Degradation of imazapic and imazapyr herbicides in the presence of optimized oil palm empty fruit bunch and rice husk biochars in soil.

Imidazolinones as a persistent and active herbicides group have potential risks to non-target organisms in the environment. Biochar is a carbon-rich sorbent used as an amendment to change soil properties and its microbial communities effective on pesticides degradation rate. The present study was the first to compare empty fruit bunch (EFB) of oil palm and rice husk (RH) biomasses as biochar feedstock for remediation of imidazolinones-contaminated soils. Degradations of imazapic, imazapyr, and a mixture of them (Onduty®) was investigated in the presence of the optimized biochars in the soil during a 70-days incubation. Based on the results, the polar herbicides were resistant to hydrolysis degradation. Photolysis rates of the herbicides reduced significantly in the presence of the biochars in the soil. EFB biochar had greater effects due to its chemical compositions and surface functional groups. Photo-degradation of imazapyr was more affected by biochars amendment. The imidazolinones bio-degradation, however, accelerated significantly with the presence of EFB and RH biochars in soil with the greater effects of RH biochar. It was concluded that the application of the optimized EFB and RH biochars as an innovative sustainable strategy has the potential to decrease the persistence of the imidazolinones and minimize their environmental hazards.

Multi-targeting effects of a new synthetic molecule (JM-20) in experimental models of cerebral ischemia.

Ischemic stroke is a major cause of death and disability worldwide. Thrombolysis by tissue plasminogen activator is the only pharmacological treatment approved for clinical practice, but has a narrow therapeutic window and poor efficacy when the cell death cascade is activated. Numerous drugs that are thought to protect neurons against injury have previously failed in human trials despite showing efficacy in experimental models of stroke. Herein, we reviewed the main pre-clinical results of the neuroprotective effects of JM-20, a new hybrid molecule, against brain ischemia. JM-20 appears to protect the brain from ischemic damage by interfering with several elements of the ischemic cascade: antiexcitotoxic, anticalcic, antioxidant, antiapoptotic, and anti-inflammatory. Its ability to protect not only neurons but also glial cells together with its ability to target and preserve mitochondrial function makes JM-20 a promising molecule that may be able to shield the whole neurovascular unit. The multimodal and multi-cell action of JM-20 may explain the high degree of protection observed in a rat model of brain ischemia, as assayed through histological (hematoxylin-eosin, and luxol fast blue staining), neurochemical (glutamate and aspartate levels in cerebrospinal fluid), mitochondrial functionality and behavioural (neurological scale) analysis at doses of 4 and 8mg/kg. Furthermore, the wide therapeutic window of JM-20 of 8h also suggests that this molecule could be of potential interest in situations where brain perfusion is compromised.

Urinary Excretion of Niacin Metabolites in Humans After Coffee Consumption.

SCOPE: Coffee is a major natural source of niacin in the human diet, as it is formed during coffee roasting from the alkaloid trigonelline. The intention of our study was to monitor the urinary excretion of niacin metabolites after coffee consumption under controlled diet. METHODS AND RESULTS: We performed a 4-day human intervention study on the excretion of major niacin metabolites in the urine of volunteers after ingestion of 500 mL regular coffee containing 34.8 µmol nicotinic acid (NA) and 0.58 µmol nicotinamide (NAM). In addition to NA and NAM, the metabolites N1 -methylnicotinamide (NMNAM), N1 -methyl-2-pyridone-5-carboxamide (2-Py), and nicotinuric acid (NUA) were identified and quantified in the collected urine samples by stable isotope dilution analysis (SIVA) using HPLC-ESI-MS/MS. Rapid urinary excretion was observed for the main metabolites (NA, NAM, NMNAM, and 2-Py), with tmax values within the first hour after ingestion. NUA appeared in traces even more rapidly. In sum, 972 nmol h-1 of NA, NAM, NMNAM, and 2-Py were excreted within 12 h after coffee consumption, corresponding to 6% of the ingested NA and NAM. CONCLUSION: The results indicate regular coffee consumption to be a source of niacin in human diet.

4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis.

The continued emergence of bacteria resistant to current standard of care antibiotics presents a rapidly growing threat to public health. New chemical entities (NCEs) to treat these serious infections are desperately needed. Herein we report the discovery, synthesis, SAR and in vivo efficacy of a novel series of 4-hydroxy-2-pyridones exhibiting activity against Gram-negative pathogens. Compound 1c, derived from the N-debenzylation of 1b, preferentially inhibits bacterial DNA synthesis as determined by standard macromolecular synthesis assays. The structural features of the 4-hydroxy-2-pyridone scaffold required for antibacterial activity were explored and compound 6q, identified through further optimization of the series, had an MIC90 value of 8 µg/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8 mg/kg in mice infected with a lethal dose of E. coli. This novel series of 4-hydroxy-2-pyridones serves as an excellent starting point for the identification of NCEs treating Gram-negative infections.

Dihydropyridines' metabolites-induced early apoptosis after myocardial infarction in rats; new outlook on preclinical study with M-2 and M-3.

Our previous studies established cardio-protective effects of furnidipine and its active metabolites called M-2 and M-3. The aim of current research was to compare the effects of single oral pretreatment with 20 mg kg(-1) of M-2 and M-3 on mortality, different forms of arrhythmias, blood pressures parameters and ST-segment changes during occlusion (for 90 min) and reperfusion in the model of myocardial infarction in rats evoked by left anterior descending coronary artery occlusion. Additionally, the development of programmed cell death and biochemical parameters in blood serum were studied at 4th day after infarction. Furnidipines' metabolites effectively reduced mortality index while did not markedly influence on blood pressures parameters, arrhythmias, ST-segment changes as well as biochemical parameters. Intriguingly, programmed cell death study (TUNEL) showed distinct increase in the amount of apoptotic nuclei in post-infarcted myocardium, granulation tissue and what is more in arteriolar walls after M-2 and M-3 application. Moreover, M-2 turned out to be more powerful in stimulation of apoptosis in granulation tissue surrounding infarcted area whereas M-3 presented balanced profile in this matter. Taking into account that programmed cell death plays positive role in post-infarcted heart healing, M-2 presents itself as more attractive agent for oral pretreatment in early stages of ischemia by non-stable individuals due to its more specific action in stimulation repairing processes in granulation tissue as well as in arteriolar walls. While M-2 and M-3 are common metabolites present in degradation pathways of many widely used dihydropyridines in clinic, this key fact put the new outlook on understanding additional mechanism and effects of not only furnidipines' metabolites but also other dihydropyridines.

Structure and antibacterial property of a new diterpenoid from Euphorbia helioscopia.

The present study was designed to isolate and evaluate the antibacterial activity of the compounds from the whole plant of Euphorbia helioscopia L.. Various chromatographic techniques were used to isolate and purify the compound. The structure of the compound was elucidated on basis of spectral data ((1)H NMR, (13)C NMR, (1)H-(1)H COSY, HSQC, HMBC, NOESY, IR, and HR-ESI-MS). A new jatrophone-type diterpenoid (14α,15ß-diacetoxy-3ß-benzoyloxy-7ß-nicotinoyloxy-9-oxo-jatropha-5E,11E-diene), named euphoheliosnoid E (1), was isolated from the whole plant of E. helioscopia L. Compound 1 showed significant anti-microbial activity against oral pathogens.

Plant-derived anti-inflammatory compounds: hopes and disappointments regarding the translation of preclinical knowledge into clinical progress.

Many diseases have been described to be associated with inflammatory processes. The currently available anti-inflammatory drug therapy is often not successful or causes intolerable side effects. Thus, new anti-inflammatory substances are still urgently needed. Plants were the first source of remedies in the history of mankind. Since their chemical characterization in the 19th century, herbal bioactive compounds have fueled drug development. Also, nowadays, new plant-derived agents continuously enrich our drug arsenal (e.g., vincristine, galantamine, and artemisinin). The number of new, pharmacologically active herbal ingredients, in particular that of anti-inflammatory compounds, rises continuously. The major obstacle in this field is the translation of preclinical knowledge into evidence-based clinical progress. Human trials of good quality are often missing or, when available, are frequently not suitable to really prove a therapeutical value. This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG), and quercetin. We will highlight their clinical potential and/or pinpoint an overestimation. Moreover, we will sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound.

Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia.

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.

Characterization of the anxiolytic and sedative profile of JM-20: a novel benzodiazepine-dihydropyridine hybrid molecule.

OBJECTIVES: The aim of this study was to investigate the effects of oral administration of a novel benzodiazepine derivative, JM-20, on the neurological behavior of different rodent models, focusing on the GABAergic effect. We have also investigated the acute toxicity of oral administration of JM-20 in mice. METHODS: Mice or rats received oral administration of JM-20 at 2, 4, 8, and 10 mg/kg to evaluate the sedative/hypnotic, anxiolytic, and anticonvulsant effects, as well as the influence on the stereotyped behavior induced by amphetamine. Diazepam (DZP) was used as a positive control. In addition, the mice received a single oral JM-20 dose of 2000 mg/kg to evaluate the acute toxicity. RESULTS: In a dose-dependent manner, JM-20 (i) increased the number of crossings and decreased the number of rearings in the open-field test; (ii) decreased the aggressive behavior of socially-isolated mice; and (iii) increased the latency period for tonic seizure's onset and the percentage of survival of animals with seizures. Moreover, JM-20 increased the sleeping time induced by barbiturates and the time spent and the number of entries in the open arms of the elevated plus-maze test. In the JM-20 toxicity test, no mortality was observed and only minor signs of toxicity associated with sedation were detected. CONCLUSIONS: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice.

Prospects for malaria elimination in non-Amazonian regions of Latin America.

Latin America contributes 1-1.2 million clinical malaria cases to the global malaria burden of about 300 million per year. In 21 malaria endemic countries, the population at risk in this region represents less than 10% of the total population exposed worldwide. Factors such as rapid deforestation, inadequate agricultural practices, climate change, political instability, and both increasing parasite drug resistance and vector resistance to insecticides contribute to malaria transmission. Recently, several malaria endemic countries have experienced a significant reduction in numbers of malaria cases. This is most likely due to actions taken by National Malaria Control Programs (NMCP) with the support from international funding agencies. We describe here the research strategies and activities to be undertaken by the Centro Latino Americano de Investigación en Malaria (CLAIM), a new research center established for the non-Amazonian region of Latin America by the National Institute of Allergy and Infectious Diseases (NIAID). Throughout a network of countries in the region, initially including Colombia, Guatemala, Panama, and Peru, CLAIM will address major gaps in our understanding of changing malaria epidemiology, vector biology and control, and clinical malaria mainly due to Plasmodium vivax. In close partnership with NMCPs, CLAIM seeks to conduct research on how and why malaria is decreasing in many countries of the region as a basis for developing and implementing new strategies that will accelerate malaria elimination.

Direct trapping of acrylamide as a key mechanism for niacin's inhibitory activity in carcinogenic acrylamide formation.

The inhibitory mechanism of niacin, which was found in our previous study to effectively reduce acrylamide (AA) formation in both chemical models and fried potato strips, was investigated in the present study. Maillard chemical models containing the amino acid asparagine and glucose with or without niacin were closely examined by liquid chromatography/tandem mass spectrometry. Comparison of the chemical profiles revealed two additional peaks in models where niacin was present together with the AA precursors, which thus suggests the formation of compounds from reactions between niacin and other chemical species in the model systems. The predicted molecular weights of these two analytes were consistent with adducts formed between niacin and asparagine or AA, respectively. The niacin-acrylamide adduct was also detected in fried potato strips pretreated with niacin. In addition, the niacin-acrylamide adduct was subsequently purified and characterized by NMR spectroscopy as 1-propanamide-3-carboxy pyridinium, a novel compound that has never been reported previously. Furthermore, incubation of niacin with AA in simulated physiological conditions showed that niacin was capable of significantly reducing the level of AA. Findings from this study suggest that niacin not only has the potential to remove AA from food products during heat treatment by directly trapping it but also is a potential agent to scavenge AA in human body.

Differential effects of furnidipine and its active metabolites in rat isolated working heart.

1,4,-dihydropyridines, belonging to the class of "privileged structures", are known to protect the heart from stunning, ischemia and ventricular arrhythmias and mainly used in hypertension. The aim of this study was to compare the continuous infusion of parent drug, furnidipine, with its two active metabolites (M-2; M-3) in rat isolated working heart model, where the following parameters were measured and calculated: heart rate, preload pressure, aortic systolic and diastolic pressures (AoD), as well as +/-dP/dt, aortic (AF) and coronary flow (CF), oxygen and carbon dioxide partial pressures and pH values in pulmonary effluent, myocardial oxygen consumption. At first, the optimal vasodilatatory dose of M-2 was estimated and afterwards it was compared with equivalent doses of both remaining substances. The strongest vasodilatatory effects were observed after the lowest dose of M-2 was used (10(-7) M), at the same time being without marked influence on pressure parameters. The pro-drug evoked significantly weaker influence on both flows. Furthermore, furnidipine significantly reduced AoD and AF in comparison to control as well as +dP/dt in comparison to the initial values, while M-2 did not. Both metabolites caused a significant CF increase, but M-3 additionally the AoS and AoD decrease in comparison to the control. Regarding clear differences in the measured parameters between the pro-drug and its metabolites found, the obtained results allow to claim that the metabolites vs. furnidipine possess a beneficial influence. The distinct flow shift from aorta into the coronaries was observed only after M-2 and to a lesser extent--M-3. The cardio-depressant potency of both metabolites is overcome by advantageous vasodilatatory effect. M-2, being a final product, easier to control and at the same time a precursor of the new chemical class of therapeutics, is promising as a cardio-protective agent.

Effect of myristyl nicotinate on retinoic acid therapy for facial photodamage.

Based on the hypothesis that skin barrier impairment is a contributor to side-effects associated with retinoic acid therapy, a double-blind, placebo-controlled pilot study examined the combined use of retinoic acid with myristyl nicotinate (MN), a lipophilic derivative of niacin that enhances skin barrier function, in female subjects with mild to moderate facial photodamage. The study involved a 1-month run-in period with placebo or MN prior to initiation of retinoic acid therapy for 3 months. Analysis of skin biopsies revealed that retinoic acid therapy resulted in stratum corneum thinning of approximately 25% (P = 0.006 versus baseline) that was ameliorated by MN use (P < 0.005). Therapy resulted in an increased rate of transepidermal water loss (TEWL) of approximately 45% (P = 0.001 versus baseline) and use of MN protected against the increase in TEWL with the strongest protection provided by prior use of MN (P = 0.056 versus placebo). MN use reduced the incidence of side-effects of the therapy and again prior use provided the greatest reduction of side-effects. Subjects showed statistically significant clinical improvement (P < 0.05 versus baseline) during the study. MN use did not interfere with any clinical improvement parameters and improved effects on temple laxity (P = 0.01 versus placebo). Analysis of changes in epidermal thickness, Ki67-positive cells and intensity of loricrin staining demonstrated that MN either improved or did not interfere with retinoic acid efficacy. These results show that prior and concurrent use of MN can mitigate barrier impairment and improve the tolerability of retinoic acid therapy for facial photodamage without interfering with efficacy.

Comparison of pre- and/or postphotodynamic therapy and intense pulsed light treatment protocols for the reduction of postprocedure-associated symptoms and enhancement of therapeutic efficacy.

Photodynamic therapy (PDT) and intense pulsed light therapy (IPL) are commonly used in the setting of photorejuvenation. Patient expectations for minimal to no downtime associated with these procedures has become an increasingly important issue. In an attempt to define a topical skin care regimen that would reduce procedure-related symptoms and possibly enhance therapeutic efficacy, 4 separate topical products were examined. Avène Thermal Spring Water (Laboratoires Dermatologiques Avène, Les Cauquillous, France), NIA 24 (Niadyne, Inc, Research Triangle Park, NC), MimyX cream (Stiefel Laboratories, Coral Gables, FL), and Biafine (OrthoNeutrogena, Los Angeles, CA) were studied individually in the setting of either PDT or IPL treatments. The results of these studies indicate that a pre- and/or postprocedure topical skin care regimen can be beneficial in reducing postprocedure symptoms.

Anticonvulsant and acute neurotoxic characteristics of nicotinic acid benzylamide: a preclinical study.

The aim of this study was to evaluate time-course and dose-response relationships of nicotinic acid benzylamide (Nic-BZA) with regard to its anticonvulsant activity in the maximal electroshock (MES)-induced seizures and acute neurotoxic effects in terms of motor coordination impairment in the chimney test in mice. The experimental determination of both median effective dose (ED(50)) and median toxic dose (TD(50)) allowed for the calculation of protective index (PI) values characterizing a preclinical profile of Nic-BZA. Results indicated that Nic-BZA produced the time-dependent and clear-cut anticonvulsant activity in the MES test and its ED(50) values ranged between 35.7 and 84.0 mg/kg (after the ip administration of the agent at 5 and 60 min, respectively), and between 72.0 and 152.1 mg/kg (at 5 and 60 min, respectively, following the po administration of Nic-BZA). In the chimney test, the TD(50) values for Nic-BZA, after its ip administration ranged between 188.5 and 509.9 mg/kg, whereas following its po administration the TD(50) values for Nic-BZA were between 552 and 1222.1 mg/kg. The PI values for Nic-BZA, calculated at various times after its ip and po administrations (ranging between 3.56 and 17), revealed that the agent has a favorable profile, when considering its both anticonvulsant and acute neurotoxic effects in this preclinical study. Based on this study, one can conclude that Nic-BZA might occur advantageous as a potential antiepileptic drug for breaking seizure attacks in patients with epilepsy.

A comparative toxicologic and genotoxic study of the herbicide arsenal, its active ingredient imazapyr, and the surfactant nonylphenol ethoxylate.

The herbicide arsenal 250 NA, its technical-grade active ingredient imazapyr, and the surfactant nonylphenol ethoxylate (NP) were evaluated through genotoxicity and toxicity studies in different organisms. A comparative study of these three compounds was carried out to assess how the addition of surfactant components may pose the highest toxicological risk to pesticide formulations. The results showed that arsenal, imazapyr, and NP did not cause chromosome aberration in Allium cepa nor increase the frequency of micronuclei in mice. However, toxicological evaluations showed that NP was the most toxic compound to mice, A. cepa, Drosophila melanogaster, and Biomphalaria tenagophila. In this evaluation, it was observed that the adverse effects were produced by the surfactant additive of the pesticide formulation.

Use of imazapyr against Equisetum arvense on Swedish railway tracks.

Since glyphosate has been used extensively for weed control in Swedish railway tracks, common horsetail (Equisetum arvense L), previously relatively rare, has become very common. Glyphosate, although effective against most other weeds found on railway tracks, gives poor control of E. arvense, so that heavy infestation with this weed is now common. Imazapyr (applied as a 250g AE litre(-1) SL, Arsenal) has controlled E. arvense, but is known to be very mobile. Adequate control of the weed requires application of > or = 4 litres ha(-1) of imazapyr SL but environmental factors preclude the use of > 2 litres ha(-1). A suitable strategy was found to be one application of imazapyr SL at 2 litres ha(-1) in each of two successive years but best weed control was obtained by supplementing imazapyr in the first year with glyphosate 360 g AE litre(-1) SL (RoundUp Bio) at 3 litres ha(-1).

Chemical constituents of Euphorbia marschalliana Boiss.

Acetone extract of aerial parts of Euphorbia marschalliana collected from Iran has been subjected to different chromatography techniques for fractionation and purification. The stereo-structures of the myrsinol esters 15-O-acetyl-3-O-propionyl-5-O-butanoyl-7-O-nicotinoylmyrsinol (1) and 15-O-acetyl-3,5-O-dibutanoyl-7-O-nicotinoylmyrsinol (2) have been probed using ROESY spectroscopy and modified for the stereochemistry at C-6, C-12 and C-13. Beta-sitosterol (3), 29-norcycloart-5-ene (4), 5,8-lanostadiene-3beta-ol (5), 3beta,24(S),25-trihydroxycycloartane (6), 3beta,24(R),25-trihydroxycycloartane (7) and 24-methylenecycloartan-3beta-ol (8) were identified for the first time in this plant.

Evaluation of visual and olfactory cues for sampling three thrips species (Thysanoptera: Thripidae) in deciduous forests of the northern United States.

The introduced basswood thrips, Thrips calcaratus Uzel pear thrips, Taeniothrips inconsequens (Uzel), and native basswood thrips, Neohydatothrips tiliae (Hood), form a thrips complex that attacks buds and foliage of basswood, Tilia americana L., trees in the northern United States. We assessed the potential for exploiting visual and olfactory cues to monitor these forest thrips. We tested blue, green, red, white, and yellow for thrips' response to visual stimuli, and anisaldehyde, ethyl nicotinate, and polar and nonpolar extracts of basswood buds or leaves for thrips' response to olfactory stimuli over a 2-yr period. Generally, yellow traps tended to elicit the greatest visual response from all three species. None of the species showed significant attraction to the test volatiles compared with controls. The introduced basswood thrips, which is closely associated with expanding buds, was the most abundant species, and occurred earlier in the spring than the two flower- or foliage-associated species. The implications of these behaviors are discussed with respect to a forest pest monitoring program.