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| 2. |
- Argov, Mirit, et al.
(författare)
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Novel steroid carbamates reverse multidrug-resistance in cancer therapy and show linkage among efficacy, loci of drug action and P-glycoprotein's cellular localization
- 2010
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 1879-0720 .- 0928-0987. ; 41:1, s. 53-59
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Tidskriftsartikel (refereegranskat)abstract
- P-glycoprotein (Pgp) is a major ABC transporter responsible for multidrug-resistance (MDR) in cancer chemotherapy. Pre-clinical MDR modulation studies identified promising chemosensitizers, but none are in the clinic yet. Two novel progesterone-derived carbamates (11-carbamic acid N,N-dibenzyl progesterone ester and 11-carbamic acid N,N-dibutyl progesterone ester) were examined as potential chemosensitizers in the Pgp-expressing human colon cancer line HCT-15, applying the classical MDR-drugs paclitaxel and doxorubicin. The major findings were: (1) Pgp was expressed in the HCT-15 cells in both the cell and the nuclear membranes, (2) at the low dose range of 1-5 mu M, each new candidate: (i) increased cytotoxicity of doxorubicin (15-fold) and (separately) of paclitaxel (40-fold), (ii) induced an increase in intracellular accumulation, 60% (4 h) for doxorubicin and 300% (18 h) for paclitaxel, (iii) reduced drug efflux from the cell, 2-fold and 4-fold for doxorubicin and for paclitaxel, respectively. Based on detailed kinetic analysis, using liposomes to model paclitaxel diffusion through cell membranes, efflux slowdown can be attributed to reduction in the rate constant of drug diffusion through Pgp, and not to Pgp blockage. Chemosensitization was consistently-better for paclitaxel (cytosol-operating) than for doxorubicin (nuclear-operating) implying linkage between P-glycoprotein localization and loci of drug action. Mapping intracellular locations of MDR-pumps may assist therapeutic strategies. (C) 2010 Elsevier B.V. All rights reserved.
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| 3. |
- Batra, Satish, et al.
(författare)
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Important differences in nitric oxide synthase activity and predominant isoform in reproductive tissues from human and rat.
- 2003
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Ingår i: Reproductive Biology and Endocrinology. - : Springer Science and Business Media LLC. - 1477-7827. ; , s. 10-10
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Tidskriftsartikel (refereegranskat)abstract
- For the extrapolation of data obtained from experimental animals to the human situation, it is important to know the similarities and differences between human and animal species. Some important characteristics of nitric oxide synthase (NOS) in myometrium and vagina from human and rat were compared. NOS-activity was measured by the formation of 14C-citrulline from 14C-arginine and the expression of NOS isoforms was examined by Western blotting. NOS activity in human uterus and vagina was significantly lower than in the tissues from rat. In contrast to the rat where NOS activity was predominantly found in the cytosolic fractions, NOS activity in particulate and cytosolic fractions from both human myometrium and vagina was similar. Data from Western blots confirmed that eNOS and nNOS isoforms were concentrated in the particulate and cytosolic fractions, respectively. Estrogen treatment of rats resulted in a down regulation of uterine cytosolic NOS activity. A down regulation of NOS in the cytosolic fraction was also seen in the human pregnant myometrium as compared with the nonpregnant myometrium. The vaginal NOS activity was considerably higher than the uterus in both species. In spite of some clear-cut qualitative and other differences between human and rat tissues, there are some interesting similarities. Downregulation in pregnancy of human uterine NOS is probably due to, at least in part, the influence of estrogen and progesterone.
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| 5. |
- Batra, Satish, et al.
(författare)
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Release of intracellular calcium and stimulation of cell growth by ATP and histamine in human ovarian cancer cells (SKOV-3)
- 1994
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 77:1, s. 57-63
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Tidskriftsartikel (refereegranskat)abstract
- The effects of ATP and histamine on cell proliferation and intracellular calcium concentrations ([Ca2+]i) were examined in the human ovarian cancer cell line SKOV-3. Micromolar concentrations of ATP induced a biphasic increase in [Ca2+]i representing a rapid rise to a peak level followed by a smaller but more sustained phase. When influx of extracellular calcium was blocked by calcium chelation to EGTA, the ATP-stimulated rise in [Ca2+]i was rapid and only monophasic. Histamine, in contrast to ATP, caused only a monophasic rise in [Ca2+]i both in the presence and absence of external calcium. The histaminergic H1 receptor antagonist pyrilamine, but not the H2 receptor antagonist cimetidine, totally blocked rises in [Ca2+]i caused by histamine. Fetal calf serum (FCS) induced a slow and monophasic increase in [Ca2+]i in these cells, distinctly different from rises in [Ca2+]i caused by ATP and histamine. Inclusion of low micromolar concentrations of ATP in the growth medium stimulated proliferation of these cells, while higher concentrations (100 microM-1 mM) significantly decreased cellular proliferation. Histamine, in micromolar concentrations, also stimulated cell proliferation. From these results it was concluded that the release of intracellularly bound Ca2+ following receptor stimulation is sufficient to induce cellular proliferation in SKOV-3 cells.
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| 6. |
- Brodszki, Jana, et al.
(författare)
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Altered vascular function in healthy normotensive pregnant women with bilateral uterine artery notches.
- 2002
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Ingår i: BJOG: An International Journal of Obstetrics & Gynaecology. - : Wiley. - 1471-0528 .- 1470-0328. ; 109:5, s. 546-552
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To assess endothelial function and vascular mechanical properties in normotensive pregnant women with high resistance in the uteroplacental circulation. DESIGN: Cross-sectional prospective study. SETTING: Doppler ultrasound laboratory at university department of obstetrics and gynaecology referral centre for high risk pregnancies. PARTICIPANTS: Forty-two caucasian normotensive pregnant women: 23 with uncomplicated pregnancies and 19 with bilateral uterine artery notches. METHODS: Flow-mediated dilatation of the brachial artery was measured by ultrasonography at 25 gestational weeks. Concentrations of nitrite and nitrate in the plasma were established at 25 and 32 gestational weeks. The elastic properties of the common carotid artery, abdominal aorta and popliteal artery were measured with an ultrasonic echo-tracking system. RESULTS: Flow-mediated dilatation at two minutes after cuff deflation was significantly lower in the bilateral notch group compared with the control group, 8.3% and 13.7%, respectively (P = 0.0007). The ability to sustain vasodilatation was reduced in the bilateral notch group (P = 0.02). Lower values of nitrite and nitrate in the plasma were found at 32 gestational weeks in the bilateral notch group than in the control group (mean 24.76 microM/L (SD 5.6) and 30.93 microM/L (8.2), respectively; P = 0.008). Nitrite and nitrate levels tended to be lower in the bilateral notch group even at 25 gestational weeks (29.45 microM/L (8.3) and 35.73 microM/L (11.0) in the bilateral notch and control group, respectively; P = 0.09). There was no difference in aortic, carotid or popliteal elasticity between the two groups. CONCLUSIONS: Healthy normotensive pregnant women with bilateral uterine artery notches show impaired endothelial function, but no differences in vascular mechanical properties.
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| 7. |
- Kannisto, Päivi, et al.
(författare)
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Extracellular and intracellular calcium sources mediating contractile responses of smooth muscle in bovine ovarian follicle and ovarian artery
- 1987
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 144:3, s. 299-308
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Tidskriftsartikel (refereegranskat)abstract
- The relative importance of extracellular and intracellular calcium sources mediating smooth muscle contraction in ovarian follicle and ovarian artery was assessed in experiments on the influence of nifedipine, D-600, amrinone, diethylstilbestrol (DES), lanthanum and/or calcium removal on contractions induced by K+ depolarization, by noradrenaline, histamine and acetylcholine. The K+-induced response was biphasic in the ovarian artery but not in the ovarian follicle. The K+-induced contraction in both preparations was greatly inhibited by nifedipine (1 μM), D-600 (10 μM) and lanthanum (2 mM). Although both phases of the responses in the ovarian artery appeared to be completely dependent on extracellular calcium, phase I was significantly more sensitive to nifedipine than phase II. Incubation in calcium-free medium for 15 min almost abolished the K+-induced contraction. Noradrenaline- and histamine-induced contractions of ovarian follicle were essentially unaffected by nifedipine (1 μM) and D-600 (10 μM) whereas the noradrenaline-induced contraction in ovarian artery was inhibited significantly by D-600 (1 and 10 μM) but not nifedipine (1 μM). In calcium-free medium containing EGTA (1 mM) the responses of ovarian follicle to noradrenaline and histamine were reduced by 26 and 22% respectively. When preparations were stimulated with noradrenaline more than one in calcium-free medium, the contraction decreased progressively compared to time-matched controls. The response was 34% of the control after 50 min in calcium-free medium containing EGTA. In the ovarian artery the response obtained (6% of control) was significantly smaller (P < 0.05) than that in the follicle. Amrinone (100 μM) inhibited both noradrenaline- and K+-induced contractions to a similar degree (about 40%) in the follicle wall. The results indicate that agonist-induced responses of ovarian follicle and artery are mediated by the release of calcium from intracellular stores in addition to influx of extracellular calcium. In contrast, the K+-induced contraction seems to be totally dependent on extracellular calcium. The difference in sensitivity to nifedipine of the two phases of the K+ response in ovarian artery strongly suggests the presence of two different types of K+-activated calcium channels in this smooth muscle.
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| 8. |
- Kostrzewska, Ama, et al.
(författare)
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Effect of nitric oxide on responses of the human uterine arteries to vasopressin
- 2008
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Ingår i: Vascular Pharmacology. - : Elsevier BV. - 1537-1891. ; 48:1, s. 9-13
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Tidskriftsartikel (refereegranskat)abstract
- Nitric oxide (NO) is known to be an important relaxant of contractile activity in various muscles including the human uterine arteries. It has been suggested that NO plays a role in modulation of vascular action of arginin vasopressin (AVP), a strong vasoconstrictor of the human uterine arteries. Therefore, the purposes of this study were to investigate an involvement of endogenous NO in regulation of responses of the human intrauterine arteries to AVP and examine the effect of exogenous NO on contractions of the human intrauterine arteries evoked by AVP. Pretreatment of the artery rings with L-NA, an inhibitor of NO synthase significantly increased the resting force and enhanced the artery responses to AVP. The opposite effect has been observed after administration of 10(-6) mol/L sodium nitroprusside (SNP). Pretreatment of the artery rings with 10(-7) M CTX, a blocker of Ca2+-sensitive potassium channels with large conductance, did not change significantly their responses to ANT. Glibenclamide (1.5 10(-6) mol/L), a blocker of ATP-dependent potassium channels and apamin (10(-8) M), a specific blocker of Ca2+-sensitive potassium channels with small conductance strongly enhanced the maximum responses of the artery rings to AVP. Pretreatment with CTX significantly decreased the relaxation induced by SNP while apamin attenuated the sensitivity to SNP resulted in rightward shift of the concentration-response curve to SNP. In conclusion, this study indicates that: NO plays a role in regulation of both the vascular tone of the human intramyometrial arteries and their response to AVP. Ca2+-sensitive K+ channels with small and large conductance are involved in the SNP-induced relaxation of these arteries. The pathways of this relaxation cannot be sufficiently explained at this moment and need further investigation. (C) 2007 Elsevier Inc. All rights reserved.
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| 9. |
- Liuba, Petru, et al.
(författare)
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Acute Chlamydia pneumoniae infection causes coronary endothelial dysfunction in pigs.
- 2003
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Ingår i: Atherosclerosis. - 1879-1484. ; 167:2, s. 215-222
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Tidskriftsartikel (refereegranskat)abstract
- Background: Coronary endothelial dysfunction contributes to the pathogenesis of acute coronary syndromes (ACSs). Acute Chlamydia pneumoniae infection has been epidemiologically associated with ACS. In this study, we investigated whether acute C. pneumoniae infection could alter the endothelial vasomotor function of porcine coronary vessels. Methods and results: Twenty pigs, 7–9 kg in weight, were inoculated intratracheally with C. pneumoniae (n=12) or saline (n=8), and investigated at 3 days (five infected/four non-infected) and 2 weeks (5+2 infected/four non-infected) after inoculation. The endothelium-dependent reactivity of coronary microcirculation was assessed at both time points by measuring peak coronary flow velocity (CFV) in response to bradykinin, before and after infusions with glutathione, an antioxidant, and Image-arginine, a substrate for nitric oxide synthase (NOS). CFV after bradykinin was significantly decreased in infected animals at both time points. At 2 weeks, both glutathione and Image-arginine significantly improved CFV after bradykinin. CFV after sodium nitroprusside (SNP) was similar in both groups. At 3 days, the relaxation responses of bradykinin-induced pre-contracted left anterior descending (LAD) coronary rings to bradykinin were significantly less in infected animals. NG-nitro-Image-arginine-methyl-ester, an NOS inhibitor, had significantly greater inhibitory effect on bradykinin-induced relaxation in infected animals. Plasma nitrate–nitrite and fibrinogen, and NOS activity from LAD coronary samples were significantly increased in infected animals. Conclusion: Acute C. pneumoniae infection causes endothelial dysfunction of both resistance and epicardial coronary vessels, and favours a pro-coagulant status. These effects could in part account for the epidemiologically suggested association between acute infection and ACS.
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