bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of transcription factor NF‐κB by enantiomers of the nonsteroidal drug ibuprofen
Authors: Scheuren Nicole , Bang Holger , Münster Tino , Brune Kay , Pahl Andreas 
Published: January 2005

The nonsteroidal drug ibuprofen exists as an R(−)‐ and S(+)‐enantiomer. Only the S(+)‐enantiomer is an effective cyclo‐oxygenase inhibitor, while the R(−)‐enantiomer is inactive in this respect. Thus the molecular mechanism by which R(−)‐ibuprofen exerts its anti‐inflammatory and antinociceptive effects remains unknown.
In this study the effects of the enantiomers of ibuprofen on modulation of transcription factors have been examined with electrophoretic mobility‐shift assay (EMSA), transient transfection experiments, confocal immunofluorescence and nuclear import experiments, to determine their selectivity and potency as inhibitors of the activation of transcription factor nuclear factor‐κB (NF‐κB).
R(−)‐ibuprofen (IC50: 121.8 μM) as well as the S(+)‐enantiomer (IC50: 61.7 μM) inhibited the activation of NF‐κB in response to T‐cell stimulation. The effect of ibuprofen was specific because, at concentrations up to 10 mM, ibuprofen did not affect the heat shock transcription factor (HSF) and the activation of NF‐κB by prostaglandin E2 (PGE2). Very high concentrations of ibuprofen (20 mM) did not prevent NF‐κB binding to DNA in vitro. Immunofluorescence and nuclear import experiments indicate that the site of ibuprofen action appeared to be upstream of the dissociation of the NF‐κB‐IκB‐complex.
Our data raise the possibility that R(−)‐ibuprofen exerts some of its effects by inhibition of NF‐κB activation.

British Journal of Pharmacology (1998) 123, 645–652; doi:10.1038/sj.bjp.0701652
Mechanism of antidiuresis caused by bendroflumethiazide in conscious rats with diabetes insipidus
Authors: Grønbeck Lene , Marples David , Nielsen Søren , Christensen Sten 
Published: January 2005

The mechanism underlying the antidiuretic effect of thiazide diuretics in diabetes insipidus (DI) is unknown. This study addressed two specific questions: is the reduction in urine flow rate (V) related to a decrease in the delivery of fluid from the pars recta of the proximal tubules (‘distal delivery’), and are there any changes in the expression and/or intracellular distribution of vasopressin stimulated water channels (AQP2) in the collecting ducts, during chronic thiazide‐induced antidiuresis?
Nine Brattleboro rats with vasopressin‐deficient DI were treated for 5 days with bendroflumethiazide (BFTZ), 9 mg kg−1 day−1 orally, and 9 Brattleboro rats were left untreated. BFTZ‐treated DI rats showed a fall in V from ∼200 to ∼75 ml day−1 and an increase in urine osmolality from ∼130 to ∼400 mosmol kg−1.
BFTZ‐induced antidiuresis was associated with a persistent loss of sodium, but not of potassium. After 5 days of treatment, clearance studies in conscious rats showed a tendency towards decreases in effective renal plasma flow (−7%), GFR (−12%) and lithium clearance (CLi; used as marker for distal delivery) (−25%), compared with untreated controls, but none of these changes were statistically significant. There was no apparent relationship between CLi and V in BFTZ‐treated or untreated DI rats.
BFTZ treatment did not change the expression of AQP2 in homogenates of cortex, outer or inner medulla from DI rats, or from normal Long Evans rats. Light and electron microscopic immunocyto‐chemistry revealed no changes in intracellular distribution of AQP2 in principal cells from inner medullary collecting ducts of BFTZ‐treated DI rats.
We concluded, (i) that although the antidiuretic effect of BFTZ in rats with DI is associated with a net loss of Na, the decrease in V shows no association with changes in distal delivery, as estimated by CLi. (ii) Antidiuretic treatment with BFTZ does not alter the expression of subcellular distribution of AQP2 water channels in the collecting ducts. The mechanism underlying the chronic antidiuresis caused by thiazide diuretics in DI remains elusive.

British Journal of Pharmacology (1998) 123, 737–745; doi:10.1038/sj.bjp.0701653
Functional and morphological damage of endothelium in rabbit ear artery following irradiation with cobalt60
Authors: Qi Fazhi , Sugihara Tsuneki , Hattori Yuichi , Yamamoto Yuhei , Kanno Morio , Abe Kazuhiro 
Published: January 2005

The relaxant actions of acetylcholine and A23187 were examined in the rabbit central ear artery at different intervals following exposure to different doses of radiation with a cobalt60 unit. The artery was irradiated with a dose of 10 Gy, 20 Gy and 45 Gy. Radiation caused dose‐ and time‐dependent impairment of the endothelium‐dependent relaxations. The impaired endothelium‐dependent relaxations occurred as early as 1 week postirradiation and persisted throughout the experimental period (10 weeks).
The endothelium‐independent response to sodium nitroprusside was well preserved up to 6 weeks after irradiation. The contractile response to noradrenaline was unaltered by irradiation throughout the experimental period, but in contrast to control vessels, an increase in the sensitivity to noradrenaline in the presence of the nitric oxide synthase (NOS) inhibitor NG‐nitro‐L‐arginine was not observed in the irradiated vessels.
The impaired endothelium‐dependent relaxations in the irradiated vessels were not improved by pretreatment with the NOS substrate L‐arginine, the cyclo‐oxygenase inhibitor indomethacin or the free radical scavengers superoxide dismutase and catalase.
Scanning electron microscopy indicated morphologically intact endothelial cells within the first 4 weeks after irradiation.
Western blot analysis showed a significant decrease in the expression of endothelial NOS (eNOS) in the irradiated vessels.
These data indicate that endothelial cell function is specifically impaired in the irradiated vessels before morphological endothelial cell damage can be detected. This impairment may be related to diminished eNOS expression.

British Journal of Pharmacology (1998) 123, 653–660; doi:10.1038/sj.bjp.0701654
Influence of excitatory amino acids on basal and sensory stimuli‐induced release of 5‐HT in the locus coeruleus
Authors: Singewald Nicolas , Kaehler Stefan T. , Hemeida Ramadan , Philippu Athineos 
Published: January 2005

The interactions between 5‐hydroxytryptaminergic neurones and excitatory amino acid utilizing neurones were studied in the locus coeruleus of conscious, freely moving rats. The locus coeruleus was superfused with artificial cerebrospinal fluid through a push‐pull cannula and 5‐hydroxytryptamine (5‐HT) was determined in the superfusate that was continuously collected in time periods of 10 min.
Superfusion of the locus coeruleus with the NMDA receptor antagonist AP5 (10 μM), kynurenic acid (1 mM), or the AMPA/kainate receptor antagonist DNQX (10 μM) reduced the 5‐HT release in the locus coeruleus.
Superfusion with the agonists NMDA (50 μM), kainic acid (50 μM) or AMPA (10 μM) enhanced the release rate of 5‐HT. AP5 (10 μM) blocked the stimulant effect of NMDA, while tetrodotoxin (1 μM) failed to influence the NMDA‐induced release of 5‐HT. In the presence of 10 μM DNQX, the releasing effect of 50 μM kainic acid was abolished.
Pain elicited by tail pinch, as well as noise‐induced stress, increased the release of 5‐HT. Superfusion of the locus coeruleus with 10 μM AP5 reduced the tail pinch‐induced 5‐HT release. AP5 (10 μM) did not affect the noise‐induced release of 5‐HT which was reduced, when the locus coeruleus was superfused simultaneously with this concentration of AP5 and 1 μM kynurenic acid. DNQX (10 mM) failed to influence the release of 5‐HT induced by tail pinch or noise.
The findings suggest that 5‐hydroxytryptaminergic neurones of the locus coeruleus are tonically modulated by excitatory amino acids via NMDA and AMPA/kainate receptors. The release of 5‐HT elicited by tail pinch and noise is mediated to a considerable extent through endogenous excitatory amino acids acting on NMDA receptors, while AMPA/kainate receptors are not involved in this process.

British Journal of Pharmacology (1998) 123, 746–752; doi:10.1038/sj.bjp.0701656
Different efficacy of specific agonists at 5‐HT3 receptor splice variants: the role of the extra six amino acid segment
Authors: Niemeyer M‐I. , Lummis S C R. 
Published: January 2005

Whole cell voltage clamp electrophysiology and radioligand binding were used to examine the agonist characteristics of the two splice variants of the 5‐HT3 receptor which have been cloned from neuronal cell lines. Homo‐oligomeric 5‐HT3 receptors were examined in HEK 293 cells stably transfected with either long (5‐HT3‐L) or short (5‐HT3‐S) receptor subunit DNAs.
Functional homo‐oligomeric receptors were formed from both subunits, and responses to 5‐HT3 receptor agonists (5‐hydroxytryptamine (5‐HT), 2‐methyl 5‐HT and m‐chlorophenylbiguanide) were qualitatively similar.
Maximum currents (Rmax) elicited by the 5‐HT3 receptor agonists m‐chlorophenylbiguanide (mCPBG) and 2‐methyl‐5‐HT (2‐Me‐5‐HT), as compared to 5‐HT, differed in the two splice variants: Rmax mCPBG/Rmax 5‐HT values were 0.68±0.04 and 0.91±0.01 in 5‐HT3‐L and 5‐HT3‐S receptors, respectively. Comparable values for 2‐Me‐5‐HT were 0.30±0.02 and 0.23±0.02.
Radioligand binding data showed no difference in affinity of agonist or antagonist binding sites; thus the six amino acid deletion appears to cause differences in agonist efficacy.
The role of the 6 amino acid insertion was further investigated by use of site‐directed mutagenesis to create two mutant receptors, one where serine 286 was replaced with alanine, and the second where all 6 amino acids were replaced with alanines.
Examination of the mutant receptors when stably expressed in HEK 293 cells revealed agonist properties resembling long and not short 5‐HT3 receptors. Thus specific amino acids in this region are not responsible for the observed differences.
The data show intracellular structure can have significant effects on ligand‐gated ion channel function, and suggest that minor changes in structure may be responsible for differences in function observed when ligand‐gated ion channel proteins are modulated intracellularly.

British Journal of Pharmacology (1998) 123, 661–666; doi:10.1038/sj.bjp.0701657
P2U‐receptor mediated endothelium‐dependent but nitric oxide‐independent vascular relaxation
Authors: Malmsjö M. , Edvinsson L. , Erlinge D. 
Published: January 2005

The dilator effect of extracellular adenosine triphosphate (ATP) has mainly been characterized as a direct effect on smooth muscle or as an endothelium‐dependent effect mediated by nitric oxide (NO) or prostaglandins. We tested the hypothesis that endothelium‐derived hyperpolarizing factor (EDHF) may also be involved. Dilator effects were studied in vitro by continuous recording of isomeric tension in cylindrical segments of rat blood vessels precontracted by noradrenaline (NA), in the presence of indomethacin (10 μM).
By screening different blood vessels in the rat we found that both acetylcholine (ACh) and ATP dilate mesenteric arteries with a resting tone of 1 mN by an endothelium‐dependent non‐NO mechanism. With an increased resting tone (4 mN) the dilatation was mediated by NO. Thus by varying the resting tension the different dilator mechanisms could be examined. However, in the carotid artery the dilatation was solely mediated by an endothelium‐dependent NO mechanism, even at different resting tones (1 and 4 mN).
The N‐nitro‐L‐arginine methyl ester (L‐NAME)‐resistant dilatation to ACh and ATP was further inhibited by the NO‐scavenger 2‐phenyl‐4,4,5,5‐tetramethylimidazoline‐1‐oxyl‐3‐oxide (PTIO), indicating L‐NAME insensitive NO‐synthesis.
In carotid arteries and mesenteric arteries at high resting tones (4 mN) the ATP‐dilatation was totally inhibited by endothelium removal or L‐NAME (10−3 M). In mesenteric arteries at low resting tone (1 mN) the ATP, UTP (uridine‐triphosphate) and 2‐MeSATP (2methylthioATP)‐dilatation was totally inhibited by endothelium removal. However, L‐NAME in combination with indomethacin attenuated only 5% of the UTP dilatation, 70% of the ATP dilatation but all of the 2‐MeSATP‐dilatation. The inhibitors of Ca2+‐activated K+ channels charybdotoxin (0.5×10−7 M) together with apamin (10−6 M), and the cytochrome P450 inhibitor, SKF 525A (10−4 M), each in combination with indomethacin, L‐NAME and PTIO (0.5×10−3 M) totally abolished the remaining ATP and UTP‐dilatation. This indicates a dilatation mediated by an endothelium‐dependent non‐NO factor, probably EDHF.
Agonist potency (UTP>ATP≈#62;2‐MeSATP), indicates that the EDHF‐mediated dilatation was stimulated by a P2U‐receptor, possibly by a selective pyrimidine‐receptor. In contrast, a P2Y‐receptor stimulated NO‐mediated dilatation (2‐MeSATP=ATP>UTP).
In conclusion, the dilator effects of ATP and especially UTP can be mediated by an endothelium‐dependent non‐NO‐mediated mechanism, probably EDHF, mediated by a P2U‐receptor, possibly a selective pyrimidine‐receptor, while NO‐mediated dilatation is stimulated mainly by a P2Y1‐receptor. Furthermore, the EDHF‐dilatation is dependent on the resting tone of the blood vessel.

British Journal of Pharmacology (1998) 123, 719–729; doi:10.1038/sj.bjp.0701660
Metabotropic glutamate receptors depress glutamate‐mediated synaptic input to rat midbrain dopamine neurones in vitro
Authors: Wigmore Mark A. , Lacey Michael G. 
Published: January 2005

Glutamate (AMPA receptor‐mediated) excitatory postsynaptic potentials (e.p.s.ps.), evoked by electrical stimulation rostral to the recording site, were examined by intracellular microelectrode recording from dopamine neurones in parasagittal slices of rat ventral midbrain.
The e.p.s.p. was depressed by the group III metabotropic glutamate (mGlu) receptor agonist L‐2‐amino‐4‐phosphonobutyric acid (L‐AP4; 0.01–30 μM) by up to 60% with an EC50 of 0.82 μM. The depression induced by L‐AP4 (3 μM) was reversed by the group III preferring mGlu receptor antagonist, α‐methyl‐4‐phosphonophenylglycine (MPPG; 250 μM).
The group I and II mGlu agonist, 1S,3R‐aminocyclopentanedicarboxylic acid (ACPD; 3–30 μM) also depressed the e.p.s.p. in a concentration‐dependent manner. The effect of ACPD (10 μM) was reversed by (+)‐α‐methyl‐4‐carboxyphenylglycine (MCPG; 1 mM; 4 cells). This effect of ACPD was also partially antagonized (by 50.3±15.7%, 4 cells) by MPPG (250 μM).
The selective agonist at group I mGlu receptors, dihydroxyphenylglycine (DHPG; 100 μM), decreased e.p.s.p. amplitude by 27.1±8.2% (7 cells), as did the group II mGlu receptor‐selective agonist (1S,1′R,2′R,3′R)‐2‐(2,3‐dicarboxycyclopropyl)glycine (DCG‐IV; 1 μM) by 26.7±4.3% (5 cells).
DHPG (10–100 μM) caused a depolarization of the recorded cell, as did ACPD (3–30 μM), whereas no such postsynaptic effect of either L‐AP4 or DCG‐IV was observed.
These results provide evidence for the presence of presynaptic inhibitory metabotropic glutamate autoreceptors from the mGlu receptor groups II and III on descending glutamatergic inputs to midbrain dopamine neurones. Group I mGlu receptors mediate a postsynaptic depolarization, and can also depress glutamatergic transmission, but may not necessarily be localized presynaptically. These sites represent novel drug targets for treatment of schizophrenia and movement disorders of basal ganglia origin.

British Journal of Pharmacology (1998) 123, 667–674; doi:10.1038/sj.bjp.0701662
The mechanism of action of cantharidin in smooth muscle
Authors: Knapp Jörg , Bokník Peter , Huke Sabine , Lüss Hartmut , Müller Frank U. , Müller Thorsten , Nacke Peter , Schmitz Wilhelm , Vahlensieck Ute , Neumann Joachim 
Published: January 2005

The aim of this study was to investigate the mechanism(s) of the vasoconstrictor effect of cantharidin in bovine preparations.
Catalytic subunits of protein phosphatase type 1 (PP 1) and type 2A (PP 2A) were immunologically identified in coronary arteries, isolated smooth muscle cells and ventricular myocardium.
The mRNAs coding for catalytic subunits of PP 1α, PP 1β and PP 2Aα were identified by hybridization with specific cDNA‐probes in total RNA from coronary arteries, isolated smooth muscle cells and ventricles.
The activities of catalytic subunits of PP 1 and PP 2A separated by column chromatography from coronary arteries, isolated smooth muscle cells and ventricles were inhibited by cantharidin in a concentration‐dependent manner.
Cantharidin increased the phosphorylation state of smooth muscle proteins including the regulatory light chains of myosin in 32P‐labelled intact smooth muscle cells in a concentration‐dependent manner.
Cantharidin did not affect cytosolic calcium concentrations in aortic smooth muscle cells.
It is suggested that cantharidin contracts smooth muscle preparations by increasing the phosphorylation state of regulatory proteins due to inhibition of phosphatase activities. Thus, cantharidin might be a useful tool to study the function of phosphatases in smooth muscle.

British Journal of Pharmacology (1998) 123, 911–919; doi:10.1038/sj.bjp.0701668
Reversion of muscarinic autoreceptor agonist‐induced acetylcholine decrease and learning impairment by dynorphin A (1–13), an endogenous κ‐opioid receptor agonist
Authors: Hiramatsu Masayuki , Murasawa Hiroyasu , Mori Hiromasa , Kameyama Tsutomu 
Published: January 2005

We investigated whether carbachol, a muscarinic receptor agonist, induces learning and memory impairment, and if so, dynorphin A (1–13), an endogenous κ‐opioid receptor agonist, ameliorates the impairment of learning and memory induced by carbachol, by use of a step‐through type passive avoidance task.
Carbachol induced a dose‐related dual response. Carbachol (1.66 pmol per rat) administered directly into the hippocampus significantly shortened the step‐through latency, while lower (0.166 pmol per rat) and higher (16.6 pmol per rat) doses of carbachol did not induce learning or memory impairment.
Dynorphin A (1–13) (0.5 nmol per rat, i.c.v.) administered 5 min after carbachol injection significantly reversed carbachol‐induced impairment of learning and memory.
Perfusion with carbachol (3×10−4 M) significantly decreased acetylcholine release in the hippocampus during perfusion as determined by in vivo brain microdialysis. This decrease in acetylcholine release was suppressed by co‐perfusion with a low dose of atropine (10−7 M).
Dynorphin A (1–13) (0.5 nmol per rat, i.c.v.) immediately before carbachol perfusion completely blocked this decrease in extracellular acetylcholine concentration induced by carbachol.
These antagonistic effects of dynorphin A (1–13) were abolished by treatment with nor‐binaltorphimine (5.44 nmol per rat, i.c.v.), a selective κ‐opioid receptor antagonist, 5 min before dynorphin A (1–13) treatment.
These results suggest that the neuropeptide dynorphin A (1–13) ameliorates the carbachol‐induced impairment of learning and memory, accompanied by attenuation of the reductions in acetylcholine release which may be associated with dysfunction of presynaptic cholinergic neurones via κ‐opioid receptors.

British Journal of Pharmacology (1998) 123, 920–926; doi:10.1038/sj.bjp.0701671
Selective cyclo‐oxygenase‐2 inhibitors and their influence on the protective effect of a mild irritant in the rat stomach
Authors: Gretzer Britta , Ehrlich Karlheinz , Maricic Nenad , Lambrecht Nils , Respondek Michael , Peskar Brigitta M. 
Published: January 2005

The effects of the non‐selective cyclo‐oxygenase (COX) inhibitor indomethacin and the selective COX‐2 inhibitors, N‐[2‐(cyclohexyloxy)‐4‐nitrophenyl] methanesulphonamide (NS‐398), 5‐methanesulphonamido‐6‐(2,4‐difluorothio‐phenyl)‐1‐indanone (L‐745,337) and 5,5‐dimethyl‐3‐(3‐fluorophenyl)‐4‐(4‐methylsulphonyl) phenyl‐2(5H)‐furanone (DFU), on the protection induced by the mild irritant 20% ethanol were investigated in the rat stomach.
Instillation of 20% ethanol (1 ml, p.o.) effectively protected against gastric mucosal injury induced by subsequent instillation of 70% or 96% ethanol (1 ml, p.o.).
Oral administration of indomethacin (1.25–20 mg kg−1) dose‐dependently counteracted the protective effect of 20% ethanol (ID50: 3.5 mg kg−1).
Likewise, NS‐398 (0.1–1 mg kg−1), L‐745,337 (0.2–2 mg kg−1) and DFU (0.02–0.2 mg kg−1) inhibited the protective effect of 20% ethanol in a dose‐dependent manner with ID50 values of 0.3 mg kg−1, 0.4 mg kg−1 and 0.06 mg kg−1, respectively.
Inhibition of mild irritant‐induced protection was also found when NS‐398 (1 mg kg−1) was administered s.c. or when 96% ethanol was used to damage the mucosa.
Pretreatment with 16,16‐dimethyl‐prostaglandin (PG)E2 at 4 ng kg−1, a dose that did not protect against ethanol (70%)‐induced mucosal damage when given alone, completely reversed the effect of the selective COX‐2 inhibitors on the mild irritant‐induced protection.
Pretreatment with dexamethasone (3 mg kg−1, 24 and 2 h before instillation of 20% ethanol) did not affect the protective activity of the mild irritant, indicating that enzyme induction is not involved.
Indomethacin (20 mg kg−1, p.o.) did not prevent the protection conferred by sodium salicylate (100 mg kg−1), dimercaprol (30 μg kg−1), iodoacetamide (50 mg kg−1) and lithium (20 mg kg−1). Likewise, the protective effect of these agents was not counteracted by NS‐398 (1 mg kg−1, p.o.).
Whereas indomethacin (20 mg kg−1, p.o.) near‐maximally inhibited gastric mucosal formation of PGE2, 6‐keto‐PGF1α and thromboxane (TX) B2 as well as platelet TXB2 release, the selective COX‐2 inhibitors were ineffective.
The findings show that selective COX‐2 inhibitors, although lacking in ulcerogenic activity, prevent the protection conferred by a mild irritant. Prostaglandis generated by a constitutive COX‐2 could thus contribute to physiological functions involved in gastric homeostasis, although at present a non‐COX‐2‐related mechanism underlying the effect of the selective COX‐2 inhibitors tested on mild irritant‐induced protection cannot be completely excluded.

British Journal of Pharmacology (1998) 123, 927–935; doi:10.1038/sj.bjp.0701673
Emodin‐induced muscle contraction of mouse diaphragm and the involvement of Ca2+ influx and Ca2+ release from sarcoplasmic reticulum
Authors: Cheng Y W. , Kang J J. 
Published: January 2005

The effects on skeletal muscle of emodin, an anthraquinone, were studied in the mouse isolated diaphragm and sarcoplasmic reticulum (SR) membrane vesicles.
Emodin dose‐dependently caused muscle contracture, simultaneously depressing twitch amplitude. Neither tubocurarine nor tetrodotoxin blocked the contraction suggesting that it was caused myogenically.
The contraction induced by emodin persisted in a Ca2+ free medium with a slight reduction in the maximal force of contraction. The contraction induced by emodin in the Ca2+ free medium was completely blocked when the internal Ca2+ pool of the muscle was depleted by ryanodine. These data suggest that the contraction caused by emodin is due to the release of Ca2+ from the intracellular ryanodine‐sensitive pool.
In contrast to the effect seen in the Ca2+ free medium, emodin induced a small but consisted contraction in the ryanodine‐treated muscle in Krebs medium. The contraction was blocked in the presence of dithiothreitol and was partially blocked by nifedipine, suggesting that oxidation of a sulphhydryl group on the external site of dihydropyridine receptor is involved.
Emodin dose‐dependently increased Ca2+ release from actively loaded SR vesicles and this effect was blocked by ruthenium red, a specific Ca2+ release channel blocker, and the thiol reducing agent, DTT, suggesting that emodin induced Ca2+ release through oxidation of the critical SH of the ryanodine receptor.
[3H]‐ryanodine binding was dose‐dependently potentiated by emodin in a biphasic manner. The degree of potentiation of ryanodine binding by emodin increased dose‐dependently at concentrations up to 10 μM but decreased at higher concentrations of 10–100 μM.
These data suggest that muscle contraction induced by emodin is due to Ca2+ release from the SR of skeletal muscle, as a result of oxidation of the ryanodine receptor and influx of extracellular Ca2+ through voltage‐dependent Ca2+ channels of the plasma membrane.

British Journal of Pharmacology (1998) 123, 815–820; doi:10.1038/sj.bjp.0701677