Biomedical subjects

S Hafizi

Publications and source records attributed to S Hafizi.

17 recordsLinked to original sources

PubMed2006

Effect of sub-chronic treatment with Jarsin (extract of St John's wort, Hypericum perforatum) at two dose levels on evening salivary melatonin and cortisol concentrations in healthy male volunteers.

OBJECTIVE: The aim of the present study was to measure the effect of two doses of extracts from Hypericum perforatum (HP), Jarsin, on evening salivary cortisol and NA-mediated melatonin in healthy male volunteers. METHODS: Twenty healthy male volunteers were randomly given a low or high dose of Jarsin for 7 days. Saliva samples for cortisol and melatonin, and overnight urine samples were collected for cortisol and 6-sulfatoxymelatonin and measured by specific radioimmunoassays. RESULTS: Treatment significantly increased salivary cortisol throughout the whole collection period in the low dose group but had no discernable effect in the high dose group. Salivary melatonin was not increased in either dose group following treatment. CONCLUSION: Salivary cortisol was enhanced in the low dose group only and melatonin was not affected by either treatment. We suggest that HP may enhance salivary cortisol via a U-shaped dose-response relationship and that this may be mediated through a 5-HT2 mechanism.

Adult↗

PubMed2002

Acute citalopram administration produces correlated increases in plasma and salivary cortisol.

RATIONALE: Intravenous administration of the selective serotonin (5-HT) re-uptake inhibitor, citalopram, increases plasma cortisol. This would be expected to produce a parallel increase in salivary cortisol concentration. OBJECTIVE: To find out whether IV citalopram produces correlated increases in plasma and salivary cortisol levels. METHODS: Twelve healthy volunteers were tested on two occasions receiving either citalopram (10 mg IV) or saline in a double-blind, randomised, cross-over design. Plasma and salivary cortisol levels were measured before and for 150 min after each infusion. RESULTS: Relative to placebo, citalopram significantly increased cortisol levels in both plasma and saliva. The size of the increases in plasma and saliva cortisol correlated significantly with each other. CONCLUSIONS: Monitoring changes in salivary cortisol might be a valid and acceptable means of measuring 5-HT-mediated cortisol release.

Adult↗

PubMed2001

Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats.

The primary role of the orexins was originally believed to be appetite regulation, but is now believed to be the regulation of sleep, arousal and locomotor activity. Orexin A immunoreactivity (orexin A-IR) and prepro-orexin mRNA were measured in the CNS of obese and lean Zucker rats. There were no differences in orexin A-IR or prepro-orexin mRNA levels between obese and lean Zucker rats. The orexins are therefore unlikely to be important in this model of obesity. Levels of orexin A-IR and prepro-orexin mRNA were measured in the CNS of Wistar-Kyoto (WKY) rats, which are hypoactive and have abnormal sleep architecture. Compared to Wistar rats, WKY rats had significantly lower orexin A-IR (with differences of up to 100% in some brain regions) and prepro-orexin mRNA levels. These observations suggest that the sleep and activity phenotype of the WKY strain may be related to orexin deficiency and that this strain may be a useful model of partial orexin deficiency.

Animals↗

PubMed2000

Vascular endothelial growth factor release following coronary artery bypass surgery: extracorporeal circulation versus 'beating heart' surgery.

AIMS: The aim of this study was to examine the circulating levels of vascular endothelial growth factor, following coronary artery bypass graft surgery performed using both standard cardiopulmonary bypass or the 'octopus technique' on the beating heart. BACKGROUND: Vascular endothelial growth factor has a number of effects that are beneficial in the setting of coronary artery bypass graft surgery including cardioprotection, potent angiogenic activity and amelioration of intimal hyperplasia. Hypoxia is a powerful stimulator of vascular endothelial growth factor expression yet the ability of ischaemia, occurring during coronary artery bypass graft surgery, to induce vascular endothelial growth factor production is unknown. METHODS AND RESULTS: Serum vascular endothelial growth factor levels were determined in patients undergoing coronary artery bypass graft surgery with standard cardiopulmonary bypass (CPB-CABG group; n=20), with off-pump coronary artery bypass; (OP-CABG; n=12) and in patients undergoing non-cardiac major surgery (n=6). The effect of hypoxia on vascular endothelial growth factor release by neonatal rat cardiac myocytes in vitro was studied. In the CPB-CABG group vascular endothelial growth factor levels were significantly increased to 78.5+/-39.3 and 110.5+/-16.3 pg. microl(-1)8 and 24 h post-operatively, declining to 14.9+/-9.9 pg. microl(-1)by 48 h to pre-operative values (14.4+/-8.6 pg. microl(-1)). Significantly higher vascular endothelial growth factor levels were also present in the OP-CABG group 3, 6 and 24 h post-operatively (levels 136. 6+/-29.3, 143+/-26.12 pg. microl(-1)and 93.5+/-20.1 pg. microl(-1), respectively). However, non-cardiac major surgery did not result in elevated vascular endothelial growth factor levels post-operatively (46.36+/-9.76 vs pre-surgery levels of 26.84+/-6.1 pg. microl(-1)). Either 15 min or 3 h of hypoxia stimulated vascular endothelial growth factor release from neonatal rat cardiac myocytes in vitro. Twenty-four and 48 h post hypoxia, levels of vascular endothelial growth factor were significantly elevated by approximately 17.5- and 48.5-fold respectively. CONCLUSIONS: These data demonstrate myocardial ischaemia secondary to CPB-CABG and OP-CABG to be a potent stimulator of vascular endothelial growth factor production, which may have implications for graft endothelialization and cardiovascular haemodynamics post-operatively.

Animals↗

PubMed2000

Mitogenic and secretory responses of human valve interstitial cells to vasoactive agents.

BACKGROUND AND AIM OF THE STUDY: The vasoactive agent 5-hydroxytryptamine (5-HT) has been implicated in valve disease due to possible trophic effects on valve interstitial cells (IC). The present study was aimed at characterizing the responses of cultured human heart valve IC to 5-HT in terms of intracellular calcium concentration ([Ca2+]i), mitogenesis and collagen synthesis. The effects of angiotensin II (Ang II) were also studied in parallel. METHODS: IC were obtained by collagenase digestion of valve leaflets isolated from transplant recipient hearts. Changes in [Ca2+]i were measured from fluorescence of the ratiometric calcium dye, fura 2. Mitogenic and collagen synthetic responses of valve IC were measured by 3H-thymidine incorporation (DNA synthesis) and 3H-proline incorporation assays respectively, in quiescent cells. RESULTS: Human valve IC responded to 5-HT and Ang II with mean maximal increases in [Ca2+]i of 249 +/- 47 nM and 397 +/- 159 nM, respectively. 5-HT stimulated DNA synthesis in quiescent IC, although to varying degrees among different isolations, with a maximum 43.4 +/- 20.1% increase by 10(-7) M 5-HT (p <0.05). Ang II did not stimulate IC DNA synthesis. Valve IC also responded to 5-HT with a maximum increase in collagen synthesis of 15.7 +/- 2.0% by 10(-6) M 5-HT (p <0.05). Ang II provoked a more powerful collagen synthesis response (maximum 50.5 +/- 15.1% increase by 10(-5) M Ang II; p <0.05). CONCLUSION: We have shown that 5-HT and Ang II promote the prolonged processes of growth and collagen synthesis in cultured human valve IC. Thus, these vasoactive agents may play a role in the development of heart valve disease.

Angiotensin II↗

PubMed1999

Endothelin-1 stimulates proliferation of human coronary smooth muscle cells via the ET(A) receptor and is co-mitogenic with growth factors.

We investigated the effects of endothelin-1 (ET-1) on growth of cultured human coronary artery smooth muscle cells (cSMC). ET-1 alone stimulated DNA synthesis in growth-arrested cSMC as measured by [3H]thymidine incorporation, with a maximum 63 +/- 23% increase above control by 10(-7) M (P < 0.05). ET-1 (10(-7) M) also stimulated increases in cyclin D1 protein levels after 24 h, and in absolute cell number after 4 days. Furthermore, ET-1 stimulated protein synthesis (maximum 73 +/- 32% increase in [3H]leucine incorporation by 10(-7) M (P < 0.05)), as well as triggering intracellular calcium transients in human cSMC, as visualised under fura-2 fluorescence microscopy. The selective ET(A) receptor antagonist BQ123 inhibited the increases in DNA synthesis, cell number, protein synthesis and intracellular calcium concentration in response to ET-1, whereas the ET(B) receptor antagonist BQ788 had no such effects. Furthermore, the ET(B) agonist sarafotoxin 6c had no effect on cSMC DNA synthesis. In addition, co-incubation of ET-1 with threshold concentrations of the growth factors, platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), resulted in pronounced synergistic increases in DNA synthesis over that observed with the factors alone. In conclusion, we have shown that ET-1 stimulates proliferation of human cSMC via the ET(A) receptor and is also a co-mitogen with the growth factors tested. These findings indicate a role for ET-1 in the development of coronary intimal hyperplasia in man.

Becaplermin↗

PubMed1999

Inhibition of human cardiac fibroblast mitogenesis by blockade of mitogen-activated protein kinase and phosphatidylinositol 3-kinase.

1. Interstitial fibroblast proliferation is an elemental feature in the development of cardiac fibrosis. The effects of inhibitors of the intracellular signalling proteins, MEK, a kinase involved in the mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol 3-kinase (PI3-K), were tested on growth of cultured human cardiac fibroblasts. 2. Cardiac fibroblasts were isolated from transplant recipient myocardium and made quiescent by serum deprivation for 48 h. Cells were incubated for 24 h with the inhibitors PD 098059 (0.3-30 mumol/L) and LY294002 (1-25 mumol/L) in the presence and absence of platelet-derived growth factor-AB (PDGF-AB, 10 ng/mL). DNA synthesis was measured by [3H]-thymidine incorporation assay (20-24 h). 3. Both compounds markedly inhibited both basal and PDGF-stimulated increases in DNA synthesis in a concentration-dependent manner. Cardiac fibroblast DNA synthesis was reduced to near control levels by PD 098059, while it was inhibited completely by LY294002. 4. These results implicate the importance of MAPK and PI3-K activation in the signal transduction pathways necessary for cardiac fibroblast replication.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed1998

Expression of functional angiotensin-converting enzyme and AT1 receptors in cultured human cardiac fibroblasts.

BACKGROUND: Angiotensin II (Ang II) has been implicated in the development of cardiac fibrosis. The aims of the present study were to examine expression and activity of ACE and of angiotensin receptors in human cardiac fibroblasts cultured from dilated cardiomyopathic and ischemic hearts. The effects of Ang II on fibroblasts were also investigated. METHODS AND RESULTS: Human cardiac fibroblasts were cultured from ventricular and atrial myocardium and characterized immunohistochemically. Expression of ACE and the angiotensin AT1 receptor was demonstrated in cardiac fibroblasts by reverse transcriptase-polymerase chain reaction and radioligand binding. Functional ACE activity, measured by radiolabeled substrate conversion assay, was detected in both ventricular (Vmax. Km-1. mg-1, 0.031+/-0.010; n=13) and atrial (0. 034+/-0.012; n=6) fibroblasts. Fibroblast ACE activity was increased after 48 hours of treatment with basic fibroblast growth factor, dexamethasone, and phorbol ester. Ang II did not affect DNA synthesis but stimulated [3H]proline incorporation in cardiac fibroblasts (20.0+/-4.0% increase above control by 10 micromol/L; P<0.05, n=7), which was abolished by losartan 10 micromol/L but not PD123319 1 micromol/L. Ang II also stimulated a rise in intracellular calcium (basal, 56+/-1 nmol/L; Ang II, 355+/-24 nmol/L) via the AT1 receptor, as shown by complete inhibition with losartan. CONCLUSIONS: We have demonstrated expression and activity of ACE and AT1 receptor in cultured human cardiac fibroblasts. In addition, cardiac fibroblasts respond to Ang II with AT1 receptor-mediated collagen synthesis. The presence of local ACE and AT1 receptors in human fibroblasts suggests their involvement in the development of cardiac fibrosis.

Calcium↗

PubMed1998

Induction of nitric oxide synthase in human vascular smooth muscle: interactions between proinflammatory cytokines.

OBJECTIVE: We have attempted to demonstrate the induction of inducible nitric oxide synthase in human vascular tissue and define the capacity of different cytokines to induce this enzyme. METHODS: Segments of human arteries were stimulated with lipopolysaccharide (10 micrograms/ml), interleukin-1 beta (5 U/ml), tumor necrosis factor-alpha (10 U/ml), and interferon-gamma (200 U/ml). Cytokines were either used alone or in certain combinations, as well as in the presence of L-NG-monomethyl-arginine (100 mumol/l) or cycloheximide (1 mumol/l). Induction was assessed by measurement of mRNA expression, immunocytochemical localisation of the expressed protein, nitric oxide synthase activity and levels of nitrite, a product of nitric oxide formation. RESULTS: PCR analysis showed the presence of mRNA for iNOS in stimulated samples which could be inhibited by cycloheximide. There was positive staining with an antibody against human iNOS in the media of stimulated vessel segments. Stimulated segments were also shown to contain Ca(2+)-independent nitric oxide synthase activity. The cytokines and lipopolysaccharide together gave a significant rise in levels of nitrite in the medium after 36 and 48 h, which was inhibited by L-NG-monomethyl-arginine and cycloheximide. Only interferon-gamma incubated alone was capable of increasing nitrite levels. This effect was enhanced by co-incubation with either interleukin-1 beta, tumor necrosis factor-alpha or lipopolysaccharide. CONCLUSION: We have shown that increased production of nitrite by human vascular tissue in response to cytokines is associated with induction of iNOS as shown at the molecular and protein levels, and further supported by the presence of increased Ca(2+)-independent nitric oxide synthase activity following cytokine stimulation.

Cycloheximide↗

PubMed1998

Contrasting effects of platelet-derived growth factor (PDGF) isomers on mitogenesis, contraction and intracellular calcium concentration in human vascular smooth muscle.

The present study was aimed at characterizing the responses of human vascular smooth muscle to all three dimeric isomers of platelet-derived growth factor (PDGF-AA, -AB and -BB) in terms of mitogenesis, contraction and intracellular calcium concentration. The potential of interaction between PDGF and endothelin-1 (ET-1) was also investigated. All three PDGF isoforms (0.1-20 ng mL-1) stimulated DNA synthesis in cultured human coronary artery and saphenous vein vascular smooth muscle cells (VSMC), measured by [3H]thymidine incorporation. PDGF-AB and -BB elicited comparable large increases in DNA synthesis of maximum 595 +/- 149% (P = 0.001, n = 9) and 576 +/- 17% (P < 0.001, n = 5), respectively, whereas PDGF-AA was only weakly mitogenic (61 +/- 16% increase; P < 0.05, n = 3). At a threshold concentration, PDGF acted in synergy with ET-1 to enhance DNA synthesis (816 +/- 337% increase; P < 0.05, n = 7). In contrast to mitogenesis, none of the three PDGF isomers had any effect on contraction of human saphenous veins in vitro, nor did they affect the contractile response to ET-1, 5-HT or the thromboxane mimetic U46619. The effects of the three PDGF isomers on intracellular calcium ([Ca2+]i) rises in cultured human VSMC were heterogeneous, with PDGF-BB inducing the largest increase in [Ca2+]i (442 +/- 53 nmol L-1) vs. PDGF-AB (290 +/- 28 nmol L-1), whilst PDGF-AA had no effect. Both the responses to PDGF-AB and-BB relied upon intracellular calcium release, whilst only PDGF-AB showed additional dependence on influx of extracellular calcium. In summary, PDGF is strongly mitogenic and comitogenic with ET-1, despite not being a vasoconstrictor, for human VSMC. Also, human VSMC showed heterogeneous responses to the three PDGF isoforms. These results implicate PDGF, and in particular the PDGF receptor-beta, as important role players in the development of vascular smooth muscle-mediated intimal thickening in humans.

Anticoagulants↗

PubMed1998

Growth response of human coronary smooth muscle cells to angiotensin II and influence of angiotensin AT1 receptor blockade.

BACKGROUND: The renin-angiotensin system has been implicated in the development of vascular wall thickening in cardiovascular disease, through the growth-promoting actions of the vasoconstrictive agent, angiotensin II, on vascular smooth muscle cells. OBJECTIVE: To investigate the effect of angiotensin II on growth of human coronary artery smooth muscle cells (cSMCs) in culture, and to identify the angiotensin receptor(s) mediating such a response. METHODS: Human cSMCs were isolated from coronary arteries of recipient hearts obtained during transplantation, and characterized by immunohistochemistry. The effect of angiotensin II on protein synthesis by cSMCs was measured by [3H]leucine incorporation and protein concentration assays. Human cSMC proliferation was assessed by [3H]thymidine incorporation assay and cell count. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect angiotensin receptor expression. Transient increases in intracellular calcium concentration in cSMCs in response to angiotensin II stimulation were visualized under fura-2 fluorescence microscopy. RESULTS: Angiotensin II (1 nmol/l-10 mumol/l) stimulated protein synthesis in cSMCs (maximum 24 +/- 2% increase in incorporation of [3H]leucine over 48 h; n = 4, P < 0.01). An increase in cellular protein content was also measured. However, angiotensin II had no effect on proliferation of quiescent cSMCs. The increased protein synthesis was completely inhibited by pretreatment with the angiotensin AT1 receptor antagonist, losartan, but not the AT2 receptor antagonist, PD123319. Expression of the angiotensin AT1 receptor subtype was detected in cSMCs by RT-PCR. Angiotensin II stimulation of cells triggered transient increases in intracellular calcium concentration, which were abolished by losartan, but were insensitive to PD123319 and pertussis toxin. CONCLUSIONS: The results of this study in human coronary VSMCs indicate that angiotensin II and the AT1 receptor may be involved in the development of coronary artery disease in man.

Angiotensin II↗

PubMed1997

Angiotensin II receptor type 1 mRNA is upregulated in atria of patients with end-stage heart failure.

There is increasing evidence that pathological changes in the myocardium during chronic heart failure (CHF) are partly regulated through the activation of the renin-angiotensin system (RAS), an effect mediated by the angiotensin II type 1 receptor (AT1R). We examined the expression of cardiac AT1R mRNA in normal (atria, n=7; ventricle, n=3) and end-stage CHF human hearts (atria, n=8; ventricle, n=14). Tissue was snap-frozen immediately after explantation during orthotopic cardiac transplantation; control specimens were obtained from healthy donor hearts rejected for technical reasons. Northern blots of purified total mRNA from each tissue were hybridized with a random primed radiolabeled probe for the coding sequence of AT1R. Stringent conditions were used for both hybridization (5X SSC, 65 degrees C) and washing (0.5X SSC, 0.1% SDS, 65 degrees C) of the membrane. Left and right atrial tissue showed low levels of AT1R mRNA expression in the controls, with statistically significant upregulation of expression in tissue from pathological hearts; CHF atria 1.28+/-0.86 optical density (OD) units, control atria 0.56+/-0.31 OD units, P=0.05 (mean+/-s.d.). There were undetectable levels in ventricles from either control (2/2) or dilated hearts (7/7). The results were independent of the etiology of the heart failure and suggest that increased levels of atrial AT1R mRNA may occur in response to elevated atrial pressures in heart failure.

Adult↗

PubMed1997

Molecular mechanisms of vascular smooth muscle cell growth.

In recent years, much progress has been made in elucidating the complex but orchestrated series of molecular events that drives a vascular smooth muscle cell to undergo proliferation. These events are initiated by mitogenic stimuli, such as platelet-derived growth factor binding to its receptor and triggering an intracellular signal transduction cascade, leading ultimately to cell-cycle progression and cell division. The signaling pathways that take place in response to both hyperplastic and hypertrophic agents, which include the mitogen-activated protein kinase and p70 S6 kinase, are discussed. In addition, novel protein kinase mediators, such as phosphatidylinositol 3-kinase and protein kinase B, and mechanisms that have recently been implicated in vascular smooth muscle cell growth are described.

Animals↗

PubMed1996

Alloproliferation of purified CD4+ T cells to adult human heart endothelial cells, and study of second-signal requirements.

Human endothelial cells have been shown to be capable of causing direct allostimulation of T cells. However, the majority of immunological studies of human endothelial cells have been performed on cells of fetal origin. Here we use endothelial cells isolated from the adult human heart, both large vessel (coronary artery, pulmonary artery and aorta) and also microvascular. We have examined the ability of all these endothelial cells to cause direct allostimulation of T cells, and show that purified CD4+ T cells can proliferate in response to adult human heart endothelial cells, the response being dependent on pretreatment of the endothelial cells with interferon-gamma (IFN-gamma) and inhibited by anti-HLA-DR monoclonal antibody. The proliferative responses of CD8+ T cells to adult but not fetal endothelial cells was inconsistent and weak. Proliferative responses were not blocked by CTLA4-Ig, which inhibits T-cell responses to "classical' antigen-presenting cells (APC), but > 50% inhibition was achieved with monoclonal antibody to lymphocyte function-associated antigen-3 (LFA-3). These results show that adult human cardiovascular endothelial cells are capable of causing allostimulation of resting CD4+ T cells, using a different second signal to classical APC. In view of these findings endothelial cells should be considered as APC following solid organ transplantation.

Adult↗

PubMed1994

Electrospray mass spectrometric characterization of the components of protein mixtures and its application to members of the chemokine family of interleukins.

Electrospray mass spectrometry has been employed to detect and characterize the members of a closely related family of immunologically active proteins (chemokines) produced in cell culture by stimulated fibroblasts. The reliability of the method to produce precise data concerning the relative proportions of proteins present in mixtures was investigated in a model system and found to be satisfactory in a range of 10:1 in concentration.

Cells, Cultured↗

PubMed1992

Activity of two primary human metabolites of nomifensine on stimulated efflux and uptake of dopamine in the striatum: in vitro voltammetric data in slices of rat brain.

Several antidepressant drugs have active metabolites. This study sought to establish whether two of the main human metabolites of nomifensine (M2: 8-amino-2-methyl-4-(3-methoxy-4-hydroxyphenyl)-1,2,3,4- tetrahydroisoquinoline and M3: 8-amino-2-methyl-4-(3-hydroxy-4-methoxyphenyl)-1,2,3,4- tetrahydroisoquinoline) had actions on the release and uptake of dopamine (DA). Experiments were conducted in superfused striatal slices of the rat. The efflux of DA was evoked by single constant-current pulses (0.1 msec, 10 mA) and trains (20 pulses, 50 Hz), applied alternately every 10 min and monitored using fast cyclic voltammetry at carbon fibre microelectrodes. Nomifensine (5 x 10(-7) M) significantly increased the efflux of DA on both single pulse (302% of pre-drug) and train stimuli (529%) and increased the uptake half-life (178% of pre-drug). The M2 metabolite had similar potency on the efflux of DA (260%: pulse, 570%: train) but without any effect on uptake of DA. Nomifensine and M2 increased efflux of DA more on trains than on single pulses. The M3 metabolite (5 x 10(-7) M) increased efflux of DA only moderately. The selective blocker of the uptake of DA, GBR 12909 (3 x 10(-7) M), increased efflux of DA on single pulse (430%) and train stimuli (645%) and blocked uptake of DA (t1/2: 292%). Amfonelic acid, the psychomotor stimulant (10(-7) M) blocked uptake of DA (t1/2: 234%) and elevated efflux of DA to a greater extent on trains (1007%) than on single pulses (495%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Fast cyclic voltammetry: improved sensitivity to dopamine with extended oxidation scan limits.

Fast cyclic voltammetry at carbon fibre microelectrodes has been used in vitro and in vivo mainly to monitor the release and uptake of dopamine. The 'standard' input voltage waveform (-1000 to +1000 mV, vs. Ag/AgCl, 300 V/s scan rate) has a lower limit of detection for dopamine of about 200 nM. In the present study, the scan rate and cathodic limit (-1000 mV) were kept constant while the range of the anodic scan was altered between 800 and 1400 mV. Extension of the oxidation scan to 1400 mV led to a sevenfold increase in dopamine oxidation current relative to the 'standard' waveform. This was accompanied by a decrease in the dopamine oxidation peak potential. Increased reactant adsorption for both dopamine and DOPAC was the likely cause of enhanced sensitivity. In vivo experiments indicate that, when used with the 1400 mV scan, the carbon fibre electrodes do not poison on contact with brain tissue and can measure dopamine concentrations lower than 50 nM.

3,4-Dihydroxyphenylacetic Acid↗