Another Activity for Vinpocetine

Vinpocetine is the semi-synthetic derivative (ethyl ester) of the alkaloid, apovincamine, found in the Lesser Periwinle (Vinca minor). It has previously been reported to have neuroprotective properties and to increase cerebral blood flow. Although it is used in Eastern Europe to treat cerebrovascular disorders and age-related memory loss, clinical studies have not conclusively demonstrated efficacy. Nevertheless, the compound is also widely used as a dietary supplement.

Vinpocetine is known to inhibit sodium-gated ion channels and has also been identified as a weak inhibitor (IC50 ~ 10µM) of phosphodiesterase-1 (PDE-1). These activities have been used to explain the neuroprotective and vasorelaxant properties of the molecule.

Vinpocetine
vinpocetine structure
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Researchers at University of Rochester Medical Center have now reported potent activity of vinpocetine in a mouse model of lung inflammation, showing promise for the treatment of chronic inflammatory diseases such as COPD, rheumatoid arthritis and psoriasis. The scientists have demonstrated that the mechanism of action is via inhibition of IκB kinase (IKK) resulting in suppression of the proinflammatory transcription factor, NFκB.

Since the compound has a long history of human use, the researchers hope that development of vinpocetine as an antiinflammatory therapy will be easier than for a novel molecule. The university has applied for a patent for vinpocetine for use as an IKK-inhibitor for the treatment of COPD and Yan and Berk, lead scientists of the study, have formed a start-up company, Rock Pharmaceuticals, with the hope of licensing the intellectual property rights.

Full details of the study are currently in press at PNAS, entitled “Vinpocetine inhibits inflammation via an IKK-dependent but PDE-independent mechanism”.

High Altitude Metabolism

High Altitude
Image: Flickr – Blue Turban Photography
The cellular responses to low oxygen levels (hypoxia), as occurs at high altitude, are critical for survival. The transcription factor, hypoxia inducible factor 1 (HIF-1), is a key player in this setting, upregulating genes that preserve function. Included in these are glycolysis enzymes, which allow ATP synthesis in an O2-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis. HIFs are also important in development and deletion of HIF-1 in mammals is perinatally lethal.

HIF-1 occurs as a heterodimer of HIF-1α and the constitutively expressed HIF-1β. Under normal oxygen conditions, HIF-1α is a substrate for HIF-1 prolyl hydroxylases and the asparagine hydroxylase, factor inhibiting HIF-1α (FIH). The action of the prolyl hydroxylases results in the targeting of HIF-1α by an E3 ubiquitin ligase and subsequent degradation by the proteasome, whilst hydroxylation by FIH represses activity of its carboxy terminal transactivation domain (CAD). Both hydroxylation processes therefore serve to down-regulate the activity of HIF-1. When oxygen levels are low, however, the prolyl hydroxylases and FIH become inactive since they are dependent on O2.

A team led by researchers at University of California at San Diego have now reported on a FIH-knockout mouse. Despite the importance of HIF-1 in development, the FIH-deleted mice were healthy, although smaller than wild-type littermates. Where they differed significantly was in their metabolic profile. The FIH-null mice exhibited elevated metabolic rate, enhanced insulin sensitivity, hyperventilation and improved lipid and glucose homeostasis. On a high-fat diet, the animals were resistant to weight gain and had reduced central adiposity.

The team went on to explore the effects of tissue-specific FIH deletion, demonstrating that most of the features of the metabolic phenotype of the FIH-null mice could be replicated when only neuronal FIH was deleted.

The study, published in Cell Metabolism, identifies FIH as an essential regulator of metabolism and opens up the possibility of FIH inhibitors for the treatment of metabolic disorders.

Open Access Drug Target Database Launched

drugs
Image: Flickr – psyberartist

SciClips has launched an online database of drug targets, based on information collected from US and International patent applications. Currently the database contains around 4000 targets linked to their respective diseases and the data are updated on a weekly basis. As well as the association of the biological targets with diseases, the database is also organised according to type of drug (such as antibodies, proteins, siRNA, miRNA or small molecules).

All targets are linked to PubMed, Google Scholar, GeneBank, UniProt, the USPTO database, WO(PCT) database and Google Patents, allowing the user to access additional information, and searches can be conducted on the biological target, drug type or disease.

Whilst the web interface seems a little idiosyncratic, feedback from users will allow SciClips to refine it.

According to the SciClips website:

“SciClips is a web-based scientific platform for open innovation as well as for sharing information and ideas related to various scientific areas. Currently we are offering services and inviting ideas in several areas involving stem cells, proteomics, biomarkers, metabolomics and drug discovery tools. …. We believe that by offering scientific services to cutting edge research areas, we will be able to attract scientists (from) all over the world to think collectively, share ideas and achieve scientific breakthroughs. We will add services in other scientific areas in (the) coming months.”

Enhancing Drug Penetration of Tumours

perforation
Image: Flickr - elektroholunder
One problem associated with the treatment of solid tumours is that chemotherapeutic agents have difficulty in penetrating more than a few cell diameters from the vasculature. Higher doses of drug are required and, because some tumour cells are not reached, the risk of recurrence is high. To address this issue, researchers at Sanford-Burnham Medical Research Institute have now described a peptide able to enhance the ability of drugs to access tumour tissue.

Some years ago it was shown that peptides containing the RGD (Arg-Gly-Asp) sequence recognise a family of cell-surface receptors, integrins, which mediate the interaction of cells with the extracellular matrix (ECM) components fibronectin and type I collagen and are important for the migration and invasion of tumour cells. RGD peptides have been used for homing to malignant tissue and the Sanford-Burnham team have taken this a step further. The new agent is a cyclic nona-peptide (CRGDK/RGPD/EC), referred to as iRGD. The contained RGD sequence targets the agent to tumour tissue where it is cleaved to reveal a ‘CendR’ sequence that binds to neuropilin-1, mediating an active transport system.

In a paper published in Cancer Cell late last year, the research team showed that coupling iRGD to anti-cancer drugs allowed them to penetrate deep into tumours, effectively increasing the activity of the drugs. In their latest study, published in Science, the team have shown that the chemotherapeutic agents do not need to be conjugated to the peptide. Co-administration of iRGD with a variety of drugs, including a small molecule (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and a monoclonal antibody (trastuzumab), improved their therapeutic index.

The team hope that iRGD may be a valuable adjunct to enhance efficacy of anti-cancer agents, whilst reducing side-effects.

Medpedia Adds Video

Last week Medpedia announced the addition of video to its collaborative online medical encyclopaedia. The platform launched with hundreds of medical and health videos from sources including the CDC, the FDA, other institutes of the NIH, as well as from Big Think and other organizations. The videos cover topics ranging from diabetes and H1N1 education, to medical procedures and health care reform.

Like the Clinical Trials system on Medpedia, medical videos are delivered in the appropriate context online. A video can show up in a Medpedia article covering the same topic, it can appear in a personalized feed of someone interested in that disease, or in a patient community related to that condition.

Big Think and other organizations are making hundreds of videos available with more to come. Big Think is an online venue for the growing global conversation about where we are and where we’re headed. Taking cues from elite private institutions and conferences that convene thought leaders from a variety of backgrounds and perspectives to share ideas about pressing global issues, Big Think adapts these models to the web medium to provide public access to expert thinking and the opportunity to engage in dialogue around it. President and co-Founder of Big Think, Peter Hopkins, said:

“Big Think is delighted to share this collection of expert insights and analysis with the Medpedia community. We trust that the addition of this video content will be useful in supporting and enhancing the valuable collaborative efforts being put forth by the medical community.”

As an example, the video below is taken from the Medpedia entry on ‘Hallucination’ and features Oliver Sacks, Professor of Psychiatry at Columbia University.

Challenging the Role of PI3 Kinase in Alzheimer’s

Reflection
Image: Flickr – Richard0
Conventional wisdom, supported by in vitro experiments, has previously suggested that phosphoinositide 3-kinase (PI3K) plays a protective role in Alzheimer’s disease. However, a team led by researchers at Cold Spring Harbor has now implicated PI3K in the pathogenesis of the disorder.

The team used fruit-flies (Drosophila) that were engineered to produce human β-amyloid in their brains – a model that mimics many of the features of Alzheimer’s, including age-dependent memory loss, neurodegeneration, β-amyloid deposits and plaque formation. In the model, the presence of β-amyloid enhances long term depression (LTD), a process in which nerve signal transmission at particular synapses is depressed for an extended period. The research demonstrated that the enhanced LTD was a consequence of increased PI3K activity and could be abrogated by genetic silencing or pharmacological inhibition of PI3K.

PI3K inhibition restored LTD to a normal level, rescued β-amyloid peptide (Aβ)-induced memory loss and reduced β-amyloid deposits in the Drosophila brain. The data suggest that Aβ42 stimulates PI3K, which in turn causes memory loss in association with increased accumulation of Aβ42 aggregates.

The researchers note that the up-regulation of PI3K may also explain the insulin-resistance observed in the brains of Alzheimer’s victims. Insulin is one of the molecules that normally induce PI3K activity, which in turn mediates the cell’s response to insulin. Since PI3K is already hyperactivated in response to β-amyloid, it may no longer be able to respond to insulin.

The study is published in PNAS.

Sibling Rivalry in the Bacterial World

Paenibacillus dendritiformis
Competing Paenibacillus dendritiformis colonies

Credit: Eshel Ben-Jacob

Bacterial colonies cultured on agar avoid each other when forced to compete for nutrients, but the mechanism behind the observed growth inhibition has been unclear. Now a new study by collaborating scientists at UC San Diego, University of Texas and Tel Aviv University has explored the behaviour of Paenibacillus dendritiformis cultures, identifying the factors responsible.

The team found that it was not a shortage of food that halted the growth. They found nutrients in the no-man’s land between the colonies, but also a protein that wasn’t present elsewhere on the dish. When a sample of the purified protein was introduced to a fresh dish inoculated with P. dendritiformis, the bacteria formed a lopsided colony that shied away from the spot. In addition, the bacteria at the edge of the colony closest to the suspect protein were dead.

Analysis of the secretions from P. dendritiformis identified the protease, subtilisin, and a 12 kDa protein, termed sibling lethal factor (Slf). Whilst subtilisin promotes growth and expansion of P. dendritiformis colonies, Slf lyses the bacterial cells in culture. Slf is encoded by a gene belonging to a large family of bacterial genes of unknown function, and the gene is predicted to encode a protein of approximately 20 kDa. The team generated recombinant 20 kDa protein, which was found to be inactive. Exposure to subtilisin, however, resulted in cleavage to the active, 12 kDa form. The experimental results, combined with mathematical modelling, show that subtilisin regulates growth of the colony. Below a threshold concentration subtilisin promotes colony growth and expansion, but once it exceeds a threshold, as occurs at the interface between competing colonies, Slf is then secreted into the medium to rapidly reduce cell density by lysis of the bacterial cells. The presence of genes encoding homologs in other bacterial species suggests that this mechanism for self-regulation of colony growth might not be limited to P. dendritiformis.

The study is published in PNAS.

Novel Strategy to Fight TB

chess board
Image: Flickr – gcfairch
The bacterium responsible for tuberculosis (TB), mycobacterium tuberculosis (Mtb), is notoriously difficult to kill. The most commonly used antibiotics, rifampicin and isoniazid, need to be used for extended periods of time (typically 6-24 months) to effectively eliminate infection. In addition, emergence of antibiotic-resistant strains is an increasing problem.

Researchers at Albert Einstein College of Medicine of Yeshiva University have now identified a new biochemical pathway in Mtb and two novel ways to kill the bacterium. The pathway involves four enzymatic steps in the conversion of the disaccharide, trehalose, to α-glucan mediated by TreS, Pep2, GlgE (which has been identified as a maltosyltransferase that uses maltose 1-phosphate) and GlgB. Focusing on GlgE, the researchers found that blocking the enzyme induced toxic accumulation of maltose-1-phosphate, killing the bacteria in vitro and in a mouse model of infection. Inhibition of another enzyme in the pathway was non-lethal until combined with inactivation of Rv3032, a glucosyltransferase involved in a distinct α-glucan pathway. Inhibition of Rv3032 alone was also non-lethal to the bacteria.

The research validates inhibition of GlgE as therapy for TB but also highlights the potential for targeting two α-glucan pathways – a strategy that potentially leads to reduced incidence of resistance. Both approaches are also distinct from the mechanisms of currently used antibiotics.

The study is published in Nature Chemical Biology.

Controlling Fat Distribution

Fat
Image: Patrick Hoesly
Extreme accumulation of fat in muscle tissue is associated with cardiovascular disease and is a contributory factor in insulin resistance and type II diabetes. It is therefore important to understand the mechanisms by which fat is taken up from the bloodstream and metabolised by tissues. Surprisingly, the role of blood vessels themselves in the transport of lipids has not been clearly established. Researchers at the Karolinska Institutet have now identified a role for vascular endothelial growth factor-B (VEGF-B) in endothelial targeting of lipids to peripheral tissues.

The VEGFs and their receptors are major regulators of angiogenesis and pharmacological intervention, for example with bevacizumab (a monoclonal antibody specific for VEGF-A), has been successfully exploited in oncology. This latest study has shown that VEGF-B, in mice, controls endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. Mice that were deficient in VEGF-B (Vegfb-/-) showed reduced uptake and accumulation of lipids in muscle, heart and brown adipose tissue. Instead, the Vegfb-/- mice preferentially transported lipids to white adipose tissue, resulting in a small weight increase. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium.

The authors of the study, published in Nature, propose that this new role for VEGF-B could potentially lead to novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.

Blocking Lipid Droplet Hydrolysis May Be Beneficial

oil drops
Image: Flickr - Fox Kiyo
Fatty acids can be stored as triacylglycerol in lipid droplets, typically within adipose tissue, and then later released by the action of triacylglycerol hydrolase (TGH, also known as carboxylesterase-3, Ces3). Under normal circumstances, the released fatty acids provide an energy source, but excessive accumulation of triacylglycerol in peripheral tissues is associated with obesity and is a risk factor for type II diabetes and cardiovascular disease.

Researchers at the University of Alberta, Canada, reasoned that blocking the action of TGH would lead to better blood lipid profiles, but might also result in accumulation of triacylglycerol in the liver. However, they have found that mice lacking TGH (tgh-/-) display global metabolic benefits with no obvious down-side. In both fasted- and fed-states, the animals had reduced plasma triacylglycerol, apolipoprotein B, and fatty acid levels. Despite the attenuation of very low-density lipoprotein (VLDL) secretion, TGH deficiency did not increase hepatic triacylglycerol levels. The tgh-/- mice exhibited increased food intake and energy expenditure without change in body weight, and these metabolic changes are accompanied by improved insulin sensitivity and glucose tolerance.

The authors of the study, published in Cell Metabolism, suggest that pharmacological inhibition of TGH could be a useful therapeutic target, although cautioning that further work is required. It may be desirable to target TGH in specific tissues (e.g. hepatic versus adipose) but those subtleties have yet to be established.