Biomedical subjects

S C Kuo

Publications and source records attributed to S C Kuo.

At least 73 records · Page 4Linked to original sources

PubMed1996

Mechanism of action of p-chlorobiphenyl on the inhibition of platelet aggregation.

p-Chlorobiphenyl (1-50 microM) concentration-dependently inhibited the aggregation and release reaction of rabbit washed platelets induced by arachidonic acid and collagen, but not those induced by platelet-activating factor (PAF), U46619 and thrombin. The IC50 values of p-chlorobiphenyl on the arachidonic acid and collagen-induced platelet aggregation were 2.9 +/- 0.5 and 12.8 +/- 2.3 microM, respectively. The formation of both platelet thromboxane B2 and prostaglandin D2 caused by arachidonic acid was inhibited by p-chlorobiphenyl concentration-dependently. In myo-[3H]inositol-labeled and fura-2-loaded platelets. [3H]inositol monophosphate generation and the rise in intracellular Ca2- stimulated by arachidonic acid were inhibited by p-chlorobiphenyl. In human platelet-rich plasma, p-chlorobiphenyl and indomethacin prevented the secondary aggregation and blocked ATP release from platelets induced by adenosine 5'-diphosphate and adrenaline without affecting the primary aggregation. It is concluded that p-chlorobiphenyl may be a cyclo-oxygenase inhibitor and its antiplatelet action is mainly due to the inhibition of thromboxane formation.

Adenosine Triphosphate↗

PubMed1996

Synthesis and antiplatelet, antiinflammatory and antiallergic activities of 2,3-disubstituted 1,4-naphthoquinones.

Modification of 2-acetamido-3-chloro-1,4-naphthoquinone, which has potent antiplatelet, antiallergic and antiinflammatory activities, led to a series of 2,3-disubstituted 1,4-naphthoquinones. Some of these compounds showed significant antiplatelet, antiallergic and antiinflammatory activities. Among them, 2-methoxy-3-chloro-1,4-naphthoquinone (15) and 2-ethoxy-3-chloro-1,4-naphthoquinone (17) exhibited potent inhibitory effects on neutrophil and mast cell degranulation. 2-Methoxy-1,4-naphthoquinone (20) and 2-ethoxy-1,4-naphthoquinone (21) exhibited potent inhibitory effect on neutrophil superoxide formation. These four compounds were thus selected for further evaluation.

Animals↗

PubMed1995

Inhibition on platelet activation by shikonin derivatives isolated from Arnebia euchroma.

Acetylshikonin, teracrylshikonin, beta,beta-dimethylacrylshikonin and shikonin, isolated from Arnebia euchroma, inhibited collagen (10 micrograms/ml)-induced aggregation of washed rabbit platelets in a concentration-dependent manner with IC50 values of 2.1 +/- 0.2, 2.8 +/- 0.3, 4.2 +/- 0.5 and 10.7 +/- 0.7 microM, respectively. Acetylshikonin also inhibited the aggregation and ATP release of washed rabbit platelets induced by arachidonic acid (AA, 100 microM), U46619 (1 microM), platelet-activating factor (PAF, 3.6 nM) and thrombin (0.1 U/ml) in a concentration-dependent manner. The IC50 values of acetylshikonin on the inhibition of these four agonists-induced platelet aggregation were 3.1 +/- 0.4, 2.2 +/- 0.2, 8.0 +/- 0.6 and 12.7 +/- 1.0 microM, respectively. The thromboxane B2 formation caused by collagen, PAF and thrombin was inhibited by acetylshikonin, while formations of thromboxane B2 and prostaglandin D2 caused by AA were not inhibited. Acetylshikonin did not inhibit cyclooxygenase activity since it did not attenuate prostaglandin E2 formation after incubation of sheep vesicular gland microsomes with AA. Acetylshikonin suppressed both the rise of intracellular Ca2+ concentration and the generation of [3H]inositol monophosphate caused by these five aggregation inducers. Platelet cyclic AMP level was unaffected by acetylshikonin. These data indicate that acetylshikonin inhibits platelet activation by suppression of phosphoinositide breakdown.

Animals↗

PubMed1995

Endothelium-dependent relaxation of rat aorta by butein, a novel cyclic AMP-specific phosphodiesterase inhibitor.

Butein, isolated from Dalbergia odorifera T. Chen, caused endothelium-dependent relaxation of rat aorta precontracted with phenylephrine. This effect was abolished in endothelium-denuded aorta and in endothelium-intact aorta in the presence of NG-monomethyl-L-arginine, oxyhemoglobin and methylene blue, whereas the effect was unaltered by indomethacin or charybdotoxin. These results indicate that the vasorelaxant effect of butein depended on the endothelium and was mediated by endothelium-derived relaxing factor (EDRF). Incubation of endothelium-intact aorta with butein increased not only cAMP but also cGMP content. Four phosphodiesterase forms were isolated by diethylaminoethyl (DEAE)-Sephacel chromatography from rat aorta. cAMP-specific phosphodiesterase (type IV) activity was potently inhibited by butein with an IC50 of 10.4 +/- 0.4 microM. In contrast, phosphodiesterase I, III and V activities were inhibited by butein above 100 microM. Adenylate cyclase and guanylate cyclase activities were unchanged by butein. These results suggest that the increase of cAMP formation elicited by butein is due to the inhibition of cAMP-specific phosphodiesterase. The specific phosphodiesterase IV inhibitor (rolipram) and V inhibitor (zaprinast) both produced endothelium-dependent relaxations, whereas the phosphodiesterase III inhibitor (trequinsin) produced relaxation of rat aorta independent of the endothelium. In the presence of a functional endothelium, relaxations produced by butein were significantly potentiated by isoprenaline, forskolin, trequinsin and sodium nitroprusside. It is concluded that butein, a novel cAMP-specific phosphodiesterase inhibitor, produced relaxation of rat aorta, an effect dependent on an intact endothelium. The relaxant effect of butein was markedly enhanced by cGMP-elevating agents.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1995

Mechanism of anti-proliferation caused by YC-1, an indazole derivative, in cultured rat A10 vascular smooth-muscle cells.

An indazole derivative, YC-1, was identified in this study to be capable of reversibly and effectively inhibiting proliferation of rat A10 vascular smooth-muscle cells (VSMCs) in vitro. YC-1 (1-100 microM) dose-dependently inhibited [3H]thymidine incorporation into DNA in rat A10 VSMCs that were synchronized by serum depletion and then restimulated by addition of 10% foetal calf serum (FCS), whereas FCS-induced [3H]thymidine incorporation into rat synchronized endothelial cells was unaffected by this agent. The dose of YC-1 required to cause inhibition of FCS-induced proliferation was similar to that necessary for the formation of cellular cyclic GMP (cGMP). Guanylate cyclase activity in soluble fractions of VSMCs was activated by YC-1 (1-100 microM), whereas cGMP-specific phosphodiesterase activity was unaffected by this compound. The anti-proliferative effect of YC-1 was mimicked by 8-bromo-cGMP, a membrane-permeable cGMP analogue, and was antagonized by KT 5823 (0.2 microM), a selective inhibitor of protein kinase G. The anti-proliferative effect of YC-1 was also antagonized by Methylene Blue (50 microM), a guanylate cyclase inhibitor, and was potentiated by 3-isobutyl-1-methylxanthine (500 microM), a phosphodiesterase inhibitor. These results verified that YC-1 is a direct soluble guanylate cyclase activator in A10 VSMCs, and the anti-proliferative effect of YC-1 is mediated by cGMP. YC-1 still inhibited FCS-induced DNA synthesis even when added 10-18 h after restimulation of the serum-deprived A10 VSMCs with 10% FCS. Flow cytometry in synchronized populations revealed an acute blockage of FCS-inducible cell-cycle progression at a point in the G1/S-phase in YC-1 (100 microM)-treated cells. The inhibition of proliferation by YC-1 was demonstrated to be independent of cell damage, as documented by several criteria of cell viability. In conclusion, YC-1 reversibly and effectively inhibited the proliferation of VSMCs, suggesting that it has potential as a therapeutic agent in the prevention of vascular diseases.

Animals↗

PubMed1995

Inhibition of plasma extravasation by abruquinone A, a natural isoflavanquinone isolated from Abrus precatorius.

Polymyxin B-induced hind-paw edema was suppressed by abruquinone A, an isoflavanquinone isolated from Abrus precatorius, in normal as well in adrenalectomized mice. Unlike dexamethasone, abruquinone A did not increase the liver glycogen content in fasting adrenalectomized mice. The volume of exuded plasma was significantly reduced by abruquinone A in neurogenic inflammation, passive cutaneous anaphylactic reaction and compound 48/80-induced ear edema. Histamine-, serotonin-, bradykinin- and substance P-induced plasma extravasation in ear edema was also suppressed by abruquinone A. Abruquinone A, like isoproterenol, significantly reduced the bradykinin- and substance P-induced plasma extravasation in normal as well as in compound 48/80-pretreated mice. In addition, abruquinone A suppressed the bradykinin- and substance P-induced ear edema to a significantly greater extent than diphenhydramine/methysergide did. In the in vitro experiments, abruquinone A suppressed the compound 48/80-induced histamine and beta-glucuronidase released from isolated rat peritoneal mast cell preparations. These results suggest that the anti-inflammatory effect of abruquinone A is mediated partly via the suppression of the release of chemical mediators from mast cells and partly via the prevention of vascular permeability changes caused by mediators. The glucocorticoid activity and the release of glucocorticoid hormones from the adrenal gland are probably not involved.

Adrenalectomy↗

PubMed1995

Inhibition of hind-paw edema and cutaneous vascular plasma extravasation in mice by acetylshikonin.

Acetylshikonin, a naphthoquinone isolated from the Chinese herb medicine, tzu ts'ao, was demonstrated to inhibit the polymyxin B-induced hind-paw edema in normal as well as in adrenalectomized mice. Liver glycogen content was increased in adrenalectomized mice pretreated with dexamethasone, but not with acetylshikonin. Like diphenhydramine, methysergide and isoproterenol, acetylshikonin reduced the plasma exudation evoked in dorsal hind-paw skin by antidromic stimulation of the saphenous nerve, and in passive cutaneous anaphylactic reaction, bradykinin-, substance P-, compound 48/80-, histamine- and serotonin-induced ear edema. Indomethacin was ineffective in these respects. Bradykinin- and substance P-induced plasma exudation were also significantly reduced when [Thi5,8,D-Phe7]bradykinin and [D-Pro2,D-Trp7,9]substance P were coinjected with bradykinin and substance P, respectively. In isolated rat peritoneal mast cell preparation, acetylshikonin produced a concentration-dependent inhibition of histamine and beta-glucuronidase release from mast cells challenged by compound 48/80. In compound 48/80-pretreated mice, acetylshikonin and isoproterenol produced significantly more inhibitory effect on bradykinin- and substance P-induced plasma exudation than did diphenhydramine in combination with methysergide. Pretreatment with diphenhydramine/methysergide in compound 48/80-pretreated mice significantly further reduced the bradykinin- and substance P-induced plasma exudation if [Thi5,8,D-Phe7]bradykinin and [D-Pro2,D-Trp7,9]substance P were coinjected with bradykinin or substance P, respectively. The results suggest that the inhibitory effect of acetylshikonin on the edematous response is due neither to the release of steroid hormones from the adrenal gland nor to the glucocorticoid activity, but probably partly to the suppression of mast cell degranulation and partly to protection of the vasculature from mediator challenge.

Adrenalectomy↗

PubMed1995

The antiallergic activities of synthetic acrophylline and acrophyllidine.

The antiallergic activities of synthetic acrophylline [1] and acrophyllidine [2] have been demonstrated. Both compounds 1 and 2 at 30 mumol/kg reduced the plasma leakage in mouse ear in a passive cutaneous anaphylactic (PCA) reaction. In addition, compound 1 suppressed mast cell degranulation in a dose-dependent manner, while compound 2 at 100 microM produced no significant inhibition of the release of preformed inflammatory mediators. These results suggest that the antiallergic effect of compound 1 probably occurs through the suppression of mast cell degranulation, and that of compound 2 by protection of the vasculature against challenge by mediators of inflammation.

Alkaloids↗

PubMed1995

Potent antiplatelet, anti-inflammatory and antiallergic isoflavanquinones from the roots of Abrus precatorius.

Five isoflavanquinones have been isolated from the roots of Abrus precatorius L. (Leguminosae). Three of them are new and designated as abruquinones D, E, and F. The pharmacological activities of the isoflavanquinones have been evaluated. The results indicated that abruquinones A, B, and D exhibited remarkable inhibitory effects on the platelet aggregation. The IC50 of abruquinones A and B for the inhibition of the platelet aggregation induced by arachidonic acid (AA) and collagen were less than 5 micrograms/ml, and of abruquinone D, was less than 10 micrograms/ml for that induced by AA. On the other hand, abruquinones A, B, D, and F showed strong anti-inflammatory and antiallergic effects. The IC50 of abruquinones A, B, D, and F for the inhibition of superoxide formation were less than 0.3 micrograms/ml, for the inhibition of the release of both beta-glucuronidase and lysozyme from rat neutrophils and the release of both beta-glucuronidase and histamine from mast cells were less than 1 microgram/ml.

Animals↗

PubMed1995

Antiproliferative effects of A02011-1, an adenylyl cyclase activator, in cultured vascular smooth muscle cells of rat.

1. The effects of A02011-1, a pyrazole derivative, on the proliferation of rat vascular smooth muscle cells (VSMCs) were examined. 2. A02011-1 (1-100 microM) concentration-dependently inhibited [3H]-thymidine incorporation into DNA in rat VSMCs that were synchronized by 48 h serum depletion and then re-stimulated by addition of foetal calf serum (FCS, 10%), platelet-derived growth factor (PDGF, 10 ng ml-1), 5-hydroxytryptamine (10 microM) or ADP (10 microM). The inhibitory effect of A02011-1 was fully reversible. However, FCS-induced [3H]-thymidine incorporation into rat endothelial cells was unaffected by A02011-1. 3. The concentration of A02011-1 necessary for inhibition of the FCS-induced proliferation was similar to that necessary for adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation. Adenylyl cyclase activity was increased in A02011-1-treated VSMCs, whereas cyclic AMP-specific phosphodiesterase activity was unchanged. 4. A02011-1 was equipotent with forskolin but was more potent than 8-bromo-cyclic AMP against FCS (10%)-induced proliferation. 5. The antiproliferative action of A02011-1 was mimicked by 8-bromo-cyclic AMP, a membrane-permeable cyclic AMP analogue and was antagonized by 2',5'-dideoxyadenosine, an adenylyl cyclase inhibitor and by Rp-cyclic AMPS, a competitive inhibitor of cyclic AMP-dependent protein kinase (PKA) type I and II. 3-Isobutyl-1-methylxanthine (IBMX) caused significant potentiation of the antiproliferative activity of A02011-1. However, Rp-8-bromo-cyclic GMPS and staurosporine did not affect the antiproliferative activity of A02011-1. 6. A02011-1 still inhibited the FCS-induced DNA synthesis even when added 10-18h after restimulation of the serum-starved VSMCs with 10% FCS. Flow cytometry in synchronized cells revealed an acute blockade of FCS-inducible cell cycle progression at a point in the G,/S phase in A02011-1-treated cells. The inhibition of proliferation by A0201 1-1 was shown to be independent of cell damage,as documented by several criteria of cell viability.7. These results indicate that A0201 1-1 inhibition of VSMC proliferation was mediated by cyclic AMP and was due to a delay in the progression from the G1 into S phase of the cell cycle. A02011-1 did not cause cell toxicity and may thus hold promising potential for the prevention of atherosclerosis or vascular diseases.

Adenylyl Cyclases↗

PubMed1995

Vasorelaxant effect of isoliquiritigenin, a novel soluble guanylate cyclase activator, in rat aorta.

1. The vasorelaxant activity of isoliquiritigenin, isolated from Dalbergia odorifera T, was investigated in the phenylephrine-precontracted rat aorta by measuring tension, guanylate and adenylate cyclase activities, guanosine 3':5'-cyclic monophosphate (cyclic GMP) and adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 2. Isoliquiritigenin concentration-dependently relaxed rat aorta contracted with phenylephrine, KCl, U-46619, endothelin and 5-hydroxytryptamine, with EC50s of 7.4 +/- 1.6, 10.5 +/- 2.3, 14.3 +/- 3.3, 11.8 +/- 2.0 and 13.6 +/- 3.7 microM, respectively. 3. Isoliquiritigenin caused endothelium-independent relaxation of phenylephrine-precontracted rat aortic rings. Neither NG-monomethyl-L-arginine (L-NMMA) (an inhibitor of the L-arginine-NO pathway) nor oxyhaemoglobin (which binds NO) modified the relaxant effect of isoliquiritigenin. The relaxant action of isoliquiritigenin also persisted in intact aorta in the presence of indomethacin or glibenclamide. However, methylene blue, an inhibitor of soluble guanylate cyclase, abolished relaxation induced by isoliquiritigenin. 4. Incubation of rat aorta with isoliquiritigenin not only increased aortic cyclic GMP content but also caused small increases in aortic cyclic AMP content, and greatly potentiated the increases in cyclic AMP observed in the presence of forskolin. The maximum increase in cyclic GMP by isoliquiritigenin was reached earlier than the increase in cyclic AMP. This result suggests that the increases in cyclic GMP caused by isoliquiritigenin might stimulate the accumulation of cyclic AMP. 5. Concentration-dependent increases in soluble guanylate cyclase activity were observed in isoliquiritigenin (1-100 microM)- or sodium nitroprusside (SNP)-treated rat aortic smooth muscle cells, while adenylate cyclase activity was unchanged in isoliquiritigenin (100 microM)-treated cells. 6. Relaxation and cyclic AMP formation of rat aorta caused by isoliquiritigenin was potentiated in the presence of forskolin (10 nM), which had little effect when given alone. 2',5'-Dideoxyadenosine (DDA,200 microM), an adenylate cyclase inhibitor, diminished the relaxation and cyclic AMP formation of rat aorta by isoliquiritigenin only in the presence of forskolin. DDA did not affect the increases in cyclic GMP formation induced by isoliquiritigenin. These results suggest that elevated levels of cyclic GMP may mediate the majority of the relaxation of the phenylephrine-precontracted aorta induced byisoliquiritigenin, while the synergistic interaction with a low concentration of forskolin depends on an enhanced accumulation of cyclic AMP.7. Relaxation of phenylephrine-precontracted rat aorta and carbachol-precontracted guinea-pig trachea by rolipram (phosphodiesterase, PDE IV inhibitor) was markedly enhanced by isoliquiritigenin, while response to cilostamide (PDE III inhibitor) was not significantly changed by isoliquiritigenin.8. It is concluded that isoliquiritigenin exerts a vasorelaxant effect by activating soluble guanylatecyclase and increasing cyclic GMP. Synergistic effects of isoliquiritigenin and forskolin on muscle relaxation and cyclic AMP accumulation indicate that inhibition of cyclic AMP breakdown by cyclic GMP via the inhibition of PDE III (cyclic GMP-inhibited PDE) is the dominant mechanism.

Aldehyde Reductase↗

PubMed1995

YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase.

1. Our previous study demonstrated that YC-1, a derivative of benzylindazole, is a novel activator of soluble guanylate cyclase (sGC) in rabbit platelets. This work investigated whether the antiplatelet effect of YC-1 was mediated by a nitric oxide (NO)/sGC/cyclic GMP pathway in human platelets. 2. In human washed platelets, YC-1 inhibited platelet aggregation and ATP released induced by U46619 (2 microM), collagen (10 micro ml(-1)) and thrombin (0.1 u ml(-1)) in a concentration-dependent manner with IC50 values of (microM) 2.1 +/- 0.03, 11.7 +/- 2.1 and 59.3 +/- 7.1, respectively. 3. In a 30,000 g supernatant fraction from human platelet homogenate, YC-1 (5-100 microM) increased sGC activity in a concentration-dependent manner. At the same concentration-range, YC-1 elevated cyclic GMP levels markedly, but only slightly elevated cyclic AMP levels in the intact platelets. 4. MY-5445, a selective inhibitor of cyclic GMP phosphodiesterase, potentiated the increases in cyclic GMP caused by YC-1, and shifted the concentration-anti-aggregation curve of YC-1 to the left. In contrast, HL-725, a selective inhibitor of cyclic AMP phosphodiesterase, did not affect either the increases in cyclic nucleotides or the anti-aggregatory effect caused by YC-1. 5. Methylene blue, an inhibitor of sGC, blocked the increases of cyclic GMP caused by YC-1, and attenuated markedly the anti-aggregatory effect of YC-1. The adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA) did not affect YC-1-induced inhibition of platelet aggregation. 6. Haemoglobin, which binds NO, prevented the activation of sGC and anti-aggregatory effect caused by sodium nitroprusside, but did not affect YC-1 response. 7. These results would suggest that YC-1 activates sGC of human platelets by a NO-dependent mechanism, and exerts its antiplatelet effects through the sGC/cyclic GMP pathway.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

The anti-inflammatory and anti-hyperuricemic effects of Chinese herbal formula danggui-nian-tong-tang on acute gouty arthritis: a comparative study with indomethacin and allopurinol.

The traditional Chinese antirheumatic herb Danggui-Nian-Tong-Tang (DGNTT) was studied comparatively with indomethacin and allopurinol to evaluate its anti-inflammatory and antihyperuricemic effects in patients with gout. Results in this study did not show any significant improvement in reducing the total number of painful and swollen joints, articular index and pain score (P > 0.05) by treatment with DGNTT. Unlike allopurinol, DGNTT did not lower the high serum level of uric acid. In vitro study in rats showed that DGNTT significantly inhibits the activity of beta-glucuronidase (P < 0.05) and lysozyme release (P < 0.01) from neutrophils. In conclusion, despite the effect of inhibition on enzyme release from neutrophils, DGNTT is not effective in treating acute arthritis or hyperuricemia.

Adolescent↗

PubMed1995

The pharmacology of SCH 50911: a novel, orally-active GABA-beta receptor antagonist.

Experiments were conducted to characterize the pharmacology of SCH 50911 ((+)-5,5-dimethyl-2-morpholineacetic acid hydrochloride), a structurally novel GABA-B receptor antagonist. Although more potent GABA-B antagonists have been reported, in this study SCH 50911 was compared with CGP 35348, a moderately potent and selective GABA-B antagonist with acceptable in vivo activity. SCH 50911 was more potent to inhibit the binding of GABA to the GABA-B receptor in rat brain (IC50 = 1.1 microM) than CGP 35348 (IC50 = 62 microM). SCH 50911 had no binding affinity for GABA-A, histamine H1, histamine H3, dopamine D1, dopamine D2, serotonin 5-HT2, or muscarinic m1, m2, or m4 receptors. However, SCH 50911 (IC50 = 2.2 microM) was active in a nonspecific muscarinic receptor binding assay, but was devoid of muscarinic agonist or antagonist activity in the isolated guinea pig ileum. SCH 50911 blocked inhibitory responses to baclofen of the guinea pig trachea in a competitive manner (pA2 = 5.8 +/- 0.004). CGP 35348 was 19-fold less potent in this assay (pA2 = 4.6 +/- 0.15). In vivo, SCH 50911 (ED50 = 2.9 mg kg-1, s.c.) and CGP 35348 (ED50 = 5.8 mg kg-1, s.c.) blocked the antitussive effects of baclofen in the guinea pig. In the cat, both SCH 50911 (10 mg kg-1, i.v.) and CGP 35348 (10 mg kg-1, i.v.) shifted the antitussive dose response relationship for baclofen to the right.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1995

Surgical treatment of extensive discovertebral destruction in ankylosing spondylitis: a report of two cases.

Extensive discovertebral destruction in ankylosing spondylitis is rare and difficult in diagnosis and management. We present two such cases who were treated with anterior decompression, autogenous strut iliac bone graft and fixed with anterior locking plate system (ALPS) instrumentation. After operation the patients' symptoms improved and the spinal deformities were corrected. Our experiences in these two patients emphasize the importance of early recognition, early detection and aggressive surgical treatment in the lesion.

Adult↗

PubMed1995

Single kinesin molecules stressed with optical tweezers.

Using the optical tweezers to pull on microtubules, we have stretched and twisted single kinesin molecules adsorbed to glass surfaces. Preliminary measurements suggest that the mechanical system is very compliant, with an apparent stretch of 120 nm with < 2 pN of force. Although measurements of the series compliance of the bead-microtubule structure are still in progress, the kinesin attachment site does not slip with stretch. However, under torsional stress, kinesin appears to slip. With torques < 2 pN-microns approximately 1 Hz in 2 mM AMP-PNP, there is no apparent limit to the number of revolutions that the microtubule can rotate around the kinesin attachment site (n = 44). Preliminary data from other nucleotide conditions are similar. Although there are rare instances of torsional elasticity where the attachment site unwinds, the restoring forces are not constant with angular position, also indicating slippage. Mechanisms of mechanochemical transduction must account for linear force generation in the presence of angular "slippage."

Adenylyl Imidodiphosphate↗

PubMed1994

YC-1, a novel activator of platelet guanylate cyclase.

YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole] inhibited the aggregation of and ATP release from washed rabbit platelets induced by arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), and thrombin in a concentration-dependent manner. YC-1 also disaggregated the clumped platelets caused by these inducers. The thromboxane B2 formation caused by collagen, PAF, and thrombin was inhibited by concentrations of YC-1 that did not affect formation of thromboxane B2 and prostaglandin D2 caused by AA. YC-1 suppressed the increase of intracellular Ca2+ concentration and generation of inositol 1,4,5-trisphosphate caused by these five aggregation inducers. Both the cAMP and cGMP contents of platelets were increased by YC-1 in a concentration- and time-dependent manner. Like sodium nitroprusside, YC-1 potentiated formation of cAMP caused by prostaglandin E1 but not that by 3-isobutyl-1-methylxanthine. Adenylate cyclase and cAMP phosphodiesterase activities were not altered by YC-1. Activity of cGMP phosphodiesterase was unaffected by YC-1. Activities of guanylate cyclase in platelet homogenate and cytosolic fraction were activated by YC-1, whereas particulate guanylate cyclase activity was unaffected. The antiplatelet effect of sodium nitroprusside but not that of YC-1 was blocked by hemoglobin and potentiated by superoxide dismutase. After intraperitoneal administration for 30 minutes, YC-1 prolonged the tail bleeding time of conscious mice. These data indicate that YC-1 is a direct soluble guanylate cyclase activator in rabbit platelets. It may also possess antithrombotic potential in vivo.

1-Methyl-3-isobutylxanthine↗

PubMed1994

Antitumor agents. 155. Synthesis and biological evaluation of 3',6,7-substituted 2-phenyl-4-quinolones as antimicrotubule agents.

A series of 3',6,7-substituted 2-phenyl-4-quinolones were designed and synthesized as antimitotic antitumor agents. All compounds showed cytotoxic effects (log GI50 < or = -4.0; log drug molar concentration required to cause 50% inhibition) against the growth of a variety of human tumor cell lines, including those derived from solid tumors such as non-small cell lung, colon, central nervous system, ovary, prostate, and breast cancers, when evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. The most potent compound (26) demonstrated strong cytotoxic effects with GI50 values in the nanomolar or subnanomolar range in almost all the tumor cell lines. Compound 26 was also a potent inhibitor of tubulin polymerization and radiolabeled colchicine binding to tubulin, with activity comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4.

Animals↗