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PubMed2006

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach.

We describe a comprehensive translational approach for identifying candidate genes for alcoholism. The approach relies on the cross-matching of animal model brain gene expression data with human genetic linkage data, as well as human tissue data and biological roles data, an approach termed convergent functional genomics. An analysis of three animal model paradigms, based on inbred alcohol-preferring (iP) and alcohol-non-preferring (iNP) rats, and their response to treatments with alcohol, was used. A comprehensive analysis of microarray gene expression data from five key brain regions (frontal cortex, amygdala, caudate-putamen, nucleus accumbens and hippocampus) was carried out. The Bayesian-like integration of multiple independent lines of evidence, each by itself lacking sufficient discriminatory power, led to the identification of high probability candidate genes, pathways and mechanisms for alcoholism. These data reveal that alcohol has pleiotropic effects on multiple systems, which may explain the diverse neuropsychiatric and medical pathology in alcoholism. Some of the pathways identified suggest avenues for pharmacotherapy of alcoholism with existing agents, such as angiotensin-converting enzyme (ACE) inhibitors. Experiments we carried out in alcohol-preferring rats with an ACE inhibitor show a marked modulation of alcohol intake. Other pathways are new potential targets for drug development. The emergent overall picture is that physical and physiological robustness may permit alcohol-preferring individuals to withstand the aversive effects of alcohol. In conjunction with a higher reactivity to its rewarding effects, they may able to ingest enough of this nonspecific drug for a strong hedonic and addictive effect to occur.

Alcohol Drinking↗
PubMed2000

Parathyroid hormone-activated volume-sensitive calcium influx pathways in mechanically loaded osteocytes.

This paper documents for the first time a volume-sensitive Ca(2+) influx pathway in osteocytes, which transmits loading-induced signals into bone formation. Stretch loading by swelling rat and chicken osteocytes in hypo-osmotic solution induced a rapid and progressive increase of cytosolic calcium concentration, [Ca(2+)](i). The influx of extracellular Ca(2+) explains the increased [Ca(2+)](i) that paralleled the increase in the mean cell volume. Gadolinium chloride (Gd(3+)), an inhibitor of stretch- activated cation channels, blocked the [Ca(2+)](i) increase caused by hypotonic solutions. Also, the expression of alpha1C subunit of voltage-operated L-type Ca(2+) channels (alpha1C) is required for the hypotonicity-induced [Ca(2+)](i) increase judging from the effect of alpha1C antisense oligodeoxynucleotides. Parathyroid hormone (PTH) specifically potentiated the hypotonicity-induced [Ca(2+)](i) increase in a dose-dependent manner through the activation of adenyl cyclase. The increases induced by both PTH and hypotonicity were observed primarily in the processes of the osteocytes. In cyclically stretched osteocytes on flexible-bottomed plates, PTH also synergistically elevated the insulin-like growth factor-1 mRNA level. Furthermore, Gd(3+) and alpha1C antisense significantly inhibited the stretch-induced insulin-like growth factor-1 mRNA elevation. The volume-sensitive calcium influx pathways of osteocytes represent a mechanism by which PTH potentiates mechanical responsiveness, an important aspect of bone formation.

Animals↗
PubMed2002

Mechanisms and pathways of inflammatory responses in CNS trauma: spinal cord injury.

Numerous mechanisms contribute to neural damage following central nervous system (CNS) injury. Inflammatory response has emerged as an important interaction between the CNS and the immune system in spinal cord injury that can have beneficial as well as detrimental consequences. This relationship has important implications for the development of therapeutic interventions for injuries and diseases of the spinal cord. This article details the innate and adaptive arms of the immune response, including cell-mediated and humoral pathways, and describes their relevance to the processes of degeneration and regeneration.

Antibody Formation↗
PubMed1975

The choline incorporation pathway: primary mechanism for de novo lecithin synthesis in fetal primate lung.

The two pathways of de novo lecithin synthesis, choline incorporation (I) and phosphatidylethanolamine methylation (II), were examined in lung slices from rhesus monkey fetuses throughout the last half of gestation. Incorporation rates of pathway-specific radioactive precursors were used as a measure of lecithin production. At all stages of development studied, pathway I incorporated 10-50 times more precursor ([14C]choline) into lecithin than did pathway II ([14C]methionine or [14C]ethanolamine). In addition, although methylation activity did not change significantly during gestation, choline incorporation showed three distinct phases: (1) a stable, relatively low rate in early gestation, (2) an abrupt, twofold increase at approximately 90 percent of term, and (3) a return to lower activity levels in late gestation. This correlates with reports that lung lecithin concentration in fetal primates increases significantly in the last 10 percent of gestation. The lecithin to spingomyelin (L/S) ratios measured in amniotic fluid samples obtained at abdominal delivery were compared with pathway activities in lung slices from the same fetuses. Significant correlation was found between the amniotic fluid L/S ratio and pathway I activity (r = 0.77, P less than 0.001); in contrast, pathway II activity showed no relationship to the amniotic fluid L/S ratio. Thus, the L/S ratio appears to be a reflection of lung lecithin synthesis through the choline pathway. The conclusion that the choline pathway is the primary route of de novo lecithin synthesis in the nonhuman fetal primate lung is supported by three lines of evidence, (1) the predominance of choline incorporation into lecithin, (2) the late gestational rise in conversion of choline to lecithin, and (3) the correlation between pathway I activity and both lung lecithin concentration and amniotic fluid L/S ratio.

Adenosine Triphosphate↗
PubMed2004

Atrioventricular nodal fast pathway modification: mechanism for lack of ventricular rate slowing in atrial fibrillation.

OBJECTIVES: Atrioventricular node (AVN) modification is one of the alternatives for ventricular rate control in patients with drug refractory atrial fibrillation (AF). However, the underlying mechanisms, and in particular the role of the dual pathway electrophysiology is not clear. By using a novel index, His electrogram (HE) alternans, we have previously demonstrated in rabbits that both the slow (SP) and the fast pathways (FP) are involved in AVN conduction during AF. This electrophysiological-morphological study was designed to address the role of selective FP ablation on AVN conduction during AF. METHODS AND RESULTS: In 12 rabbit AVN preparations dual pathway conduction was confirmed by HE alternans during A1A2 pacing protocol, as well as during AF. On average 48% of the conducted beats during AF utilized the FP. Selective FP ablation (n=12) guided by HE alternans resulted in only-SP conduction, with longer AVN conduction time at basic beats, but without change of AVN effective refractory period (ERP). Interestingly, despite elimination of all FP-conducted beats during AF, the selective FP ablation allowed previously concealed SP beats to be conducted, resulting in little net effect on the ventricular rate (average His-His interval 199+/-10 ms before versus 201+/-13 ms after FP ablation, p>0.05). Morphological evidence indicated that FP ablation created lesions within the transitional cells of the superior approaches at the junction between the central fibrous body and the AVN. However, extension of FP ablation lesion into the compact AVN domain resulted in non-selective AVN modification and slowing of ventricular rate during AF. CONCLUSIONS: Despite its longer ERP, FP is responsible for a substantial number of ventricular beats during AF. However, selective FP ablation has a minor effect on ventricular rate. The most likely mechanism for this phenomenon is that FP ablation allows previously concealed SP beats to be conducted. On the other hand, ventricular rate slowdown could be achieved if FP ablations caused collateral damage in the compact node. This study highlights the usefulness of HE alternans as a novel tool to monitor dual pathway conduction during AF and to guide AVN modification.

Animals↗
PubMed1985

Evolution of antibody structure and effector functions: comparative hemolytic activities of monomeric and tetrameric IgM from rainbow trout, Salmo gairdnerii.

Monomeric and tetrameric IgM anti-haptin antibodies isolated from the sera of rainbow trout (S. gairdnerii) by immunoaffinity chromatography were compared both immunochemically and with regard to their functional abilities to lyse haptenated trout erythrocytes in the presence of trout complement. The two populations had similar binding affinities for hapten and apparently identical L chains, but differed in H chain peptide maps and immunoreactivity with rabbit anti-trout H chain serum. These differences could not be attributed to J-chain. The abilities of the two antibody subpopulations to activate C to lyse haptenated trout erythrocytes also differed dramatically. Such functional differences are not simply explained by the greater avidity of the tetrameric form since preliminary studies show that the monomeric form of trout IgM activates C via an alternative pathway mechanism while the tetrameric form activates both classical and alternative pathway mechanisms. Results suggest divergent evolution of antibody structures involved in the familiar effector functions (C activation, transport, etc.).

Animals↗
PubMed1997

Induction of neurite outgrowth in PC12 cells by gamma-lactam-related compounds via Ras-MAP kinase signaling pathway independent mechanism.

Rat pheochromocytoma cells, PC12 cells, undergo differentiation in response to nerve growth factor (NGF). Although the Ras-MAP kinase signaling pathway has been shown to play a central role in the response to NGF, the precise mechanism which induces differentiation remains unclarified. Recently, several gamma-lactam-related microbial products were identified to induce neurite outgrowth in neuroblastoma cells. Therefore, we synthesized a series of gamma-lactam-related compounds and tested for their ability to induce neurite outgrowth in PC12 cells. We found that two compounds, MT-19 and MT-20, induced neurite outgrowth at concentrations as low as 1 microg/ml. MT-19 and MT-20 have an n-hexadecyl group and an n-dodecyl group, respectively, at the position N-1 of the gamma-lactam ring, and the modification of this group leads to partial or complete loss of activity. In addition, the modification of the methyl and hydroxyl group at C-5 leads to complete loss of activity, indicating a strict structure-activity relationship. Interestingly, MT-19 and MT-20 induced neurite outgrowth of PC12 cells which lack normal Ras function. Furthermore, these compounds did not induce MAP kinase activation, suggesting that MT-19 and MT-20 do not require the Ras-MAP kinase signaling pathway which is shown to be necessary and sufficient for NGF-induced neurite outgrowth. Consistent with this, none of the early- or late-response genes tested, which include fos, zif268, Nur77, vgf, and transin, was induced. However, the protein level of three neurofilaments was increased after the incubation with these compounds. Since the level of other cytoskeleton proteins including actin and tubulin remained constant, MT-19 and MT-20 specifically affected neurofilament synthesis and/or turnover. Taken together, these findings indicate that MT-19 and MT-20 induce neurite outgrowth by activating the downstream target of MAP kinase or by a novel mechanism which is distinct from the NGF-activated pathway.

Actins↗
PubMed1990

Mechanism and pathway of glucose transportation in a digenetic trematode Ceylonocotyle scoliocoelium.

The mode of absorption, kinetics and mechanism of transportation of 14C--glucose in a digenetic trematode, Ceylonocotyle scoliocoelium were studied by culturing the trematodes under in vitro condition in Hank's saline supplemented with radioactive tracer. It was then followed separately by autoradiography and liquid scintillation. Autoradiographic study reveals that the maximum amount of glucose uptake occurs through cuticle whereas the role of intestinal canal is insignificant in this respect. Maximum cpm is recorded in the precipitate followed by TCA treatment. This is due to the presence of a protein-bound 14C-glucose which is assumed as the carrier protein. The inhibitor, phlorizin, used here presumably acts noncompetitively.

Absorption↗
PubMed2001

Role of the haeme oxygenase/carbon monoxide pathway in mechanical nociceptor hypersensitivity.

The cleavage of haeme by haeme oxygenase (HO) yields carbon monoxide (CO), a biologically active molecule which exerts most of its effects via activation of soluble guanylate cyclase (sGC). In the present study, we tested the hypothesis that endogenous CO could modulate inflammatory hyperalgesia. The intensity of hyperalgesia was investigated in a model of mechanical nociceptor hypersensitivity in rats. The intra-plantar (i.pl.) administration of the HO inhibitor, ZnDPBG (Zinc deuteroporphyrin 2,4-bis glycol), potentiated in a dose-dependent manner the mechanical nociceptor hypersensitivity evoked by i.pl. administration of carrageenan. The mechanical hypersensitivity evoked by i.pl. injection of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), but not interleukin-8 (IL-8), prostaglandin E(2) (PGE(2)) or dopamine, was also enhanced by ZNDPBG: Moreover, the haeme (HO substrate) injection in the paws reduced the hypersensitivity evoked by IL-1beta, but not PGE(2). Furthermore, i.pl. administration of the gas CO reduced the hypersensitivity elicited by PGE(2). The inhibitory effect of haeme and CO upon mechanical nociceptor hypersensitivity were counteracted by a soluble guanylate cyclase (sGC) inhibitor, ODQ (1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one), suggesting that this effect of CO is mediated via cyclic GMP. Finally, the inhibitory effect of CO upon mechanical nociceptor hypersensitivity was prevented by the NO synthase blocker, L-NMMA (N(G)-monomethyl L-arginine), suggesting that the impairment of mechanical hypersensitivity elicited by CO depends on the integrity of the NO pathway. In conclusion, the results presented in this paper imply that endogenously CO produced by HO plays an anti-hyperalgesic role in inflamed paws, probably by increasing the intracellular levels of cyclic GMP in the primary afferent neurone.

Animals↗
PubMed2000

Sorting and targeting of melanosomal membrane proteins: signals, pathways, and mechanisms.

Newly synthesized melanosomal proteins, like many other cellular proteins, traverse through a series of intracellular compartments en route to melanosomes. Entry and exit of proteins through these compartments is orchestrated by cellular sorting machinery that recognize specific sorting signals. Melanosomal membrane proteins begin their intracellular journey upon co-translational importation into the endoplasmic reticulum (ER). The biosynthetic output of tyrosinase, the key melanogenic enzyme, appears to be regulated by quality-control events at the ER, the 'port of entry' to the secretory pathway. Following maturation in the ER and through the Golgi, the sorting of these proteins in the trans-Golgi network for intracellular retention and transport along endosome/lysosome pathway requires cytoplasmically exposed signals. A di-leucine motif, present in the cytoplasmic tails of most melanosomal proteins, and its interaction with adaptor protein (AP) complexes, specifically AP-3, are critical for these events. Defects in sorting signals and the cytosolic components that interact with these signals result in a number of murine coat color phenotypes and cause human pigmentary disorders. Thus, missense or frame-shift mutations that produce truncated tyrosinase lacking the melanosomal sorting signal(s) appear to be responsible for murine platinum coat color phenotypes and a proportion of human oculocutaneous albinism-1; mutations in AP-3 appear to be responsible for the mocha phenotype in mice and Hermansky-Pudlak-like syndrome in man. Additional signals and sorting steps downstream of AP-3 appear to be required for endosomal sorting and targeting proteins to melanosomes. Signals and mechanisms that sequester melanosomal proteins from endosomes/lysosomes are not understood. Potential candidates that mediate such processes include proteins encoded by lyst and pallid genes. The common occurrence of abnormalities in melanosomes in many storage-pool disorders suggests that melanocytes utilize signals, pathways, and mechanisms shared by other proteins and cell types to assemble a number of specialized proteins and produce unique cell-type-specific organelles.

Amino Acid Sequence↗
PubMed1996

Degradation kinetics and isomerization of cefdinir, a new oral cephalosporin, in aqueous solution. 2. Hydrolytic degradation pathway and mechanism for beta-lactam ring opened lactones.

Hydrolysis of cefdinir leads to pH-dependent isomerizations and beta-lactam ring-opening. Lactam ring opened gamma-lactones were produced as a mixture of four diastereoisomers based on the lactone methyl, and C-6 isomerizations in acidic to neutral solutions. Cefdinir and its 7-epimer were hydrolyzed to clarify the pathway leading to these lactones and the mechanism of C-6 epimerization with the aid of chiral separation techniques. Chiral separation using a bovine serum albumin column was employed to detect the beta-lactam ring opened products of cefdinir and its 7-epimer; the C-6 and C-7 isomerization was thereby observed; however, it was found to be pH-dependent at pH > or = 9. Optical activity detection applied to the lactones produced from cefdinir and its 7-epimer demonstrated that the corresponding peaks of these lactones were enantiomeric pairs. In addition, the smallest rate constant at pH 4 was observed for C-6 epimerization of the lactones, and it was found to proceed without deprotonation at C-6 by 1H-NMR spectroscopy. From the results of these studies, a plausible mechanism for C-6 epimerization has been proposed. Additionally, it was confirmed that two degradation pathways were involved during hydrolysis of cefdinir to the lactone.

Administration, Oral↗
PubMed2005

Reaction pathways and mechanisms of the electrochemical degradation of phenol on different electrodes.

Laboratory experiments were carried out on the kinetics and pathways of the electrochemical (EC) degradation of phenol at three different types of anodes, Ti/SnO2-Sb, Ti/RuO2, and Pt. Although phenol was oxidised by all of the anodes at a current density of 20 mA/cm2 or a cell voltage of 4.6 V, there was a considerable difference between the three anode types in the effectiveness and performance of EC organic degradation. Phenol was readily mineralized at the Ti/SnO2-Sb anode, but its degradation was much slower at the Ti/RuO2 and Pt anodes. The analytical results of high-performance liquid chromatography (HPLC) and gas chromatography coupled with mass spectrometry (GC/MS) indicated that the intermediate products of EC phenol degradation, including benzoquinone and organic acids, were subsequently oxidised rapidly by the Ti/SnO2-Sb anode, but accumulated in the cells of Ti/RuO2 and Pt. There was also a formation of dark-coloured polymeric compounds and precipitates in the solutions electrolyzed by the Ti/RuO2 and Pt anodes, which was not observed for the Ti/SnO2-Sb cells. It is argued that anodic property not only affects the reaction kinetics of various steps of EC organic oxidation, but also alters the pathway of phenol electrolysis. Favourable surface treatment, such as the SnO2-Sb coating, provides the anode with an apparent catalytic function for rapid organic oxidation that is probably brought about by hydroxyl radicals generated from anodic water electrolysis.

Acids↗
PubMed2003

Proton transfer pathways and mechanism in bacterial reaction centers.

The focus of this minireview is to discuss the state of knowledge of the pathways and rates of proton transfer in the bacterial reaction center (RC) from Rhodobacter sphaeroides. Protons involved in the light driven catalytic reduction of a quinone molecule QB to quinol QBH2 travel from the aqueous solution through well defined proton transfer pathways to the oxygen atoms of the quinone. Three main topics are discussed: (1) the pathways for proton transfer involving the residues: His-H126, His-H128, Asp-L210, Asp-M17, Asp-L213, Ser-L223 and Glu-L212, which were determined by a variety of methods including the use of proton uptake inhibiting metal ions (e.g. Zn2+ and Cd2+); (2) the rate constants for proton transfer, obtained from a 'chemical rescue' study was determined to be 2 x 10(5) s(-1) and 2 x 10(4) s(-1) for the proton uptake to Glu-L212 and QB-*, respectively; (3) structural studies of altered proton transfer pathways in revertant RCs that lack the key amino acid Asp-L213 show a series of structural changes that propagate toward L213 potentially allowing Glu-H173 to participate in the proton transfer processes.

Binding Sites↗
PubMed2003

Ascending pathways for mechanical allodynia in a rat model of neuropathic pain.

To determine what the routes by which mechanical allodynia is transmitted following peripheral nerve injury, we assessed the effects of the dorsal column (DC) lesion performed before and 2 weeks after the partial injury of nerves innervating the tail on mechanical allodynia. Ipsilateral DC lesion 2 weeks after neuropathic surgery significantly, but not completely, attenuated mechanical allodynia. In addition, the DC lesion before peripheral nerve injury did not prevent the generation of mechanical allodynia, which was completely blocked by subsequent contralateral hemisection of the spinal cord. However, unlike mechanical allodynia, DC lesion did not change thermal allodynia. These results suggest that the signals for mechanical allodynia following peripheral nerve injury are transmitted via the ipsilateral DC and the contralateral pathway(s).

Animals↗
PubMedDate not supplied

Combined quantum mechanical and molecular mechanical reaction pathway calculation for aromatic hydroxylation by p-hydroxybenzoate-3-hydroxylase.

The reaction pathway for the aromatic 3-hydroxylation of p-hydroxybenzoate by the reactive C4a-hydroperoxyflavin cofactor intermediate in p-hydroxybenzoate hydroxylase (PHBH) has been investigated by a combined quantum mechanical and molecular mechanical (QM/MM) method. A structural model for the C4a-hydroperoxyflavin intermediate in the PHBH reaction cycle was built on the basis of the crystal structure coordinates of the enzyme-substrate complex. A reaction pathway for the subsequent hydroxylation step was calculated by imposing a reaction coordinate that involves cleavage of the peroxide oxygen-oxygen bond and formation of the carbon-oxygen bond between the C3 atom of the substrate and the distal oxygen of the peroxide moiety of the cofactor. The geometric changes and the Mulliken charge distributions along the calculated reaction pathway are in line with an electrophilic aromatic substitution type of mechanism. The energy barrier of the calculated reaction is considerably lower when the substrate hydroxyl moiety is deprotonated, in comparison with the barrier found with a protonated hydroxyl moiety. This effect of the protonation state of the substrate on the calculated energy barrier supports experimental observations that deprotonation is required for hydroxylation of the substrate. A notable event in the calculated reaction pathway is a lengthening of the peroxide oxygen-oxygen bond at an intermediate stage. Further analysis of the reaction pathway indicates that this oxygen-oxygen bond elongation is accompanied by an increase in electrophilic reactivity on the distal oxygen of the peroxide moiety, which may assist the C-O bond formation in the reaction of the C4a-hydroperoxyflavin intermediate with the substrate. Analysis of the effect of individual active site residues on the reaction reveals a specific transition state stabilization by the backbone carbonyl moiety of Pro293. The crystal water 717 appears to drive the hydroxylation step through a stabilizing hydrogen bond interaction to the proximal oxygen of the C4a-hydroperoxyflavin intermediate, which increases in strength as the hydroperoxyflavin cofactor converts to the anionic (deprotonated) hydroxyflavin.

4-Hydroxybenzoate-3-Monooxygenase↗
PubMed1999

Insulin signalling: metabolic pathways and mechanisms for specificity.

Biological actions of insulin are mediated by the insulin receptor, a member of a large family of receptor tyrosine kinases (RTK). Signal transduction by the insulin receptor follows a paradigm for RTK signalling. Many intracellular signalling molecules contain multiple modular domains that mediate protein-protein interactions and participate in the formation of signalling complexes. Phosphorylation cascades are also a prominent feature of RTK signalling. Distal pathways are difficult to dissect because branching paths emerge from downstream effectors and several upstream inputs converge upon single branch points. Thus, insulin action is determined by complicated signalling networks rather than simple linear pathways. Interestingly, many signalling molecules downstream from the insulin receptor are also activated by a plethora of RTKs. Therefore, mechanisms that generate specificity are required. In this review we discuss recent advances in the elucidation of specific metabolic insulin signalling pathways related to glucose transport, one of the most distinctive biological actions of insulin. We also present examples of potential mechanisms underlying specificity in insulin signalling including interactions between multiple branching pathways, subcellular compartmentalization, tissue-specific expression of key effectors and modulation of signal frequency and amplitude.

Animals↗