Narcissin induces developmental toxicity and cardiotoxicity in zebrafish embryos via Nrf2/HO-1 and calcium signaling pathways.

Narcissin is a natural flavonoid from some edible and traditional medicinal plants. It has been proven to have multiple biological functions and exhibits potential therapeutic effects on hypertension, cancer, and Alzheimer's disease. However, the toxicity of narcissin is largely unknown. Here, we revealed that narcissin treatment led to reduced hatchability, increased malformation rate, shorter body length, and slowed blood flow in zebrafish. Furthermore, bradycardia, pericardial edema, increased SV-BA distance, diminished stroke volume, ejection fraction, and ventricular short-axis shortening rate were also found. A large accumulation of ROS, increased apoptotic cells, and histopathological changes were detected in the heart region. Moreover, the gene expression profiles and molecular docking analysis indicated that Nrf2/HO-1 and calcium signaling pathways were involved in narcissin-induced toxicity. In conclusion, here we provide the first evidence that demonstrates narcissin-induced developmental toxicity and cardiotoxicity in zebrafish via Nrf2/HO-1 and calcium signaling pathways for the first time.

Simultaneous and dynamic measurement of Schisandrol A changes in rat blood and brain and its comparative pharmacokinetic study in control and Parkinson's disease rats by dual-probe in vivo microdialysis.

Schisandrol A (SchA) is the main active ingredient of Schisandra chinensis (Turcz.) Baill., which is a famous traditional Chinese herbal medicine. SchA can penetrate the blood-brain barrier and has a significant neuroprotective effect. A group of multiplexed stable isotope mass tags (MSIMTs, m/z 332, 338, 346, 349, 351, 354, 360, 363, 374 and 377) were synthesized to perform multiplexed stable isotope labeling derivatization (MSILD) of SchA in rat microdialysates and standards. A new magnetic molecularly imprinted polymer was prepared using MSIMT-375-SchA as dummy template. All the 10-plexed derivatives of MSIMTs-SchA can be efficiently and selectively enriched and purified using this adsorbent by magnetic dispersive solid phase extraction (MDSPE) before ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) analysis. It should be pointed out that the MSIMT-346-SchA standard derivative was used as internal standard in the process of MDSPE and UHPLC-MS/MS. On these bases, 9 different rat microdialysate samples can be determined by UHPLC-MS/MS in a single run. The utilization of MSIMTs significantly increased the sensitivity, accuracy, selectivity and analysis throughput. Under the optimized conditions, satisfactory linearity (R2> 0.987), limit of detection (LODs, 0.15-0.26 pg/mL) and lower limit of quantitative (LLOQ, 0.8-2.0 pg/mL) were obtained. Intra- and inter-day precisions were in the range of 2.2% -12.5%, and recoveries 94.2% -106.2%. The matrix effects were very low, and the average derivatization efficiency of 10-plex MSIMTs to SchA was as high as 97.8%. Using the developed dual-probe in vivo microdialysis sampling technique, the proposed analytical method has been applied for comparative pharmacokinetics of SchA in the brain and blood of control and Parkinson's disease (PD) rats.

WMNN: Wearables-Based Multi-Column Neural Network for Human Activity Recognition.

In recent years, human activity recognition (HAR) technologies in e-health have triggered broad interest. In literature, mainstream works focus on the body's spatial information (i.e. postures) which lacks the interpretation of key bioinformatics associated with movements, limiting the use in applications requiring comprehensively evaluating motion tasks' correctness. To address the issue, in this article, a Wearables-based Multi-column Neural Network (WMNN) for HAR based on multi-sensor fusion and deep learning is presented. Here, the Tai Chi Eight Methods were utilized as an example as in which both postures and muscle activity strengths are significant. The research work was validated by recruiting 14 subjects in total, and we experimentally show 96.9% and 92.5% accuracy for training and testing, for a total of 144 postures and corresponding muscle activities. The method is then provided with a human-machine interface (HMI), which returns users with motion suggestions (i.e. postures and muscle strength). The report demonstrates that the proposed HAR technique can enhance users' self-training efficiency, potentially promoting the development of the HAR area.

Pore types, genesis, and evolution model of lacustrine oil-prone shale: a case study of the Cretaceous Qingshankou Formation, Songliao Basin, NE China.

A comprehensive characterisation of the pore structure in shale oil reservoirs is essential for forecasting oil production and exploration risks. This study forecasted these risks in the oil-rich Songliao Basin using combination of high-resolution field emission scanning electron microscopy and quantitative X-ray diffraction to analyze the pore genesis and evolution mode within the first member of the Cretaceous Qingshankou Formation (K2qn1). The results showed the dominance of inorganic pores over organic pores, wherein diagenetic processes, such as compaction, pressure solution, and cementation, were responsible for the destruction of pore structure in the formation. Notably, the pores formed by dissolution and shrinkage cracks resulting from clay mineral transformation improved the oil storage space. Furthermore, according to the geochemical data and clay composition, the K2qn1 shale is in the middle diagenetic stage A, which can be further subdivided into A1 and A2 stages from top to bottom. The porosity slowly decreased in both sub-stages A1 and A2, wherein the decrease was stable in the latter. The diagenetic observations in this study are significant for the exploration of unconventional shale oil in petroliferous basins worldwide.

Involvement of Nrf2-HO-1/JNK-Erk Signaling Pathways in Aconitine-Induced Developmental Toxicity, Oxidative Stress, and ROS-Mitochondrial Apoptosis in Zebrafish Embryos.

Aconitine (AC), one of the bioactive diterpenoid alkaloids extracted from Aconitum plants, is widely used in traditional herbal medicine to treat various diseases. Emerging evidence indicates that AC has attracted great interest for its wide cardiotoxicity and neurotoxicity. However, the toxic effects of AC on embryonic development and its underlying mechanisms remain unclear. Here, a developmental toxicity assay of AC was performed on zebrafish embryos from 4 to 96 h post fertilization (hpf), and its underlying mechanisms were discussed. AC exposure impaired the cardiac, liver, and neurodevelopment. Especially, a high dose of AC (7.27 and 8.23 µM) exposure resulted in malformations at 72 and 96 hpf, including reduced body length, curved body shape, pericardial edema, yolk retention, swim bladder and brain developmental deficiency, and degeneration of dopaminergic neurons. High-concentration AC exposure caused a deficient cardiovascular system with cardiac dysfunctions, increased heart rates at 72 and 96 hpf, and reduced locomotor behavior at 120 hpf. AC treatment significantly increased the ROS level and triggered cell apoptosis in the heart and brain regions of embryos at 96 hpf in 7.27 and 8.23 µM AC treatment zebrafish. Oxidative stress was confirmed by reduced levels of T-SOD activity associated with accumulation of lipid peroxidation in larvae. The expression levels of oxidative stress-related genes (Nrf2, HO-1, Cat, and Sod-1) Erk1/2 and Bcl-2 were significantly downregulated at 96 hpf. The expression pattern of JNK and mitochondrial apoptosis-related genes (Bad, Bax, Cyto C, Casp-9, and Casp-3) was significantly upregulated. Taken together, all these parameters collectively provide the first evidence of AC-induced developmental toxicity in zebrafish embryo/larvae through ROS-medicated mitochondrial apoptosis involving Nrf2/HO-1 and JNK/Erk pathways.

Cytotoxic compound triacremoniate from Marine Fungus Acremonium citrinum. MMF4.

Two new compounds, triacremoniate (1) and dietziamide C (2) along with known compounds ß-Adenosine (3) and acrepyrone A (4) were obtained from the mangrove-derived fungus Acremonium citrinum. MMF4. Their structures were unambiguously determined by extensive spectroscopic methods, including UV, IR, HRESIMS and NMR. Triacremoniate (1) can promote apoptosis of HeLa cells by increasing the PARP cleavage and the phosphorylation of JNK and p38.

Dietary Supplementation with Phytase and Protease Improves Growth Performance, Serum Metabolism Status, and Intestinal Digestive Enzyme Activities in Meat Ducks.

Two experiments were conducted to investigate the effects of dietary supplementation with protease and phytase on growth performance, serum physiochemical parameters, and activities of digestive enzymes in jejunal digesta of meat ducks. Experiment 1 was carried out to determine the effects of different protease or phytase on growth performance, serum physiochemical parameter, and activities of digestive enzymes in jejunal digesta of meat ducks to select the optimal phytase or protease. According to the hatching age and initial weight, a total of 5040 Cherry Valley ducks (15 days of age) were randomly assigned into six treatments. Treatments included a basal control diet (CON) and 5 basal diets supplemented with different enzyme preparations, which were phytase preparation A (PA, 160 g/t), phytase preparation B (PB, 800 g/t), protease preparation A (PTA, 80 g/t), protease preparation B (PTB, 300 g/t) and protease preparation C (PTC, 200 g/t). The enzyme activities were as follows: Phytase A and B as well as protease A, B, and C were 50,000, 10,000, 250,000, 50,000, and 60,000 U/g, respectively. Each treatment had 7 replicates with 120 meat ducks per replicate. Experiment 1 lasted for 28 days. The results showed that: compared with the CON group, the PA group significantly decreased contents of serum phosphorus and calcium (p < 0.05), and the PTA, PTB, and PTC groups had higher activities of trypsin in jejunal digesta (p < 0.05), and the activity of jejunal chymotrypsin in PTA group was greater (p < 0.05). Experiment 2 was carried out to determine the effects of dietary supplementation with protease and phytase in low-energy and low-protein diet on growth performance, serum physiochemical parameters, and activities of digestive enzymes in jejunal digesta of meat ducks. According to the hatching age and initial weight, a total of 5760 Cherry Valley ducks (15 days of age) were randomly assigned into four treatments on the basis of a trial of 2 × 2 factorial design. Treatments included a basal control diet (PC), basal diet supplemented with enzymes (PCE), low-energy and low-protein diet (LEP), and low-energy and low-protein diet supplemented with enzymes (LEPE), the nutrient levels of energy and CP of basal diet were 2747.2 cal·ME/kg and 16.80%, respectively, and the nutrient levels of energy and CP of low-energy and low-protein diet decreased 45.90 kcal·ME/kg and 0.52% on the basis of basal diet, respectively. According to the results of experiment 1, phytase A and protease A were determined as the optimal enzyme combination of Experiment 2, and additional dosage of which were identical with Experiment 1. Each treatment had 6 replicates with 240 meat ducks per replicate. Experiment 2 lasted for 28 days. The results showed that: compared with PC and LEP groups, PCE and LEPE groups had higher final weight and average daily gain (ADG) (p < 0.05), higher activities of trypsin and chymotrypsin in jejunal digesta (p < 0.05), lower contents of serum calcium and phosphorus as well as higher levels of high-density lipoprotein in the serum (p < 0.05). In conclusion, dietary supplementation with phytase and protease in different energy and protein diets could increase digestive enzymes in jejunal digesta, effect serum physiochemical parameters, improve metabolic status, and increase the growth performance of meat ducks. Meanwhile, with the dietary supplementation with phytase and protease in the lower energy and protein diet, the growth performance could reach to the degree of the higher energy and increased protein diet, but without the addition of phytase and protease.

Secondary metabolites of petri-dish cultured Antrodia camphorata and their hepatoprotective activities against alcohol-induced liver injury in mice.

Antrodia camphorata, a well-known and highly valued edible medicinal mushroom with intriguing activities like liver protection, has been traditionally used for the treatment of alcoholic liver disease. A. camphorata shows highly medicinal and commercial values with the demand far exceeds the available supply. Thus, the petri-dish cultured A. camphorata (PDCA) is expected to develope as a substitute. In this paper, nineteen triterpenes were isolated from PDCA, and thirteen of them were the unique anthroic acids in A. camphorata, including the main content antcin K, which suggested that PDCA produced a large array of the same anthroic acids as the wild one. Furthermore, no obvious acute toxicity was found suggesting the edible safety of PDCA. In mice alcohol-induced liver injury model, triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) had been reduced by the PDCA powder as well as the main content antcin K, which indicated that the PDCA could protect alcoholic liver injury in mice model and antcin K could be the effective component responsible for the hepatoprotective activities of PDCA against alcoholic liver diseases.

Stigmastane-type steroids with unique conjugated Δ7,9(11) diene and highly oxygenated side chains from the twigs of Vernonia amygdalina.

Veramyosides A-J, eleven undescribed stigmastane-type steroids, including one aglycone and ten glycosides, along with three known homologues were isolated from the twigs of Vernonia amygdalina Delile (compositae). All compounds featured a stigmastane-type steroid skeleton with a unique conjugated Δ7,9(11) diene segment and highly oxygenated side chains with a γ-lactone or an α, ß-unsaturated five-membered lactone ring. The structures of veramyosides A-J and their absolute configurations were unambiguously elucidated by HR-ESI-MS, extensive NMR spectroscopy, in situ dimolybdenum CD methods, modified Mosher's method, quantum chemical calculation of their ECD curves, and CD comparison methods on basis of their biogenetic pathway. In addition, all isolates were investigated for their effects on RXRα transcription, and their effects on the NF-κB signaling pathway were also evaluated.

Systems-Mapping of Herbal Effects on Complex Diseases Using the Network-Perturbation Signatures.

The herbs have proven to hold great potential to improve people's health and wellness during clinical practice over the past millennia. However, herbal medicine for the personalized treatment of disease is still under investigation owing to the complex multi-component interactions in herbs. To reveal the valuable insights for herbal synergistic therapy, we have chosen Traditional Chinese Medicine (TCM) as a case to illustrate the art and science behind the complicated multi-molecular, multi-genes interaction systems, and how the good practices of herbal combination therapy are applicable to personalized treatment. Here, we design system-wide interaction map strategy to provide a generic solution to establish the links between diseases and herbs based on comprehensive testing of molecular signatures in herb-disease pairs. Firstly, we integrated gene expression profiles from 189 diseases to characterize the disease-pathological feature. Then, we generated the perturbation signatures from the huge chemical informatics data and pharmacological data for each herb, which were represented the targets affected by the ingredients in the herb. So that we could assess the effects of herbs on the individual. Finally, we integrated the data of 189 diseases and 502 herbs, yielding the optimal herbal combinations for the diseases based on the strategy, and verifying the reliability of the strategy through the permutation testing and literature verification. Furthermore, we propose a novel formula as a candidate therapeutic drugs of rheumatoid arthritis and demonstrate its therapeutic mechanism through the systematic analysis of the influencing targets and biological processes. Overall, this computational method provides a systematic approach, which blended herbal medicine and omics data sets, allowing for the development of novel drug combinations for complex human diseases.

Cytoskyrin C, an unusual asymmetric bisanthraquinone with cage-like skeleton from the endophytic fungus Diaporthe sp.

Cytoskyrin C (1), a new bisanthraquinone with asymmetrically cytoskyrin type skeleton, together with a known symmetrical analogue (+)-epicytoskyrin (2), were isolated from an endophytic fungus ARL-09 (Diaporthe sp.). Cytoskyrin C (1) featured an asymmetrically cage-like structural motif arising from the dimerization of anthraquinone monomers by three carbon­carbon bonds 9a/3', 3/9a' and 1/1'. The structure and absolute configuration of compound 1 were determined by spectroscopic analyses, ECD calculation and exciton chirality methods. Moreover, a plausible biogenetic pathway of 1-2 was predicted. Their cytotoxicities against SMMC-7721 cell as well as effects on NF-κB signaling pathway were evaluated. 2009 Elsevier Ltd. All rights reserved.

Liquiritin induces apoptosis and autophagy in cisplatin (DDP)-resistant gastric cancer cells in vitro and xenograft nude mice in vivo.

Gastric cancer is reported as one of the leading factors resulting in tumor-related death worldwide. However, the therapies to suppress gastric cancer are still limited and the emergence of drug resistance makes it necessary to develop new and effective anticancer drugs and combinational chemotherapy schemes. Liquiritin (LIQ) is a major constituent of Glycyrrhiza Radix, exhibiting various pharmacological activities, including anticancer. In this study, we investigated the role of LIQ in human gastric cancer cells with cisplatin (DDP) resistance. The findings suggested that LIQ, when applied in single therapy, could moderately inhibit the proliferation and migration of DDP-resistant gastric cancer cells, SGC7901/DDP. DDP and LIQ in combination induced G0/G1 cell cycle arrest to suppress the proliferation of gastric cancer cells, which were associated with the decrease of cyclin D1, cyclin A and cyclin-dependent kinase 4 (CDK4) and increase of p53 and p21. In addition, LIQ combined with DDP significantly induce apoptosis and autophagy both in vitro and in vivo through enhancing cleavage of caspase-8/-9/-3 and PARP, as well as LC3B and Beclin 1 expression. Significantly, the two drugs, when used in combination, prevented gastric cancer cell xenografts in nude mice in vivo. Together, the results revealed that application of DDP and LIQ in combination possessed a potential value against the growth of human gastric cancer with DDP resistance.

CancerHSP: anticancer herbs database of systems pharmacology.

The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

Exploration of the safe upper level of iodine intake in euthyroid Chinese adults: a randomized double-blind trial.

BACKGROUND: The beneficial health effects associated with Universal Salt Iodization are well known. Yet, little is known about the possible adverse health effects in people with high iodine intake and the safe daily intake upper limit in the Chinese population. OBJECTIVE: The objective of this study was to explore the safe upper level of total daily iodine intake among adults in China. DESIGN: A 4-wk, double-blind, placebo-controlled, randomized controlled trial was conducted in 256 euthyroid adults. Participants were randomly assigned to 12 intervention groups with various iodine supplement doses ranging from 0 to 2000 µg/d. Total iodine intake included iodine from both supplements and diet. Multiple outcome measures were used to evaluate possible adverse effects, including thyroid function, thyroid size, and urinary iodine. RESULTS: The mean iodine intake from the diets and salt intake of the participants were 105 ± 25 and 258 ± 101 µg/d, respectively. In comparison with the placebo group, all iodide-supplemented groups responded with significant increases in median urinary iodine concentrations (P < 0.05) and in thyroid-stimulating hormone concentration (P < 0.05). Thyroid volume decreased after 4 wk in the high-iodine intervention groups (1500-2000 µg). Subclinical hypothyroidism appeared in the groups that received 400 µg I (5%) and 500-2000 µg I (15-47%). CONCLUSIONS: This study showed that subclinical hypothyroidism appeared in the participants who took the 400-µg I supplement, which provided a total iodine intake of ∼800 µg/d. Thus, we caution against a total daily iodine intake that exceeds 800 µg/d in China and recommend further research to determine a safe daily upper limit.

High-performance liquid chromatographic determination and pharmacokinetic study of vitexin-2''-O-rhamnoside in rat plasma after intravenous administration.

A simple and specific high-performance liquid chromatographic (HPLC) method was developed for the pharmacokinetic study of vitexin-2''-O-rhamnoside (VOR) in rat after intravenous administration. The plasma samples were deproteinized with methanol after addition of internal standard (i.s.) hesperidin. HPLC analysis was performed on a Diamonsil ODS C18 analytical column, using acetonitrile-0.3% formic acid (20:80, v/v) as the mobile phase with UV detection at 270 nm. The standard curve was linear over the range of 0.1070-21.41 microg/mL in rat plasma. The average extraction recovery of VOR was 97.9+/-3.1%, and the relative standard deviations (R.S.D.s) of the intra- and inter-day precisions were no more than 7.4 and 8.5%, respectively. The lower limit of quantification (LLOQ) was 0.1070 microg/mL. The AUC of VOR was proportional to the dose after intravenous administration of 15, 30, 60 and 120 mg/kg body weight, and the elimination half-life (t1/2beta), systemic clearance (Cl) and apparent volume of distribution (Vc) were not significantly different among the four doses, and all the results indicated that the pharmacokinetics of VOR in rat obeyed first-order kinetics.

[PET study of effects of combination of different points on glucose metabolism in the patient of cerebral infarction].

OBJECTIVE: To observe effects of combination of different points on glucose metabolism in the patient of cerebral infarction. METHODS: Neiguan (PC 6), Shuigou (GV 26), Fengchi (GB 20), Sanyinjiao (SP 6), Yinlingquan (SP 9), Taichong (LR 3) were selected for the Xingnao Kaiqiao group (n =7), and Hegu (LI 4), Quchi (LI 11), Zusanli (ST 36), Yanglingquan (GB 34) and Xuanzhong (GB 39) for the routine acupuncture group (n = 5). PET-CT was used to observe the local cerebral glucose metabolism. RESULTS: The cerebral regions activated in the the Xingnao Kaiqiao group included infarction center, gyrus temporalis superior, thalamus, gyrus temporalis inferior, gyrus rectus, insula, lateral occipital lobe, parietal lobe and cerebellum, and in the routine acupuncture group included gyrus frontalis inferior, caudate nucleus, cingulated gyrus, hippocampus, precuneus and parietal lobe. CONCLUSION: PET is very suitable for exploring acupuncture mechanisms in treatment of cerebral infarction, and further shows the specificity of acupoints-brain functional region.