ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2914626

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Biotechnology has begun to realize the enormous potential of transgenic technology: mice with human genes that produce human proteins of therapeutic value in their milk, pigs that express bovine genes that help them gain weight and lose backfat, animals with engineered gene defects that mimic human genetic diseases.— Westphal, H. Transgenic mammals and biotechnology.FASEB J.3: 117‐120; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2492478

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

We review the mechanisms underlying the feedback regulation of pancreatic enzyme secretion in response to a meal. Pancreatic enzyme secretion in the rat and pig is known to be regulated by a negative feedback mechanism mediated by intestinal trypsin and chymo‐trypsin. Such a mechanism has recently been noted in humans. The presence of these enzymes in the small intestine suppresses pancreatic enzyme secretion, whereas their removal increases it. Two novel peptides have been proposed to account for the stimulation of pancreatic enzyme secretion in response to feeding trypsin inhibitor. One was assumed to be present in rat pancreatic juice and the other to be spontaneously secreted from the rat small intestine. In either case, trypsin and trypsin inhibitors do not directly interact with the luminal surface of the small intestine, but their actions are mediated by a trypsin‐sensitive, cholecystokinin‐releasing peptide. This is a novel explanation of the well‐recognized stimulation of pancreatic enzyme secretion in response to dietary protein intake.— Fushiki, T.; Iwai, K. Two hypotheses on the feedback regulation of pancreatic enzyme secretion.FASEB J.3: 121‐126; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2644146

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

The enteric nervous system plays a key role in maintenance of body fluid homeostasis by regulating the transport of ions by the intestinal epithelium. The epithelial cells normally absorb large volumes of fluid and ions daily, but tonically active submucosal neurons continuously suppress ion transport and limit the absorptive capacity of the intestine. Specialized nerve endings detect chemical, osmotic, or thermal alterations of the luminal contents or mechanical activity of the gut wall and encode this information as action potentials that propagate along nerve processes to the ganglia. Information transfer within the ganglia occurs at nicotinic cholinergic or other synapses. Ion transport is altered when neurotransmitters released from motor neurons interact with receptors on epithelial cells to initiate stimulus‐response coupling. The signals that transduce changes in epithelial ion transport are largely unknown, except for acetylcholine, but may include vasoactive intestinal peptide or other peptides. These trigger changes in intracellular messengers that influence the state of ionic channels in the epithelial cells and thereby inhibit absorptive processes or stimulate secretory mechanisms. When conservation of salt and water is necessary, command signals from the central nervous system, and perhaps from the myenteric ganglia, will shut down the synaptic circuits in the submucosal ganglia and enhance the absorptive capacity of the bowel.—Cooke, H. J. Role of the “little brain” in the gut in water and electrolyte homeostasis.FASEB J.3: 127‐138; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2464517

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Based on a review of literature in various fields of research related to hypertension, we develop a new working hypothesis on the pathophysiology of genetically determined increases in blood pressure. According to our hypothesis, the primary defect is located in the kidneys. Renal α‐adrenergic receptor density is increased in the early stages of the disease, before increases in blood pressure occur. Most renal α‐adrenergic receptors are located in the proximal tubules and enhance Na+reabsorption. A genetically determined increase of α1−or α2−or of both α‐adrenergic receptor subtypes would impair Na+excretion and, together with increased Na+intake, would lead to positive Na+balance. Subsequently, various mechanisms would be activated to restore a neutral Na+balance, including the secretion of a natriuretic factor that inhibits Na+/K+‐ATPase. Inhibition of Na+/K+‐ATPase in extrarenal tissues would increase the intracellular concentration of Na+and, via Na+/Ca2+exchange, of Ca2+. Elevated intracellular Ca2+would enhance vascular smooth muscle contractility and neuronal transmitter release, thereby leading to vasoconstriction and to increases in blood pressure. We thus hypothesize that hypertension is a homeostatic response designed to protect blood volume from a genetically determined renal α‐adrenergic receptor‐mediated increase in Na+retention.— Michel, M. C.; Insel, P. A.; Brodde, O‐E. Renal α‐adrenergic receptor alterations: a cause of essential hypertension?FASEB J.3: 139‐144; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2536629

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

This report summarizes the recent rapid development of research on neutral endopeptidase 24.11 (enkephalinase; NEP) and on two other metalloenzymes, meprin and endopeptidase 24.15. NEP cleaves a variety of active peptides, including enkephalins, at the amino side of hydrophobic amino acids. The cDNA for human, rat, and rabbit NEP has been cloned and the deduced protein sequences revealed a high degree of homology (93‐94%). Site‐directed mutagenesis proved that an active site glutamic acid is involved in catalysis and two active site histidines are responsible for binding the zinc cofactor. Although NEP was originally discovered in the kidney, it is widely distributed in the body including specific structures in the central nervous system, lung, male genital tract, and intestine and in neutrophils, fibroblasts, and epithelial cells. In tissues and cells NEP is bound to plasma membrane through a hydrophobic membrane‐spanning domain near the NH2terminus, but it is present in soluble form in urine and blood. In addition to enkephalins, NEP cleaves kinins, chemotactic peptide, atrial natriuretic factor (ANF), and substance P in vivo. NEP in the lung is a major inactivator of substance P, which constricts the airway smooth muscles. Because of the possible involvement of NEP in the metabolism of opioid peptides and the cardiac hormone ANF, orally active inhibitors have been synthesized. Compounds that inhibit both aminopeptidase and NEP were reported to prolong the analgesic effects of enkephalins. Other inhibitors given per os prolonged the renal effects of exogenous ANF. A newly synthesized specific inhibitor of NEP was also active in animal experiments as an analgesic. Studies on the structure and function of NEP should lead to further development of therapeutically applicable inhibitors.— Erdös, E. G.; Skidgel, R. A. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones.FASEB J.3: 145‐151; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2521610

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Enzyme replacement has long been considered only a remote possibility in the treatment of a wide range of genetic disorders, many manifested as lysosomal storage diseases. The complexity of having a particular enzyme gain access to the lysosomal compartment in a specific cell seemed insurmountable. We report here on an attempt to introduce the enzyme cholesteryl esterase into fibroblasts from a patient with cholesteryl ester storage disease (CESD). The enzyme gains access to the lysosomal compartment and the accumulating cholesteryl ester by virtue of being carried into the cell conjugated to a ligand (insulin or apoprotein B [apoB]) that binds to its own specific receptor and is internalized by the well‐described process of receptor‐mediated endocytosis. Regardless of whether the enzyme enters the cell via the insulin receptor or via the low‐density lipoprotein (ApoB) receptor, it can be found associated with a lysosomal fraction and is effective in lowering levels of accumulated substrate, cholesteryl ester. The time course of the substrate degradation and the dependence on the receptor density and receptor‐ligand interaction indicate that the enzyme is simply being carried to the site of substrate accumulation by virtue of the fact that that is the destination of the ligand (along with its conjugated enzyme) following internalization.— Poznansky, M. J.; Hutchison, S. K.; Davis, P. J. Enzyme replacement therapy in fibroblasts from a patient with cholesteryl ester storage disease.FASEB J.3: 152‐156; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2644147

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Danazol, an attenuated androgen, is useful in endometriosis, idiopathic thrombocytopenic purpura (ITP), and autoimmune hemolytic anemia (AIHA). However, its mechanism of action is unknown. We investigated the possibility that danazol affects cell membranes directly. Red cell osmotic fragility was studied in patients receiving danazol. A significant decrease in osmotic fragility was observed. Accompanying the change, peripheral blood smears showed many target cells and electron microscopy revealed extra folds in erythrocyte membranes. Twenty‐two patients were studied prospectively before and after danazol. Osmotic fragility decreased significantly (P<0.001) in 1 month of therapy and progressed with further treatment. A rebound increase (P<0.01) was observed in 1 month after discontinuation of danazol among 16 patients. Incubation experiments showed that danazol‐induced changes are not reversed with normal sera. Patient sera did not induce the changes in normal red cells. Danazol in vitro protected red cells from osmotic lysis at low concentrations but enhanced lysis at high concentrations. We suggest that danazol alters red cell membranes directly to increase their surface area, inducing target cell formation and increasing their resistance to osmotic lysis.—Ahn, Y. S.; Kim, C. I.; Mylvaganam, R.; Fernandez, L. F.; Temple, J. D, Jr.; Cayer, M. L.; Harrington, W. J. Danazol therapy renders red cells resistant to osmotic lysis.FASEB J.3: 157‐162; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2914627

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

Chinese hamster ovary (CHO) cells exhibit increased sensitivity to a wide variety of microtubule inhibitory drugs when verapamil is present in the growth medium. The extent of this increased sensitivity is drug specific: some drugs such as taxol and vinblastine respond greatly to the presence of verapamil, whereas other drugs such as griseofulvin respond very poorly. For the majority of drugs examined, however, a 2‐ to 10‐fold increase in drug sensitivity is observed in the presence of verapamil at 5 μg/ml. The effects of verapamil are even more dramatic when drug‐resistant mutant cells with a presumed alteration in membrane permeability are examined. In the presence of appropriate levels of verapamil, these mutants demonstrate a level of drug sensitivity comparable to that of the wild‐type parental cells. Drug‐resistant cells from similar selections but with well‐defined alterations in α‐ or β‐tubulin and no evidence of alterations in membrane permeability, however, continue to exhibit increased resistance to the selecting drug even in the presence of verapamil. These studies support the conclusion that verapamil affects the membrane permeability to or transport of a wide variety of hydrophobic drugs. In addition, we have used this information to devise selections that virtually eliminate the isolation of drug‐resistant permeability mutants. This methodology should be generally applicable to genetic studies of drug action that are complicated by the isolation of large numbers of mutants with permeability alterations.— Schibler, M. J.; Barlow, S. B.; Cabral, F. Elimination of permeability mutants from selections for drug‐resistance in mammalian cells.FASEB J.3: 163‐168; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2563346

出版商:Wiley    

年代:1989

数据来源: WILEY

摘要:

We have shown that restricted calorie intake retards age‐associated loss in androgen responsiveness of the rat liver. Sustained androgen receptivity delays age‐dependent decline in the synthesis of the androgen‐inducible α2u globulin and derepression of the androgen‐repressible senescence marker protein (SMP‐2). Quantitation of mRNAs for α2u globulin and SMP‐2 in the liver of animals of various ages maintained on either ad libitum or restricted diets revealed that, although the 27‐month‐old ad libitum‐fed rat had only 5% as much α2u mRNA as the 6‐month‐old rat; the mRNA level was as high as 45% in the 27‐month‐old food‐restricted rat. Conversely, the 27‐month‐old food‐restricted rat had a much reduced amount (45%) of SMP‐2 mRNA compared to the age‐matched control that was allowed unlimited access to food. Furthermore, we have correlated the effect of dietary restriction on age‐dependent changes in specific gene expression with the hepatic level of the immunoreactive cytoplasmic androgen‐binding (CAB) protein. We observed that senescence in the male causes a substantial decrease in the circulating level of testosterone. However, dietary restriction does not retard the rate of decline in the plasma level of the male hormone during aging. These results indicate that age‐dependent changes in the expression of androgen‐responsive genes (α2u globulin and SMP‐2) reflect changing androgen sensitivity and that food restriction may directly influence the androgen receptivity of the liver.— Chatterjee, B.; Fernandes, G.; Yu, B. P.; Song, C.; Kim, J. M.; Demyan, W.; Roy, A. K. Calorie restriction delays age‐dependent loss in androgen responsiveness of the rat liver.FASEB J.3: 169‐173; 1989.

ISSN:0892-6638    

DOI:10.1096/fasebj.3.2.2464518

出版商:Wiley    

年代:1989

数据来源: WILEY