Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human phosphoribosylpyrophosphate synthetase has been purified 4500-fold to electrophoretic homogeneity from the erythrocytes of normal individuals and of two brothers in whom excessive activity of this enzyme results in excessive rated of purine nucleotide and uric acid synthesis de novo and gouty arthritis. Structural differences between the normal and mutant enzymes are indicated by a lower isoelectric point for the mutant enzyme (pI 4.85) than for the normal enzyme (pI 5.10); decreased electrophoretic mobility of the mutant preparation on cellulose acetate gel at low inorganic phosphate concentrations; increased (2.4-fold) inactivation of the mutant enzyme activity relative to the normal by identical amounts of a specific antiserum which precipitates identical quantities of normal and mutant enzyme; increased thermal lability of the mutant enzyme at 55 degrees; and an increased (2.2-fold) specific enzyme activity for the mutant enzyme despite the comparable purity of the preparations. Antibody inactivation, quantitative precipitin, and immunodiffusion studies as well as the disparity in specific enzyme activities during the course of purification suggest that a structural alteration in the mutant enzyme leads to increased catalytic activity per enzyme molecule, either from a primary alteration in the structural gene(s) for phosphoribosylpyrophosphate synthetase or from a post-transcriptional alteration in the enzyme. Purified preparations of normal and mutant enzymes showed nearly identical affinity constants for magnesium and the substrates, ATP and ribose 5-phosphate, as well as similar inhibition constants for the products, PP-ribose-P and AMP, and the inhibitors ADP, GDP, and 2,3-diphosphoglycerate. An increased maximal velocity of the reaction was, thus, the sole kinetic difference identified. The increased velocity of the mutant enzyme reaction was constant over a range of inorganic phosphate concentrations from 0.1 to 100 mM. Subunit molecular weights of the enzyme preparations, estimated by sodium dodecyl sulfate-polyacrylamide electrophoresis, were identical (32,000), although the undenatured mutant enzyme showed a greater proportion of stainable protein in the smaller of two molecular weight forms (both greater than 500,000) of the enzyme demonstrated on polyacrylamide gel electrophoresis in the presence of 1 mM sodium phosphate.
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PMID:Human phosphoribosylpyrophosphate synthetase. Comparison of purified normal and mutant enzymes. 16 59

A series of intracellular events occurring after treatment of rabbit synovial fibroblasts with 0.01 micrograms/ml phorbol myristate acetate (PMA) were measured. Ten minutes after addition of PMA, there was a temporary increase in intracellular cyclic AMP levels, followed by a transient decrease in incorporation of 3H-thymidine into DNA. Approximately 500 ng/mg cell protein of PGE2 were found in culture medium from the 12- to 24-hour incubation period, but significant collagenase was not detectable until 24 to 36 hours. Treatment with aspirin or indomethacin abolished PGE2 production but did not affect collagenase levels. Production of enzyme was associated with a cessation of cell proliferation, measured by protein content/culture and cell number. No enzyme was detectable in untreated cultures. Synovial fibroblasts treated with phorbol myristate acetate may provide a good model for studies on the mechanism of induction of collagenase production.
Arthritis Rheum 1979 Oct
PMID:Collagenase production by synovial fibroblasts treated with phorbol myristate acetate. 22 97

Connective tissue activating peptide-III (CTAP-III) isolated from human platelets is a potent mitogen for human connective tissue cells in culture in addition to stimulating glycosaminoglycan synthesis, glucose consumption, and lactate formation. The amino acid composition of apparently homogeneous CTAP-III was determined, confirming the presence of two disulfide links and providing a calculated molecular weight of 11,633 daltons. Comparison of the mitogenic activity of serum and plasma-serum suggests that CTAP-III is a major mitogenic component of human serum. Seventeen strains of human connective tissue cells (synovial, cartilage, dermal and thyroid) incorporated [3H]-thymidine at up to 30 times control at levels under the influence of microgram quantities of CTAP-III and caused detectable increases in thymidine incorporation at levels as low as 10-29 ng/ml. Prostaglandin E1 (0.01 microgram/ml) and dibutyryl cyclic AMP (25 microgram/ml) potentiated the glycosaminoglycan stimulating effect of CTAP-III, but not its mitogenic effect. Cycloheximide and actinomycin D blocked the biologic actions of CTAP-III. Cortisol and penicillamine had little effect on the mitogenic activity of CTAP-III, whereas antirheumatic agents such as acetylsalicylic acid and phenylbutazone opposed the mitogenic activity when added to cultures at clinically relevant concentrations. A weak antiheparin factor secreted by platelets, low affinity platelet factor 4 (LA-PF4), was shown to be similar to CTAP-III in biologic actions, electrophoretic mobility, amino acid composition, and antigenic determinants.
Arthritis Rheum 1979 Mar
PMID:Connective tissue activation. XIV. Composition and actions of a human platelet autacoid mediator. 42 Jul 16

A deficiency of adenine phosphoribosyltransferase (APRT) enzyme activity to approximately 40% of normal has been found in erythrocytes from a young woman aged 24 years, who had suffered from recurrent gouty arthritis since 11 years of age. She also demonstrated considerable, although asymptomatic, renal impairment with a creatinine clearance of one-third normal. Her father had suffered from gouty arthritis but had a normal APRT activity; he was obese, had a high purine intake and was a regular beer drinker. The patient's mother was asymptomatic with a normal serum urate concentration, but demonstrated a similar reduction in APRT activity to that of her daughter. Eleven other asymptomatic members of the family also demonstrated a similar reduction in APRT activity in erythrocyte lysates. The pattern of inheritance was consistent with autosomal transmission. Concentrations of phosphoribosylpyrophospate (PRPP) in erythrocytes were within normal limits both in the subjects with deficient, and in those with normal, APRT activity. Partial purification of APRT enzyme from erythrocytes of the index case did not reveal any difference from the normal enzyme as far as Michaelis constants, heat stability, or mobility in polyacrylamide gel was concerned. No primary abnormality of lipoprotein metabolism was demonstrated either in the propositus or in other members of her family. Study of urate metabolism in the propositus indicated that, although urate production was within the normal range in absolute terms, there was increased incorporation of glycine into produced urate, usually taken as one index of de novo urate production. Impaired renal excretion of urate was also shown. Although detailed study of urate metabolism has not been undertaken in other family members with APRT deficiency, no conclusive relationship has yet been demonstrated between APRT deficiency and disordered urate metabolism.
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PMID:Adenine phosphoribosyltransferase deficiency: its inheritance and occurrence in a female with gout and renal disease. 106 47

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAIDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated. A major effect of NSAIDs is inhibition of cyclooxygenase, the rate-limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E2 (PGE2), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of G1-to-S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAIDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAIDs can also interfere with transmembrane ion fluxes and with cell-to-cell binding. Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for macrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vitro and in vivo. A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention. 130 81

Local responses to cytokines and their induced products play a critical role in outcome in the arthritic joint. Using a bovine nasal cartilage culture model, chondrocyte mediated breakdown was stimulated by lipopolysaccharides or tumor necrosis factor. Cartilage breakdown was inhibited in a dose dependent manner by prostaglandin E2, cyclic AMP enhancement and interferon alpha. The possible regulatory roles played by these agents in cytokine activated cartilage breakdown suggest potential therapeutic strategies in human arthritis.
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PMID:Chondrocyte mediated cartilage degradation: regulation by prostaglandin E2, cyclic AMP and interferon alpha. 185 Dec 30

Three brothers who developed acute gouty arthritis at ages 16, 20 and 26 years were found to have increased plasma urate. Erythrocyte hypoxanthine phosphoribosyltransferase (HPRT) activity was less than 1% of normal and adenine phosphoribosyltransferase (APRT) activity was increased 2-3-fold. This variant, HPRTEdinburgh, was further studied using lymphoblast lines established from these patients and the following observations are consistent with a mutation involving a single amino acid substitution. Lymphoblasts from these patients had 0.9-1.6% of control HPRT activity which was 8-fold more labile than control activity at 75 degrees C. Isoelectric focusing of the variant protein in polyacrylamide gels indicated a pI of 6.5-6.7 which is more basic than normal HPRT, pI 6.0-6.3. The Michaelis constants were increased: 10-fold for hypoxanthine from 1.3 to 13 mumol/L, and 5-fold for PP-ribose-P from 6 to 30 mumol/L, for control and variant respectively. The Ki for product inhibition by GMP was marginally increased in the variant. Northern blot analysis of variant lymphoblast RNA indicated normal amounts of the expected 1.6 kilobase messenger RNA.
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PMID:Hypoxanthine-guanine phosphoribosyltransferase deficiency in three brothers with gout: characterization of a variant, HPRTEdinburgh, having altered isoelectric point, increased thermal lability and normal levels of messenger RNA. 251 72

Extracellular generation of inorganic pyrophosphate (PPi) in cartilage organ culture is markedly augmented by ATP.ATP, not an ATP metabolite (ADP, AMP, adenosine) is necessary for this augmentation. Excess PPi production is effectively blocked by known inhibitors of nucleoside triphosphate (NTP) pyrophosphohydrolase (EDTA, EGTA, dithiothreitol). Excess 32P-PPi is generated directly from gamma 32P-ATP by cartilage, as substrate and product have similar specific activities. These findings strongly favor ecto-NTP pyrophosphohydrolase as the source of extracellular PPi generation in the presence of NTP. Additionally, active nucleotide and nucleoside catabolism is demonstrated in these cartilage organ cultures.
Arthritis Rheum 1985 Apr
PMID:Cartilage nucleoside triphosphate pyrophosphohydrolase. II. Role in extracellular pyrophosphate generation and nucleotide metabolism. 298 90

The application of the principles of basic sciences in anesthesiology not only has succeeded in allaying man's pain on Earth, but also within this decade has provided him with a controlled safe environment for successive journeys into outer space and to the moon and soon to planets beyond. These same principles have made possible his exploration of the ocean floors in artifical atmospheres and pressures and his escape, without breathing devices, from depths of 300 feet. The science of anesthesia has contributed immeasurably to the active treatment of paralytic poliomyelitis and to resuscitation. Furthermore, it has introduced needless jet injection for drug and vaccine therapy in epidemics and with increasing rapidity to diabetcs. This accumulating body of knowledge within the past 13 decades has contributed to the development of modern surgery, obstetrics, and dentistry, and provided techniques for the control of pain from metastatic cancer, from trauma, from arthritis, and during postoperative convalescence. The anesthesiologist shares with the surgeon and clinical pathologist the responsibility for the safe use of fluid and blood replacement therapy; and with the internist, psychiatrist, and general practitioner the proper sequential medication of analgesics, anesthetics, ataractics, cortisone, antihypertensive and antihistaminic agents, and prompt reversal of many undesirable depressions during emergence. A new concept is the reversal of many narcotic states with cyclic AMP. Major advances in anesthesia have been developed on every continent. The fact that there are at least 30 anesthetic techniques and 62 agents in worldwide use reemphasizes our present lack of an ideal single anesthetic agent and technique. Iti is encouraging to note that the science of anesthesiology has made more progress during the past three decades than in all of the previous century. The great preponderance of that progress has been largely confined to Canada, the United States, the British Commonwealth, Western Europe, and a few of the metropolitan areas in South America. Happily, the significant progress in the last decade has added monitors and other safeguards, understanding, tecyniques, agents, and pioneer investigators, in increasing proportions for a world that will double its population in the present half-century. Surely, there is no more important field toward the direction of world scientific effort for human betterment than in this broad area of universal agreement.
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PMID:Delivery of anesthesia services throughout the world. 444 13

Prostaglandins are analogs of the parent 20 carbon prostanoic acid. They are divided into 4 series: PGE; PGF; PGA; PGB, according to the presence of functionalities in the cyclopentane structure. Biosynthesis of prostaglandins were first independently reported by Bergstrom et.al. and van Dorp et.al. who showed that certain w-6-unsaturated fatty acids were biological precursors of prostaglandins. Later, various investigators reported the biosynthesis of prostaglandins of the different series. The 2 most widely used routes of prostaglandins synthesis are 1) the Corey cyclopentyl-lactone route, and 2) the bicyclohexane route. The synthesis is divided into 1) naturally occuring primary prostaglandins and 2) the prostaglandin analogs and derived prostaglandins. Because of the general instability of natural prostaglandins in the basic and acidic milieu, various preparations of prostaglandins and chemically stable dosage forms have been developed. Various methods used in analyzing prostaglandins include: 1) TLC; 2) GLC; 3) spectral methods; 4) radioimmunoassay; and 5) enzymatic assay. In vitro and in vivo studies on the metabolism and catabolism of various prostaglandins showed that they are rapidly metabolized in various animal systems and humans. The major routes for this metabolic transformation are: 1) oxidation of the secondary C15 hydroxy group; 2) reduction of the C13 double bond; 3) B-oxidation; 4) w-hydroxylation; and 5) w-oxidation. Prostaglandins produce a wide range of biological effects on animal and human systems (the reproductive; gastrointestinal; respiratory; and cardiovascular systems). The biological actions of prostaglandins on animal and human reproductive tissue vary depending on the particular prostaglandin studied and hormonal state of the tissue. Certain prostaglandins can decrease the tonus, frequency, and amplitude of spontaneous contractions of human uterine strips while other prostaglandins can cause contraction of isolated myometrial strips. Prostaglandins are widely used in labor induction; induction of therapeutic abortion; and fertility control. Prostaglandins have also been found to either increase or decrease cyclic AMP; inhibit ADP-induced platelet aggregation; lower blood pressure in animals; affect lipid and carbohydrate metabolism, and prevent adjuvant arthritis.
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PMID:Prostaglandins. 456 72


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