Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protease inhibitor alpha-1-antichymotrypsin, which binds to chymotrypsin-like enzymes in a sodium dodecyl sulfate-resistant manner, has been shown recently to be both a normal constituent of brain and an integral component of the neuritic plaques that form in Down's syndrome and Alzheimer's disease. We have now identified in rat brain a Mr 25,000 alpha-1-antichymotrypsin-binding protein classified as a chymotrypsin-like protease by its inhibitor profile and substrate specificity. Release of 125I-labeled breakdown products from bands containing the protease in substrate-linked polyacrylamide gels was examined in parallel with hydrolysis of tetrapeptide chromogenic substrates in vitro to establish conditions under which the Mr 25,000 protease was the only activity being measured in vitro. The protease was completely membrane associated but was extractable using 1 M MgCl2; prior extraction of detergent- and low ionic strength-soluble proteins from membranes was used to increase its specific activity. The formation of sodium dodecyl sulfate-resistant bonds between human alpha-1-antichymotrypsin and the protease (kassoc = 2.9 X 10(6) M-1 s-1) was used to titrate the concentration of free protease solubilized from membranes. The protease cleaved both succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, and methoxy-succinyl-Ala-Ala-Pro-Met-p-nitroanilide, the latter being of interest because cleavage after a methionine residue is predicted to generate the amino terminus of the neuritic plaque component beta-amyloid from its precursor protein. In fact, the solubilized protease degraded 90% of membrane-associated beta-amyloid precursor protein detected by Western blot analysis. The protease was kinetically distinct from both chymotrypsin and cathepsin G in direct comparisons and did not match kinetic values published for the rat mast cell proteases against comparable substrates; we therefore refer to the protease with the descriptive acronym clipsin (for chymotrypsin-like protease). Proteases similar to and potentially identical to clipsin were detected by enzymography in other organs from rat (most notably spleen and adult lung). The enzyme in brain was distinguished by a narrow window of elevated activity surrounding postnatal day 5, which was 12-14-fold higher than levels in day 1 or adult brain. Because independent lines of evidence suggest that a brain chymotrypsin-like protease may be involved in the etiology of Down's syndrome and Alzheimer's disease, clipsin is discussed as a candidate for such a role.
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PMID:Clipsin, a chymotrypsin-like protease in rat brain which is irreversibly inhibited by alpha-1-antichymotrypsin. 230 81

The concentration of histamine (HA) has been determined by high-performance liquid chromatography (HPLC) with fluorometric detection in 21 different regions of brains from patients with senile dementia of the Alzheimer type (SDAT) and subjects (CB) whose causes of death were not related to neuropsychiatric, neurological and/or neurodegenerative diseases. The highest levels of HA in the central nervous system (CNS) of both control (CB) and SDAT samples were found in the posterior hypothalamus (CB = 3.13 +/- 0.63 pmol/mg; SDAT = 7.75 +/- 1.43 pmol/mg, p less than 0.005), where the HA neurons are located, and in the anterior hypothalamus (CB = 1.77 +/- 0.33 pmol/mg; SDAT = 2.82 +/- 0.45 pmol/mg, p less than 0.005). The lowest HA levels were detected in the cerebellum (CB = 0.12 +/- 0.04 pmol/mg; SDAT = 0.24 +/- 0.09 pmol/mg, p less than 0.01) and medulla oblongata. HA levels were significantly higher in SDAT than in CB in the following areas: motor cortex (Brodmann's area 4) (A4), premotor cortex (A6), postcentral gyrus (A1,2), posterior parietal cortex (A5,7), superior temporal gyrus (A41,42), temporal pole (A38), primary and secondary visual cortices (A17,18), anterior and posterior regions of the hypothalamus, putamen, caudate nucleus, nucleus accumbens, thalamus, hippocampus, pons, medulla oblongata and cerebellum. No changes were seen in globus pallidus and corpus callosum. Since the origin of HA in the brain is dependent upon three main compartments (neuronal, mast cell, vascular smooth muscle), with approximately 60-80% of the total HA belonging to the neuronal pool, on the basis of neurochemical data we postulate that the increase in the levels of HA in SDAT might account for or be associated with alterations in neuroendocrine, cognitive, neurovascular and sleep-wakefulness functions.
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PMID:Brain histamine in Alzheimer's disease. 275 82

Cleavage after Met596 of the beta-amyloid precursor protein to generate the N-terminus of beta-protein indicates the activity of a protease having chymotrypsin-like specificity. A chymotrypsin-like protease is further implicated in Alzheimer's disease by the increased synthesis of the protease inhibitor alpha 1-antichymotrypsin in pathologically affected brain regions and by the presence in the amyloid deposits of inactivated forms of alpha 1-antichymotrypsin (indicating irreversible binding to a target chymotrypsin-like protease). In the present report, we have purified from rat brain a chymotrypsin-like protease that (a) binds with high affinity to human alpha 1-antichymotrypsin, (b) proteolytically generates a beta-protein-containing C-terminal fragment from full-length recombinant human beta-amyloid precursor protein, and (c) selectively cleaves methoxysucinyl-Glu-Val-Lys-Met- p-nitroanilide (a substrate modeling the protease recognition domain for the beta-protein N-terminal cleavage site). Amino acid sequences of tryptic fragments of the purified rat brain chymotrypsin-like protease indicate an identity with rat mast cell protease I. Moreover, the ontogeny and compartmentalization of rat brain chymotrypsin-like protease are consistent with those of connective tissue-type mast cells in the meningeal and intracortical perivasculature. Because these areas in human brain form extensive beta-amyloid deposits in Alzheimer's disease, Down's syndrome, and hereditary cerebral hemorrhage with amyloidosis of Dutch origin, the present findings suggest that a brain mast cell chymotrypsin-like protease may participate in generating perivascular beta-protein, which ultimately aggregates into beta-amyloid deposits.
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PMID:Identification of a chymotrypsin-like mast cell protease in rat brain capable of generating the N-terminus of the Alzheimer amyloid beta-protein. 833 43

alpha 1-Antichymotrypsin, a member of the serine proteinase inhibitor (serpin) family, inhibits neutrophil proteinase cathepsin G and mast cell chymases, and protects the lower respiratory tract from damage by proteolytic enzymes. It contains a reactive centre loop, which interacts with cognate proteinases, resulting in loop cleavage and a major conformational change. Recently, alpha 1-antichymotrypsin has been identified as a major constituent of the neurofibrillary plaques associated with Alzheimer's disease, and in vitro studies have shown that it enhances the rate of amyloid-fibril formation. These observations and recent genetic evidence suggest that alpha 1-antichymotrypsin is important in the pathogenesis of Alzheimer's disease.
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PMID:Alpha 1-antichymotrypsin. 893 Jan 18

Due to increases in life expectancy, women are living 30 years or more beyond menopause. This has led to an increasing interest in the association between postmenopausal estrogen deficiency and degenerative diseases associated with aging such as cardiovascular disease, osteoporosis and dementia. Women are two times more likely to develop late-onset Alzheimer's disease (AD) than age-matched men. A large number of observational reports and a few randomized clinical trials have indicated that estrogen replacement therapy (ERT) may retard the development and severity of dementia in postmenopausal women. The mechanism underlying the protective action of estrogen in AD is under active investigation. A chronic inflammatory reaction mediated by abnormal deposition of proteins such as amyloid-beta (A beta) is central to the pathology of AD. We investigated the effect of low doses of conjugated estrogen (Premarin) in an animal model of A beta-induced vascular disruption and inflammatory reaction. This rodent model allows live videomicroscopic recording and electron microscopic analysis of peripheral vascular disruption and inflammatory reaction triggered by A beta. Estrogen prevented vascular deposition of A beta, endothelial and vessel wall disruption with plasma leakage, platelet and mast cell activation, and characteristic features of an inflammatory reaction: adhesion and transmigration of leukocytes. The beneficial effect was lost when estrogen treatment was discontinued. Estrogen also protected the cerebral blood vessels from endothelial dysfunction induced by A beta. This novel protective effect of estrogen against A beta cytotoxicity in peripheral and cerebral vasculature may contribute to the therapeutic efficacy of estrogen in AD and coronary vascular disease.
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PMID:Estrogen protects peripheral and cerebral blood vessels from toxicity of Alzheimer peptide amyloid-beta and inflammatory reaction. 1068 97

Women are two to three times more likely to develop late-onset Alzheimer's disease (AD) than age-matched men. A large number of observational reports and a few randomized clinical trials have indicated that estrogen replacement therapy (ERT) may retard the development and severity of dementia in postmenopausal women. A chronic inflammatory reaction mediated by abnormal deposition of proteins such as amyloid-beta (A beta) is central to the pathology of AD. We investigated the effect of low doses of conjugated estrogen (Premarin) in an animal model of A beta-induced vascular disruption and inflammatory reaction. Estrogen prevented vascular deposition of A beta, endothelial and vessel wall disruption with plasma leakage, platelet and mast cell activation, and characteristic features of an inflammatory reaction: adhesion and transmigration of leukocytes. The beneficial effect was lost when estrogen treatment was discontinued. This novel protective effect of estrogen against A beta-induced vascular dysfunction may contribute to the therapeutic efficacy of estrogen in AD and coronary vascular disease.
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PMID:Vascular actions of estrogen and Alzheimer's disease. 1081 45

A2B adenosine receptor is involved in the control of mast cell degranulation, interleukin-8 synthesis and cell growth. A2B adenosine receptor antagonists may serve as novel drugs for asthma, Alzheimer' s disease, cystic fibrosis and type-II diabetes. Therefore, seeking for the highly selective A2B adenosine receptor antagonists has been one of great interest. The molecular basis, structure-activity relationship of selective A2B adenosine receptor antagonists and their interactions with A2B adenosine receptor were reviewed.
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PMID:[Advances in the study of A2B adenosine receptor antagonists]. 1863 Feb 58

Mast cells are found in the brain, where they contribute to immune responses. They have been implicated in multiple sclerosis, but their potential role in Alzheimers disease (AD), another inflammatory disease of the central nervous system, remains elusive. In the present study, we examined mast cell responses to amyloid beta (Abeta) peptides 1-40 and 1-42, the major components of the Alzheimer amyloid plaques. Rat peritoneal mast cells were used as experimental model for human brain serosal mast cells. Fibrillar Abeta1-40 and Ami1-42 peptides induced concentration-dependent exocytosis, as assessed by measurement of histamine secretion; exocytosis was reduced by pre-treatment with pertussis toxin and with antibodies against the CD47 receptor and the beta1-integrin subunit. Fibrillar Abeta1-40 and Abeta1- 42 peptides coated on heat-inactivated yeast particles and soluble fibrillar Abeta1-40 and Abeta1-42 peptides were also recognized and phagocyted by mast cells. Uptake of the peptides was decreased in the presence of 4N1, a peptide agonist of the CD47 receptor, but remained unchanged in the presence of 4NGG, a peptide derived from 4N1 which does not bind to CD47. Non-fibrillar forms of Abeta1-40 and 1-42 peptides were unable to elicit mast cell responses. These results show that fibrillar Abeta peptides can trigger mast cells and elicit exocytosis and phagocytosis. The Abeta-induced activation of mast cells operates through a CD47/beta1-integrin membrane complex coupled with Gi-protein. The present data support the hypothesis that mast cells, similarly to microglial cells, could play a major role in AD pathogenesis.
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PMID:Amyloid beta peptides trigger CD47-dependent mast cell secretory and phagocytic responses. 1950 77

In what corresponds to a life span, metallocarboxypeptidases (MCPs) have jumped from being mere contaminants in animal pancreas powders (in depression year 1929) to be key players in cellular and molecular processes (in yet-another-depression years 2009-2010). MCPs are unique zinc-dependent enzymes that catalyze the breakdown of the amide bond at the C-terminus of peptide and protein substrates and participate in the recovery of dietary amino acids, tissue organogenesis, neurohormone and cytokine maturation and other important physiological processes. More than 26 genes code for MCPs in the human genome, many of them still waiting to be fully understood in terms of physiological function. A variety of MCPs have been linked to diseases in man: acute pancreatitis and pancreas cancer, type 2 diabetes, Alzheimer's Disease, various types of cancer, and fibrinolysis and inflammation. Many of these discoveries have been made possible thanks to recent advances, as exemplified by plasma carboxypeptidases N and B, known for fifty and twenty years, respectively, which have had their structures released only very recently. Plasma carboxypeptidase B is a biological target for therapy because of its involvement in the coagulation/fibrinolysis processes. Besides, the widespread use of carboxypeptidase A as a benchmark metalloprotease since the early days of Biochemistry has allowed the identification and design of an increasingly vast repertory of small molecular weight inhibitors. With these two examples we wish to emphasize that MCPs have become part of the drug discovery portfolio of pharmaceutical companies and academic research laboratories. This paper will review key developments in the discovery and design of MCP small molecular weight inhibitors, with an emphasis on the discovery of chemically diverse entities. Although encouraging advances have been achieved in the last few years, the specificity and oral bioavailability of the new chemotherapeutic agents seem to pose a challenge to medicinal chemists.
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PMID:Progress in metallocarboxypeptidases and their small molecular weight inhibitors. 2046 32

The mast cells are multi-effector cells with wide distribution in the different body parts and traditionally their role has been well-defined in the development of IgE-mediated hypersensitivity reactions including bronchial asthma. Due to the availability of genetically modified mast cell-deficient mice, the broadened pathophysiological role of mast cells in diverse diseases has been revealed. Mast cells exert different physiological and pathophysiological roles by secreting their granular contents, including vasoactive amines, cytokines and chemokines, and various proteases, including tryptase and chymase. Furthermore, mast cells also synthesize plasma membrane-derived lipid mediators, including prostaglandins and leukotrienes, to produce diverse biological actions. The present review discusses the pathophysiological role of mast cells in different diseases, including atherosclerosis, pulmonary hypertension, ischemia-reperfusion injury, male infertility, autoimmune disorders such as rheumatoid arthritis and multiple sclerosis, bladder pain syndrome (interstitial cystitis), anxiety, Alzheimer's disease, nociception, obesity and diabetes mellitus.
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PMID:Mast cells: an expanding pathophysiological role from allergy to other disorders. 2256 73


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