Down-Regulation of Platelet Imidazoline-1-Binding Sites after Bupropion Treatment

An elevation of I1 (imidazoline-1)-binding sites on platelets may be a state marker for depression. Herein, platelet I1 sites were compared in two groups of unipolar depressed patients given different regimens of bupropion treatment : Regimen 1 (n=13 titrated up to 300 mg}d by week 4 and held constant until week 6) ; Regimen 2 (n=15 titrated up to 300 mg}d by week 2, to 450 mg}d by week 6, and held constant until week 8). Platelet I1 sites were quantified by p-[125I]iodoclonidine binding (0.5–15 nm) and displaced by moxonidine under a saturating concentration of norepinephrine to mask α2-adrenoceptors. I1 Bmax values were confirmed to be high at pretreatment in depressed patients (n=28) compared to healthy control subjects (n=18 ; p=0.02). Highest Bmax values at pretreatment were found in patients who responded worst to treatment. More than two-thirds of patients recovered from depression (69 and 80% in Regimens 1 and 2, respectively) after treatment. Dose and/or time of exposure to bupropion were relevant variables since (1) only Regimen 2 led to platelet I1 down-regulation and (2) the extent of down-regulation correlated with plasma concentrations of bupropion. The data suggest a dissociation exists between I1 down-regulation and therapeutic response, or else platelet I1 down-regulation lags behind clinical antidepressant response before becoming measurable

Transepithelial Anti-Neuroblastoma Response to Kale among Four Vegetable Juices Using In Vitro Model Co-Culture System

Juicing vegetables is thought to be an anticancer treatment. Support exists for a rank order of anticancer greens (kale \u3e dandelion \u3e lettuce \u3e spinach) based on degrees of bioavailability of different phytochemicals, also offset by some noxious molecules (i.e., calcium-oxalate). We developed a new in vitro transepithelial anti-neuroblastoma model system. The juices were diluted as predicted once in the small intestine. They were applied to apical Caco-2Bbe1 cells atop dividing SH-SY5Y neuroblastoma cells, and changes in transepithelial electrical resistance (TEER) and cell growth were considered with juice spectroscopies. Studied first in monoculture, kale and dandelion were the most cytostatic juices on SH-SY5Ys, lettuce showed no effect, and high (4.2%) spinach was cytotoxic. In co-culture, high (4.2%) kale was quickest (three days) to inhibit neuroblastoma growth. By five days, dandelion and kale were equally robust. Lettuce showed small anti-proliferative effects at five days and spinach remained cytotoxic. Spinach’s cytotoxicity corresponded with major infrared bands indicative of oxalate. Kale juice uniquely induced reactive oxygen species and S-phase cell cycle arrest in SH-SY5Y. The superiority of kale and dandelion was also apparent on the epithelium, because raising TEER levels is considered healthy. Kale’s unique features corresponded with a major fluorescent peak that co-eluted with kaempferol during high performance liquid chromatography. Because the anticancer rank order was upheld, the model appears validated for screening anticancer juices

Evidence for the gastric cytoprotective effect of centrally injected agmatine

Agmatine (decarboxylated arginine) exerts cytoprotective action in several tissues, such as in the brain, heart or kidneys, but there is still controversy over the effects of agmatine on the gastric mucosa. The aim of the present study was to reveal the potential gastroprotective action of agmatine by using an acid-independent ulcer model to clarify which receptors and peripheral factors are involved in it. Gastric mucosal damage was induced by acidified ethanol. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. It was found that agmatine given intracerebroventricularly (i.c.v., 0.044-220nmol/rat) significantly inhibited the development of ethanol-induced mucosal damage, while in the case of intraperitoneal injection (0.001-50mg/kg i.p.) it had only a minor effect. The central gastroprotective action of agmatine was completely antagonized by mixed alpha2-adrenoceptor and imidazoline I1 receptor antagonists (idazoxan, efaroxan), but only partially by yohimbine (selective alpha2-adrenoceptor antagonist) and AGN 192403 (selective I1 receptor ligand, putative antagonist). It was also inhibited by the non-selective opioid-receptor antagonist naloxone and the selective δ-opioid receptor antagonist naltrindole, but not by β-funaltrexamine and nor-Binaltorphimine (selective μ- and κ-opioid receptor antagonists, respectively). Furthermore, the effect of agmatine was antagonized by bilateral cervical vagotomy and by pretreatment with indomethacin and NG-nitro-l-arginine. Agmatine also reversed the ethanol-induced reduction of gastric mucosal CGRP and somatostatin content, but did not have any significant effect on gastric motor activity. These results indicate that agmatine given centrally induces gastric cytoprotection, which is mediated by central imidazoline I1 receptors, alpha2-adrenoceptors and δ-opioid receptors. Activation of these receptors induces the release of different mucosal protective factors, such as NO, prostaglandins, CGRP and somatostatin by a vagal-dependent mechanism. Alterations of gastric motility are not likely to contribute to the observed protective effect

Sustained remission of rheumatoid arthritis with a specific serotonin reuptake inhibitor antidepressant: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>The mainstay of pharmacologic therapy for rheumatoid arthritis includes the use of disease-modifying agents like sulfasalazine and methothrexate, and more recently, anti-tumor necrosis factor-α agents. Depression remains a major co-morbidity in patients with rheumatoid arthritis and is thought to contribute to disability and mortality in these patients. Evidence now suggests that a biologic link exists between substrates responsible for inflammatory conditions and mood disorders. Most of this evidence comes from preclinical studies. Nevertheless, more research into this area is helping us to understand the possible mechanisms through which these conditions interact with each other.</p> <p>Case presentation</p> <p>We describe a 60-year-old Indian man with rheumatoid arthritis diagnosed 15 years ago who had minimal response to multiple therapies with disease-modifying agents and whose arthritis symptoms surprisingly remitted when he was started on a specific serotonin reuptake inhibitor antidepressant, three years ago, for co-morbid major depression. This remission has been maintained with this medication, and the patient is currently not taking any antirheumatoid medications.</p> <p>Conclusion</p> <p>Possible mechanisms linking substrates of mood disorders and inflammation are reviewed in this case report, particularly the serotonergic system. Evidence seems to suggest a significant interaction between the serotonergic systems and inflammation. This interaction seems to be bidirectional. An understanding of this relation is most important to gain insight not only into pathophysiological mechanisms underlying this condition, but also into how treatments for these conditions may complement each other and possibly provide greater therapeutic options in both of these disabling conditions.</p

Evolution of major milk proteins in Mus musculus and Mus spretus mouse species: a genoproteomic analysis

<p>Abstract</p> <p>Background</p> <p>Due to their high level of genotypic and phenotypic variability, <it>Mus spretus </it>strains were introduced in laboratories to investigate the genetic determinism of complex phenotypes including quantitative trait loci. <it>Mus spretus </it>diverged from <it>Mus musculus </it>around 2.5 million years ago and exhibits on average a single nucleotide polymorphism (SNP) in every 100 base pairs when compared with any of the classical laboratory strains. A genoproteomic approach was used to assess polymorphism of the major milk proteins between SEG/Pas and C57BL/6J, two inbred strains of mice representative of <it>Mus spretus </it>and <it>Mus musculus </it>species, respectively.</p> <p>Results</p> <p>The milk protein concentration was dramatically reduced in the SEG/Pas strain by comparison with the C57BL/6J strain (34 ± 9 g/L <it>vs</it>. 125 ± 12 g/L, respectively). Nine major proteins were identified in both milks using RP-HPLC, bi-dimensional electrophoresis and MALDI-Tof mass spectrometry. Two caseins (β and α_s1) and the whey acidic protein (WAP), showed distinct chromatographic and electrophoresis behaviours. These differences were partly explained by the occurrence of amino acid substitutions and splicing variants revealed by cDNA sequencing. A total of 34 SNPs were identified in the coding and 3'untranslated regions of the SEG/Pas <it>Csn1s1 </it>(11), <it>Csn2 </it>(7) and <it>Wap </it>(8) genes. In addition, a 3 nucleotide deletion leading to the loss of a serine residue at position 93 was found in the SEG/Pas <it>Wap </it>gene.</p> <p>Conclusion</p> <p>SNP frequencies found in three milk protein-encoding genes between <it>Mus spretus </it>and <it>Mus musculus </it>is twice the values previously reported at the whole genome level. However, the protein structure and post-translational modifications seem not to be affected by SNPs characterized in our study. Splicing mechanisms (cryptic splice site usage, exon skipping, error-prone junction sequence), already identified in casein genes from other species, likely explain the existence of multiple α_s1-casein isoforms both in SEG/Pas and C57BL/6J strains. Finally, we propose a possible mechanism by which the hallmark tandem duplication of a 18-nt exon (14 copies) may have occurred in the mouse genome.</p

ADHDgene: a genetic database for attention deficit hyperactivity disorder

With a worldwide prevalence of ∼5%, attention deficit hyperactivity disorder (ADHD) has become one of the most common psychiatric disorders. The polygenetic nature of ADHD indicates that multiple genes jointly contribute to the development of this complex disease. Studies aiming to explore genetic susceptibility of ADHD have been increasing in recent years. There is a growing need to integrate the genetic data from various genetic studies to provide a comprehensive data set and uniform access for convenience of in-depth data mining. So far, there has been no such effort for ADHD. To address the genetic complexity of ADHD, we developed the ADHDgene database by integrating ADHD-related genetic factors by profound literature reading. Based on the data from the literature, extended functional analysis, including linkage disequilibrium analysis, pathway-based analysis and gene mapping were performed to provide new insights into genetic causes of ADHD. Moreover, powerful search tools and a graphical browser were developed to facilitate the navigation of the data and data connections. As the first genetic database for ADHD, ADHDgene aims to provide researchers with a central genetic resource and analysis platform for ADHD and is freely available at http://adhd.psych.ac.cn/

Chronic ethanol attenuates centrally-mediated hypotension elicited via alpha-2-adrenergic, but not I1-imidazoline, receptor activation in female rats

Aims—This study dealt with the effect of chronic ethanol administration on hemodynamic responses elicited by α2-adrenergic (α-methyldopa) or I1-imidazoline (rilmenidine) receptor activation in telemetered female rats. Main methods—The effects of α-methyldopa or rilmenidine on blood pressure (BP), heart rate (HR) and their variability were investigated in rats that received liquid diet without or with ethanol (5% w/v) for 12 weeks. To evaluate the effect of each drug on cardiovascular autonomic control (BP and HR variability) in the absence or presence of ethanol, three time-domain indices of hemodynamic variability were measured: (i) standard deviation of mean arterial pressure (SDMAP), (ii) standard deviation of beat-to-beat intervals, and (iii) root mean square of successive differences in R-R intervals. Key findings—In liquid diet-fed control rats, i.p. rilmenidine (600 μg/kg) or α-methyldopa (100 mg/kg) reduced BP along with decreases and increases, respectively, in HR. Both drugs had no effect on HR variability but reduced BP variability (SDMAP), suggesting a reduced vasomotor sympathetic tone. Ethanol feeding attenuated reductions in BP and SDMAP evoked by α-methyldopa but not by rilmenidine. Significance—We conclude that chronic ethanol preferentially compromises α2- but not I1- receptor-mediated hypotension in female rats probably via modulation of vasomotor sympathetic activity. These findings highlight the adequacy of rilmenidine use to lower BP in hypertensive alcoholic females

Trappin-2/Elafin Modulate Innate Immune Responses of Human Endometrial Epithelial Cells to PolyI∶C

BACKGROUND: Upon viral recognition, innate and adaptive antiviral immune responses are initiated by genital epithelial cells (ECs) to eradicate or contain viral infection. Such responses, however, are often accompanied by inflammation that contributes to acquisition and progression of sexually transmitted infections (STIs). Hence, interventions/factors enhancing antiviral protection while reducing inflammation may prove beneficial in controlling the spread of STIs. Serine antiprotease trappin-2 (Tr) and its cleaved form, elafin (E), are alarm antimicrobials secreted by multiple cells, including genital epithelia. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated whether and how each Tr and E (Tr/E) contribute to antiviral defenses against a synthetic mimic of viral dsRNA, polyinosine-polycytidylic acid (polyI:C) and vesicular stomatitis virus. We show that delivery of a replication-deficient adenovector expressing Tr gene (Ad/Tr) to human endometrial epithelial cells, HEC-1A, resulted in secretion of functional Tr, whereas both Tr/E were detected in response to polyI:C. Moreover, Tr/E were found to significantly reduce viral replication by either acting directly on virus or through enhancing polyI:C-driven antiviral protection. The latter was associated with reduced levels of pro-inflammatory factors IL-8, IL-6, TNFα, lowered expression of RIG-I, MDA5 and attenuated NF-κB activation. Interestingly, enhanced polyI:C-driven antiviral protection of HEC-Ad/Tr cells was partially mediated through IRF3 activation, but not associated with higher induction of IFNβ, suggesting multiple antiviral mechanisms of Tr/E and the involvement of alternative factors or pathways. CONCLUSIONS AND SIGNIFICANCE: This is the first evidence of both Tr/E altering viral binding/entry, innate recognition and mounting of antiviral and inflammatory responses in genital ECs that could have significant implications for homeostasis of the female genital tract