EFFECT OF LYSERGIC ACID DIETHYLAMIDE ON POTENTIALS EVOKED IN THE SPECIFIC SENSORY PATHWAYS.
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Animals↗
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Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease.
Ulcerative colitis and Crohn's disease are the two entities of chronic inflammatory bowel diseases (IBD). One of the main pathogenic mechanisms is probably a dysregulated immune response triggered by products of the enteric bacterial flora. The goal of this study was to evaluate the effects of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 on inflammatory responses using the DSS-induced experimental colitis model in mice reflecting human IBD. We found that SB203580 improved the clinical score, ameliorates the histological alterations, and reduces the mRNA levels of proinflammatory cytokines. In addition to p38 kinase activity, the "classical" and the "alternative" NF-kappaB pathways were also strongly activated during colitis induction. All three pathways were drastically down-regulated by SB203580 treatment. An analysis of the molecular basis of NF-kappaB activation revealed that Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK), a key component of a pathway leading to NF-kappaB induction, is also strongly inhibited by SB203580. Since RICK is an effector kinase of NOD2, an intracellular receptor of bacterial peptidoglycan, these results support the notion that NOD signaling could play a pivotal role in the IBD pathogenesis. Thus, RICK could represent a novel target for future therapies in human IBD.
Animals↗
Photosynthetic Characteristics of C(3)-C(4) Intermediate Flaveria Species : I. Leaf Anatomy, Photosynthetic Responses to O(2) and CO(2), and Activities of Key Enzymes in the C(3) and C(4) Pathways.
Four species of the genus Flaveria, namely F. anomala, F. linearis, F. pubescens, and F. ramosissima, were identified as intermediate C(3)-C(4) plants based on leaf anatomy, photosynthetic CO(2) compensation point, O(2) inhibition of photosynthesis, and activities of C(4) enzymes. F. anomala and F. ramosissima exhibit a distinct Kranz-like leaf anatomy, similar to that of the C(4) species F. trinervia, while the other C(3)-C(4) intermediate Flaveria species possess a less differentiated Kranz-like leaf anatomy. Photosynthetic CO(2) compensation points of these intermediates at 30 degrees C were very low relative to those of C(3) plants, ranging from 7 to 14 microliters per liter. In contrast to C(3) plants, net photosynthesis by the intermediates was not sensitive to O(2) concentrations below 5% and decreased relatively slowly with increasing O(2) concentration. Under similar conditions, the percentage inhibition of photosynthesis by 21% O(2) varied from 20% to 25% in the intermediates compared with 28% in Lycopersicon esculentum, a typical C(3) species. The inhibition of carboxylation efficiency by 21% O(2) varied from 17% for F. ramosissima to 46% for F. anomala and were intermediate between the C(4) (2% for F. trinervia) and C(3) (53% for L. esculentum) values. The intermediate Flaveria species, especially F. ramosissima, have substantial activities of the C(4) enzymes, phosphoenolpyruvate carboxylase, pyruvate, orthophosphate dikinase, NADP-malic enzyme, and NADP-malate dehydrogenase, indicating potential for C(4) photosynthesis. It appears that these Flaveria species may be true biochemical C(3)-C(4) intermediates.
Journal Article↗
Importance of medullary events in ammonium excretion: studies in acute respiratory and acute metabolic acidosis.
The renal medulla can play an important role in acid excretion by modulating both hydrogen ion secretion in the medullary collecting duct and the medullary PNH3. The purpose of these experiments was to characterize the intrarenal events associated with ammonium excretion in acute acidosis. Cortical events were monitored in two ways: first, the rates of glutamine extraction and ammoniagenesis were assessed by measuring arteriovenous differences and the rate of renal blood flow; second, the biochemical response of the ammoniagenesis pathway was examined by measuring glutamate and 2-oxoglutarate, key renal cortical metabolites in this pathway. There were no significant differences noted in any of these cortical parameters between acute respiratory and metabolic acidosis. Despite a comparable twofold rise in ammonium excretion in both cases, the urine pH, PNH3, and the urine minus blood PCO2 difference (U-B PCO2) were lower during acute hypercapnia. In these experiments, the urine PCO2 was 34 mmHg (1 mmHg = 133.322 Pa) lower than that of the blood during acute respiratory acidosis while the U-B PCO2 was 5 +/- 3 mmHg in acute metabolic acidosis. Thus there were significant differences in medullary events during these two conditions. Although the urine pH is critical in determining ammonium excretion in certain circumstances, these results suggest that regional variations in the medullary PNH3 can modify this relationship.
Acidosis↗
Co-targeting Deregulated WNT and MAPK Signaling Pathways Limits Phenotypic Reprogramming of Intestinal Stem Cell Progeny in KRAS-Hyperactivated Colorectal Cancer.
In their recent article, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer growth is driven by a reprogramming of Lgr5+ intestinal stem cell (ISC) progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related ISCs and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insights into genomic patterns of colorectal cancer and targeted therapy strategies.
Colorectal Neoplasms↗
Effects of insulin, glucocorticoids and thyroid hormones on the activities of key enzymes of glycolysis, glutaminolysis, the pentose-phosphate pathway and the Krebs cycle in rat macrophages.
In the present study the effects of insulin, glucocorticoids and thyroid hormones on macrophage metabolism and function were investigated. The maximum activities of hexokinase, glucose-6-phosphate dehydrogenase, glutaminase and citrate synthase were determined in macrophages obtained from hormone-treated rats and those cultured for a period of 48 h in the presence of hormones. Macrophage phagocytosis was markedly inhibited by dexamethasone and thyroid hormones, remaining unchanged when insulin was added to the culture medium, however. The changes in the enzyme activities caused by hormone treatments of the rats were very similar to those found in culture. Insulin enhanced citrate synthase and hexokinase activities and diminished those of glutaminase and glucose-6-phosphate dehydrogenase. Dexamethasone had a similar effect except on glucose-6-phosphate dehydrogenase. The addition of thyroid hormones to the culture medium raised the activities of glutaminase and hexokinase and reduced that of citrate synthase. The results presented support the suggestion that the effects of insulin, glucocorticoids and thyroid hormones on immune and inflammatory responses could well be mediated through changes in macrophage metabolism.
Animals↗
Opsonization of Legionella pneumophila in human serum: key roles for specific antibodies and the classical complement pathway.
Legionella pneumophila has previously been shown to require serum factors for efficient uptake by phagocytic cells. In this investigation, the roles of specific antibody and complement in phagocytosis of L. pneumophila by human polymorphonuclear leucocytes (PMN) and tissue macrophages were determined. Opsonization was assessed by quantitating the uptake of [3H]-labelled Legionellae. Compared to other Gram-negative and to Gram-positive bacterial species, L. pneumophila was highly resistant to the opsonic activity of normal pooled human serum (PHS). Of 12 donor sera tested, only four promoted significant L. pneumophila uptake when used at full strength. Experiments with immune antibody, and with human sera deficient in immunoglobulins, or the complement components C2, C3, or C5, revealed that L. pneumophila opsonization was dependent on antibody-mediated activation of the classical complement pathway; activation of the alternative pathway could not be detected. At high concentrations, immune antibody alone could adequately opsonize L. pneumophila. Human alveolar and peritoneal macrophages required very similar amounts and types of opsonins for L. pneumophila phagocytosis as did human PMN. Heating L. pneumophila to temperatures greater than or equal to 80 degrees abolished its resistance to opsonization by diluted PHS; however, activation of complement via the alternative pathway or via other antibody-independent routes remained undetectable. These studies show that, in addition to immune antibody, the classical pathway of complement plays an important role in the opsonization of L. pneumophila. The limited ability of these bacteria to interact with human complement provides a likely explanation for their resistance to opsonization and may be partly based on heat-sensitive structures on the surface of L. pneumophila.
Antibodies, Bacterial↗
Bacterial lactoferrin receptors.
Lactoferrin is thought to play a pivotal role in prevention of infection in the host and its ability to sequester iron from potential pathogens has been considered an important component of its antimicrobial function. A number of bacterial species in the Neisseriaceae have developed a mechanism for acquiring iron directly from this host glycoprotein which involves surface receptors capable of specifically binding lactoferrin. Initial attempts at identifying the receptor proteins in Neisseria and Moraxella species using affinity isolation with immobilized lactoferrin under high stringency conditions presumptively identified a single 100 kDa receptor protein, LbpA (formerly Lbp1). Under modified affinity isolation conditions a second 84 kDa lactoferrin binding protein was isolated and had been presumptively identified as LbpB. This protein was not isolated from a CopB-ve isogenic mutant of Moraxella catarrhalis, indicating that it was in fact CopB. However, another lactoferrin binding protein isolated under high stringency conditions, that comigrated with LbpA in most, but not all, M. catarrhalis strains, was identified by convalescent antisera. Its biochemical properties suggested that it indeed was LbpB. The identity of these proteins was confirmed by preparing isogenic mutants with the lbpA and lbpB genes. Growth studies with isogenic mutants deficient in LbpB, LbpA, CopB or FbpA were performed to evaluate their role in iron acquisition from lactoferrin. LbpA and FbpA were essential for this process, supporting prior models of the iron acquisition pathway. LbpB was not essential which is remniscent of studies with the bacterial transferrin receptors. The isogenic CopB-ve isogenic mutants were deficient in iron acquisition from both transferrin and lactoferrin, suggesting that it is a key component in both pathways. A model providing an alternate explanation of the data is presented. The role and surface accessibility of the lactoferrin receptor proteins suggests that they might be useful vaccine antigens and the preferentially reactivity of convalescent antisera with LbpB suggests that it may be the prime candidate.
Bacteria↗
Interferon regulatory factor-5-regulated pathways as a target for colorectal cancer therapeutics.
Colorectal cancer is the second most common cause of cancer-related death. A significant obstacle to successful management of patients with colorectal cancer is intrinsic drug resistance or, in patients who initially responded to chemotherapy, acquired drug resistance. Failure in normal apoptotic pathways often contributes to resistance to anticancer drugs or radiotherapy. As a result, the identification of genes that control cell death and apoptosis has come to the forefront of cancer research, leading to new targets and novel therapeutic strategies in the treatment of colorectal cancer. To this effect, the authors have recently identified a new apoptotic signaling pathway that occurs through the transcription factor interferon regulatory factor-5. Here, the different strategies for targeting the interferon regulatory factor-5 signaling pathway in colorectal cancer are discussed. These strategies can be applied to a new generation of cytotoxic agents, as well as to novel biological compounds that are directed at inducing and/or activating interferon regulatory factor-5 or key components of this pathway.
Apoptosis↗
Accumulation of unusual carotenoids in the spheroidene pathway, demethylspheroidene and demethylspheroidenone, in an alkaliphilic purple nonsulfur bacterium Rhodobaca bogoriensis.
Carotenoids extracted from cells of a novel alkaliphilic purple nonsulfur bacterium Rhodobaca bogoriensis strain LBB1 included unusual carotenoids in the spheroidene pathway; demethylspheroidene, demethylspheroidenone, neurosporene and spheroidenone. Spheroidene was present in only small amounts, and the demethyl-carotenoids demethylspheroidene and demethylspheroidenone predominated in phototrophic cultures. Furthermore, the keto-carotenoids spheroidenone and demethylspheroidenone constituted nearly half of the total carotenoids, even in strict anaerobic phototrophic cultures. Spheroidenone was, however, the sole carotenoid in aerobic cultures. Phototrophic cultures of Rbc. bogoriensis were yellow in colour and quite distinct from the brown-red colour of cultures of Rhodobacter species. The carotenogenesis pathways of Rhodobaca and Rhodobacter species are compared with special reference to two key enzymes of the spheroidene pathway, CrtA and CrtF, whose activities are thought to be responsible for the unusual carotenoid composition of Rhodobaca. This bacterium also contained bacteriochlorophyll a (p) and ubiquinone-10.
Journal Article↗
How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex.
Rel/NF-kappaB transcription factors are primarily regulated by association with inhibitor IkappaB proteins. Thus, in most cells NF-kappaB exists in the cytoplasm in an inactive complex bound to IkappaB. Most agents that activate NF-kappaB do so through a common pathway based on phosphorylation-induced, proteasome-mediated degradation of IkappaB. The key regulatory step in this pathway involves activation of a high molecular weight IkappaB kinase (IKK) complex, whose catalysis is generally carried out by a heterodimeric kinase consisting of IKKalpha and IKKbeta subunits. This review describes the identification of proteins in the IKK complex, and the regulation and physiological functions of IKK.
Animals↗
Antibody production in mice deficient for complement receptors 1 and 2 can be induced by IgG/Ag and IgE/Ag, but not IgM/Ag complexes.
Deficiencies in C factors C2, C3, or C4 as well as lack of C receptors 1 and 2 (CR1/2) lead to impaired Ab production. Classical pathway activation plays a major role, as mice deficient in factor B, a key factor in the alternative pathway, have normal Ab production. Abs in complex with their specific Ag are known to feedback regulate the Ab response, and enhanced responses are initiated by IgM, IgE, and IgG. IgM acts via the C system, whereas IgE and IgG can operate independently of C via Fc receptors. Here we have investigated whether these isotypes are able to enhance Ab responses in mice lacking CR1/2. SRBC-specific IgM, administered with SRBC, does not enhance Ab responses in these animals. In contrast, 2,4, 6-trinitrophenyl-specific IgE and IgG2a, administered with BSA-2,4, 6-trinitrophenyl, induce potent Ab responses in CR1/2-deficient mice. Additionally, BSA administered with CFA or alum induced strong Ab responses in the absence of CR1/2. These results indicate that CR1/2 is needed to promote IgM-mediated induction of primary Ab responses. The data also show that the need for CR1/2 can be circumvented by Abs typical of a secondary immune response forming complexes with Ag or by conventional adjuvants, presumably mimicking physiological inflammatory reactions.
Adjuvants, Immunologic↗
Induction of hepatic heme oxygenase and its effect on drug metabolizing enzyme by DL-, D- and L-ethionine administration to rats.
The chronic administration of ethionine, an analogue of methionine and alkylating hepatocarcinogen, to rats resulted in the decrease of hepatic drug metabolizing enzyme activities and cytochrome P-450 content. In contrast, the activity of hepatic heme oxygenase, a first enzyme of heme degradative pathway, was increased following ethionine administration. delta-Aminolevulinic acid (ALA) synthetase, a key enzyme of heme biosynthesis pathway, was also increased except during 9 to 15 weeks of the experimental period. Changes of cytochrome P-450 content and heme oxygenase activity were proportional to the carcinogen provided period. Further, ethionine induced neoplastic nodules showed more profound changes in heme oxygenase, ALA synthetase and drug metabolizing enzyme activities than the surrounding liver. Similar changes in the enzyme activities were also obtained by a single administration of ethionine to rats and these effects were dependent upon dose levels of the carcinogen except ALA synthetase activity. These results revealed that ethionine is a mild inducer of hepatic heme oxygenase. It is thus likely that induction of heme oxygenase produced by ethionine could lead to the decrease of cytochrome P-450 and drug metabolizing enzyme activities in the liver. The decrease of heme availability due to induction of heme oxygenase by ethionine may be one of the explanations for the decrease of cytochrome P-450 content under the experimental conditions.
5-Aminolevulinate Synthetase↗
Cyclic nucleotide signaling in cavernous smooth muscle.
INTRODUCTION: Penile erection depends on cavernous smooth muscle relaxation that is principally regulated by cyclic nucleotide signaling. It is hoped that a comprehensive review of publications relevant to this subject will be helpful to both scientists and clinicians who are interested in the sciences of erectile function/dysfunction. AIMS. To review the roles of extracellular signaling molecules, their receptors, intracellular effectors, and phosphodiesterases in cyclic nucleotide signaling that leads to cavernous smooth muscle relaxation. The involvement of these molecules in the development of erectile dysfunction and the possibility of using them as therapeutic agents or targets are also discussed. METHODS: Entrez, the search engine for life sciences, was used to search for publications relevant to the topics of this review. Keywords used in the searches included vascular, cavernous, penis, smooth muscle, signaling molecules (adenosine, nitric oxide, etc.), and key elements in the cyclic nucleotide signaling pathways (cAMP, cGMP, cyclases, PKG, PKA, etc.). Articles that are dedicated to the study of erectile function/dysfunction were prioritized for citation. RESULTS: More than 1,000 articles were identified, many of which are studies of the vascular system and are therefore reviewed but not cited. Studies on erectile function have identified both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways in cavernous smooth muscle. Many signaling molecules of these two pathways have been shown capable of inducing erection when administered intracavernously. However, for sexually induced erection, nitric oxide (NO) is the responsible signaling molecule and it passes on the signal through soluble guanyl cyclase (sGC), cGMP, and protein kinase G (PKG). CONCLUSIONS: The NO/sGC/cGMP/PKG pathway is principally responsible for sexually stimulated erection. Detumescence is mainly carried out by the degradation of cGMP by phosphodiesterase 5. Both cAMP and cGMP signaling pathways are susceptible to genetic and biochemical alterations in association with erectile dysfunction. Several key elements along these pathways are potential therapeutic targets.
Cyclic AMP↗
The valine catabolic pathway in human liver: effect of cirrhosis on enzyme activities.
The activities of key enzymes in the valine catabolic pathway--branched-chain aminotransferase, branched-chain alpha-keto acid dehydrogenase complex, methacrylyl (MC)-coenzyme A (CoA) hydratase (crotonase), and 3-hydroxyisobutyryl-CoA (HIB-CoA) hydrolase--were measured in normal and cirrhotic human livers. Unlike rat liver, which does not contain branched-chain aminotransferase, the aminotransferase activity in the normal liver was measurable and is increased somewhat in cirrhosis of the human liver. The total activity of branched-chain alpha-keto acid dehydrogenase complex in the normal human liver was approximately 1% of that in rat liver, and 20% to 30% of the complex was in the active form in both normal and cirrhotic livers. Only the actual activity of the enzyme was significantly decreased by cirrhosis. These results suggest that human liver is less active than rat liver in the catabolism of branched-chain amino and alpha-keto acids. Activities of MC-CoA hydratase and HIB-CoA hydrolase in human liver were very high compared with that of branched-chain alpha-keto acid dehydrogenase complex, suggesting an important role for these enzymes in catabolism of a potentially toxic compound, MC-CoA, formed as an intermediate in the catabolism of valine and isobutyrate. Cirrhosis resulted in a significant decrease in HIB-CoA hydrolase activity but had no effect on the citrate synthase activity, suggesting that the decrease in HIB-CoA hydrolase activity does not reflect a general decrease in mitochondria but that it may contribute to cellular damage that culminates in liver failure.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Inflammation and cancer: the role of the immune response and angiogenesis.
The link with chronic inflammation and cancer has been recognized for certain cancers for several decades. However, only recently has the biology of chronic inflammation begun to be understood, to the point that it may play a major role in tumour development. The biology of chronic inflammation has many similarities with that of wound healing. In particular, local cell mediated immunity is attenuated and angiogenesis is increased along with other growth factors. When present long-term, this provides the ideal environment for mutated cells to be nurtured and escape immune surveillance. It is of note that this process still appears to take two or three decades, as witnessed by the close association between chronic ulcerative colitis and colon cancer as well as chronic hepatitis and hepatocellular carcinoma. Closer study of the inflammatory pathways show the close interaction with apoptosis and anti-apoptotic pathways, as well as the main tumour suppressor genes, such as p53, as well as a number of growth factors, such as the insulin-like growth factor. A full study of these processes reveals that there are key molecules in these pathways which may provide therapeutic as well as anti-inflammatory targets.
Apoptosis↗
RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins.
The RIG-G gene, originally isolated from an acute promyelocytic leukemia cell line NB4, codes for a 60-kDa cytoplasmic protein that is induced by all-trans retinoic acid (ATRA) treatment along with the induction of morphological differentiation of NB4 cells. Here, we provide evidence that ectopic expression of Rig-G in U937 cells can lead to a significant accumulation of cells at G(1)/S transition. Growth arrest seems to occur by modulating several major cell cycle regulatory players. Interestingly, Rig-G alters JAB1 cellular distribution through interacting with this protein and increases the intracellular level of p27 by preventing it from the JAB-1-dependent and ubiquitin/proteasome-mediated degradation. Furthermore, we demonstrate a role of Rig-G for c-myc down-regulation that results in an up-regulation of p21, tightly associated with cell cycle arrest. In addition, our studies reveal that Rig-G is a direct target of STAT1, a key transcription factor in regulating IFN responses, and may be one of the first experimentally proven molecular mediators for the antiproliferative effect of IFN-alpha. Considering that IFN-alpha and ATRA synergistically inhibit growth along the intracellular pathways triggered by the two compounds in many cell types, we suggest that Rig-G may also represent one of the key molecular nodes of signaling cross-talk between ATRA and IFN-alpha.
Base Sequence↗
Molecular mechanisms of non-apoptosis by Fas stimulation alone versus apoptosis with an additional actinomycin D in cultured cardiomyocytes.
OBJECTIVE: In cultured cardiomyocytes, apoptosis is induced not by Fas stimulation, a popular inducer of apoptosis, but by an additional treatment with actinomycin D (AD), a transcription inhibitor, although the mechanism is unknown. Our hypothesis is that Fas stimulation not only activates pro-apoptotic signals but also may inhibit some of them, and this inhibition is blocked by AD. METHODS: Cultured neonatal mouse cardiomyocytes were treated with agonistic anti-Fas antibody (FA), AD, or both (FA+AD). In this system, apoptotic signals related to Fas-induced apoptotic pathways were examined by RT-PCR and immunoblotting. In addition, antisense oligonucleotide (AS) studies were carried out. RESULTS: The treatment with FA+AD induced up-regulation of Fas, activation of c-Jun N-terminal kinase (JNK), which is one of the key molecules of the alternate pathway of Fas-induced apoptosis, up-regulation of Bax, up-regulation and activation of caspase-3, activation of caspase-3-dependent DNase (CAD), and final DNA fragmentation and apoptotic morphologies in cardiomyocytes. FA alone or AD alone did not affect any part of the above pathway. However, mRNA of mitogen-activated protein kinase phosphatase-1 (MKP-1), an inactivator of JNK, was up-regulated by FA alone, but not by FA+AD or AD alone. Pretreatment with AS against MKP-1 induced apoptosis in FA alone-treated cardiomyocytes, whereas AS against JNK1 prevented apoptosis induced by FA+AD. On the other hand, FA+AD did not result in the activation of either caspase-8, one of the key molecules of the classic pathway in Fas-induced apoptosis, p38 MAPK, or extracellular signal-regulated kinase (ERK). CONCLUSIONS: Cardiomyocyte apoptosis by FA+AD depends on the alternate pathway through the JNK, Bax and caspase-3, and CAD-dependent pathways including a positive feedback mechanism of Fas up-regulation. The molecular mechanism that prevents Fas stimulation alone from inducing apoptosis involves up-regulation of MKP-1, an inhibitor of JNK; this up-regulation is inhibited by AD.
Animals↗