PolygenicBlog

Caprospinol: discovery of a steroid drug candidate to treat Alzheimer's disease based on 22R-hydroxycholesterol structure and properties.

noreply@blogger.com (Chris Carter) — Sat, 02 Jun 2012 12:39:41 PDT

The overall ability of the brain to synthesise neuroactive steroids led us to the identification of compounds that would reproduce aspects of neurosteroid pharmacology. The rate-determining step in neurosteroid biosynthesis is the import of the substrate cholesterol into the mitochondria, where it is metabolised into pregnenolone via the intermediate 22R-hydroxycholesterol. The levels of translocator protein 18-kDa, mediating the import of cholesterol into mitochondria, correlated with increased pregnenolone formation and reduced levels of 22R-hydroxycholesterol in biopsies from Alzheimer's disease (AD), but not age-matched control, brains. 22R-hydroxycholesterol was shown to protect against β-amyloid (Aβ(42) )-induced neurotoxicity. In search of 22R-hydroxycholesterol stable analogues, we identified the naturally occurring heterospirostenol, (22R,25R)-20α-spirost-5-en-3β-yl hexanoate (caprospinol) and derivatives that protect neuronal cells against Aβ(1-42) neurotoxicity. The neuroprotective effect of caprospinol is the result of a combination of overlapping properties, including: (i) the ability to bind to Aβ(42) and reduce plaque formation in the brain in vivo; (ii) interaction with components of the mitochondria respiratory chain resulting in an anti-uncoupling effect; (iii) the capacity to scavenge Aβ(42) monomers present in mitochondria; and (iv) the property of being a sigma-1 receptor ligand. In vivo, caprospinol crosses the blood-brain barrier, accumulates in the brain, and restores cognitive impairment in a pharmacological rat model of AD. Caprospinol is stable, does not bind to known steroid receptors, is devoid of mutagenic and genotoxic properties, and is devoid of acute toxicity in rodents. The pharmacokinetics and pharmacodynamics of caprospinol were studied, and long-term toxicity studies are under investigation, aiming to develop this compound as a disease-modifying drug for the treatment of AD.

Preteen food choices may help predict eating disorders later

noreply@blogger.com (Chris Carter) — Sat, 02 Jun 2012 00:12:31 PDT

The study, presented recently at the International Conference on Eating Disorders in Austin, Texas, found the percentage of carbohydrates and fats girls ate at around the age of 11 helped to predict increasing dissatisfaction with the body by the age of 14. The researchers noted 15-year-old girls who ate little fat and a lot of carbohydrates were more likely to have erratic eating habits by age 19. This was particularly true for girls who were considered perfectionists.

PLoS Pathogens: Gammaherpesvirus Latency Accentuates EAE Pathogenesis: Relevance to Epstein-Barr Virus and Multiple Sclerosis

noreply@blogger.com (Chris Carter) — Fri, 01 Jun 2012 23:48:35 PDT

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases.

Intestinal microbiota determine severity of myocardial infarction in rats.

noreply@blogger.com (Chris Carter) — Fri, 01 Jun 2012 12:23:07 PDT

Signals from the intestinal microbiota are important for normal host physiology; alteration of the microbiota (dysbiosis) is associated with multiple disease states. We determined the effect of antibiotic-induced intestinal dysbiosis on circulating cytokine levels and severity of ischemia/reperfusion injury in the heart. Treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin, in the drinking water, decreased circulating leptin levels by 38%, resulted in smaller myocardial infarcts (27% reduction), and improved recovery of postischemic mechanical function (35%) as compared with untreated controls. Vancomycin altered the abundance of intestinal bacteria and fungi, measured by 16S and 18S ribosomal DNA quantity. Pretreatment with leptin (0.12 μg/kg i.v.) 24 h before ischemia/reperfusion abolished cardioprotection produced by vancomycin treatment. Dahl S rats fed the commercially available probiotic product Goodbelly, which contains the leptin-suppressing bacteria Lactobacillus plantarum 299v, also resulted in decreased circulating leptin levels by 41%, smaller myocardial infarcts (29% reduction), and greater recovery of postischemic mechanical function (23%). Pretreatment with leptin (0.12 μg/kg i.v.) abolished cardioprotection produced by Goodbelly. This proof-of-concept study is the first to identify a mechanistic link between changes in intestinal microbiota and myocardial infarction and demonstrates that a probiotic supplement can reduce myocardial infarct size.

Autoantibodies to αS1-casein are induced by breast-feeding.

noreply@blogger.com (Chris Carter) — Fri, 01 Jun 2012 08:16:50 PDT

The generation of antibodies is impaired in newborns due to an immature immune system and reduced exposure to pathogens due to maternally derived antibodies and placental functions. During nursing, the immune system of newborns is challenged with multiple milk-derived proteins. Amongst them, caseins are the main constituent. In particular, human αS1-casein (CSN1S1) was recently shown to possess immunomodulatory properties. We were thus interested to determine if auto-antibodies to CSN1S1 are induced by breast-feeding and may be sustained into adulthood.

62 sera of healthy adult individuals who were (n = 37) or were not (n = 25) breast-fed against human CSN1S1 were investigated by a new SD (surface display)-ELISA. For cross-checking, these sera were tested for anti Epstein-Barr virus (EBV) antibodies.
IgG-antibodies were predominantly detected in individuals who had been nursed. At a cut-off value of 0.4, the SD-ELISA identified individuals with a history of having been breast-fed with a sensitivity of 80% and a specificity of 92%. Under these conditions, 35 out of 37 sera from healthy donors, who where breast-fed, reacted positively but only 5 sera of the 25 donors who were not breast-fed. The duration of breast-feeding was of no consequence to the antibody reaction as some healthy donors were only short term breast-fed (5 days minimum until 6 weeks maximum), but exhibited significant serum reaction against human CSN1S1 nonetheless.

CONCLUSION:

We postulate that human CSN1S1 is an autoantigen> The antigenicity is orally determined, caused by breast-feeding, and sustained into adulthood.

Certain Features Of Autism May Be Improved By Antioxidant (N-acetyl cysteine)

noreply@blogger.com (Chris Carter) — Thu, 31 May 2012 23:04:39 PDT

The antioxidant, N-Acetylcysteine, or NAC, lowered irritability in children with autism as well as reducing the children's repetitive behaviors. The researchers emphasized that the findings must be confirmed in a larger trial before NAC can be recommended for children with autism.

Injection offers hope for treating auto-immune disease

noreply@blogger.com (Chris Carter) — Thu, 31 May 2012 22:34:58 PDT

Australian researchers have uncovered a potential new way to regulate the body’s natural immune response, offering hope of a simple and effective treatment for auto-immune diseases.The new approach involves increasing good regulating cells in the body, unlike most current research which focuses on stopping “bad” or “effector” cells, says lead researcher Dr. Suzanne Hodgkinson, from UNSW’s Faculty of Medicine and Liverpool Hospital.
The researchers induced the body’s T-cell front-line defences by injecting cell-signalling proteins called cytokines, in particular cytokine Interleukin-5 (II-5 cytokine).

To spread, nervous system viruses sabotage cell, hijack transportation

noreply@blogger.com (Chris Carter) — Wed, 30 May 2012 16:03:51 PDT

Herpes and other viruses that attack the nervous system may thrive by disrupting cell function in order to hijack a neuron's internal transportation network and spread to other cells.

Ketamine improved bipolar depression within minutes

noreply@blogger.com (Chris Carter) — Wed, 30 May 2012 15:59:33 PDT

A group of researchers at the National Institute of Mental Health, led by Dr. Carlos Zarate, previously found that a single dose of ketamine produced rapid antidepressant effects in depressed patients with bipolar disorder. They have now replicated that finding in an independent group of depressed patients, also with bipolar disorder. Replication is an important component of the scientific method, as it helps ensure that the initial finding wasn't accidental and can be repeated.

Researchers complete the first epigenome in Europe

noreply@blogger.com (Chris Carter) — Wed, 30 May 2012 15:55:55 PDT

A study led by Manel Esteller, director of the Epigenetics and Cancer Biology Program at the Bellvitge Biomedical Research Institute (IDIBELL), professor of genetics at the University of Barcelona and ICREA researcher, has completed the first epigenome in Europe. The finding is published in the latest issue of the international scientific journal Epigenetics.

Too much vitamin D can be as unhealthy as too little, study suggests

noreply@blogger.com (Chris Carter) — Wed, 30 May 2012 06:35:57 PDT

Scientists know that Vitamin D deficiency is not healthy. However, new research from the University of Copenhagen now indicates that too high a level of the essential vitamin is not good either. The study is based on blood samples from 247,574 Copenhageners. The results have just been published in the reputed scientific Journal of Clinical Endocrinology and Metabolism.

Immune self-reactivity triggered by drug-modified HLA-peptide repertoire : Nature : Nature Publishing Group

noreply@blogger.com (Chris Carter) — Wed, 30 May 2012 01:44:48 PDT

Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens–Johnson syndrome (SJS), are associated with specific HLA alleles However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 . We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in ‘immunological self’. The resultant peptide-centric ‘altered self’ activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.

Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling

noreply@blogger.com (Chris Carter) — Wed, 30 May 2012 01:29:17 PDT

Dietary fish oil containing ω3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit cardioprotective and anti-inflammatory effects through unresolved mechanisms that may involve competition and inhibition at multiple levels. Here, we report the effects of arachidonic acid (AA), EPA, and DHA supplementation on membrane incorporation, phospholipase A₂ catalyzed release, and eicosanoid production in RAW264.7 macrophages. Using a targeted lipidomics approach, we observed that Toll-like receptor 4 and purinergic receptor activation of supplemented cells leads to the release of 22-carbon fatty acids that potently inhibit cyclooxygenase pathways. This inhibition was able to shunt metabolism of AA to lipoxygenase pathways, augmenting leukotriene and other lipoxygenase mediator synthesis. In resident peritoneal macrophages, docosapentaenoic acid (DPA) was responsible for cyclooxygenase inhibition after EPA supplementation, offering fresh insights into how EPA exerts anti-inflammatory effects indirectly through elongation to 22-carbon DPA.

Cancer Exosomes Promote Metastasis | The Scientist

noreply@blogger.com (Chris Carter) — Tue, 29 May 2012 12:25:10 PDT

Exosomes, small membrane vesicles once thought to do little more than clean up a cell’s trash, have recently been recognized for their ability to carry diverse and complex messages around the body.A new study published this week (May 27) in Nature Medicine demonstrates the importance of exosomes in promoting melanoma metastasis

Parkinson's Risk Prediction From Colonic Tissue Samples

noreply@blogger.com (Chris Carter) — Tue, 29 May 2012 11:19:25 PDT

Colonic tissue samples taken during flexible sigmoidoscopy or colonoscopy can be used to predict whether or not a patient will develop Parkinson's disease, researchers from Rush University Medical Center reported. The scientists reported findings from two studies in Movement Disorders.

Treatment for Helicobacter pylori infection and risk of parkinson's disease in Denmark.

noreply@blogger.com (Chris Carter) — Tue, 29 May 2012 11:15:18 PDT

It has been speculated that gastrointestinal infection with Helicobacter pylori (HP) contributes to the development of Parkinson'sdisease (PD). We used nationwide Danish registers to investigate this hypothesis. Methods: We identified 4484 patients with a first time PD diagnosis between 2001 and 2008 from the Danish National Patient Register (DNPR) and 22 416 population controls from the Danish Civil Registration System (CRS). Information on drug use was obtained from the National Prescription Registry (NPR). We used logistic regression to compute odds ratios (OR) for the association between treatment for HP and risk of PD. Results: Prescriptions for HP-eradication drugs and proton pump inhibitors (PPI) 5 or more years prior to the diagnosis of PD were associated with a 45% and 23% increase in PD risk, respectively. Hospitalizations and outpatient visits for gastritis and peptic/duodenal ulcers, however, were not associated with PD. Conclusions: Our population-based study suggests that chronic HP infections and/or gastritis contribute to PD or that these are PD-related pathologies that precede motor symptoms.

MicrobeWorld - How Curry Spice Helps The Immune System Kill Bacteria

noreply@blogger.com (Chris Carter) — Tue, 29 May 2012 06:42:12 PDT

American and Danish scientists have found curcumin increases levels of a protein called (cathelicidin antimicrobial peptide or CAMP) that helps the immune system to fight off bacteria, viruses and fungi the first time they try to attack

T cells 'hunt' parasites like animal predators seek prey, study shows

noreply@blogger.com (Chris Carter) — Mon, 28 May 2012 22:13:54 PDT

By pairing an intimate knowledge of immune-system function with a deep understanding of statistical physics, a cross-disciplinary team at the University of Pennsylvania has arrived at a surprising finding: T cells use a movement strategy to track down parasites that is similar to strategies that predators such as monkeys, sharks and blue-fin tuna use to hunt their prey.

Scientists unravel mechanism that causes liver cancer

noreply@blogger.com (Chris Carter) — Mon, 28 May 2012 22:12:07 PDT

Scientists at the Genome Institute of Singapore (GIS) have unraveled the mechanism that causes liver cancer (hepatocellular carcinoma, HCC), one of the most common solid tumors worldwide. Essentially, the Hepatitis B virus (HBV) integrates its own DNA into human genes: Their analyses revealed that the incidences of HBV integrations were high – 76 of the 88 patients had HBV integration. Specifically, they discovered that the HBV will integrate into genes CCNE1, SENP5 and ROCK1, causing an increase in the expression levels in these genes, and subsequently enhancing the tumor growth. This discovery is in addition to the previously reported integration into the TERT and MLL4 genes.

MicrobeWorld - Garlic Constituent Blocks Biofilm Formation, Could Benefit Cystic Fibrosis Patients and Others

noreply@blogger.com (Chris Carter) — Mon, 28 May 2012 14:15:29 PDT

Bacterial biofilms are far more resistant than individual bacteria to the armories of antibiotics we have devised to combat them. Now Tim Holm Jakobsen and Michael Givskov of the University of Copenhagen, and their many collaborators have pinpointed a constituent of garlic that attacks a key step in the development of biofilms

IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression.

noreply@blogger.com (Chris Carter) — Sun, 27 May 2012 13:38:54 PDT

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and depression are considered to be neuro-immune disorders (Maes and Twisk, BMC Medicine 8:35, 2010). There is also evidence that depression and ME/CFS are accompanied by oxidative and nitrosative stress (O&NS) and by increased autoantibodies to a number of self-epitopes some of which have become immunogenic due to damage by O&NS. The aim of this study is to examine IgM-mediated autoimmune responses to different self-epitopes in ME/CFS versus depression. We examined serum IgM antibodies to three anchorage molecules (palmitic and myristic acid and S-farnesyl-L-cysteine); acetylcholine; and conjugated NO-modified adducts in 26 patients with major depression; 16 patients with ME/CFS, 15 with chronic fatigue; and 17 normal controls. Severity of fatigue and physio-somatic (F&S) symptoms was measured with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale. Serum IgM antibodies to the three anchorage molecules and NO-phenylalanine were significantly higher in ME/CFS than in depression. The autoimmune responses to oxidatively, but not nitrosatively, modified self-epitopes were significantly higher in ME/CFS than in depression and were associated with F&S symptoms. The autoimmune activity directed against conjugated acetylcholine did not differ significantly between ME/CFS and depression, but was greater in the patients than controls. Partially overlapping pathways, i.e. increased IgM antibodies to a multitude of neo-epitopes, underpin both ME/CFS and depression, while greater autoimmune responses directed against anchorage molecules and oxidatively modified neo-epitopes discriminate patients with ME/CFS from those with depression. These autoimmune responses directed against neoantigenic determinants may play a role in the dysregulation of key cellular functions in both disorders, e.g. intracellular signal transduction, cellular differentiation and apoptosis, but their impact may be more important in ME/CFS than in depression.

International Symposium on HIV & Emerging Infectious Diseases (Open access abstracts)

noreply@blogger.com (Chris Carter) — Sun, 27 May 2012 01:10:57 PDT

The Abstracts of the International Symposium on HIV & Emerging Infectious Diseases held May 23-25 in Marseilles, France are available online. They are published on www.retrovirology.com as individual articles and a PDF file of 54 pages. You can go and have a look at them on the website of this top quality open access journal that have an impact factor of 5.24: http://www.retrovirology.com/supplements/9/S1

Diabetes Treatment - Potential New Target ( APOA4)

noreply@blogger.com (Chris Carter) — Sun, 27 May 2012 00:03:42 PDT

The online edition of Proceedings of the National Academy of Sciences reports that Cincinnati University (UC) researchers have discovered that apolipoprotein A-IV (apoA-IV), a naturally produced protein that has the ability to reduce blood sugar levels and enhance insulin secretion, could be a potential target for a new diabetes treatment.

Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers

noreply@blogger.com (Chris Carter) — Sat, 26 May 2012 06:47:48 PDT

Ihe objective was to evaluate the effect of a moderate intake of red wine polyphenols on select gut microbial groups implicated in host health benefits.

Design: Ten healthy male volunteers underwent a randomized, crossover, controlled intervention study. After a washout period, all of the subjects received red wine, the equivalent amount of de-alcoholized red wine, or gin for 20 d each. Total fecal DNA was submitted to polymerase chain reaction(PCR)–denaturing gradient gel electrophoresis and real-time quantitative PCR to monitor and quantify changes in fecal microbiota. Several biochemical markers were measured.

Results: The dominant bacterial composition did not remain constant over the different intake periods. Compared with baseline, the daily consumption of red wine polyphenol for 4 wk significantly increased the number of Enterococcus, Prevotella, Bacteroides, Bifidobacterium, Bacteroides uniformis, Eggerthella lenta, and Blautia coccoides–Eubacterium rectale groups (P < 0.05). In parallel, systolic and diastolic blood pressures and triglyceride, total cholesterol, HDL cholesterol, and C-reactive protein concentrations decreased significantly (P < 0.05). Moreover, changes in cholesterol and C-reactive protein concentrations were linked to changes in the bifidobacteria number.

Conclusion: This study showed that red wine consumption can significantly modulate the growth of select gut microbiota in humans, which suggests possible prebiotic benefits associated with the inclusion of red wine polyphenols in the diet.

Cystic fibrosis breakthrough reveals why females fare worse than males

noreply@blogger.com (Chris Carter) — Sat, 26 May 2012 03:15:38 PDT

Researchers from the Respiratory Research Division of the Department of Medicine, Royal College of Surgeons in Ireland (RCSI) have published a study which represents a major breakthrough in understanding why females with cystic fibrosis do worse than males. The study is the first to show that the female hormone estrogen promotes the presence of a particular form of bacteria ( Pseudomonas aeruginosa) which results in more severe symptoms for female cystic fibrosis patients. In addition, females who were taking the oral contraceptive pill, which decreases the amount of naturally occurring estrogen in their bodies, were found to have lower levels of the problematic bacteria.