions between January 2008 and December 2016. In the training cohort, significant risk factors associated with overall survival (OS) were identified by univariate and multivariate analyses. The prognostic nomograms and ANN were established and then validated in 2 validation cohorts. Results A total of 838 patients (548, 115, and 175 in the training cohort and validation cohorts 1 and 2, respectively) were included. The median OS was 10.4, 15.7, and 9.2 months in the training cohort and validation cohorts 1 and 2, respectively. In the training cohort, both ALBI grade and CTP score were identified as significant risk factors. The ALBI grade and CTP score based on nomograms were established separately and showed similar prognostic performance when assessed externally in validation cohorts (C-index in validation cohort 1: 0.823 vs 0.802, P = .417; in validation cohort 2: 0.716 vs 0.729, P = .793). ANN showed that ALBI grade had higher importance on survival prediction than CTP score. Conclusions ALBI grade performs at least no worse than CTP score regarding survival prediction for HCC receiving transarterial chemoembolization. Considering the easy application, ALBI grade has the potential to be regarded as an alternative to CTP score.

Stroke is a deadly disease without effective pharmacotherapies, which is due to two major reasons. First, most therapeutics cannot efficiently penetrate the brain. Second, single agent pharmacotherapy may be insufficient and effective treatment of stroke requires targeting multiple complementary targets. Here, we set to develop single component, multifunctional nanoparticles (NPs) for targeted delivery of glyburide to the brain for stroke treatment. Methods: To characterize the brain penetrability, we radiolabeled glyburide, intravenously administered it to stroke- bearing mice, and determined its accumulation in the brain using positron emission tomography-computed tomography (PET/CT). To identify functional nanomaterials to improve drug delivery to the brain, we developed a chemical extraction approach and tested it for isolation of nanomaterials from E. ulmoides, a medicinal herb. To assess the therapeutic benefits, we synthesized glyburide-loaded NPs and evaluated them in stroke- bearing mice. Results: We found that glyburide has a limited ability to penetrate the ischemic brain. We identified betulinic acid (BA) capable of forming NPs, which, after intravenous administration, efficiently penetrate the brain and significantly reduce ischemia-induced infarction as an antioxidant agent. We demonstrated that BA NPs enhance delivery of glyburide, leading to therapeutic benefits significantly greater than those achieved by either glyburide or BA NPs. Conclusion: This study suggests a new direction to identify functional nanomaterials and a simple approach to achieving anti-edema and antioxidant combination therapy. The resulting glyburide- loaded BA NPs may be translated into clinical applications to improve clinical management of stroke.

It is challenging to improve the hemocompatibility of commercial dialyzers packaging more than 10,000 fibers. Herein, we report the preparation and evaluation of a self-anticlotting Polysulfone dialyzer via an interface crosslinking approach. By modulating the conformation of sulfate, carboxyl groups and pyrrolidone (VP) in heparin-like polymers, the hemocompatibility of the dialyzer was significantly improved. It was found that the sequential structure of functional groups influenced the anticoagulant performances substantially. The hollow fiber modified by the blended polymer (Poly (N-vinyl-2-pyrrolidone-co-triethoxyvinylsilane) and poly (Sodium 4-vinylbenzenssulfonate-co-triethoxyvinylsilane-co-Acrylic acid) (P(VP-VTES)-b-P(SSNa-VTES-AA))) exhibited better hemocompatibility than the contrast membrane modified by poly (Acrylic acid-co-triethoxyvinylsilane-co -N-vinyl-2-pyrrolidone-co- -co-Sodium 4-vinylbenzenssulfonate) (P(AA-VTES-VP-SSNa)). The chemical composition was determined by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectra (FTIR). The morphology of the hollow fiber membranes was observed by a scanning electron microscopy (SEM). The thrombin time (TT), plasma fibrinogen (FIB), activated partial thromboplastin time (APTT), prothrombin time (PT) and protein adsorption were measured to examine the hemocompatibility. The modified hollow fiber showed self-anticlotting properties with excellent protein resistance, remarkably prolonged coagulation time (APTT > 600 s), suppressed complement activation and nontoxicity to osteoblasts. The modified dialyzer showed practicable ultrafiltration coefficient and clearance performance, indicating its great potential application in dialysis treatment.

The pure-phase BiFeO3 crystals with distinguished micro-morphologies were successfully prepared by a novel coprecipitation-hydrothermal collaborative synthesis method. Hydroxylation technique was innovatively employed to hydroxylate BiFeO3 samples. XPS and PL spectra proved that hydroxylation treatment indeed introduced more ·OH radicals on the surfaces of the BiFeO3 samples. Sample E (hydroxylated BiFeO3 ultra-thin slices) showed the highest photocatalytic activity. Hydroxylated BiFeO3 prepared in this work also showed high activities in water photo-oxidation reactions for producing oxygen gas. All hydroxylated samples showed notably enhanced photocatalytic activities due to the large specific surface areas, strong visible light responses, diminished recombination rates of the photo-excited carriers and excess ·OH radicals introduced by surface hydroxylation. All BiFeO3 samples showed good photochemical stabilities for reusage. This work provides valuable contributions in the future preparations and applications for BiFeO3 photocatalysts.

Dialysis membranes capable of preventing coagulation and inflammation and achieving high toxin clearances are highly desired for clinical hemodialysis. Here, we constructed an electro-neutral and hydrophilic surface on Polysulfone (PSf) membrane, which both improved the hemocompatibility and toxin clearance. The membrane surface was modified with trimethylamine N-oxide (TMAO) through Michael addition reaction and subsequent crosslinking with glycidyl ether oxypropyl trimethoxysilane (KH560). Saltwater fish inspired zwitterionic monomer TMAO without spacers between positive and negative headgroups is thought to generate a hydrated and net-charged layer that prevents non-specific plasma proteins and platelets adsorption and activation. Coagulation time, serine protease Factor XIIa, bradykinin (BK), kallikrein (KLK) and anaphylatoxins (C3, C5 and SC5b-9) were examined to explore blood compatibility. All results showed that the highly hydrated and electro-neutral surface could efficiently alleviate the activation of the coagulation cascade, kallikrein-kinin system (KKS) and complement system simultaneously. Furthermore, the modified PSf membrane is favorable to toxins clearance (e.g., urea, creatine, lysozyme and vitamin B12) during simulated dialysis process. It is manifested that the TMAO based surface modification is feasible for improving the hemocompatibility and toxin clearance of dialysis membranes.

Potassium availability in soil is one of the most important factors affecting the growth and metabolism of industrial hemp, having a major influence on plant growth and crop yield. SWATH proteomics was used to perform differential proteomics on rapidly-growing stems and leaves of a potassium-deficiency resistant (BM) and a potassium deficiency sensitive hemp variety (Y1), under potassium deficiency stress (0.2 mmol/L K+ in irrigation water). The differentially expressed proteins (DEPs) in BM and Y1 were identified through LC-ESI-MS/MS, finding 288 and 353 stem DEPs and 226 and 256 leaf DEPs, respectively. KEGG pathway analysis of the two varieties revealed that the DEPs in Y1 leaf, BM leaf, Y1 stem and BM stem were significantly enriched in 15, three, 11 and four pathways, respectively. Comparison and analysis of the DEPs, revealed that BM adapted to potassium deficiency stress through the following mechanisms: chlorophyll synthesis in both stem and leaf decreased and photosynthesis slowed; stem increased starch metabolism, oxidative stress resistance, lignin metabolism, cell membrane biosynthesis, cell division and ethylene biosynthesis; leaf regulated stomatal closure, enhanced photo-respiration and light energy transfer and activated protein anabolism. These findings provide important reference proteins and genetic information for future molecular study of the highly-efficient absorption of potassium by industrial hemp plants.

An ultrahigh-performance liquid chromatography–tandem mass spectrometry method was developed and validated for the simultaneous determination of sterigmatocystin, verruculogen, enniatin A, ...

Kernel color is an important trait for assessing the commercial and nutritional quality of foxtail millet. Yellow pigment content (YPC) and carotenoid components (lutein and zeaxanthin) of 270 foxtail millet accessions, including 50 landraces and 220 improved cultivars, from four different eco-regions in China were surveyed using spectrophotometry and high performance liquid chromatography methods. Results indicated that YPC had rich variance, ranging from 1.91 to 28.54 mg kg−1, with an average value of 17.80 mg kg−1. The average YPC of improved cultivars (18.31 mg kg−1) was significantly higher than that of landraces (15.51 mg kg−1). The YPC in cultivars from the Loess Plateau spring sowing region (LPSSR) was the highest (20.59 mg kg−1), followed by the North China summer sowing region (NCSSR, 18.25 mg kg−1), the northeast spring sowing region (NSSR, 17.25 mg kg−1), and the Inner Mongolia Plateau spring sowing region (IMPSSR, 13.92 mg kg−1). The variation coefficients of YPC in cultivars from NSSR, LPSSR, and IMPSSR were higher than that from NCSSR. A similar carotenoid profile was also obtained for 270 foxtail millet cultivars. Lutein and zeaxanthin accounted for approximately 55–65% of YPC in accessions. The lutein content was higher than zeaxanthin content in all cultivars. The ratio of lutein to zeaxanthin ranged from 1.51 to 6.06 with an average of 3.34. YPC was positively correlated with lutein (r=0.935, P

The aim of this study is to investigate the effects of a nitric oxide (NO) donor S-nitrosoglutathione (GSNO) on the metabolism and improvement of preservation quality in apheresis platelets. A GSNO solution with a certain concentration was added into fresh apheresis platelets, and the parameters associated with platelet morphology, metabolism and function were temporally monitored for 7 days. The results showed that the NO level in GSNO group were remarkably higher than those in the control group during the whole storage stage. No significant morphology or function difference was observed between the control and GSNO groups such as Platelet count, platelet distribution width, mean platelet volume and mitochondrial metabolic activity. But in metabolism there are something differences from morphology data: pCO2, pO2, cHCO3 − were also found to have no clear difference between the control and GSNO groups; the lactic acid content, sugar consumption and Lactate dehydrogenase activity in the GSNO group were lower than that in the control group at some time point; and pH values in the GSNO group were higher than the control group. Our study discovered that the NO donor GSNO can reduce the metabolism and maintain the cellular characteristics of platelets in vitro during the platelet storage period.

Aqueous two-phase micellar system (ATPMS), as an alternative liquid-liquid extraction technique, has been extensively exploited for the precise separation or large-scale concentration of biomolecules. In this article, a novel affinity-based ATPMS composed of mixed micelles was constructed by introducing a Copper-chelated Triton X-114 (TX-Cu(II)) into an aqueous solution of hydrophobically modified ethylene oxide polymer (HM-EO). Phase diagram of the HM-EO/TX-Cu(II) system was measured, and the partitioning behavior of model proteins (YND, BSA, lysozyme) were studied by using this new system. The addition of HM-EO can result in formation of the micellar network in the micelle-rich phase, making the phase separation easier and stabler. In addition, the extractive performance of ATPMS was enhanced due to the existence of the mixed micelles composed by HM-EO and Cu(II)-chelated TX. It was found in the partitioning experiments that the hexahistidine-tagged Yeast 3',5'-bisphosphate nucleotidase (YND) was selectively extracted into the micelle-rich phase, while the histidine-poor proteins (BSA and lysozyme) remained in the micelle-poor phase. Finally, HM-EO/TX-Cu(II) was used directly to process the fermentation broth. The target protein, YND could be recovered from the cell lysate with a recovery yield of 49.23% and purification factor of 2.63. The results indicated that the new affinity-based HM-EO/TX-Cu(II) system had high partitioning performance which is promising for effectively separation of the histidine-tagged proteins.

Guanosine (GUO) is neuroprotective when administered acutely for the treatment of cerebral ischemia. The aim of the present study was to investigate whether delayed administration of GUO improved long-term functional recovery following stroke, as well as to explore the potential underlying mechanisms. GUO (8 mg/kg) or a vehicle was administered intraperitoneally for 7 consecutive days beginning 24 h prior to photothrombosis-induced stroke in male C57/B6J mice. Behaviour tests were performed at days 1, 3, 7, 14 and 28 post-stroke. Infarct volume was measured using Nissl staining at day 7 post-stroke. Neurogenesis and angiogenesis were evaluated by co-labelling bromodeoxyuridine (BrdU) with doublecortin (DCX), neuronal nuclei (NeuN) and von Willebrand factor, in immunohistochemical studies. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) levels in the ipsilesional brain at day 28 post-stroke were detected by western blot analysis. Delayed administration of GUO did not reduce infarct volume or affect neurological function at day 7 post-stroke; however, it did improve functional recovery from day 14 post-stroke, when compared with the vehicle group. GUO significantly increased the number of BrdU+ and BrdU+/DCX+ cells in the subventricular zone and subgranular zone at all examined time points, the number of Brdu+/NeuN+ cells in the peri-infarction region at days 14 and 28 post-stroke and microvessel density in the peri-infarction region at day 28 post-stroke compared with the vehicle group. In addition, the BDNF and VEGF levels in the ipsilesional brain were significantly elevated. Delayed administration of GUO at 24 h post-stroke enhanced neurogenesis and angiogenesis, and increased BDNF and VEGF levels, which likely contributes to long-term functional recovery following stroke.

Different from intensively used anticoagulant heparin, hirudin as a representative of natural bio-molecular inhibitors can form specific hirudin-thrombin complex and function as a serine proteinase to efficiently prevent blood coagulation with less bleeding adverse effect, no allergic reaction and immune of non-toxic reaction. We aim to develop a novel anticoagulant polylactide (PLA) membrane via immobilizing natural hirudin through the hydrogen bonding interaction. High amount of PVP (17.4 wt%) was first immobilized on the membrane surface through the interfacial crosslinking of P(VP-VTES). The abundant carbonyl groups with high inter-association constant (K=6000) on the membrane surface dominated the hydrogen bonding interaction with the carboxyl groups of hirudin [44] . The anti-clotting activity of PLA membrane increased with the active hirudin concentration. XPS, ATR-FTIR was conducted to confirm the chemistry evolution of PLA membranes immobilized by PVP and hirudin respectively. The intermediate PVP spacer promoted the hydrophilicity and effectively inhibited the platelet adhesion. While the enhanced hemocompatibility was distinctly revealed by the blood concretion four items (APTT, PT, TT and FIB) mainly thanks to the surface immobilization of hirudin. The anti-clotting stability of PLA membrane was evaluated with varied incubation time. The complement activation was also measured in terms of C3a and C5a. The anti-clotting PLA membrane showed excellent dialysis performances in terms of cleaning urea, creatinine, lysozyme while preserving BSA respectively.

Harmine (HAR) is a beta-carboline alkaloid widely distributed in nature. It exhibits psychopharmacological effects of improving learning and memory. However, excessive dose of HAR can cause central tremor toxicity, which may be related to the glutamate system. Memantine (MEM) is a non-competitive N-methyl-d-aspartate receptor antagonist. It can be used for the treatment of Alzheimer&rsquo, s disease and also can block the neurotoxicity caused by glutamate. Therefore, combination of HAR and MEM would be meaningful and the pharmacokinetics investigation of HAR and MEM in combination is necessary. A ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the simultaneous quantitative determination of MEM, HAR and harmol (HOL), a main metabolite of HAR, in rat plasma after oral administration of HAR and MEM in combination (5.0 mg/kg of MEM combined with 20.0, 40.0, 80.0 mg/kg of HAR). The contents of HAR and HOL were determined after oral administration of HAR (20.0, 40.0 and 80.0 mg/kg), and the content of MEM was determined after oral administration of MEM (5.0 mg/kg). Blood samples were collected from each rat at 0 (pre-dose), 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after administration. The maximum peak concentration (Cmax) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (AUC(0-t)) and mean residence time (MRT) were significantly increased after combination with HAR. The Cmax and AUC(0-t) of HAR and its metabolite HOL were increased after combination with MEM. These findings suggested that co-administration of HAR and MEM could extend their residence time in rats, and then might increase the efficacy for treatment of Alzheimer&rsquo, s disease. Therefore, this study will provide a basis for the rational combined application of HAR and MEM.

Industrial hemp has an excellent lead (Pb) tolerance and accumulation capacity. Further enhancing the Pb tolerance and its accumulation in industrial hemp is of great significance for its future application in phytoremediation. In present study, a pot experiment using Pb-contaminated soil was conducted to investigate the accumulation of Pb contents in various organs of industrial hemp and its subcellular distribution and extractable form in the leaves. It was found that under Pb stress, the Pb content in plants increased significantly with an increase in the soil Pb concentration. Lead was mainly concentrated in the roots, followed by stems and leaves, while the lowest Pb contents were found in seeds ( Pb W (deionized water)>Pb HAc (acetic acid) >Pb NaCl (sodium chloride), indicating that Pb in industrial hemp mainly exists in the form of insoluble oxalate precipitates, thereby alleviating the toxicity of Pb. The results of this study provide a scientific reference for the use of industrial hemp to remediate Pb polluted soils.

Stem/progenitor cells serve an important role in the process of blood vessel repair. However, the mechanism of vascular repair mediated by C-X-C chemokine receptor type 4-positive (CXCR4+) bone marrow-derived mesenchymal stem cells (BMSCs) following myocardial infarction remains unclear. The aim of the present study was to investigate the effects of vascular endothelial growth factor (VEGF) on vessel endothelial differentiation from BMSCs. CXCR4+ BMSCs were isolated from the femoral bone marrow of 2-month-old mice and the cells were treated with VEGF. Expression of endothelial cell markers and the functional properties were assessed by reverse transcription-quantitative polymerase chain reaction, flow cytometry and vascular formation analyses. The results indicated that the CXCR4+ BMSCs from femoral bone marrow cells expressed putative cell surface markers of mesenchymal stem cells. Treatment with VEGF induced platelet/endothelial cell adhesion molecule-1 (PECAM-1) and von Willebrand factor (vWF) expression at the transcriptional and translational levels, compared with untreated controls. Moreover, VEGF treatment induced CXCR4+ BMSCs to form hollow tube-like structures on Matrigel, suggesting that the differentiated endothelial cells had the functional properties of blood vessels. The results demonstrate that the CXCR4+ BMSCs were able to differentiate into vessel endothelial cells following VEGF treatment. For cell transplantation in vascular disease, it may be concluded that CXCR4+ BMSCs are a novel source of endothelial progenitor cells with high potential for application in vascular repair.

Resveratrol, one of the major polyphenols found in red wine, is suggested to have a role as a chemo-prevention or chemotherapy agent in various human cancer models. Herein, we report that resveratrol has a profound antitumor effect on human hepatocellular carcinoma (HCC) cells by down-regulation of the HGF-c-Met signaling pathway. Resveratrol inhibited anchorage-dependent and -independent growth of HCC cells in a dose-dependent manner. Short-term resveratrol exposure substantially decreased HGF-induced c-Met signaling pathway activation, and long-term exposure to resveratrol markedly inhibited c-Met expression on the cell membrane. Additionally, resveratrol suppressed HGF-induced cell invasion, and knockdown of c-Met decreased the sensitivity of HCC cells to resveratrol treatment. Finally, the antitumor activity of resveratrol was validated in xenograft model and resveratrol prominently restrained tumor growth in vivo. In summary, our results suggested that c-Met offers a candidate molecular target for hepatocellular carcinoma management.

Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular diseases. Aldosterone was reported to be increased in patients with OSA and correlated with OSA severity. Many studies investigated the effect of continuous positive airway pressure (CPAP) therapy on plasma aldosterone concentrations (PAC) in OSA patients. The results, however, were inconsistent. In the present study, we aimed to evaluate the effects of CPAP therapy on PAC by performing a meta-analysis. Literature search was carried out in electronic databases including PubMed/Medline, Cochrane Library, Embase and Web of Science. Eligible full-text articles were identified, and important data were extracted. Pooled analysis was performed using the STATA12.0 and RevMan 5.2. Standardized mean difference (SMD) was calculated to estimate the treatment effects. A total of eight studies involving 219 patients were included for our final analysis. PAC was found unchanged after CPAP treatment in OSA patients (SMD=-0.36, 95% CI:-0.91 to 0.18, Z=1.32, P=0.19). Meanwhile, CPAP therapy showed no impact on PAC (SMD=-0.21, 95% CI:-0.85 to 0.42, Z=0.66, P=0.51) in a separate meta-analysis including 3 randomized controlled trials. In conclusion, the evidence for the use of CPAP therapy to decrease PAC in OSA patients is low, and further studies are still warranted.

The industrial hemp varieties ‘Yunma 5’ and ‘Bamahuoma,’ which demonstrate growth vigor and environmental adaptability, have been primarily cultivated in Yunnan and Guangxi, China, respectively, for fiber and seeds. The results of physiological measurements showed the phenotypic differences between the two varieties in response to salt stress. RNA-Seq analysis was first performed on leaves of both varieties sampled at four time intervals (0, 2, 4, 6 days) after treatment with salt (500 mM NaCl) We identified 220 co-up-regulated differentially expressed genes (DEGs) in the two varieties, while 26 up-regulated DEGs and 24 down-regulated DEGs were identified exclusively in the single varieties after 2 days of salt stress. Among the 220 DEGs, we identified 22 transcription factors, including key transcription factors involved in salt stress, such as MYB, NAC, GATA, and HSF. We applied gene expression profile analysis and found that ‘Yunma 5’ and ‘Bamahuoma’ have variety-specific pathways for resisting salt stress. The DEGs of ‘Yunma 5’ were enriched in spliceosome and amino acid metabolism genes, while the DEGs of ‘Bamahuoma’ were enriched in fatty acid metabolism, amino acid metabolism, and endoplasmic reticulum protein processing pathway. Although there were common DEGs, such as genes encoding cysteine protease and alpha/beta-hydrolase superfamily, the two varieties’ responses to salt stress impacted different metabolic pathways. The DEGs that were co-expressed in both varieties under stress may provide useful insights into the tolerance of cultivated hemp and other bast fiber crops to saline soil conditions. These transcriptomes also represent reference sequences for industrial hemp.

Thirteen kinds of steroid hormones in raw milk (cow, goat and buffalo milk) were analyzed with ultra performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-QTOF-MS) after extraction and cleanup with the modified QuEChERS method. These steroid hormones included 17β-estradiol, estriol, estrone, diethylstilbestrol, progesterone, melengestrol acetate, megestrol acetate, chlormadinone acetate, 19-nortestosterone, metandienone, boldenone, epitestosterone, and testosterone. The limits of detection for the raw milk basing on 3 times the signal to noise ratios (S/N=3) was in range of 0.07–0.51 µg kg −1 , and the limits of quantification (basing on S/N=10 method) covered the ranges from 0.23 to 1.7 µg kg −1 . With matrix external standard method, the substances presented recoveries over the range 74.2–99.7%. Qualitative analysis was also done in the mass/mass spectrum (MS/MS) mode and each debris structure of 13 kinds of steroid hormones was achieved. The methodology was then applied in real raw milk samples which were collected in several areas of China and the progesterone was detected with high level.

A fast analytical method for the simultaneous determination of 9 mycotoxins, including aflatoxins (B1, B2, G1, and G2), fumonisins (B1, B2 and B3), zearalenone, and deoxynivalenol in corn using dispersive solid-phase extraction method and ultra-performance liquid chromatography coupled to tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was developed and validated. Samples were extracted with acetonitrile-water (84:16, v:v, containing 1% acetic acid) using ultrasonic extraction. The extracts were purified with a dispersive SPE method using C18 as a cleaning agent. The final clear extracts were dried by nitrogen blowing and subsequently redissolved in methanol-water (5:5, v:v). The samples were then analyzed by UPLC-Q-TOF-MS with 0.1% formic acid in ammonium acetate-methanol as mobile phase. The mean recoveries were ranged from 68.0 to 120.0%, and the relative standard deviation (RSD) ranged from 0.18 to 6.29%. Limits of detections ranged from 0.05 to 50 μg kg−1, and limits of quantification ranged from 0.1 to 200 μg kg−1, which were below the legal limits set by the European Union for the legislated mycotoxins. The developed method was applied to 130 corn samples. Among the mycotoxins studied, aflatoxins B1 and fumonisins B1, B2 and B3 were the most predominant mycotoxins, and their concentrations were 0–593.12, 0–2.01×104, 0–6.94×103 and 0–3.05×103 μg kg−1, respectively.

Industrial hemp is one of the important natural green fiber crops and, up to now, there has been a lack of research on its salt tolerance and the metabolic molecular mechanisms involved. Study on the adaptive mechanisms to salt stress in hemp through comparative proteome analysis is one important way to solve this problem. In this paper, iTRAQ-based proteomics technology was first used to study the differential proteomics of leaves of seedling under salt stress (600 mM sodium chloride) for 4 days in salt-resistant industrial hemp and salt-sensitive varieties. There were 403 and 252 differential proteins identified through LC-ESI–MS/MS mass spectrometry, respectively, and these were classified into 14 categories: primary metabolism, energy, protein destination and storage, disease/defense, protein synthesis, photosynthesis, transport, transcription, signal transduction, cell structure, secondary metabolism, intracellular traffic, cell growth/division and unknown. Hemp adapted to stress mainly by improved ATP metabolism, regulating photosynthesis according to light intensity, strengthening chlorophyll synthesis, promoting cell relaxation and enlargement, improving synthesis of osmoregulation substances, enhancing flow of inorganic sulfur in the body, regulating aquaporins, strengthening transmission of ion transport signals, improving signal transmission between proteins and between proteins and cytomembranes, improving selective absorption and transportation speed of organic and inorganic molecular, degrading hemicellulose cell walls, controlling transport of cellular material in and out, and promoting metabolism and cell stability. The results provide important reference information for research on molecular mechanisms of salt-stress adaption in hemp.

A novel green solvent, CO2-expanded ethanol (CXE), was employed to extract oil from grape seeds, which is one of the main by-products generated by the grape-processing industry. The optimum extraction conditions were obtained by response surface methodology (RSM) coupled with Box-Behnken design (BBD): a pressure of 7.4 MPa, a temperature of 314 K and a CO2 mole fraction of 0.3. The highest oil yield of 13.6 % by CXE extraction was equivalent to or even higher than that obtained with conventional methods, including organic solvent and supercritical CO2 extraction. In terms of reducing solvent consumption and extraction time, the CXE-based process was superior than the conventional methods. CXE oil contained 87.5 % total unsaturated fatty acids, especially linoleic acid was up to 75.5 %, presenting a higher antioxidant capacity.

Ethnopharmacological relevance The seeds of Peganum harmala Linn have been widely used for the treatment of nervous, cardiovascular, gastrointestinal, respiratory, and endocrine diseases and many other human ailments. However, tremor toxicity occurs after overdose and is tolerated following multiple dosing. Thus far, little is known about the underlying mechanisms of tremors and tremor tolerance. Aim of the study To investigate the potential mechanisms of tremors and tremor tolerance induced in rats by the repeated administration of total alkaloid extracts from the seeds of P. harmala (TAEP). Materials and methods A tremor model was induced in male Wistar rats by administering TAEP at a dose of 150 mg/kg/day. To evaluate tremor action, behavioral assessment was conducted by using a custom-built tremor acquisition and analysis system. To investigate the relationships between tremors and neurotransmitter levels in the brain, various neurotransmitters were simultaneously quantified by an ultra-performance liquid chromatography combined with electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) system, and the association between these two parameters was analyzed using Pearson correlation coefficients. To further elucidate the potential mechanisms of the alterations of neurotransmitter levels in cortical tissues, the protein expression levels of several important enzymes and transporters that are closely related to neurotransmitter levels were investigated. In addition, neuropathological analysis was conducted to assess the effect of TAEP on neurons in the brain. To further clarify the potential mechanisms of TAEP-induced neurodegeneration in the brain, c-fos was subjected to immunohistochemical analysis, and oxidative stress markers were examined. Results Tremors initially occurred in rats after the oral administration of TAEP at a dose of 150 mg/kg/day. However, they were tolerated following repeated dosing. The levels of 5-hydroxytryptamine (5-HT) and glycine (Gly) in cortical tissues were most likely associated with the tremor response. Tremor tolerance also likely resulted from the degeneration of cerebellar Purkinje cells. Furthermore, the alteration of 5-HT levels was mainly attributed to the downregulated expression of monoamine oxidase A (MAO-A). The degeneration of Purkinje neurons might have resulted from the overexpression of c-fos and increased oxidative stress in the cerebellum after the multiple dosing of TAEP. Conclusion The tremor response induced by TAEP at high doses is closely related to the concentrations of 5-HT and Gly in cortical tissues. Tremor tolerance may also be attributed to the degeneration of cerebellar Purkinje cells after the repeated dosing of TAEP. Further studies should be conducted to elucidate the interaction of the alkaloids on the neurotransmitter receptors, the expression of related neurotransmitter receptors, the specific signaling pathway involved in regulating MAO-A, and the mechanism of the loss and functional recovery of cerebellar Purkinje neurons.

Heparin free prescription is highly desired for haemodialysis. Versatile strategies have been developed to address the anti-coagulation modification of dialysis membranes. We here develop a facile and effective method to construct an anticoagulant coating on polymeric membranes or a dialyzer through hydrophobic-hydrophobic interaction. An amphiphilic heparin-like copolymer was first synthesized via a free radical polymerization based on alkyl chain lauryl methacrylate (LMA), acrylic acid (AA), and sodium 4-vinylbenze-sulfonate (SSNa) segments. The specific structure of terpolymer was characterized via Fourier transform infrared spectra (FTIR), Proton nuclear magnetic resonance (1H NMR) spectra and size exclusion chromatography (SEC). The amphiphilic copolymer was anchored onto Polylactide (PLA) membrane surface from an aqueous-based solution via hydrophobic-hydrophobic interaction. An Attenuated total reflectance Fourier transform infrared spectra (ATR-FTIR), energy dispersive spectrometer (EDS) and X-ray photoelectron spectroscopy (XPS) confirmed the successful immobilization of heparin-mimicking terpolymers. The modified membranes showed excellent antifouling property and hydrophilicity. Moreover, the membranes exhibited outstanding haemocompatibility with suppressed platelet adhesion, low complement activation (C3a and C5a), expanded coagulation time and limited haemolysis ratio. The prolonged activated partial thromboplastin time and thrombin time (APTT>600 s, TT > 140 s) certified the excellent self-anticoagulant performances. To further examine the applicability and effectiveness, a polysulfone dialyzer was modified by this strategy. The ultrafiltration coefficient and clearance performances were examined. Overall, the hydrophobic-hydrophobic interaction strategy simplified the modification procedure of dialysis membrane, implying its great potential in heparin free dialysis application.

Ethnopharmacological relevance The seeds of Peganum harmala Linn, in which the most abundant active compounds are harmaline and harmine, have been widely used as a traditional medicine in various countries to treat a broad spectrum of diseases including asthma, cough, depression, Parkinson's and Alzheimer's diseases. However, few studies on long-term or subchronic toxicity of seeds of P. harmala were reported after overdose. Aim of the study To investigate the subchronic toxicity and concomitant toxicokinetics of total alkaloid extracts from seeds of P. harmala (TAEP) after oral administration for four weeks in rats. Materials and methods The subchronic toxicity and concomitant toxicokinetics of TAEP were evaluated after 28-day oral administration in rats at daily dose levels of 15, 45, and 150 mg/kg. The signs of toxicity and mortality were monitored and recorded daily. The body weight and average food consumption were measured weekly. The analyses of hematology, biochemistry, urine, relative organ weights and histopathology were conducted at the termination of treatment and recovery phase. For concomitant toxicokinetics study, the plasma toxicokinetic parameters, tissue distribution, and excretion of predominant ingredients harmaline and harmine in TAEP and metabolites harmalol and harmol were tested. Results Following initial repeated exposure to high-dose (150 mg/kg/day) of TAEP excitotoxic reaction, such as tremor, was observed, but tolerated on the fourth day after multiple dosing. The significant alterations in blood glucose and lipid metabolism in liver were observed, but recovered after four weeks of drug withdrawal. The no-observed-adverse-effect level (NOAEL) of TAEP was considered to be 45 mg/kg/day under the present study conditions. There were no significant gender differences in most indexes of subchronic toxicity throughout the experimental period with the exception of food consumption and body weight. In concomitant toxicokinetics study, the alterations of dynamic characteristic for harmaline, harmine and metabolite harmol after multiple oral administration at three doses had been observed. Harmaline, harmine and metabolites harmalol and harmol were widely distributed in organs and there was no accumulation in the tissues examined. The reduction of harmaline and metabolite harmalol in brain after multiple dosing at dose of 150 mg/kg might be closely related to the tremor tolerance. The main excretory pathway for metabolites harmalol and harmol was urinary excretion via kidney. Conclusions The results revealed that TAEP at doses of 15 and 45 mg/kg/day in rats might be safe. Excitotoxic reaction such as tremor occurred initially at dose of 150 mg/kg/day, however, the toxicity was tolerant and reversible. In addition, harmaline and harmine in TAEP had a quick absorption into blood and metabolized to harmalol and harmol, and there was no drug accumulation in the detected tissues. Further studies should be investigated to clarify the mechanisms of tremor tolerance and neurotoxicity of TAEP.

The aim of this study is to investigate the effects of a Nitric oxide (NO) donor, S-nitrosoglutathione (GSNO), on apoptosis and the improvement of preservation quality in apheresis platelets.A GSNO solution - to make the final GSNO concentration of 100 uM was added into fresh apheresis platelets, and the parameters associated with platelet morphology, metabolism, and apoptosis were dynamically monitored for seven days.The results showed that the NO level was remarkably higher during the whole storage stageafter GSNO injection. The number of depolarized platelets and platelets with phosphatidylserine valgus were significantly reduced in the GSNO group compared to that of the control group at some time point. The expression of Bcl-xL mRNA on day 5 of storage in the experimental group was significantly higher than that of the control group, but the expression of Bcl-xL protein was not significantly higher than that in the control group. In addition, Bak and Bax mRNA expression levels in the experimental group were significantly lower than those in the control group, but Bak and Bax protein expression levels were not statistically different. Meanwhile, caspase-3 activity was significantly inhibited.These data suggest that the addition of a certain dose of GSNO as a NO donor during platelet storage could inhibit platelet apoptosis and reduce platelet storage lesion (PSL) to a certain extent.

The analogous β-carboline alkaloids, harmaline (HAL) and harmine (HAR), possess a variety of biological properties, including acetylcholinesterase (AChE) inhibitory activity, antioxidant, anti-inflammatory, and many others, and have great potential for treating Alzheimer’s disease (AD). However, studies have showed that the two compounds have similar structures and in vitro AChE inhibitory activities but with significant difference in bioavailability. The objective of this study was to comparatively investigate the effects of HAL and HAR in memory deficits of scopolamine-induced mice. In the present study, mice were pretreated with HAL (2, 5, and 10 mg/kg), HAR (10, 20, and 30 mg/kg) and donepezil (5 mg/kg) by intragastrically for 7 days, and were daily intraperitoneal injected with scopolamine (1 mg/kg) to induce memory deficits and then subjected to behavioral evaluation by Morris water maze. To further elucidate the underlying mechanisms of HAL and HAR in improving learning and memory, the levels of various biochemical factors and protein expressions related to cholinergic function, oxidative stress, and inflammation were examined. The results showed that HAL and HAR could effectively ameliorate memory deficits in scopolamine-induced mice. Both of them exhibited an enhancement in cholinergic function by inhibiting AChE and inducing choline acetyltransferase (ChAT) activities, and antioxidant defense via increasing the antioxidant enzymes activities of superoxide dismutase and glutathione peroxidase, and reducing maleic diadehyde production, and anti-inflammatory effects through suppressing myeloperoxidase, tumor necrosis factor α, and nitric oxide as well as modulation of critical neurotransmitters such as acetylcholine (ACh), choline (Ch), L-tryptophan (L-Trp), 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (γ-GABA), and L-glutamic acid (L-Glu). Furthermore, the regulations of HAL on cholinergic function, inflammation, and neurotransmitters were more striking than those of HAR, and HAL manifested a comparable antioxidant capacity to HAR. Remarkably, the effective dosage of HAL (2 mg/kg) was far lower than that of HAR (20 mg/kg), which probably due to the evidently differences in the bioavailability and metabolic stability of the two analogs. Taken together, all these results revealed that HAL may be a promising candidate compound with better anti-amnesic effects and pharmacokinetic characteristics for the treatments of AD and related diseases.

Vasicine (VAS) is a potential natural cholinesterase inhibitor for treatment of Alzheimer's disease. Due to one chiral centre (C-3) presenting in molecule, VAS has two enantiomers, d-vasicine (d-VAS) and l-vasicine (l-VAS). The study was undertaken to investigate the stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic effect and acute toxicity of VAS enantiomers. In results, the glucuronidation metabolic rate of l-VAS was faster than d-VAS in human liver microsomes and isoenzymes tests, and it was proved that the UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B15 were the major metabolic enzymes for glucuronidation of l-VAS, while only UGT1A9 for d-VAS, which take responsibility of the significantly less metabolic affinity of d-VAS than l-VAS in HLM and rhUGT1A9. The plasma exposure of d-VAS in rats was 1.3-fold and 1.6-fold higher than that of l-VAS after intravenous and oral administration of d-VAS and l-VAS, respectively. And the plasma exposure of the major glucuronidation metabolite d-VASG was one of tenth of l-VASG or more less, no matter by intravenous or oral administration. Both d-VAS and l-VAS were exhibited promising acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, and the BChE inhibitory activity of d-VAS with IC50 of 0.03 ± 0.001 μM was significantly stronger than that of l-VAS with IC50 of 0.98 ± 0.19 μM. The molecular docking results indicated that d-VAS and l-VAS could bind to the catalytic active site (CAS position) either of human AChE and BChE, and the BChE combing ability of d-VAS (the score of GBI/WAS dG -7.398) was stronger than that of l-VAS (the score of GBI/WAS dG -7.135). Both d-VAS and l-VAS could improving the learning and memory on scopolamine-induced memory deficits in mice. The content of acetylcholine (ACh) after oral administration d-VAS increased more than that of l-VAS in mice cortex, through inhibiting cholinesterase (ChE) and increasing choline acetyltransferase (ChAT). In addition, the LD50 value of d-VAS (282.51 mg·kg-1) was slight lower than l-VAS (319.75 mg·kg-1). These results indicated that VAS enantiomers displayed significantly stereoselective metabolic, pharmacokinetics, anti-amnesic effect and toxic properties in vitro and in vivo. The d-VAS might be the dominant configuration for treating Alzheimer's disease.

The synthesis of a new series of C-2-alkyl-2-methoxymethyl-salvinorin ethers and their binding affinities at κ-, μ-, and δ-opioid receptors are presented. We have developed a synthesis that enables installation of alkyl-substituents at C-2 while maintaining the integrity of the C-2 methoxymethyl ether and retaining κ-opioid receptor binding activity. Among these new compounds, 2-methyl-2-methoxymethyl-salvinorin ether (9a) is a potent full agonist at the κ receptor and shows comparable potency in Ki and EC50 with salvinorin A and U50488H. These C2-alkylated analogs have been identified as full κ agonists.

MicroRNAs (miRs) have important roles in the pathogenesis of human malignancy. It has previously been suggested that deregulation of miR‑101 is associated with the progression of intrahepatic cholangiocarcinoma (ICC); however, the exact role of miR‑101 in the regulation of ICC metastasis remains largely unknown. The present study demonstrated that the expression levels of miR‑101 were significantly decreased in ICC tissue, as compared with matched adjacent normal tissue. Furthermore, miR‑101 was downregulated in the ICC‑9810 human ICC cell line, as compared with in the normal human intrahepatic biliary epithelial cell (HIBEC) line. Vascular endothelial growth factor (VEGF)‑C was identified as a target gene of miR‑101 in ICC‑9810 cells. The expression of VEGF‑C was negatively regulated by miR‑101 at the post‑transcriptional level in ICC‑9810 cells. Further investigation demonstrated that overexpression of miR‑101 markedly suppressed the migration and invasion of ICC‑9810 cells, and these effects were similar to those observed following VEGF‑C knockdown. Conversely, restoration of VEGF‑C reversed the inhibitory effects of miR‑101 overexpression on ICC‑9810 cell migration and invasion, thus suggesting that miR‑101 may suppress ICC‑9810 cell migration and invasion, at least partly via inhibition of VEGF‑C. It was also demonstrated that the mRNA and protein expression levels of VEGF‑C were frequently upregulated in ICC tissue and cells, and its expression level was inversely correlated with that of miR‑101 in ICC tissue. In conclusion, the present study identified important roles for miR‑101 and VEGF‑C in ICC, suggesting that miR‑101/VEGF‑C signaling may be a promising diagnostic and/or therapeutic target for ICC.

The antimonate compound La3SbO7 has high chemical stability, lattice stiffness and thermal stability. Orange-red-emitting antimonate-based phosphors La3SbO7:xSm(3+) (x = 0.02, 0.05, 0.08, 0.10, 0.15, 0.20 and 0.25) were synthesized. The phase structure and photoluminescence properties of these phosphors were investigated. The emission spectrum obtained on excitation at 407 nm contained exclusively the characteristic emissions of Sm(3+) at 568, 608, 654 and 716 nm, which correspond to the transitions from (4)G5/2 to (6)H5/2, (6)H7/2, (6)H9/2 and (6)H11/2 of Sm(3+), respectively. The strongest emission was located at 608 nm due to the (4)G5/2→(6)H7/2 transition of Sm(3+), generating bright orange-red light. The critical quenching concentration of Sm(3+) in La3SbO7:Sm(3+) phosphor was determined as 10% and the energy transfer between Sm(3+) was found to be through an exchange interaction. The International Commission on Illumination chromaticity coordinates of the La3SbO7:0.10Sm(3+) phosphors are located in the orange-red region. The La3SbO7:Sm(3+) phosphors may be potentially used as red phosphors for white light-emitting diodes.

Resveratrol is a stilbenoid compound, and a promising potent chemopreventive bioactive agent. Here, we showed for the first time that the combined treatment with resveratrol and TRAIL drastically induced apoptosis in human colon cancer cells when compared to single treatments. Further, resveratrol markedly up-regulated TRAIL receptors, DR5 and DR4 and the results revealed that DR5 siRNA efficiently blocked apoptosis induced by the co-treatment with resveratrol and TRAIL, indicating that DR5 up-regulation by resveratrol helps to enhance TRAIL actions. In addition, the combined effect were tested on normal human cells. All the obtained results suggested that resveratrol is very useful for TRAIL-based treatments for cancer.

The aim of the present study was to examine the anticarcinogenic effects of emodin on the Notch signaling pathway and vascular endothelial growth factor (VEGF) in the PC3 androgen-independent prostate cancer cell line in vitro. The cell viability was assessed using an 3‑(4,5)‑dimethylthiahiazo(‑z‑y1)‑3,5‑di‑phenytetrazolium bromide assay. Cell apoptosis and cell cycle were detected using flow cytometry. Morphological alterations were observed using transmission electron microscopy. The mRNA and protein expression levels of Notch1, Jagged1, VEGF and bFGF were detected using reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. Laser scanning confocal microscope (LSCM) immunofluorescence analysis was performed to detect the levels of expression and the sub‑cellular localization of the Notch1 receptor protein. Growth of the PC3 cells was inhibited by emodin. Flow cytometry demonstrated that emodin induced apoptosis in the PC3 cells and arrested the cell cycle of the PC3 cells at the G2/M phase. The mRNA and protein expression of Notch1 in the PC3 cells was markedly increased, whereas the mRNA and protein expression levels of Jagged1, VEGF and bFGF were significantly decreased following exposure to emodin for 24 h. The LSCM assay revealed that the Notch1 was not only localized in the membrane and cytoplasm, but was also present in the nucleolus of the PC3 cells, and the expression of Notch1 in the nuclei gradually increased following treatment with emodin. These results demonstrated that emodin suppressed the growth of androgen‑independent prostate cancer cell lines and induced apoptosis and cell cycle arrest. The Notch signaling pathway was activated in the PC3 cells following exposure to emodin, which suggested that the Notch signaling pathway is involved in the prostate tumor‑suppressing mechanisms of emodin, the activation of which may depend on CBF1 protein in the nucleus by classic pathways. The antitumor function of emodin, attributed to the Notch signaling pathway, induced the downregulation of VEGF by suppressing tumorigenesis and angiogenesis, which indicated a novel mechanism underlying the emodin-mediated anti-prostate cancer effect.

Emodin is a natural active component extracted from Chinese herbs. In this study, we investigated the therapeutic effect of emodin on surgery-induced renal fibrosis in rat. Moreover, the function of Smad ubiquitination regulatory factor 2 (Smurf 2) was further studied in vitro. The renal fibrosis rat model was established via 5/6 renal mass reduction. The histopathological abnormalities of renal tissues in rats were tested via staining method and microscopic examination. Renal function indicators, the serum creatinine, blood urea nitrogen and total urinary protein were measured via spectrophotometric method. The renal tissues were tested via Western blotting and real-time quantitative PCR. Moreover, Smurf 2 protein expression under different conditions and its regulatory function in vitro was measured via Western blotting. Our results showed that the histopathological abnormalities, the decrease in rat body weight and the abnormal renal function caused by renal fibrosis were improved by emodin. Further, mRNA expression of TGF-β1 was decreased by emodin. Furthermore, extracellular matrix (ECM) components as well as TGF-β1/Smad signaling-related Smurf 2 were decreased by emodin both in vivo and in vitro. The protein level of mothers against decapentaplegic homolog 7 (Smad7) was up-regulated. In addition, ECM components were increased by Smurf 2 over-expression and these effects were weakened by emodin co-treatment in vitro. Emodin showed an anti-fibrosis effect in surgery-induced renal fibrotic rats. And this effect was potentially achieved via down-regulating expressions of TGF-β1 and Smurf 2 and up-regulating Smad7 expression.