ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2777006

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

The factors associated with a diabetes‐susceptible genotype in mice exhibiting various forms of heritable glucose intolerance syndromes are discussed. Genetic models of insulin‐dependent and non‐insulin‐dependent diabetes in mice are described. Although single gene mutations can be defined for each model that are major contributors to diabetogenic stress, polygenic interactions are required for the expression of a diabetic phenotype, and environmental factors are also contributory. Several strongly penetrant single gene mutations are capable of affecting obesity and insulin‐resistant states. Analysis of inbred strain genomic interactions with one of these recessive obesity‐producing genes, diabetes(db), suggests that development of a diabetic phenotype is dependent on the strength of an interaction between thedbgene and sulfotransferase enzymes. Specifically, diabetes‐susceptible vs. resistant inbred strain backgrounds can be distinguished by the extent to which thedbmutation elicits an accelerated sequestration by sulfoconjugation of tissue estrogens while androgens remain free. In a male gender‐ (and Y chromosome‐)associated model of transient glucose intolerance, stress as well as a requirement for both adrenal and testicular secretions are each components of the susceptibility background. In the obesity‐associated diabetes models, autoimmunity, when it occurs, is a secondary reflection of pancreatic β cell destruction. The nonobese diabetic (NOD) mouse, in contrast, represents a model in which autoimmunity against β cells is a primary event in the development of insulin‐dependent diabetes. In NOD mice, a gene that is either the unique class II gene in the major histocompatibility complex or is in linkage disequilibrium with this complex makes a major (recessivelike) contribution to diabetes susceptibility. However, diabetogenesis can be mediated only through a multifactorial interaction among this susceptibility locus and multiple unlinked genetic loci regulating immune responsiveness. In addition, the NOD mouse represents one of the best models of diabetes available for demonstrating a critical interaction between heredity and environmental factors. The polygenic nature of the various heritable forms of glucose intolerance syndromes in mice points to a comparable or even greater genetic heterogeneity underlying the major types of diabetes in humans.—Leiter, E. H. The genetics of diabetes susceptibility in mice.FASEB J.3: 2231‐2241; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2673897

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

The identification of multiple receptor subtypes for 5‐hydroxytryptamine (5‐HT) made by using radioligand binding techniques proliferated at a brisk rate in the 1980s. The application of molecular biological techniques to 5‐HT receptor studies is likely to lead to an expansion rather than a reduction in the number of distinct 5‐HT receptor subtypes. Although the current status of 5‐HT receptor pharmacology may appear to be overwhelmingly confusing to most investigators, the evolving data suggest that 5‐HT receptor subtypes can be categorized into three major families. Each family consists of multiple receptor subtypes that share similarities in their molecular biological, pharmacological, biochemical, and/or physiological properties. This review provides a summary of recent data as well as a framework for the classification of 5‐HT receptor subtypes.— Schmidt, A. W.; Peroutka, S. J. 5‐Hydroxytryptamine receptor “families.”FASEB J.3: 2242‐2249; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2673898

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Acetyl‐CoA carboxylase, the rate‐limiting enzyme in the biogenesis of long‐chain fatty acids, is regulated by phosphorylation and dephosphorylation. The major phosphorylation sites that affect carboxylase activity and the specific protein kinases responsible for phosphorylation of different sites have been identified. A form of acetyl‐CoA carboxylase that is independent of citrate for activity occurs in vivo. This active form of caboxylase becomes citrate‐dependent upon phosphorylation under conditions of reduced lipogenesis. Therefore, phosphorylation‐dephosphorylation of acetyl‐CoA carboxylase is the enzyme's primary short‐term regulatory mechanism; this control mechanism together with cellular metabolites such as CoA, citrate, and palmitoyl‐CoA serves to fine‐tune the synthesis of long‐chain fatty acids under different physiological conditions.— Kim, K.‐H.; López‐Casillas, F.; Bai, D. H.; Luo, X.; Pape, M. E. Physiological significance of covalent phosphorylation‐dephosphorylation of acetyl‐CoA carboxylase in the regulation of long‐chain fatty acids.FASEB J.3: 2250‐2256; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2570725

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

The three families of double‐stranded RNA (dsRNA) viruses and two families of retroviruses (retrotransposons) of the yeastSaccharomyces cerevisiaeare all transmitted between cells only by cell fusion, probably reflecting the high frequency of mating of yeast cells in nature. One dsRNA virus and two retroviruses apparently use ribosomal “frameshifting” to produce major coat protein‐polymerase fusion proteins. This mechanism allows regulation of the relative amounts of major coat protein and fusion protein that are made and avoids the possibility of mutant virus genomes being generated by splicing. Moreover, the fusion protein structure suggests a possible mechanism of genome packaging. The recent development of in vitro replication, transcription, and integration systems for these viruses, and the ease with which classical genetic and molecular studies are executed in yeast, are yielding detailed information about the roles of cellular and viral components in the viral replication cycles and the host defensive response. A host defense system against yeast dsRNA viruses is known and there is evidence to suggest a system active against the retroviruses.— Wickner, R. B. Yeast virology.FASEB J.3: 2257‐2265; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2550303

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Two novel methods used to study smooth muscles — electron probe X‐ray microanalysis and Ca2+‐sensitive indicators (which are used for resolving, respectively, the spatial distribution and temporal distribution of calcium) — are briefly reviewed and the major findings obtained are summarized. In smooth muscle the sarcoplasmic reticulum is the major intracellular source of Ca2+; mitochondria do not play a significant role in the physiological regulation of [Ca2+]i. Under pathological conditions mitochondria can reversibly accumulate large amounts of calcium. Resting [Ca2+]igenerally ranges from 80 to 200 nM, and is lower in phasic than in tonic smooth muscles. Removal of extracellular Ca2+and Ca2+entry blockers can reduce [Ca2+]i, but the effects of β‐adrenergic agents are variable. Increases in [Ca2+]iare triggered by electrical stimulation, depolarization with high K+, and excitatory agonists. Stretch, after a delay of several seconds, can cause an increase in [Ca2+]iin some smooth muscles. There is also a delay of approximately 200‐400 ms between the initiation of the rise of Ca2+and contraction that follows spontaneous action potentials or electrical stimulation. Agonist‐induced Ca2+release, a major mechanism of pharmacomechanical coupling, has been demonstrated in smooth muscles depolarized with high K; evidence suggests that it is mediated by G proteins that couple receptors to phospholipase C. Ca2+release can be triggered directly in permeabilized smooth muscle with inositol 1,4,5‐trisphosphate. Even though Ca2+is the major physiological regulator of contraction, Ca2+sensitivity of the regulatory‐contractile apparatus differs in different (phasic and tonic) smooth muscles, and can be modulated in a given smooth muscle. The force [Ca2+]iratio is higher during agonist‐stimulated than during high K+‐induced contractions, owing to agonist‐induced increases in Ca2+sensitivity mediated by G proteins. In some phasic smooth muscles (guinea pig ileum), the time course of the initial myosin light chain phosphorylation is extremely rapid and returns to basal levels while force remains elevated. In these smooth muscles there is also a marked decrease in the Ca2+sensitivity of the regulatory‐contractile apparatus during maintained depolarization in Ca2+‐free or low Ca2+solutions. It has been suggested that regulation of myosin light chain phosphatase plays a major role in the modulation of the Ca2+sensitivity manifested as either potentiation or desensitization to [Ca2+]i.—Somlyo, A. P.; Himpens, B. Cell calcium and its regulation in smooth muscle.FASEB J.3: 2266‐2276; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2506092

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

During refeeding after a brief period of starvation, glucose carbon is deposited into hepatic glycogen by both a direct and an indirect route. In the indirect route glucose is first metabolized to 3‐carbon precursors, which then transverse the gluconeogenic pathway before being deposited into glycogen. Recent studies have yielded widely different estimates of the percentage of glucose carbon that follows the indirect route. Work summarized here demonstrates that the relative contributions of glucose carbon to hepatic glycogen formation by the indirect and direct pathways are greatly dependent on experimental design, and at least in vitro, are possibly dependent on the extent of glycogen/glucose 1‐P recycling. Under physiological refeeding conditions in vivo, both pathways are used, each contributing approximately 50% of the amount of carbon appearing in glycogen. The level of glucokinase activity does not appear to be responsible for poor glucose utilization in liver . Poor glucose utilization in isolated liver preparations may result from the absence of a neurophysiological feedback loop that senses the arterial/portal glucose gradient and then regulates whole liver glucose uptake.—Kurland, I. J.; Pilkis, S. J. Indirect versus direct routes of hepatic glycogen synthesis.FASEB J.3: 2277‐2281; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2673899

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

The endogenous neuropeptide α‐melanocyte stimulating hormone (α‐MSH 1‐13), previously found to have marked antipyretic activity, inhibits histamine‐induced increases in vasopermeability. The primary antipyretic amino acid message sequence is believed to be the COOH‐terminal trieptide, lysine‐proline‐valine. In recent preliminary research this tripeptide inhibited increases in vasopermeability, raising the possibility that this portion of the α‐MSH molecule has general antiinflammatory activity. To test this idea, the effects of graded doses of α‐MSH [11‐13] on ear swelling induced by picryl chloride in mice were compared with the effects of saline and a large dose of corticosteroid. α‐MSH [11‐13]inhibited swelling in a dose‐related fashion. This result, together with previous findings, suggests that endogenous circulating α‐MSH and its COOH‐terminal fragments may contribute to modulation of physiological responses in host defense. If this is true, it may be possible to develop new peptide drugs or mimetics based on the tripeptide that are useful in treating inflammation.— Hiltz, M. E.; Lipton, J. M. Antiinflammatory activity of a COOH‐terminal fragment of the neuropeptide α‐MSH.FASEB J.3: 2282‐2284; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2550304

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

A 12‐lipoxygenase metabolite of arachidonic acid, 12(S)‐hydroxyeicosatetraenoic acid (12[S]‐HETE), which is produced by platelets and tumor cells, was tested for its ability to induce retraction of endothelial cell monolayers. The induction of endothelial cell retraction is a critical step in tumor cell metastasis. Endothelial cells demonstrated reversible retraction in response to 12(S)‐HETE, but did not respond to the stereoisomer 12(R)‐HETE or to unrelated 5‐lipoxygenase (i.e., 5[S]‐HETE) or 15‐lipoxygenase (i.e., 15[S]‐HETE) metabolites. Endothelial cells did not demonstrate loss of viability in response to 12(S)‐HETE. The induction of retraction was both dose and time dependent. Scanning electron microscopy confirmed that 12(S)‐HETE induced endothelial cell retraction and revealed collapsed filopodia on their surface, the appearance of spaces between endothelial cells and the underlying subendothelial matrix, in addition to large gaps between adjacent endothelial cells. Tumor cell adhesion to endothelial cell monolayers was enhanced 1 h after pretreatment of monolayers with 12(S)‐HETE but not after pretreatment with other lipoxygenase metabolites. Tumor cell adhesion to endothelial cell monolayers 36 h after pretreatment with 12(S)‐HETE was not different from adhesion to untreated monolayers. Therefore we suggest that 12(S)‐HETE generated during tumor cell‐platelet‐endothelial cell interactions may induce reversible endothelial cell retraction, allowing tumor cell access to the subendothelial matrix, which is a critical step in their eventual extravasation from the microvasculature during hematogenous metastasis.—Honn, K. V.; Grossi, I. M.; Diglio, C. A.; Wojtukiewicz, M.; Taylor, J. D. Enhanced tumor cell adhesion to the subendothelial matrix resulting from 12(S)‐HETE‐induced endothelial cell retraction.FASEB J.3: 2285‐2293; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2673900

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

The ability of aspirin to acetylate PGH synthase was determined by reacting [3H‐acetyl]‐aspirin with purified enzyme followed by high pressure liquid chromatography analysis of the protein components of the reaction mixture. Heme‐reconstituted enzyme incorporated approximately one acetyl group per 70‐kDa subunit, whereas apoprotein incorporated 0.1 acetyl group per subunit. The ability of the heme prosthetic group to enhance acetylation of the protein was correlated with its ability to protect the Arg253‐Gly254peptide bond from cleavage by trypsin. Thus, heme‐induced alteration of protein conformation may contribute to the enhanced labeling of Ser506by aspirin. The present results indicate that irreversible inactivation of prostaglandin H synthase by aspirin occurs only when the heme prosthetic group is bound to the protein. Considering its short in vivo half‐life, it is likely that aspirin inactivates only the steady‐state fraction of PGH synthase in a cell that is active but not newly synthesized apoprotein. This may contribute to the differential kinetics of inactivation and recovery of PGH synthase activity in platelets and vascular endothelial cells after administration of low dose aspirin as a prophylactic agent against cardiovascular disease.—Chen, Y.‐N. P.; Marnett, L.J. Heme prosthetic group required for acetylation of prostaglandin H synthase by aspirin.FASEB J.3: 2294‐2297; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.11.2506093

出版商:Wiley    

年代:1989

数据来源: WILEY