The study, published in the Journal of Clinical Investigation, demonstrates a role for eIF5A in inflammation-induced damage to islet cells. Since the negative effects of eIF5A depend on hypusination, DHS may represent a viable therapeutic target for diabetes. Further work will be necessary to establish the role of this pathway in development and progression of the human disease.
Tag: target identification
Study Identifies Receptor for Potentially Fatal Infection
In human endothelial cells, glucose-regulated protein 78 (GRP78) was found to play a key role in endocytosis of R. oryzae and subsequent damage; enhanced expression of the protein in the presence of high concentrations of glucose, especially when iron levels are also elevated, offers an explanation of the increased susceptibility of individuals with DKA to mucormycosis. Mice with DKA, which have elevated levels of glucose and available iron, and which are also susceptible to mucormycosis, showed increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. In further studies, treatment of DKA mice with GRP78-specific immune serum was shown to protect them from mucormycosis.
The study, which is published in the Journal of Clinical investigation, provides a new understanding of the pathogenesis of R. oryzae and may lead to new treatments for potentially lethal mucormycosis.
‘Resilience Factor’ Identified
Mice experience stress when confronted by an aggressive, larger mouse and about two thirds of animals that repeatedly undergo this ‘social defeat’ have altered behaviours including long-lasting social avoidance and anxiety-like symptoms. The other third of the ‘defeated’ mice showed relatively few behavioural effects and these resilient animals were found to have higher levels of the transcription factor ΔFosB in the nucleus accumbens, an important brain reward-associated region or “pleasure centre”. Social behaviour in ‘defeated’ mice can be normalised by chronic antidepressant treatment and the action of fluoxetine was found to require induction of ΔFosB in the nucleus accumbens. Post-mortem examination shows that ΔFosB is also depleted in the brains of people who suffered from depression, suggesting that induction of this protein is a positive adaptation that provides resilience to stress.
ΔFosB is also known to be involved in regulating responses to both drugs of abuse and natural rewards such as food, sex and exercise, although the cell populations involved in these responses differ somewhat from those involved in protection from stress. The team suggest that concentrations of ΔFosB in the nucleus accumbens are important in setting the level of an individual’s reward-seeking motivation and that reduced concentrations of the protein are linked to the impaired motivation and ability to experience pleasure seen in many people with depression. The team now hope to discover small molecules that will augment the actions of ΔFosB and lead to resilience-boosting treatments for depression.
The study is published in the journal Nature Neuroscience.
Locking out or Locking in – It’s Not the Same Key for Malaria
Researchers at Harvard School of Public Health (HSPH) were attempting to identify the mechanism by which Plasmodium falciparum merozoites enter erthyrocytes, but instead found a parasite protein that is essential for escape from the cells. When the protein, P. falciparum calcium-dependent protein kinase (PfCDPK5), was suppressed the parasites were trapped in the host cell and unable to infect new cells. In further experiments the team showed that these merozoites were still able to invade erythrocytes if released from their host cell by other means, indicating separate mechanisms for invasion and egress from erythrocytes.
The findings reveal an essential step in the biology of P. falciparum and suggest a new, parasite-specific, drug target for fighting one of the world’s most common and dangerous infections. Whilst many scientists are looking for inhibitors of parasite egress and invasion of red blood cells, no anti-malarial drugs yet target these stages of the parasite lifecycle.
The study is published in Science.
Regulating Cholesterol Levels
A new study by researchers at Massachusetts General Hospital (MGH) has now identified micro RNAs (miRNAs) that appear to play an important role in regulation of cholesterol/lipid levels. The team found that two members of the miR-33 family (miR-33a and miR-33b) target the ATP-binding cassette transporter A1 (ABCA1), an important regulator of HDL synthesis and reverse cholesterol transport, for posttranscriptional repression. Using antisense inhibition of miR-33 in mouse and human cell lines the researchers demonstrated up-regulation of ABCA1 expression and increased cholesterol efflux. Further, treatment of mice on a western-type diet with the antisense inhibitor resulted in elevated plasma HDL without affecting levels of LDL. The findings suggest that miR-33 may represent a therapeutic target for cardiovascular diseases.
The study is published in Science.
Newly Discovered Vulnerability in Tuberculosis
In vitro, Mtb is able to grow on a variety of carbon sources but fatty acids are believed to be the major source of carbon and energy for the bacterium during infection of a host. When bacterial metabolism is primarily fuelled by fatty acids, biosynthesis of sugars from intermediates of the tricarboxylic acid cycle is known to be essential for growth but the role of gluconeogenesis in the pathogenesis of Mtb had not been explored. Using genetic analyses and 13C carbon tracing, the team were able to show that phosphoenolpyruvate carboxykinase (PEPCK) – the enzyme that catalyses the first committed step of gluconeogenesis – is essential for the growth of Mtb supported by fatty acids. PEPCK was shown to be needed for growth of Mtb both in isolated macrophages derived from the bone marrow of mice and in infected mice.
Mtb lacking PEPCK failed to replicate in mouse lungs and silencing PEPCK during the chronic phase resulted in clearance of the infection, showing that Mtb relies on gluconeogenesis throughout the course of the infection. The finding that PEPCK plays a pivotal role in the growth and persistence of Mtb during both acute and latent infections in mice – and that PEPCK depletion also attenuates Mtb in IFNγ-deficient mice – suggests that this enzyme is an attractive target for chemotherapy.
The study is published in PNAS.
Stopping Cancer Spread
X-ray studies showed that macroketone binds to one of the actin-binding sites on fascin which prevents the actin fibres from bundling together and could form the basis for further drug design.
High Altitude Metabolism
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.
Novel Strategy to Fight TB
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
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.