MH_dev_203

Recent advances in the genetics of schizophrenia . The genetic etiology of schizophrenia , a common and debilitating psychiatric disorder , is supported by a wealth of data . Review of the current findings suggests that considerable progress has been made in recent years , with a number of chromosomal regions consistently implicated by linkage analysis . Three groups have shown linkage to 1q21 - 22 using similar models , with HLOD scores of 6.5 , 3.2 , and 2.4 . Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores ( 4.42 ) or Q9BXD5 values ( 4.18 ) , and 5pl4 . 1-13 . 1 , 5q21 - 33 , 8p 2l - 22 , and 10p11 - 15 , each of which have been reported as suggestive by at least three separate groups . Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage . Of these , the greatest support exists for the P35462 ( 3q13 . 3 ) , P28223 ( 13q14 . 2 ) , and P36544 ( 15q13 - q14 ) genes . The refinement of phenotypes , the use of endophenotypes , reduction of heterogeneity , and extensive genetic mapping have all contributed to this progress . The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia . A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions .

Anti-Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic-based clinical practice guidelines for the use of anti-Parkinson ' s disease drugs requires , as a pre-requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti-Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti-Parkinson ' s disease drugs , including genes coding for the corresponding drug-metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti-Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti-Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti-Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre-prescription tests .

Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP 3A ) , a phase II enzyme ( P22309 / 6/9 ) , two drug transporters ( P-gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat.The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC-MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated.The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP 3A1 / 2 with omeprazole / omeprazole-sulfone , midazolam / 1 ' - hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP 2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP 2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen-glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP 2C11 and CYP 2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .

The effects of mitiglinide ( KAD - 1229 ) , a new anti-diabetic drug , on DB00171 - sensitive K + channels and insulin secretion : comparison with the sulfonylureas and nateglinide . DB01252 ( KAD - 1229 ) , a new anti-diabetic drug , is thought to stimulate insulin secretion by closing the DB00171 - sensitive K + ( K ( DB00171 ) ) channels in pancreatic beta-cells . However , its selectivity for the various K ( DB00171 ) channels is not known . In this study , we examined the effects of mitiglinide on various cloned K ( DB00171 ) channels ( Kir 6.2 / Q09428 , Kir 6.2 / SUR 2A , and Kir 6.2 / SUR 2B ) reconstituted in COS - 1 cells , and compared them to another meglitinide-related compound , nateglinide . Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir 6.2 / Q09428 channel currents in a dose-dependent manner ( IC50 value , 100 nM ) but does not significantly inhibit either Kir 6.2 / SUR 2A or Kir 6.2 / SUR 2B channel currents even at high doses ( more than 10 microM ) . DB00731 MEN inhibits Kir 6.2 / Q09428 and Kir 6.2 / SUR 2B channels at 100 nM , and inhibits Kir 6.2 / SUR 2A channels at high concentrations ( 1 microM ) . Binding experiments on mitiglinide , nateglinide , and repaglinide to Q09428 expressed in COS - 1 cells revealed that they inhibit the binding of [ 3H ] glibenclamide to Q09428 ( IC50 values : mitiglinide , 280 nM ; nateglinide , 8 microM ; repaglinide , 1.6 microM ) , suggesting that they all share a glibenclamide binding site . The insulin responses to glucose , mitiglinide , tolbutamide , and glibenclamide in MIN 6 cells after chronic mitiglinide , nateglinide , or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment . These results indicate that , similar to the sulfonylureas , mitiglinide is highly specific to the Kir 6.2 / Q09428 complex , i . e . , the pancreatic beta-cell K ( DB00171 ) channel , and suggest that mitiglinide may be a clinically useful anti-diabetic drug .

Association of P22309 Gly 71Arg with urine urobilinogen . Bilirubin is glucoronized by uridine diphosphate-glucuronosyl transferase 1A1 ( P22309 ) mainly in the liver , and excreted into bile . The conjugated form is metabolized into the unconjugated form , and then into urobilinogen by bacteria in the intestine . Unconjugated bilirubin and urobilinogen are absorbed into the blood stream . The kidney filtrates conjugated bilurubin and urobilinogen into urine . Accordingly , the reduced enzyme activity of UGTIAI may decrease serum conjugated bilirubin levels , resulting in a lower frequency of positive results of urine bilirubin and urobilinogen . This study examined the associations of UGTIAI Gly 71Arg ( UGTIAI * 6 ) with urine bilirubin and urobilinogen , as well as serum Q9NRA2 , ALT and P19440 . Subjects were 5,172 inhabitants 35 to 69 years old who participated in a cohort study in Nagoya from June 2008 to May 2010 . Among them , data from 5,151 participants ( 1,465 males and 3,686 females ) were available for analysis . The age-sex-adjusted odds ratio ( OR ) of ArgArg relative to GlyGly was 1.37 ( 95 % confidence interval ( 95 % CI ) , 0.55- 1.23 ) for bilirubin , and 1.67 ( 95 % CI , 0.86- 3.26 ) for urobilinogen . Those of ArgArg + ArgGly were 0.87 ( 95 % CI , 0.59- 1.27 ) and 1.50 ( 95 % CI , 1.17- 1.94 ) , respectively . Q9NRA2 , ALT and P19440 levels had no associations with the genotype . Although the significant association for urobilinogen was contrary to the biological expectation , this study indicated that UGTIA 1 Gly 71Arg may be a genetic factor of urine urobilinogen .

Effects of progestins on local estradiol biosynthesis and action in the Z - 12 endometriotic epithelial cell line . Endometriosis is a common estrogen-dependent gynecological disease . In patients with endometriosis estradiol can be synthesized locally in the endometriotic lesions from inactive precursors of adrenal or ovarian origin , via the aromatase pathway . These increased estradiol levels stimulate proliferation of endometriotic tissue . The progestins have been used in the therapy of endometriosis for more than 40 years but their pharmacological action is still not understood in detail . In the present study we therefore aimed to evaluate the effects of three progestins most commonly used in the therapy of endometriosis ; medroxyprogesterone acetate , dydrogesterone and dienogest on expression of all genes encoding enzymes of the aromatase pathway and estrogen receptors in the Z - 12 model epithelial cell line of peritoneal endometriosis , by qPCR and Western blotting . Our results show that application of medroxyprogestrone acetate , dydrogesterone and dienogest significantly decreases P14061 and P11511 expression and significantly increases P37059 expression . Dydrogesterone and dienogest also significantly suppress P03372 and Q92731 transcription , whereas medroxyprogestrone acetate and dydrogesterone significantly reduce mRNA levels of Q99527 . Our results thus suggest that in peritoneal endometriosis the beneficial effects of these progestins can be explained by lower P14061 and higher P37059 mRNA and protein levels , which lead to reduced local E2 biosynthesis . Although progestins significantly decrease P11511 mRNA levels , the protein itself was not detectable by Western blotting . As progestins down-regulate expression of P03372 , Q92731 and Q99527 , they might also prevent E2 - mediated proliferation .

Species difference in glucuronidation formation kinetics with a selective P42345 inhibitor . The mammalian target of rapamycin ( P42345 ) is a protein kinase that shows key involvement in age-related disease and promises to be a target for treatment of cancer . In the present study , the elimination of potent DB00171 - competitive P42345 inhibitor 3 - ( 6 - amino - 2 - methylpyrimidin - 4 - yl ) - N - ( 1H - pyrazol - 3 - yl ) imidazo [ 1,2- b ] pyridazin - 2 - amine ( compound 1 ) is studied in bile duct-cannulated rats , and the metabolism of compound 1 in liver microsomes is compared across species . Compound 1 was shown to undergo extensive N-glucuronidation in bile duct-catheterized rats . N-glucuronides were detected on positions N1 ( M2 ) and N2 ( M1 ) of the pyrazole moiety as well as on the primary amine ( M3 ) . All three N-glucuronide metabolites were detected in liver microsomes of the rat , dog , and human , while primary amine glucuronidation was not detected in cynomolgus monkey . In addition , N1 - and N2 - glucuronidation showed strong species selectivity in vitro , with rat , dog , and human favoring N2 - glucuronidation and monkey favoring N1 - glucuronide formation . Formation of M1 in monkey liver microsomes also followed sigmoidal kinetics , singling out monkey as unique among the species with regard to compound 1 N-glucuronidation . In this respect , monkeys might not always be the best animal model for N-glucuronidation of uridine diphosphate glucuronosyltransferase ( P78381 ) 1A9 or P22309 substrates in humans . The impact of N-glucuronidation of compound 1 could be more pronounced in higher species such as monkey and human , leading to high clearance in these species . While compound 1 shows promise as a candidate for investigating the impact of pan - P42345 inhibition in vivo , opportunities may exist through medicinal chemistry efforts to reduce metabolic liability with the goal of improving systemic exposure .

Intracellular targets of cyclin-dependent kinase inhibitors : identification by affinity chromatography using immobilised inhibitors . BACKGROUND : Chemical inhibitors of cyclin-dependent kinases ( CDKs ) have great therapeutic potential against various proliferative and neurodegenerative disorders . DB02116 MEN , a 2,6 , 9 - trisubstituted purine , has been optimized for activity against P06493 / cyclin B by combinatorial and medicinal chemistry efforts to yield the purvalanol inhibitors . Although many studies support the action of purvalanols against CDKs , the actual intracellular targets of 2,6 , 9 - trisubstituted purines remain unverified . RESULTS : To address this issue , purvalanol B ( 95 . ) and an N6 - methylated , CDK-inactive derivative ( 95M . ) were immobilized on an agarose matrix . Extracts from a diverse collection of cell types and organisms were screened for proteins binding purvalanol B . In addition to validating CDKs as intracellular targets , a variety of unexpected protein kinases were recovered from the 95 . matrix . Casein kinase 1 ( CK1 ) was identified as a principal 95 . matrix binding protein in Plasmodium falciparum , Leishmania mexicana , Toxoplasma gondii and Trypanosoma cruzi . DB02733 compounds also inhibit the proliferation of these parasites , suggesting that CK1 is a valuable target for further screening with 2,6 , 9 - trisubstituted purine libraries . CONCLUSIONS : That a simple batchwise affinity chromatography approach using two purine derivatives facilitated isolation of a small set of highly purified kinases suggests that this could be a general method for identifying intracellular targets relevant to a particular class of ligands . This method allows a close correlation to be established between the pattern of proteins bound to a small family of related compounds and the pattern of cellular responses to these compounds .

New-generation Q13639 receptor agonists : potential for treatment of gastrointestinal motility disorders . IMPORTANCE OF THE FIELD : Gastrointestinal ( GI ) dysmotility is an important mechanism in functional GI disorders ( FGIDs ) including constipation , irritable bowel syndrome , functional dyspepsia , and gastroparesis . 5 - hydroxytryptamine ( 4 ) ( 5 - HT ( 4 ) ) receptors are targets for the treatment of GI motility disorders . However , older 5 - HT ( 4 ) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac Q12809 potassium channel . AREAS COVERED IN THIS REVIEW : We conducted a PubMed search using the following key words alone or in combination : 5 - HT ( 4 ) , safety , toxicity , pharmacokinetics , pharmacodynamics , clinical trial , cardiac , hERG , arrhythmia , potassium current , elderly , prucalopride , ATI - 7505 , and velusetrag ( DB05655 MEN ) , to review mechanisms of action , clinical efficacy , safety and tolerability of three new-generation 5 - HT ( 4 ) receptor agonists . WHAT THE READER WILL GAIN : DB06480 , ATI - 7505 , and velusetrag ( DB05655 MEN ) are highly selective , high-affinity 5 - HT ( 4 ) receptor agonists that are devoid of action on other receptors within their therapeutic range . Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and , to a variable degree , in clinical trials that significantly relieve chronic constipation . Currently available evidence shows that the new 5 - HT ( 4 ) receptor agonists have safe cardiac profiles . TAKE HOME MESSAGE : New-generation 5 - HT ( 4 ) receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility , particularly colonic diseases .

Follicular carcinoma presenting as autonomous functioning thyroid nodule and containing an activating mutation of the DB00024 MEN receptor ( T620I ) and a mutation of the Ki - DB01367 ( G12C ) genes . Most autonomous functioning thyroid nodules ( AFTN ) are benign thyroid follicular neoplasms . There are rare reports of malignant hot nodules , in which activating mutations of the DB00024 MEN receptor ( P16473 ) were found . We report a case of follicular carcinoma presenting as an AFTN causing subclinical hyperthyroidism in a 64 - year-old woman who had a 6 - cm hot nodule in the left thyroid lobe . Genomic DNA was extracted from paraffin-embedded tissues from the tumor and extratumoral thyroid tissue . Sequence analyses revealed point mutations in two different genes : the normal ACC sequence at codon 620 of the P16473 gene was replaced by ATC , changing the threonine by isoleucine ( T620I ) ; and the wild-type P19440 at codon 12 of Ki - DB01367 mutated to TGT , replacing glycine by cysteine ( G12C ) . In transfection experiments the T620I mutant showed constitutive activity in terms of cyclic adenosine monophosphate ( DB02527 ) production when permanently transfected in 3T3 cells . Here , we describe for the first time an activating mutation in 3codon 620 of the P16473 . In addition , the cancerous AFTN also contained a G12C Ki - DB01367 mutation . We hypothesize that the combination of these two mutations might have played an important role in both the hyperfunction of the tumor and the carcinogenetic process .

[ Antinociceptive mechanism of action of paracetamol ] . The mechanism of action of paracetamol ( acetaminophen ) is still not clearly understood . Unlike morphine , for example , paracetamol has no known endogenous high-affinity binding sites . In addition , paracetamol does not appear to share with nonsteroidal anti-inflammatory drugs ( NSAIDs ) the capacity to inhibit peripheral cyclo-oxygenase ( P36551 ) activity . There is currently considerable evidence to support the hypothesis of a central antinociceptive effect . Although various biochemical studies point to inhibition of central P35354 activity , the existence of a P36551 activity that is selectively susceptible to paracetamol ( P36551 - 3 ? ) is an alternative hypothesis . Modulation of the serotoninergic system has also been suggested on the basis of biochemical and behavioural studies supporting an indirect serotoninergic ( 5 - HT ) effect . DB00316 MEN may stimulate the activity of descending 5 - HT pathways that inhibit nociceptive signal transmission in the spinal cord . Support for this possibility has come from evidence that spinally administered antagonists of several 5 - HT receptor subtypes abolish the antinociceptive activity of paracetamol . These hypotheses have yet to be confirmed by further studies . Until then , the primary pharmacological mechanism underlying the analgesic effect of paracetamol has still to be clearly defined .

Inhibition of PI3K / AKT / P42345 pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice . Invasive pituitary adenomas ( PAs ) are often refractory to standard therapy and salvage treatment with temozolomide ( DB00853 ) . Hyperactivation of the phosphoinositide 3 - kinase ( PI3K ) / AKT / mammalian target of rapamycin ( P42345 ) pathway contributes to chemotherapy resistance in many cancers . DB05241 MEN , a novel dual-PI 3K / P42345 inhibitor , has recently shown its efficacy as a monotherapy and in combination with conventional therapeutics in many cancers . The hyperactive PI3K / AKT / P42345 pathway frequently occurs in invasive PAs . In this study , we investigated whether DB05241 MEN sensitizes PA cells to DB00853 in vitro and in vivo . Experiments were carried out to evaluate the effect of DB05241 MEN and DB00853 alone or in combination on cell proliferation and apoptosis of PA cell lines ( α DB00279 - 1 , GH3 , and MMQ ) in vitro as well as the tumor growth and serum GH and prolactin secretions in a GH3 xenograft tumor model of female nude mice . DB05241 MEN and DB00853 synergistically inhibited the growth of PA cell lines and induced apoptosis . Combination of DB05241 MEN and DB00853 synergistically inhibited tumor growth , decreased serum GH and prolactin levels , and reduced the sacrifice rate of GH3 xenograft tumor models without increased systemic side effects . In addition , DB05241 MEN in combination with DB00853 dramatically decreased phosphorylation of AKT and P42345 as well as the expression of Bcl - 2 . The increased expression of cleaved poly ( ADP-ribose ) polymerase and Bcl - 2 - associated X protein along with elevated caspase -3/7 activity were also observed in the combination group . Therefore , dual inhibitors of PI3K and P42345 may enhance alkylating agent-mediated cytotoxicity and provide a novel regimen in the treatment of invasive PAs .

Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages . 2,3 , 7,8- Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up-regulation of an important inflammation marker , P35354 mRNA expression within 1h , and by 3h , several other markers become up-regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 + ) , and activation of P47712 and P35354 . A comparative study among three different human cell lines showed that activation of P35354 within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 and P10145 mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 . Based on the rapidity of activation of P47712 and P35354 , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 has been observed , it is apparent that this unique action of TCDD is carried out through a distinct " nongenomic " pathway which , is clearly discernable from the classical , " genomic " action pathway of the P35869 by not requiring the participation of P27540 .

Molecular genetics of bipolar disorder . Bipolar disorder ( BPD ) is an often devastating illness characterized by extreme mood dysregulation . Although family , twin and adoption studies consistently indicate a strong genetic component , specific genes that contribute to the illness remain unclear . This study gives an overview of linkage studies of BPD , concluding that the regions with the best evidence for linkage include areas on chromosomes 2p , 4p , 4q , 6q , 8q , 11p , 12q , 13q , 16p , 16q , 18p , 18q , 21q , 22q and Xq . Association studies are summarized , which support a possible role for numerous candidate genes in BPD including P21964 , Q01959 , Q13639 , P21917 , P14416 , P28223 , 5 - HTT , the P59103 / G30 complex , Q9NRI5 , Q99572 , P21397 and P23560 . Animal models related to bipolar illness are also reviewed , with special attention paid to those with clear genetic implications . We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness .

Regulation of pregnane X receptor ( O75469 ) function and P22309 gene expression by posttranslational modification of O75469 protein . Human UDP-glucuronosyltransferase ( P78381 ) 1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds such as bilirubin . The present study shows how cyclin-dependent kinase ( CDK ) inhibitor roscovitine stimulated the expression of P22309 in HepG 2 cells . O75469 ( O75469 ) - mediated transactivation of P22309 reporter gene was more prominently enhanced by roscovitine , compared with the basal - , constitutive androstane receptor ( CAR ) - , and aryl hydrocarbon receptor-mediated activities . We determined the regulatory mechanism of P22309 expression through O75469 ' s stimulation by roscovitine . Although phosphomimetic mutations at Thr 290 and Thr 408 retained the O75469 protein in cytoplasm and attenuated the induction of P22309 expression by both roscovitine and rifampicin , a mutation at Ser 350 specifically reduced the activity of O75469 induced by roscovitine . Immunoprecipitation analysis revealed that the T290D but not T408D mutant protein remained in cytoplasm by forming a complex with heat shock protein 90 and cytoplasmic CAR retention protein , whereas treatment with proteasome inhibitor MG - 132 accumulated the T408D mutant protein in cytoplasm . Transfection with anti - P24941 small interfering RNA ( siRNA ) but not anti - P06493 or Q00535 siRNA led to enhanced expression of P22309 . S350D yellow fluorescent protein - O75469 fusion protein could translocate from cytoplasm to nucleus similar to the wild-type protein but was detected as an acetylated protein , whose binding with retinoid X receptor ( RXR ) and histone deacetylase was impaired . Cotransfection with coactivator steroid receptor coactivator ( P12931 ) 2 but not Q15788 partly recovered its O75469 activity . These results indicate that roscovitine stimulated the expression of P22309 by inhibiting P24941 , which phosphorylated O75469 at Ser 350 to suppress binding with RXR and coactivator and maintain the acetylation of O75469 protein .

Effects of an alpha 7 - nicotinic agonist on default network activity in schizophrenia . BACKGROUND : 3 - ( 2,4- dimethoxybenzylidene ) - anabaseine ( DB05708 MEN ) is a partial agonist at α7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia . This study examined the effects of DB05708 MEN on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia . METHODS : Placebo and two doses of DB05708 MEN were administered in a random , double-blind crossover design during a Phase 2 study of DB05708 MEN . Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task . Independent component analysis was used to identify the default network component . Default network changes were evaluated in the context of a polymorphism in P36544 , the α7 - nicotinic acetylcholine receptor subunit gene , which was previously found to be associated with schizophrenia . RESULTS : Compared with placebo , both 150 and 75 mg twice daily DB05708 MEN altered default network activity , including a reduction in posterior cingulate , inferior parietal cortex , and medial frontal gyrus activity and an increase in precuneus activity . The most robust difference , posterior cingulate activity reduction , was affected by P36544 genotype . CONCLUSIONS : The observed DB05708 MEN - related changes are consistent with improved default network function in schizophrenia . Pharmacogenetic analysis indicates mediation of the effect through the α7 - nicotinic receptor . These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents .

Estrogen in the limbic system . DB00286 MEN are a group of steroid hormones that function as the primary female sex hormone . DB00286 MENMAX DB00286 MEN not only have an important role in the regulation of the estrous or menstrual cycle but also control , for example , bone formation , the cardiovascular system , and cognitive functions . Estradiol ( E2 ) , the main representative of the group , is highly lipophylic and can easily pass the blood-brain barrier to modulate neuronal activity . Particularly the limbic system , a group of tightly interconnected forebrain areas controlling mood and emotion , is rich in estrogen receptors . To date two cytoplasmatic and / or nuclear estrogen receptors named P03372 ( ERalpha ) and Q92731 ( ERbeta ) have been identified . In the brain , ERalpha plays a critical role in regulating reproductive neuroendocrine behavior and function . ERbeta appears to play an important role in nonreproductive behaviors , such as learning and memory , anxiety , and mood . Five splice variants of ERbeta , named Erb 1 , Erb 2 , Erb 1d3 , Erb 2d3 , and Erb 1d4 , have been identified with possibly different biological activities . There is evidence of a thus far not definitely characterized membrane-linked ER receptor named Q99527 - X . In this review , the anatomy of the limbic system and the distribution of estrogen receptors ( ERs ) are described in relation to coping with stress and the higher prevalence of stress-related psychiatric disorders in women . Effects of cyclic estrogen administration and chronic stress on recovery and neuronal plasticity are illustrated with own results .

Regulatory regions of growth-related genes can activate an exogenous gene of the alpha-fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha-fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer-linked AFP promoter even in high-AFP-producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate-AFP-producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth-related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .

Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case-control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population-based case-control study . We examined nutrient density-adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT 2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0.026 ) , cooked by pan-frying ( trend P = 0.035 ) , and cooked until well-done ( trend P = 0.013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0.023 ) . A gene-by-diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0.008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .

Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid-dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .

Novel phenolic antioxidants as multifunctional inhibitors of inducible P19320 expression for use in atherosclerosis . A series of novel phenolic compounds has been discovered as potent inhibitors of P01375 - inducible expression of vascular cell adhesion molecule - 1 ( P19320 ) with concurrent antioxidant and lipid-modulating properties . Optimization of these multifunctional agents led to the identification of 3a ( DB05399 MEN ) as a clinical candidate with demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia .

Protective effects of metallothionein on isoniazid and rifampicin-induced hepatotoxicity in mice . Isoniazid ( DB00951 SUB ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine-rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against DB00951 SUB and RFP-induced hepatic oxidative stress in mice . Wild type ( MT + / + ) and MT-null ( MT - / - ) mice were treated intragastrically with DB00951 SUB ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg DB00951 SUB + 300 mg / kg RFP ) for 21 days . The results showed that MT - / - mice were more sensitive than MT + / + mice to DB00951 SUB and RFP-induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , DB00951 SUB increased the protein expression of hepatic P05181 and DB00951 SUB / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against DB00951 SUB and RFP-induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of DB00951 SUB and RFP-induced hepatotoxicity .