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Results for “regulatory module”

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At least 721 records · Page 40Linked to original sources

PubMed1997

The effect of modulating the glycogen-associated regulatory subunit of protein phosphatase-1 on insulin action in rat skeletal muscle cells.

Recent studies from this laboratory have shown that insulin rapidly stimulates a membranous protein phosphatase-1 (PP-1) in cultured rat skeletal muscle cells and isolated rat adipocytes. Stimulation of PP-1 is accompanied by the phosphorylation of a 160-kDa regulatory subunit of PP-1 (PP-1G). To further evaluate the exact role of this subunit in insulin action, L6 rat skeletal muscle cells were stably transfected with a vector containing the gene for PP-1G in the sense and antisense orientations. Transfection with the vector containing the PP-1G gene in the sense orientation yielded three stable clones with a 4- to 6-fold increase in PP-1G protein expression compared to those of wild-type L6 cells and neo control cells harboring an empty expression vector. Compared to the neo control, overexpression of PP-1G resulted in a 3-fold increase in insulin-stimulated PP-1 catalytic activity bound to PP-1G immunoprecipitates. These cell lines were examined for insulin's effect on glucose uptake, glycogen synthase activity, and glycogen synthesis. Insulin treatment resulted in an approximately 2-fold increase in 2-deoxyglucose uptake in recombinant cells compared to control cells (P < 0.05). This increase in 2-deoxyglucose transport was accompanied by an approximately 2-fold increase in insulin-stimulated glycogen synthase fractional activity (P < 0.05) and a 2- to 4-fold increase in insulin-stimulated glycogen synthesis compared to control cells. In conjunction with these observations, we found that an 85% depletion of endogenous PP-1G, using antisense constructs, resulted in a complete lack of PP-1 activation and an inhibition of basal and insulin-stimulated glucose transport. We conclude that the PP-1G holoenzyme is the major phosphatase regulated by insulin in vivo and plays an important role in insulin-stimulated glycogen synthesis by regulating the catalytic activity of bound PP-1.

Adipocytes↗

PubMed1993

Identification of an alternate promoter in the rat androgen-binding protein/sex hormone-binding globulin gene that regulates synthesis of a messenger RNA encoding a protein with altered function.

Extracellular androgen-binding proteins (ABP) are thought to modulate the regulatory functions of androgens. These proteins, which are secreted by the testis (ABP) and liver [sex hormone-binding globulin (SHBG)], are encoded by the same gene. In a previous study, the rat ABP/SHBG gene was sequenced, and a promoter (P1) was identified by primer extension. This promoter regulates synthesis of the mRNA that encodes secreted testicular ABP and fetal liver SHBG. In this study, the P1 transcriptional start site in testis and fetal liver was confirmed by RNase protection assays. We also identified an alternate promoter (PA) in the ABP/SHBG gene located 15 kilobases up-stream from the previously characterized testicular promoter (P1). The PA region has the characteristics of a GC-rich housekeeping-type promoter. RNAase protection and primer walking experiments with RNA polymerase chain reaction identified a region where the major sites of transcription initiation occur. Promoter PA directs the synthesis of alternate ABP RNAs, which contain an alternate exon 1 (exon A) sequence. One alternate ABP RNA, which contains exons A and 2-8 sequences, is expressed in testis, fetal liver, and brain. This alternate ABP RNA encodes an ABP-like protein (46,000 daltons) with an altered N-terminal sequence without a secretory signal peptide. Expression of the ABP-like protein in COS cells revealed that it is not secreted and does not appear to bind dihydrotestosterone. Another similar alternate ABP RNA is missing exon 6 sequence and encodes a nonsecretory truncated protein (28,000 daltons) that does not bind androgen. The functions of the ABP-like proteins are not obvious, but their functions are clearly different from secreted ABP and SHBG.

Amino Acid Sequence↗

PubMed2001

Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis.

The Caenorhabditis elegans genome contains three rac-like genes, ced-10, mig-2, and rac-2. We report that ced-10, mig-2 and rac-2 act redundantly in axon pathfinding: inactivating one gene had little effect, but inactivating two or more genes perturbed both axon outgrowth and guidance. mig-2 and ced-10 also have redundant functions in some cell migrations. By contrast, ced-10 is uniquely required for cell-corpse phagocytosis, and mig-2 and rac-2 have only subtle roles in this process. Rac activators are also used differentially. The UNC-73 Trio Rac GTP exchange factor affected all Rac pathways in axon pathfinding and cell migration but did not affect cell-corpse phagocytosis. CED-5 DOCK180, which acts with CED-10 Rac in cell-corpse phagocytosis, acted with MIG-2 but not CED-10 in axon pathfinding. Thus, distinct regulatory proteins modulate Rac activation and function in different developmental processes.

Amino Acid Sequence↗

PubMed2003

Oral tolerance.

Autoimmune conditions caused by injurious immune responses against self-antigens can be ameliorated if the inappropriate responses to self-components that cause tissue injury can be modulated by regulatory cells or shut off via the induction of anergy or via deletion of pathogenic immune responses. Antigen encounter at the gut mucosa can lead to suppression of injurious immune responses to self-antigen via these mechanisms. This type of immunological event is termed oral tolerance. In this review, we examine the mechanisms behind the induction of oral tolerance and provide findings from its use as a form of treatment for autoimmune diseases.

Administration, Oral↗

PubMed2005

Vaccines against myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease mediated by antibodies to nicotinic acetylcholine receptor (AChR) interfering with the neuromuscular transmission. Experimental autoimmune MG serves as an excellent animal model to study possible therapeutic modalities for MG. This review will focus on the different ways to turn off the autoimmune response to AChR, which results in suppression of myasthenia. This paper will describe the use of fragments or peptides derived from the AChR, antigen-presenting cells and anti-T cell receptor antibodies, and will discuss the underlying mechanisms of action. Finally, the authors propose new promising therapeutic prospects, including treatment based on the modulation of regulatory T cells, which have recently been found to be functionally defective in MG patients.

Animals↗

PubMed1982

Regulation of somatotrophic and lactogenic binding sites in mouse liver membranes.

Both somatotrophic and lactogenic binding sites increase markedly in pregnant mouse liver membranes. The regulatory mechanisms of these binding sites involved in pregnancy are studied. The study of the effects of various hormone administration to female mice reveals that oestradiol increases and testosterone decreases lactogenic binding sites, and that other hormones affect neither somatotrophic nor lactogenic binding sites. Hysterectomy, adrenalectomy or foetectomy of pregnant mice cause a remarkable reduction of somatotrophic binding sites to the level observed in non-pregnant or post-partum animals. In contrast, the lactogenic binding sites are not influenced by these treatments. Replacement with corticosterone after adrenalectomy does not prevent the decrease of somatotrophic binding sites. The contents of placental lactogen from both adrenalectomized and foetectomized pregnant mice are similar to those of the normal pregnant group. These observations indicate that the regulatory mechanisms modulating somatotrophic and lactogenic binding activities are quite different and that increased somatotrophic binding sites during pregnancy are supported by the factor(s) generated in the foeto-placental unit and maternal adrenal gland.

Adrenalectomy↗

PubMed1981

Progesterone and insulin-resistance: studies of progesterone action on glucose transport, lipogenesis and lipolysis in isolated fat cells of the female rat.

The effects of progesterone on isolated rat adipocytes were studied in vitro during various steps of glucose metabolism, transport, lipogenesis and lipolysis. Progesterone decreased the phosphorylation of glucose into glucose-6-phosphate as assessed by measuring the uptake of 2-deoxyglucose but it had no effect on transmembrane transport of glucose as determined by measuring the entry of 3-0-methylglucose into the cell. As glucose phosphorylation is a rate-limiting step of the pentose-phosphate pathway, these data could explain the inhibition of lipogenesis and the enhancement of lipolysis observed when progesterone is present in incubation medium. Progesterone might thus modulate a regulatory step of glucose metabolism and antagonize insulin action in the fat cell.

Adipose Tissue↗

PubMed2003

Prolactin regulation of Bcl-2 family members: increased expression of bcl-xL but not mcl-1 or bad in Nb2-T cells.

Prolactin (PRL)-dependent rat pre-T Nb2 (Nb2-11) cell lines serve as a useful model for investigation of mechanisms underlying lactogen-mediated suppression of apoptosis. Glucocorticoids, such as dexamethasone (DEX), induce apoptosis in Nb2-11 cells; the addition of PRL abrogates the cytolytic actions of DEX in this model, presumably because of increased expression of survival genes. In the present study, we investigated whether inhibition of DEX-induced apoptosis by PRL in Nb2-T cells was accompanied by altered expression of Bcl-2 family members, mcl-1, bad or bcl-x(L) determined by Northern and immunoblot analysis. The results indicated that a 0.9 kb bcl-x(L) transcript was rapidly induced by PRL. It reached maximal levels within 2 to 4 h (>20-fold) before declining toward basal values. Similar results were obtained in primary cultures of mouse thymocytes exposed to DEX in combination with PRL. In addition to increasing its mRNA expression, PRL also increased Bcl-xL protein levels by 6 h. Moreover, the effect of PRL to increase bcl-x(L) appeared to reflect direct and indirect mechanisms, since it was attenuated by the inhibition of protein synthesis. Results from other experiments suggest that PRL signaling to bcl-x(L) expression was independent of the Jak2/Stat pathway but appeared to require activation of a Src tyrosine kinase. In contrast, while a 1.1 kb mcl-1 transcript was detected in proliferating and quiescent cells, PRL did not alter its expression at either mRNA or protein levels. Moreover, neither bad mRNA nor its protein product were detectable under any of the experimental conditions evaluated. We have concluded that bad and mcl-1 are unlikely candidates for apoptosis regulatory genes modulated by PRL. However, the kinetic pattern of PRL-provoked bcl-x(L) expression is consistent with its playing a role as an apoptosis suppressor in Nb2-T cells and primary cultures of mouse thymocytes exposed to glucocorticoids.

Animals↗

PubMed2003

Quantification of common carp (Cyprinus carpio) IGF-I and IGF-II mRNA by real-time PCR: differential regulation of expression by GH.

IGFs are potent mitogens for many different cell types and play important roles in growth and development. A multitude of regulatory factors modulate the expression of IGFs. In some teleosts, liver IGF-I expression has been demonstrated to depend on the presence of GH. However, the GH dependence of IGF-II expression in teleosts is controversial. Moreover, most IGF expression studies in bony fish have been focused on the liver, and information on extrahepatic tIssues are conflicting and inconsistent. This is partly due to the fact that the traditional methods of mRNA measurement such as Northern blot and RT-PCR are not sensitive enough to detect changes in IGF levels in extrahepatic tIssues because of the low levels of IGFs in these tIssues. In addition, there have been few studies on the IGF system of non-salmonid teleosts. Our laboratory has thus begun such studies on a local tropical fast-growing fish, the common carp (Cyprinus carpio). In this study, real-time quantitative PCR assays were developed for the accurate measurement of IGF-I and IGF-II mRNA levels in common carp tIssues. This quantitative method was based on the measurement of a fluorescent labeled probe, which was cleaved by Taq polymerase during PCR by the 5'-->3' nuclease activity. The signal generated was directly proportional to the starting copy number of the target molecules in the sample. Hence, it was possible to detect and quantify the mRNA levels of both IGF-I and IGF-II reliably in very small amounts of tIssues obtained from juvenile common carp. Using these assays, the expression pattern of IGF-I and IGF-II in various common carp tIssues was studied, and their differential response to GH stimulation was also investigated.

Animals↗

PubMed2002

Biological activities, mechanisms of action and biomedical prospect of the antitumor ether phospholipid ET-18-OCH(3) (edelfosine), a proapoptotic agent in tumor cells.

The antitumor ether lipid ET-18-OCH(3) (edelfosine) is the prototype of a new class of antineoplastic agents, synthetic analogues of lysophosphatidylcholine, that shows a high metabolic stability, does not interact with DNA and shows a selective apoptotic response in tumor cells, sparing normal cells. Unlike currently used antitumor drugs, ET-18-OCH(3) does not act directly on the formation and function of the replication machinery, and thereby its effects are independent of the proliferative state of target cells. Because of its capacity to modulate cellular regulatory and signaling events, including those failing in cancer cells, like defective apoptosis, ET-18-OCH(3), beyond its putative clinical importance, is an interesting model compound for the development of more selective drugs for cancer therapy. Although ET-18-OCH(3) enhances host defense mechanisms against tumors, its major antitumor action lies in a direct effect on cancer cells, inhibiting phosphatidylcholine biosynthesis and inducing apoptosis in tumor cells. Recent progress has allowed unraveling the molecular mechanism underlying the apoptotic action of ET-18-OCH(3), leading to the notion that ET-18-OCH(3) is selectively incorporated into tumor cells and induces cell death by intracellular activation of the cell death receptor Fas/CD95. This intracellular Fas/CD95 activation is a novel mechanism of action for an antitumor drug and represents a new way to target tumor cells in cancer chemotherapy that can be of interest as a new framework in designing novel antitumor drugs. ET-18-OCH(3) and some analogues are pleiotropic agents that affect additional biomedical important diseases, including parasitic and autoimmune diseases, suggesting new therapeutic indications for these compounds.

Animals↗

PubMed2001

Specific regions of the extracellular domain of dlk, an EGF-like homeotic protein involved in differentiation, participate in intramolecular interactions.

The level of expression of dlk, an EGF-like protein possessing six EGF-like repeats in its extracellular region, is critical for 3T3-L1 fibroblasts to differentiate into adipocytes in response to IGF1. The mechanism of action of dlk is not well understood, but its localization on the cell membrane suggests that dlk may function as a receptor, as a ligand or as a regulatory protein modulating the binding, the signaling, or the expression of other molecules involved in cell differentiation and growth. In this work, we demonstrate, by using the Yeast Two-Hybrid system, that dlk interacts with itself through specific regions of its extracellular domain. The strongest interactions were observed between specific EGF-like repeats and between a non EFG-like region where unknown proteases act to generate soluble forms of dlk. These observations suggest that the interaction between two membrane dlk molecules belonging to the same or to different cells, or the interaction between soluble and membrane dlk variants, may be important to regulate dlk function.

3T3 Cells↗

PubMed2005

IL-4 modulation of CD4+CD25+ T regulatory cell-mediated suppression.

Murine CD4(+)CD25(+) T regulatory (Treg) cells were cocultured with CD4(+)CD25(-) Th cells and APCs or purified B cells and stimulated by anti-CD3 mAb. Replacement of APCs by B cells did not significantly affect the suppression of CD4(+)CD25(-) Th cells. When IL-4 was added to separate cell populations, this cytokine promoted CD4(+)CD25(-) Th and CD4(+)CD25(+) Treg cell proliferation, whereas the suppressive competence of CD4(+)CD25(+) Treg cells was preserved. Conversely, IL-4 added to coculture of APCs, CD4(+)CD25(-) Th cells, and CD4(+)CD25(+) Treg cells inhibited the suppression of CD4(+)CD25(-) Th cells by favoring their survival through the induction of Bcl-2 expression. At variance, suppression was not affected by addition of IL-13, although this cytokine shares with IL-4 a receptor chain. When naive CD4(+)CD25(-) Th cells were replaced by Th1 and Th2 cells, cell proliferation of both subsets was equally suppressed, but suppression was less pronounced compared with that of CD4(+)CD25(-) Th cells. IL-4 production by Th2 cells was also inhibited. These results indicate that although CD4(+)CD25(+) Treg cells inhibit IL-4 production, the addition of IL-4 counteracts CD4(+)CD25(+) Treg cell-mediated suppression by promoting CD4(+)CD25(-) Th cell survival and proliferation.

Animals↗

PubMed1999

Lacrimal gland HGF, KGF, and EGF mRNA levels increase after corneal epithelial wounding.

PURPOSE: To evaluate the effect of corneal epithelial wounding on lacrimal gland expression of hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), and epidermal growth factor (EGF) in the rabbit model. METHODS: Rabbits had corneal epithelial scrape injuries, and the lacrimal gland was removed at different times after wounding. HGF, KGF, and EGF mRNA expression was examined by quantitative RNase protection assay. HGF, KGF, and EGF proteins were detected in rabbit lacrimal tissue using immunoprecipitation and western blot analysis. RESULTS: HGF mRNA and EGF mRNA were significantly increased in rabbit lacrimal gland tissue within 8 hours after corneal epithelial injury. The increase in KGF mRNA expression was small and reached significance I clay after corneal injury. Lacrimal gland expression peaked at 3 days after wounding for each growth factor mRNA, the same day, on average, that the epithelial defect healed. After the peak increase in expression, there was a progressive decline in expression of each growth factor mRNA, but production was still increased compared with prewound levels. HGF protein, KGF protein, and EGF proteins were detected in rabbit lacrimal gland tissue. CONCLUSIONS: Levels of HGF, KGF, and EGF mRNAs increase in rabbit lacrimal gland tissue in response to corneal epithelial wounding. The results of this study are consistent with the existence of a cornea-nervous system-lacrimal gland regulatory loop modulating expression of these growth factor mRNAs. The lacrimal gland is a likely source of increased HGF and EGF proteins detected in tears in previous studies.

Animals↗

PubMedDate not supplied

[N-acylethanolamine--a new class of natural adrenotropic modulators].

N-acyl-ethanolamines (NAE) belong to the new class of naturally occurring biologically active regulators. Anandamide--a well known representative of NAEs--is an agonist of central (CB1) and peripheral (CB2) cannabinoid receptors. Adrenal cortex contains the CB2 receptor. The aim of present work is to investigate the influence of saturated and polyunsaturated NAEs on the corticosteroid synthesis in adrenal gland in vitro. It was shown that the rat adrenal gland is the main target of N-([1-14C]palmitoyl)ethanolamine incorporation. Saturated NAE enhanced the incorporation of [3H]-cholesterol into the aldosterone by 25% (p < 0.06) and corticosterone by 17% (p < 0.05) of rat adrenal slices in vitro. Mixture of polyunsaturated NAEs containing mainly 18:1w9, 18:2w6, 18:3w3, 20:1w9, 22:1w9 increased the labeling of aldosterone by 70% (p < 0.05) and corticosterone by 20% (p < 0.05). Thus, the saturated NAEs as well as polyunsaturated analogs, act by the similar manner on the corticosteroid synthesis. The fact that saturated NAEs possess poor affinity to CB receptors provides us opportunity to suggest the non-receptor mechanism of NAEs adrenotrophic action. Further we used the purified bovine serum albumin to test the binding kinetic of N-([I14C]palmitoyl)ethanolamine with its hydrophobic domains. It was found that NAEs have high affinity to hydrophobic domains of protein with K = 2.5 x 10(8) M-1. This finding could support the idea of the existence of putative allosteric modulation of regulatory protein function. It was concluded that NAEs exert a stimulatory effect on the corticosteroid synthesis in rat adrenal gland in vitro and this action do not mediated trough cannabinoid receptor.

Adrenal Glands↗

PubMed2000

[Evaluation of some neutrophil adhesion molecules in pregnancy complicated by diabetes mellitus type 1].

UNLABELLED: The effective functions of human peripheral blood neutrophil are modulated by regulatory molecules depending on receptor agonists and adhesion molecules. OBJECTIVES: Evaluation of percentage of neutrophil adhesion molecules in pregnancy of diabetic mothers as well as their expression on peripheral blood neutrophils. MATERIAL: A-12 pregnant diabetic women at 7-13 and 34-36 weeks of first gestation, B-11 healthy pregnant women match for gestation, age and parity; C-11 healthy non-diabetic women; D-14 diabetic, non-pregnant women. METHODS: MFI expression and percentage of CD18, CD11b, CD62L and CD54 were evaluated resting and activated by 30 min., fMLP preincubation using monoclonal antibodies anti-CD11b and anti-CD62L, employing Flow Cytometer FACSCalibur with computer program CELLquest. RESULTS: Expression of CD11b and CD18 receptor on leukocyte of A, B, D groups was higher spontaneous and after stimulation by fMLP in I-st trimester compare to group C and then lowered in IIIrd. The significant difference in CD62L percentage was noticed resting and activated neutrophils in group A, which was lower compared to C and expression of CD62L on peripheral blood neutrophils was higher in group B compared to other studied groups in Ist trimester. There was an increase in expression of CD54 on resting neutrophils of group D when compared with C. A significant difference between Ist and IIIrd trimester was noticed in group A in expression of CD62L,CD62L/fMLP,CD54 on peripheral blood neutrophils, which were higher in the third trimester. Expression of CD62L was higher in the group A when compared to B. CONCLUSIONS: Diabetes type 1 and pregnancy changed the percentage and MFI of neutrophil adhesion molecules.

Adult↗

PubMedDate not supplied

[Pathogenetic and therapeutic aspects of secondary anorexia].

Anorexia is an often underrated symptom in the clinical management of patients suffering from chronic diseases. Moreover, the anorexia accompanying chronic diseases (secondary anorexia) is often confused with anorexia nervosa, a typically neuropsychiatric disorder involving completely different pathogenic mechanisms and therapeutic strategies. Secondary anorexia is one of the main factors responsible for the development of malnutrition, which in turn negatively affects patient morbidity and mortality. Different mechanisms have been proposed to explain the pathogenesis of secondary anorexia. However, consistent experimental and clinical evidence seems to point to hypothalamic serotonergic system hyperactivity as a preeminent cause; this hyperactivity appears to be triggered by enhanced brain availability of tryptophan, the aminoacid precursor of serotonin. The hyperactive hypothalamic serotonergic system might also represent the final effector where different regulatory and modulating pathways, including cytokines, converge. The involvement of tryptophan and the hypothalamic serotonergic system is further supported by the effectiveness of a therapeutic strategy, based on the inhibition of tryptophan entry into the brain, in increasing the food intake of anorectic patients. Although these results represent an encouraging approach to the treatment of secondary anorexia, with possible beneficial effects on the nutritional status of patients, they need to be validated in larger trials.

Adolescent↗

PubMedDate not supplied

[Virulence factor expression regulation in Listeria monocytogenes].

The external and internal factors affecting the expression of L. monocytogenes virulence genes are analyzed. The role of protein PrfA, the only known factor directly affecting the transcription of virulence genes, as well as the contribution of other regulatory elements modulating the activity and/or intracellular concentration of PrfA are discussed. The environmental factors which influence the level of expression, such as temperature and the presence of metabolized carbohydrates in the cultivation medium, are analyzed. In addition, the possibility of autoregulating processes (the accumulation of L. monocytogenes-secreted autorepressor in the medium) is discussed and the possible mechanism of their action is suggested.

Animals↗

PubMed2002

[Influence of regulatory peptides on the secretion of interleukins from bronchial epithelial cells of the rabbit].

To explore the role of regulatory peptides in the secretion of bronchial epithelial cells (BECs), we observed the effects of four peptides, i.e.vasoactive intestinal peptide (VIP), epidermal growth factor (EGF), endothelin-1 (ET-1), and calcitonin gene-related peptide (CGRP), on the secretion of ILs from unstimulated or O3-stressed BECs. The results of the experiments showed that VIP exerted an inhibitory effect on the secretion of IL-1 and IL-8 from unstimulated and O3-stressed BECs, VIP also decreased the secretion of IL-5 from O3-stressed BECs; EGF promoted secretion of IL-1 and IL-8 from unstimulated BECs, but decreased the secretion of ILs from O3-stressed BECs; ET-1 and CGRP enhanced the secretion of IL-1, IL-5, and IL-8 from unstimlated BECs, CGRP also increased the secretion of ILs from O3-stressed BECs. The results obtained demonstrate that intrapulmonary regulatory peptides modulate the secretion of ILs from BECs, and may play an important part in transduction of inflammatory signals.

Animals↗