Effect of Hydralazine on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E-Deficient Mice.

The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in this field. Increased vascular inflammation and enhanced apoptosis of vascular smooth muscle cells (VSMCs) are implicated in AAA formation.

Montjuïc Hill (Barcelona): A Hotspot for Plant Invasions in a Mediterranean City.

Cities are often hotspots for biological invasions, showing much higher percentages of alien species than non-urbanized settings. The reasons are multiple and are mostly related to two main factors: their heterogeneous, highly disturbed habitats and their many gateways that allow alien species introduction (e.g.

Vascular traffic control of neutrophil recruitment to the liver by microbiota-endothelium crosstalk.

During bloodstream infections, neutrophils home to the liver as part of an intravascular immune response to eradicate blood-borne pathogens, but the mechanisms regulating this crucial response are unknown. Using in vivo imaging of neutrophil trafficking in germ-free and gnotobiotic mice, we demonstrate that the intestinal microbiota guides neutrophil homing to the liver in response to infection mediated by the microbial metabolite D-lactate. Commensal-derived D-lactate augments neutrophil adhesion in the liver independent of granulopoiesis in bone marrow or neutrophil maturation and activation in blood.

Effects of computer-based cognitive rehabilitation on working memory in patients with acquired brain injury in the chronic phase, a pilot-study.

Background: Working memory impairment is common in patients in the chronic phase after acquired brain injury (ABI), and there is a need to develop efficacious rehabilitation methods. This trial explored the effects of two different computer-based cognitive rehabilitation (CBCR) programmes on working memory in the chronic phase after ABI, as well as the role of continuous support versus no support from a health professional on the efficacy of CBCR.

Methods: A total of 72 patients were randomized into four different groups for a 12-week intervention: Two groups trained with the CBCR-programmes 'Cogmed' and 'Brain+ Health,' respectively, and one group completed active-control training.

Selective biocatalytic hydroxylation of unactivated methylene C-H bonds in cyclic alkyl substrates.

The cytochrome P450 monooxygenase CYP101B1 from Novosphingobium aromaticivorans selectively hydroxylated methylene C-H bonds in cycloalkyl rings. Cycloketones and cycloalkyl esters containing C6, C8, C10 and C12 rings were oxidised with high selectively on the opposite side of the ring to the carbonyl substituent. Cyclodecanone was oxidised to oxabicycloundecanol derivatives in equilibrium with the hydroxycyclodecanones.

Facilitating adaptive management in a government program: A household energy efficiency case study.

Interim evaluations of government programs can sometimes reveal lower than expected outcomes, leading to the question of how adjustments can be made while the program is still underway. Although adaptive management frameworks can provide a practical roadmap to address this question, a lack of successful learnings and poor implementation have hampered the progress and wider application of adaptive management. Using a case study involving an energy efficiency government program targeting low-income households, this article provides supporting evidence on how adaptive management can be facilitated and applied.

In vivo activity of benzoyl ester clerodane diterpenoid derivatives from Dodonaea polyandra.

Four new benzoyl ester clerodane diterpenoids, 15,16-epoxy-8α-(benzoyloxy)methylcleroda-3,13(16),14-trien-18-oic acid (1), 15,16-epoxy-8α-(benzoyloxy)methyl-2α-hydroxycleroda-3,13(16),14-trien-18-oic acid (2), 15,16-epoxy-8α-(benzoyloxy)methyl-2-oxocleroda-3,13(16),14-trien-18-oic acid (3), and 15,16-epoxy-2α-benzoyloxycleroda-3,13(16),14-trien-18-oic acid (4), have been isolated from the leaves and stems of Dodonaea polyandra. The anti-inflammatory activities of compounds 1, 2, and 4 were evaluated by means of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. Compounds 2 and 4 exhibited maximum inhibition of inflammation (70-76%) at doses of 0.

The potential for bias in reporting of industry-sponsored clinical trials.

Concerns about potentially misleading reporting of pharmaceutical industry research have surfaced many times. The potential for duality (and thereby conflict) of interest is only too clear when you consider the sums of money required for the discovery, development and commercialization of new medicines. As the ability of major, mid-size and small pharmaceutical companies to innovate has waned, as evidenced by the seemingly relentless decline in the numbers of new medicines approved by Food and Drug Administration and European Medicines Agency year-on-year, not only has the cost per new approved medicine risen: so too has the public and media concern about the extent to which the pharmaceutical industry is open and honest about the efficacy, safety and quality of the drugs we manufacture and sell.

Making available information from studies sponsored by the pharmaceutical industry: some current practices.

Since the web-based registry ClinicalTrials.gov was launched on 29 February 2000, the pharmaceutical industry has made available an increasing amount of information about the clinical trials that it sponsors. The process has been spurred on by a number of factors including a wish by the industry to provide greater transparency regarding clinical trial data; and has been both aided and complicated by the number of institutions that have a legitimate interest in guiding and defining what should be made available.

Proposed best practice for statisticians in the reporting and publication of pharmaceutical industry-sponsored clinical trials.

In this paper we set out what we consider to be a set of best practices for statisticians in the reporting of pharmaceutical industry-sponsored clinical trials. We make eight recommendations covering: author responsibilities and recognition; publication timing; conflicts of interest; freedom to act; full author access to data; trial registration and independent review. These recommendations are made in the context of the prominent role played by statisticians in the design, conduct, analysis and reporting of pharmaceutical sponsored trials and the perception of the reporting of these trials in the wider community.

Sequential and selective Buchwald-Hartwig amination reactions for the controlled functionalization of 6-bromo-2-chloroquinoline: synthesis of ligands for the Tec Src homology 3 domain.

Src homology 3 (SH3) domains are highly conserved protein-protein interaction domains that mediate important biological processes and are considered valuable targets for the development of therapeutic agents. In this paper, we report the preparation of a range of new 6-heterocyclic substituted 2-aminoquinolines using Buchwald-Hartwig chemistry. 6-Heterocyclic substitution of the 2-aminoquinoline has provided ligands with increased binding affinity for the SH3 domain relative to the lead compound, 2-aminoquinoline, that are the highest affinity ligands prepared to date.

Characterisation and in vitro cytotoxicity of triorganophosphinegold(i) 2-mercaptobenzoate complexes.

The preparation and full NMR ((1)H, (13)C and (31)P) characterisation of three [R(3)PAu(2mba)] complexes, Where R = Et, Ph and Cy, and 2mba is the anion derived from 2-mercaptobenzoic acid is reported. An interesting solvent dependence in the (1)H spectra is rationalised in terms of competing intra- and inter-molecular hydrogen bonding. An X-ray analysis of the [Ph(3) PAu(2mba)] species reveals a linear P-Au-S arrangement and association in the lattice via the familar carboxylic acid dimer motif.

Carbonyl-scavenging drugs & protection against carbonyl stress-associated cell injury.

This mini-review highlights the chemical and cytoprotective properties of various hydralazine analogues that block the induction of cell death by acrolein, a highly toxic contributor to "carbonyl stress" during a diverse range of human diseases. Recent work on the action of hydralazine against various carbonyl-mediated pathologies is also reviewed.

Antimicrobial compounds from the Australian desert plant Eremophila neglecta.

A crude extract from the Australian desert plant Eremophila neglecta has recently been shown to possess antibacterial activity in a survey of candidate plants that may bear novel antimicrobial compounds. Bioassay-directed fractionation of the Et(2)O extract of E. neglecta using a broth microdilution assay led to the isolation of three new serrulatane-type diterpenoids, 2,19-diacetoxy-8-hydroxyserrulat-14-ene (2), 8,19-dihydroxyserrulat-14-ene (3), and 8-hydroxyserrulat-14-en-19-oic acid (4), and a known o-naphthoquinone commonly referred to as biflorin (5).

Antimicrobial compounds from Eremophila serrulata.

We report a search for antimicrobial compounds in the Australian plant Eremophila serrulata. Bioassay directed fractionation of a diethyl ether extract prepared from the leaves of E. serrulata led to the isolation of two compounds, an omicron-naphthoquinone, 9-methyl-3-(4-methyl-3-pentenyl)-2,3-dihydronaphtho[1,8-bc]pyran-7,8-dione (2), and a serrulatane diterpenoid, 20-acetoxy-8-hydroxyserrulat-14-en-19-oic acid (3).

Michael addition of acrolein to lysinyl and N-terminal residues of a model peptide: targets for cytoprotective hydrazino drugs.

The antihypertensive drug hydralazine blocks acrolein-mediated toxicity by trapping both free aldehyde- and acrolein-adducted proteins, with the latter property more closely related to cytoprotection in cellular models. Here we report the identification of products from 'protein adduct-trapping' reactions using electrospray ionisation mass spectrometry (ESI-MS). Reaction of a 13-residue peptide containing a single lysine with acrolein for 30 min generated ions corresponding to mono- and bis-Michael-adducted peptides.

Enantioselective assay for the determination of perhexiline enantiomers in human plasma by liquid chromatography.

Effective use of the antianginal agent perhexiline is difficult because saturable metabolism by the polymorphic cytochrome P450 2D6 (CYP2D6) isoform produces elevated plasma perhexiline concentrations that have been associated with serious hepatic and neurological toxicity. Perhexiline is marketed for therapeutic use as a racemate and there is evidence for differences in the disposition of its enantiomers. The current study describes an enantioselective HPLC-fluorescent method utilising pre-column derivatization with (R)-(-)-1-(1-napthyl)ethyl isocyanate.

Hydralazine inhibits rapid acrolein-induced protein oligomerization: role of aldehyde scavenging and adduct trapping in cross-link blocking and cytoprotection.

Hydralazine strongly suppresses the toxicity of acrolein, a reactive aldehyde that contributes to numerous health disorders. At least two mechanisms may underlie the cytoprotection, both of which involve the nucleophilic hydrazine possessed by hydralazine. Under the simplest scenario, hydralazine directly scavenges free acrolein, decreasing intracellular acrolein availability and thereby suppressing macromolecular adduction.

Differences in lysine adduction by acrolein and methyl vinyl ketone: implications for cytotoxicity in cultured hepatocytes.

Acrolein is a highly toxic environmental pollutant that readily alkylates the epsilon-amino group of lysine residues in proteins. In model systems, such chemistry involves sequential addition of two acrolein molecules to a given nitrogen, forming bis-Michael-adducted species that undergo aldol condensation and dehydration to form Nepsilon-(3-formyl-3,4-dehydropiperidino)lysine. Whether this ability to form cyclic adducts participates in the toxicity of acrolein is unknown.

Synthesis of N-benzylated-2-aminoquinolines as ligands for the Tec SH3 domain.

In recent work, we have been developing 2-aminoquinolines as ligands for Src Homology 3 (SH3) domains, so far the only reported examples of small-molecule ligands for these domains. In this paper, we report the synthesis of a series of N-benzylated-2-aminoquinolines by reductive amination of aryl aldehydes with 2-aminoquinoline. These ligands bound the SH3 domain with ca.

Synthesis of 5-, 6- and 7-substituted-2-aminoquinolines as SH3 domain ligands.

The Src homology 3 (SH3) domains are small protein-protein interaction domains that mediate a range of important biological processes and are considered valuable targets for the development of therapeutic agents. We have been developing 2-aminoquinolines as ligands for SH3 domains--so far the only reported examples of entirely small-molecule ligands for the SH3 domains. The highest affinity 2-aminoquinolines so far identified are 6-substituted compounds.

Identification and specificity studies of small-molecule ligands for SH3 protein domains.

The Src Homology 3 (SH3) domains are small protein-protein interaction domains that bind proline-rich sequences and mediate a wide range of cell-signaling and other important biological processes. Since deregulated signaling pathways form the basis of many human diseases, the SH3 domains have been attractive targets for novel therapeutics. High-affinity ligands for SH3 domains have been designed; however, these have all been peptide-based and no examples of entirely nonpeptide SH3 ligands have previously been reported.

Reactivity of hydrazinophthalazine drugs with the lipid peroxidation products acrolein and crotonaldehyde.

The nucleophilic drug hydralazine strongly inhibits cell toxicity mediated by acrolein, a short chain 2-alkenal formed during lipid peroxidation. We here report the chemistry of acrolein-trapping by hydralazine, and show that together with its structural analogue dihydralazine, it also readily traps crotonaldehyde. Isolable reaction products included (1E)-acrylaldehyde phthalazin-1-ylhydrazone (E-APH), (1Z)-acrylaldehyde phthalazin-1-ylhydrazone (Z-APH), (1E,2E)-but-2-enal phthalazin-1-ylhydrazone (E-BPH) and (1Z,2E)-but-2-enal phthalazin-1-ylhydrazone (Z-BPH).

Strong protein adduct trapping accompanies abolition of acrolein-mediated hepatotoxicity by hydralazine in mice.

Acrolein is a highly reactive alpha,beta-unsaturated aldehyde that readily alkylates nucleophilic centers in cell macromolecules. Typically, such reactions proceed via Michael addition chemistry, forming adducts that retain an electrophilic carbonyl group. Since these species participate in secondary deleterious reactions, we hypothesize that inactivation of carbonyl adducts may attenuate acrolein toxicity.