Cost-effective phosphorus removal from aqueous solution by a chitosan/lanthanum hydrogel bead: Material development, characterization of uptake process and investigation of mechanisms.

Excessive phosphorus is one of the main reasons leading to eutrophication that causes severe ecosystem imbalance and negative human health impacts. In this study, several chitosan (CS)/lanthanum (La) hydrogel beads were first synthesized and tested for phosphorus removal. The stable cross-linked CS/La hydrogel bead prepared with the optimized conditions of 10 wt% La/CS and 1.5 mL of 5% glutaraldehyde demonstrated exceptional performance in the removal. It removed phosphate effectively from an aqueous solution in the pH range from 2 to 7. The complete phosphate uptake was achieved at contact time of 6 h under the completely mixing batch condition. The experimental maximum adsorption capacity of 107.7 mg g-1 was observed at solution pH 4. The phosphate adsorption was well described by the Freundlich isotherm and the intraparticle surface diffusion model. Furthermore, the adsorbent was effectively regenerated and reused in a five-cycle adsorption-desorption operation. The removal of phosphate can be attributed to electrostatic attraction and ion exchange. Moreover, the bead was capable of removing heavy metals: copper, zinc and lead. This adsorbent may be served as a cost-effective material for the treatment of phosphorus-contaminated water so as to minimize the occurrence of eutrophication.

The Early Impact of the IDEA Collaboration Results: How the Results Changed Prescribing Practice.

Background: Traditionally, adjuvant treatment for colon cancer has been 6 months of combination chemotherapy. Six phase III trials tested the hypothesis that 3 months is noninferior in efficacy to 6 months and reduces long-term side effects for patients. The results were pooled in the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration. Although this did not meet the noninferiority endpoint, a preplanned subgroup analysis by chemotherapy regimen did demonstrate noninferiority for capecitabine and oxaliplatin. Additionally, risk stratification by T and N stage was defined. Methods: In an effort to understand the real-life impact of these results, 4 months after the IDEA results, an online survey was distributed to clinicians to ask their approach to the adjuvant treatment of patients with stage III colon cancer. Results: The survey was completed by 458 clinicians from 12 countries. Assuming that 6 months of treatment was the pretrial standard of care, 89.5% of clinicians reported they had changed practice to prescribe 3 months of treatment for some patients. For patients with low-risk stage III disease, there was a preference for 3 months, and for patients with high-risk stage III disease, most clinicians still prescribed 6 months at that time. Overall, capecitabine and oxaliplatin regimen was the most popular. There were important differences in responses depending on the location of respondent and T and N stage of disease. Conclusion: This survey shows that the IDEA collaboration has been practice changing but reveals important differences in the way results are interpreted by individual clinicians.

Incorporation of lanthanum particles to polyethersulfone ultrafiltration membrane for specific phosphorus uptake: Method comparison and performance assessment.

It is known that phosphorus is a major contributor to the occurrence of eutrophication. As such, it is of importance to remove it from water. Nanofiltration (NF) has low phosphorus selectivity and requires a relatively high pressure to achieve the separation, though it is capable of removing phosphorus. In this paper, we report our findings of method development on fabrication and application of a lanthanum (La)-incorporated polyethersulfone (PES)/sulfonated polyphenylenesulfone membrane for phosphorus treatment. The performances of membranes fabricated by the in situ and ex situ methods were examined in a series of batch adsorption and dead-end filtration experiments. The membrane fabricated by the in situ method demonstrated higher adsorption capacity (48.0 mg/g), faster kinetics (equilibrium in 6 h) and higher water permeance (>100 LMH/bar), which outperformed that by the ex situ method. Furthermore, the PES/La (in situ) membrane showed a comparable phosphate removal with a much higher permeance (about 20 times) than the NF90 (a nanofiltration commercial membrane). Moreover, the multiple cycles of filtration study showed that the membrane was reused satisfactorily in treating low-phosphate contaminated water and meeting the stringent phosphate standard limit of 0.15 mg/L. The removal of phosphate by the membranes was attributed to the mechanisms of ion exchange and electrostatic attraction/complexation. The study reported here provides a better approach in fabrication of functionalized membrane for water treatment, such as phosphate removal in either batch adsorption or membrane filtration process.

Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Body Composition among Patients with Advanced or Metastatic Colorectal Cancer: A Randomized Trial.

Skeletal muscle and adipose tissue express the vitamin D receptor and may be a mechanism through which vitamin D supplementation slows cancer progression and reduces cancer death. In this exploratory analysis of a double-blind, multicenter, randomized phase II clinical trial, 105 patients with advanced or metastatic colorectal cancer who were receiving chemotherapy were randomized to either high-dose vitamin D3 (4000 IU) or standard-dose (400 IU) vitamin D3. Body composition was measured with abdominal computed tomography at enrollment (baseline) and after cycle 8 of chemotherapy (16 weeks). As compared with standard-dose vitamin D3, high-dose vitamin D3 did not significantly change body weight [-0.7 kg; (95% CI: -3.5, 2.0)], body mass index [-0.2 kg/m2; (95% CI: -1.2, 0.7)], muscle area [-1.7 cm2; (95% CI: -9.6, 6.3)], muscle attenuation [-0.4 HU; (95% CI: -4.2, 3.2)], visceral adipose tissue area [-7.5 cm2; (95% CI: -24.5, 9.6)], or subcutaneous adipose tissue area [-8.3 cm2; (95% CI: -35.5, 18.9)] over the first 8 cycles of chemotherapy. Among patients with advanced or metastatic colorectal cancer, the addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy did not result in any changes in body composition.

Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer.

IMPORTANCE: Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown. OBJECTIVE: To evaluate the association of coffee consumption with disease progression and death in patients with advanced or metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational cohort study included 1171 patients with previously untreated locally advanced or metastatic colorectal cancer who were enrolled in Cancer and Leukemia Group B (Alliance)/SWOG 80405, a completed phase 3 clinical trial comparing the addition of cetuximab and/or bevacizumab to standard chemotherapy. Patients reported dietary intake using a semiquantitative food frequency questionnaire at the time of enrollment. Data were collected from October 27, 2005, to January 18, 2018, and analyzed from May 1 to August 31, 2018. EXPOSURES: Consumption of total, decaffeinated, and caffeinated coffee measured in cups per day. MAIN OUTCOMES AND MEASURES: Overall survival (OS) and progression-free survival (PFS). RESULTS: Among the 1171 patients included in the analysis (694 men [59%]; median age, 59 [interquartile range, 51-67] years). The median follow-up time among living patients was 5.4 years (10th percentile, 1.3 years; IQR, 3.2-6.3 years). A total of 1092 patients (93%) had died or had disease progression. Increased consumption of coffee was associated with decreased risk of cancer progression (hazard ratio [HR] for 1-cup/d increment, 0.95; 95% CI, 0.91-1.00; P = .04 for trend) and death (HR for 1-cup/d increment, 0.93; 95% CI, 0.89-0.98; P = .004 for trend). Participants who consumed 2 to 3 cups of coffee per day had a multivariable HR for OS of 0.82 (95% CI, 0.67-1.00) and for PFS of 0.82 (95% CI, 0.68-0.99), compared with those who did not drink coffee. Participants who consumed at least 4 cups of coffee per day had a multivariable HR for OS of 0.64 (95% CI, 0.46-0.87) and for PFS of 0.78 (95% CI, 0.59-1.05). Significant associations were noted for both caffeinated and decaffeinated coffee. CONCLUSIONS AND RELEVANCE: Coffee consumption may be associated with reduced risk of disease progression and death in patients with advanced or metastatic colorectal cancer. Further research is warranted to elucidate underlying biological mechanisms.

Effect of B vitamins supplementation on cardio-metabolic factors in patients with stable coronary artery disease: A randomized double-blind trial.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate whether B vitamins supplementation would improve dyslipidemia, alleviate inflammatory state of patients with stable coronary artery disease (SCAD). METHODS AND STUDY DESIGN: We conducted a randomized, double-blind, 12-week, placebo-controlled trial involving adults with SCAD, and who were randomly divided into B vitamins group (folic acid and VB-6) and control group (placebo tablet). Blood tests had also been performed at baseline and endpoint. RESULTS: After 12 weeks of intervention, B vitamins supplementation significantly improved the concentration of serum TG, TC and HDL-C (p<0.05). Changes of serum homocysteine in B vitamins treatment were significantly different compared to placebo by the multivariate-adjusted analysis (3.02±2.35 vs 1.55±1.58 p<0.001). Meanwhile, the levels of IL-1ß and IL-10, significant difference were observed between two groups after adjustment for confounding factors. CONCLUSIONS: Supplementation with B vitamins significantly improves lipid metabolism, alleviate inflammation and serum homocysteine concentration in patients with SCAD.

The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.

Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.

Plasma 25-Hydroxyvitamin D Levels and Survival in Patients with Advanced or Metastatic Colorectal Cancer: Findings from CALGB/SWOG 80405 (Alliance).

PURPOSE: Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer. EXPERIMENTAL DESIGN: We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders. RESULTS: At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20-<30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (P trend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53-0.83) for OS and 0.81 (95% CI, 0.66-1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics. CONCLUSIONS: In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.

Marine ω-3 Polyunsaturated Fatty Acid and Fish Intake after Colon Cancer Diagnosis and Survival: CALGB 89803 (Alliance).

Background: Marine ω-3 polyunsaturated fatty acids (PUFAs), primarily found in dark fish, may prevent colorectal cancer progression, in part through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2). However, data in humans are limited.Methods: We examined marine ω-3 PUFAs and fish intake and survival among 1,011 colon cancer patients enrolled in Cancer and Leukemia Group B 89803 between 1999 and 2001 and followed through 2009. Diet was assessed during and 6 months after chemotherapy. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free (DFS), recurrence-free (RFS), and overall survival (OS).Results: We observed 343 recurrences and 305 deaths (median follow-up: 7 years). Patients in the highest vs. lowest quartile of marine ω-3 PUFA intake had an HR for DFS of 0.72 (95% CI, 0.54-0.97; Ptrend = 0.03). Individuals who consumed dark fish ≥1/week versus never had longer DFS (HR 0.65; 95% CI, 0.48-0.87; P-value = 0.007), RFS (HR 0.61; 95% CI, 0.46-0.86; Ptrend = 0.007), and OS (HR 0.68; 95% CI, 0.48-0.96; Ptrend = 0.04). In a subset of 510 patients, the association between marine ω-3 PUFA intake and DFS appeared stronger in patients with high PTGS2 expression (HR 0.32; 95% CI, 0.11-0.95; Ptrend = 0.01) compared with patients with absent/low PTGS2 expression (HR 0.78; 95% CI, 0.48-1.27; Ptrend = 0.35; Pinteraction = 0.19).Conclusions: Patients with high intake of marine ω-3 PUFAs and dark fish after colon cancer diagnosis may have longer DFS.Impact: Randomized controlled trials examining dark fish and/or marine ω-3 PUFA supplements and colon cancer recurrence/survival are needed. Cancer Epidemiol Biomarkers Prev; 27(4); 438-45. ©2018 AACR.

The potential of hybrid forward osmosis membrane bioreactor (FOMBR) processes in achieving high throughput treatment of municipal wastewater with enhanced phosphorus recovery.

Extensive research in recent years has explored numerous new features in the forward osmosis membrane bioreactor (FOMBR) process. However, there is an aspect, which is revolutionary but not yet been investigated. In FOMBR, FO membrane shows high rejection for a wide range of soluble contaminants. As a result, hydraulic retention time (HRT) does not correctly reflect the nominal retention of these dissolved contaminants in the bioreactor. This decoupling of contaminants retention time (CRT, i.e. the nominal retention of the dissolved contaminants) from HRT endows FOMBR a potential in significantly reducing the HRT for wastewater treatment. In this work, we report our results in this unexplored treatment potential. Using real municipal wastewater as feed, both a hybrid microfiltration-forward osmosis membrane bioreactor (MF-FOMBR) and a newly developed hybrid biofilm-forward osmosis membrane bioreactor (BF-FOMBR) achieved high removal of organic matter and nitrogen under HRT of down to 2.0 h, with significantly enhanced phosphorus recovery capacities. In the BF-FOMBR, the used of fixed bed biofilm not only obviated the need of additional solid/liquid separation (e.g. MF) to extract the side-stream for salt accumulation control and phosphorus recovery, but effectively quarantined the biomass from the FO membrane. The absence of MF in the side-stream further allowed suspended growth to be continuously removed from the system, which produced a selection pressure for the predominance of attached growth. As a result, a significant reduction in FO membrane fouling (by 24.7-54.5%) was achieved in the BF-FOMBR due to substantially reduced bacteria deposition and colonization.

Effect of vitamin B supplementation on cancer incidence, death due to cancer, and total mortality: A PRISMA-compliant cumulative meta-analysis of randomized controlled trials.

BACKGROUND: Observational studies have suggested that vitamin B supplementation is associated with cancer risk, but this association remains controversial. A pooled data-based meta-analysis was conducted to summarize the evidence from randomized controlled trials (RCTs) investigating the effects of vitamin B supplementation on cancer incidence, death due to cancer, and total mortality. METHODS: PubMed, EmBase, and the Cochrane Library databases were searched to identify trials to fit our analysis through August 2015. Relative risk (RR) was used to measure the effect of vitamin B supplementation on the risk of cancer incidence, death due to cancer, and total mortality using a random-effect model. Cumulative meta-analysis, sensitivity analysis, subgroup analysis, heterogeneity tests, and tests for publication bias were also conducted. RESULTS: Eighteen RCTs reporting the data on 74,498 individuals were included in the meta-analysis. Sixteen of these trials included 4103 cases of cancer; in 6 trials, 731 cancer-related deaths occurred; and in 15 trials, 7046 deaths occurred. Vitamin B supplementation had little or no effect on the incidence of cancer (RR: 1.04; 95% confidence interval [CI]: 0.98-1.10; P = 0.216), death due to cancer (RR, 1.05; 95% CI: 0.90-1.22; P = 0.521), and total mortality (RR, 1.00; 95% CI: 0.94-1.06; P = 0.952). Upon performing a cumulative meta-analysis for cancer incidence, death due to cancer, and total mortality, the nonsignificance of the effect of vitamin B persisted. With respect to specific types of cancer, vitamin B supplementation significantly reduced the risk of skin melanoma (RR, 0.47; 95% CI: 0.23-0.94; P = 0.032). CONCLUSION: Vitamin B supplementation does not have an effect on cancer incidence, death due to cancer, or total mortality. It is associated with a lower risk of skin melanoma, but has no effect on other cancers.

Towards high through-put biological treatment of municipal wastewater and enhanced phosphorus recovery using a hybrid microfiltration-forward osmosis membrane bioreactor with hydraulic retention time in sub-hour level.

This work uncovers an important feature of the forward osmosis membrane bioreactor (FOMBR) process: the decoupling of contaminants retention time (CRT) and hydraulic retention time (HRT). Based on this concept, the capability of the hybrid microfiltration-forward osmosis membrane bioreactor (MF-FOMBR) in achieving high through-put treatment of municipal wastewater with enhanced phosphorus recovery was explored. High removal of TOC and NH4(+)-N (90% and 99%, respectively) was achieved with HRTs down to 47min, with the treatment capacity increased by an order of magnitude. Reduced HRT did not affect phosphorus removal and recovery. As a result, the phosphorus recovery capacity was also increased by the same order. Reduced HRT resulted in increased system loading rates and thus elevated concentrations of mixed liquor suspended solids and increased membrane fouling. 454-pyrosequecing suggested the thriving of Bacteroidetes and Proteobacteria (especially Sphingobacteriales Flavobacteriales and Thiothrix members), as well as the community succession and dynamics of ammonium oxidizing and nitrite oxidizing bacteria.

Sustainable water recovery from oily wastewater via forward osmosis-membrane distillation (FO-MD).

This study proposed and investigated a hybrid forward osmosis - membrane distillation (FO-MD) system for sustainable water recovery from oily wastewater by employing lab-fabricated FO and MD hollow fiber membranes. Stable oil-in-water emulsions of different concentrations with small droplet sizes (<1 µm) were firstly prepared and applied as the feed solution in the FO process. Fouling was immediately observed in the FO mode and was low on the cellulose triacetate (CTA) - based thin film composite (TFC) membranes. Moreover, slight increment of fouling was observed in the first few hours and the water flux was then stabilized over 24 h. The characterizations of water flux and solute rejection in separate FO and MD processes revealed that a high water flux, good NaCl rejection, impressively high retention of oil droplets and partial permeation of acetic acid could be achieved. Finally, an integrated FO-MD system was developed to treat the oily wastewater containing petroleum, surfactant, NaCl and acetic acid at 60 °C in the batch mode. The water flux in FO undergoes three-stage decline due to fouling and reduction in osmotic driving force, but is quite stable in MD regardless of salt concentration. Oily wastewater with relatively high salinity could be effectively recovered by the FO-MD hybrid system while maintaining large water flux, at least 90% feed water recovery could be readily attained with only trace amounts of oil and salts, and the draw solution was re-generated for the next rounds of FO-MD run. Interestingly, significant amount of acetic acid was also retained in the permeate for further reuse as a chemical additive during the production of crude oil. The work has demonstrated that not only water but also organic additives in the wastewater could be effectively recovered by FO-MD systems for reuse or other utilizations.

Cactus pear extracts induce reactive oxygen species production and apoptosis in ovarian cancer cells.

The protective effect of natural products such as fruits and vegetables against cancer has attracted great attention because of their fewer side effects and therefore, potentially greater safety. We have previously reported that cactus pear mixture aqueous extract (CME) reduces gynecologic cancer cells growth by inducting apoptosis. This study aimed to elucidate the cellular pathway(s) triggered by CME in cancer cells. Normal, immortalized ovarian and ovarian cancer cells (OVCA420, SKOV3) were treated with 5 and 10% CME. After 2 days of treatment, immortalized cells treated with 10% CME accumulated more ROS than untreated cells, whereas cancer cells cultured with 5% and 10% CME exhibited a dramatic increase of reactive oxygen species (ROS). Greater levels of DNA fragmentation, together with a perturbed expression of apoptotic-related (Bax, Bad, caspase 3, Bcl2, p53, and p21) and ROS-sensitive (NF-kappaB, c-jun/c-fos) genes were observed in the treated cancer cells. After three days of treatment, the NF-kappaB and p-/SAPK/JNK expressions were decreased, whereas p-AKT was upregulated. The CME significantly induced apoptosis in cancer cells. The results suggest an inhibitory effect of Arizona CME on cancer cell growth through the accumulation of intracellular ROS, which may activate a cascade of reactions leading to the apoptosis.

Bioactivity-guided fractionation and GC/MS fingerprinting of Angelica sinensis and Angelica archangelica root components for antifungal and mosquito deterrent activity.

Bioassay-guided fractionation of the chloroform extract from the roots of Angelica sinensis led to isolation and characterization of (Z)-ligustilide using direct-bioautography with Colletotrichum species. The structure of (Z)-ligustilide was confirmed by (1)H and (13)C NMR spectroscopy and GC/MS. (Z)-Ligustilide deterred the biting of two mosquito species more effectively than DEET. Three different A. sinensis accessions and one Angelica archangelica root oil were evauated by GC and GC/MS, and the dominant component in A. sinensis was 61-69% (Z)-ligustilide. Two other prominent compounds in A. sinensis oils were 5.7-9.8% (E)-3-butylidene phthalide and 1.5-2.3% (Z)-3-butylidene phthalide. The main constituents that comprised A. archangelica oil were monoterpene hydrocarbons such as 24.5% alpha-pinene, 13.8% delta-3-carene, 10.1% beta-phellandrene, 8.8% p-cymene, 8.4% limonene, and 6.3% sabinene. Phthalides and monoterpene hydrocarbons were determined to be good systematic markers or chemical fingerprints for A. sinensis and A. archangelica root oils. Chemical fingerprinting by GC/MS of A. sinensis also confirmed the misidentification of one A. archangelica sample sold in the Chinese market.

Heteroaryl beta-tetralin ureas as novel antagonists of human TRPV1.

We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.

High-throughput screening for N-type calcium channel blockers using a scintillation proximity assay.

N-type calcium channels located on presynaptic nerve terminals regulate neurotransmitter release, including that from the spinal terminations of primary afferent nociceptors. Accordingly, N-type calcium channel blockers may have clinical utility as analgesic drugs. A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain. To develop a small-molecule N-type calcium channel blocker, the authors developed a 96-well plate high-throughput screening scintillation proximity assay (SPA) for N-type calcium channel blockers using [125I]-labeled omega-conotoxin GVIA as a channel-specific ligand. Assay reagents were handled using Caliper's Allegro automation system, and bound ligands were detected using a PerkinElmer TopCount. Using this assay, more than 150,000 compounds were screened at 10 microM and approximately 340 compounds were identified as hits, exhibiting at least 40% inhibition of [125I]GVIA binding. This is the 1st demonstration of the use of [125I]-labeled peptides with SPA beads to provide a binding assay for the evaluation of ligand binding to calcium channels. This assay could be a useful tool for drug discovery.

[Function of pancreatic islet beta cells and features of TCM symptoms and syndromes in the non-diabetic first-grade relatives of patients with type 2 diabetes mellitus].

OBJECTIVE: To study the function of pancreatic islet beta cells, insulin resistance (IR) and features of TCM symptoms and syndromes in the non-diabetic first-grade relatives (ND1GR) of patients with type 2 diabetes mellitus (DM2). METHODS: A total of 68 ND1GR of DM2 patients were enrolled in the observed group and 45 healthy subjects with matched sex, age and body mass index (BMI) but without family history of DM were selected into the control group. Levels of fasting blood glucose (FBG), 2 hrs postprandial glucose (2hPG), fasting insulin (FINS) and 2 hrs postprandial insulin (2h INS) in all the subjects were measured to calculate and compare the IR and beta-cell function of the homeostatic model analog (HOMA-IR and HOMA-beta), and the insulin sensitive index (ISI). Moreover, the symptoms manifested in the ND1GR were also observed to analyze the features in them. RESULTS: FBG and FINS were obviously higher in the observed group than those in the control group (P < 0.01), while no significant difference was found in 2hPG or 2h INS (P > 0.05). HOMA-IR and HOMA-beta were significantly higher (P < 0.05) and ISI were significantly lower (P < 0.01) in the observed group than those in the control group. Compared with the control group, the main symptoms such as dark purplish tongue, listlessness, thready and thin pulse, lassitude in loin and legs in the observed group were seen more frequently. In the observed group syndrome of deficiency of Qi and Yin accounted for 51.47%, syndrome of deficiency of Yin for 30.88%, subjects with syndrome of blood stasis as the main accompanying syndrome accounts for 61.76%. CONCLUSION: Higher beta cell secretion function and lower insulin sensitivity appear in ND1GR of DM2 patients, suggesting the existence of insulin resistance. The feature of TCM syndrome in them is characterized by deficiency of Qi and Yin with inner obstruction of blood stasis.