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Fibroblast growth factor 6 (FGF6) is selectively expressed during muscle development and regeneration. We examined its effect on muscle precursor cells (mpc) by forcing stable FGF6 expression in C2C12 cells in vitro. FGF6 produced in genetically engineered mpc was active, inducing strong morphological changes, altering cell adhesion and compromising their ability to differentiate into myotubes. Expression of MyoD and myogenin, but not of Myf5, was abrogated in FGF6 engineered mpc. These effects were reversed by FGF inhibitors. Ectopic expression of MyoD also restored fiber formation indicating that FGF6 interferes with the myogenic differentiation pathway upstream of MyoD. We also report that in the presence of FGF6, the minor (0.5-2%) subpopulation of cells actively excluding Hoechst 33342 in a verapamil-dependent manner (SP phenotype) was increased to 15-20% and the expression of the mdr1a gene (but not mdr1b) was upregulated by 400-fold. Our data establish a previously undescribed link between FGF6--a muscle specific growth factor--and a multidrug resistance gene expressed in stem cells, and suggest a role for FGF6 in the maintenance of a reserve pool of progenitor cells in the skeletal muscle.
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Overexpression of P-glycoprotein (Pgp) is one of the major limitations in cancer chemotherapy. Previous work has shown that amphiphilic diblock copolymers composed of methoxypolyethylene glycol-block-polycaprolactone (MePEG-b-PCL) diblock copolymers enhanced the cellular accumulation of Pgp substrates by modulating the function of this drug efflux transporter. The objective of this work was to determine whether MePEG-b-PCL diblock copolymers modulated Pgp function in multidrug resistant (MDR) cancer cells. The diblock copolymer enhanced the accumulation of various Pgp substrates in Pgp overexpressing MDR cells but did not influence substrate accumulation in non-Pgp expressing cells. Treatment of MDR cells with the diblock copolymer enhanced paclitaxel (ptx) and doxorubicin (dox) accumulation. Following uptake, ptx was rapidly effluxed from MDR cells whereas diblock copolymer treatment retained dox inside MDR cells. Treatment of MDR cells with the diblock copolymer reversed drug resistance to dox but not ptx. However, resistance to ptx was reversed by verapamil, which indicated that a sustained inhibition of Pgp was required for ptx to induce cytotoxicity in MDR cells. Taken together, these results highlight the potential of MePEG-b-PCL diblock copolymer to reverse drug resistance in MDR cancer cells through inhibition of Pgp function, making it a promising candidate for overcoming MDR.
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To characterize the activities of inorganic pyrophophatase (PPase) in the plasma membrane of Leishmania donovani promastigote and amastigote.
These results suggest that dietary phytochemicals, such as glycyrrhetinic acid found in licorice, have dual inhibitory effects on P-glycoprotein and MRP1 and might become useful to enhance the efficacy of cancer chemotherapy.
A significant improvement was observed in appearance and texture of the exaggerated scars in all cases following already 4 months of autologous micrograft treatment We have also shown that these micrografts are composed of mesenchymal stem cells and in addition, histological evaluation verified restoration of the structural layers immediately below the epidermis and a horizontal realignment of collagen fibers in the papillary dermis.
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Monensin induces cell-cycle arrest and apoptosis through regulation of cell cycle- and apoptosis-related proteins, resulting in induction of mitochondrial ROS- and Ca(2+)-dependent apoptosis, respectively.
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The objectives of this study were to determine the extent of coprescribing of statins with medications that may increase the risk of adverse events and to identify associated patient and prescriber characteristics. The authors conducted a retrospective cohort study in a large database representative of the U.S. prescription-filling population. The authors studied the U.S. retail prescription environment as reflected in prescriptions dispensed. Patients filling a prescription for a statin between October 1, 2001, and September 30, 2002 were studied. A coprescription for medications of interest as reflected in the warnings and precautions of statin product package inserts was studied: fibric acid, niacin, azole antifungal, macrolide antibiotics, nefazodone, protease inhibitors, verapamil, or warfarin within 3 weeks of a statin prescription. Patient and prescriber characteristics and proportion of coprescribing events attributable to the same prescriber were examined.A total of 5,637,918 patients filled a statin prescription during the 12-month study period. Nearly 19% had concomitant use of a medication with warnings and/or precautions for coprescribing (coprescription event). Coprescription was highest for fibrates, macrolides, and niacin accounting for 19.3%, 17.4%, and 9.4%, respectively, and did not differ across statins. One-third of coprescribing events involved same-day prescriptions, 57% occurred within 7 days of the index statin prescription, and 71.2% of all coprescription events originated from the same prescriber. Coprescribing of medications not compatible with statins occurs frequently. The extent of coprescribing indicates the need for additional intervention to assure that the risk of untoward effects is mitigated.
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Buxus papillosa extracts of leaves (BpL), stem (BpS), roots (BpR) and BpL fractions: hexane (BpL-H), aqueous (BpL-A) also plant constituent, cyclomicrobuxine effect were studied in jejunum, atria, aorta and tracheal preparations from rabbit and guine-peg.
A multicentric, open, placebo controlled study of 81 hypertensive patients older than 20 years-old followed to 8 weeks. Blood pressure was measured in doctor's office and by 24 h ambulatory monitoring (ABPM).
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To study the role of the tachykinin receptors in spontaneous contractions of longitudinal and circular smooth muscle from rabbit small intestine and to determine the mechanism of action of Substance P (SP).
During AP experiments, the hiPSC-CM were paced at 1Hz during a baseline period, and when increasing concentrations of test compound were administered at 4-minute intervals. AP parameters, including duration (APD60 and APD90), resting membrane potential, rate of rise, and amplitude, were measured throughout the entire experiment. Voltage clamp experiments with E-4031 and nifedipine were similarly conducted.
The present study focused on the evaluation of behavioural cross-sensitization, particularly in locomotor activities and conditioned rewarding effects, between nicotine and morphine, cocaine, amphetamine or MK-801. Nicotine (0.5 mg kg(-1))-experienced mice manifested an enhanced locomotor response to morphine (5 mg kg(-1)) or MK-801 (0.3 mg kg(-1)). No cross-sensitization was observed between nicotine and amphetamine (2 mg kg(-1)) or cocaine (15 mg kg(-1)). Additionally, the L-type voltage-dependent calcium-channel antagonists, nimodipine and verapamil, but not diltiazem, at a dose of 20 mg kg(-1) injected before morphine or MK-801 challenge, blocked the expression of this cross-sensitization. In the second test, an enhancement of morphine place conditioning in rats pre-exposed to nicotine (0.5 mg kg(-1), injected daily for 5 days) was demonstrated. After two conditioning sessions, morphine (5 mg kg(-1)) induced a clear place preference only in animals that had previously received nicotine injections. The administration of nimodipine (10 and 20 mg kg(-1)), verapamil (10 and 20 mg kg(-1)) and diltiazem (10 and 20 mg kg(-1)) prior to nicotine dose-dependently prevented this sensitization to the rewarding effect of morphine produced by prior injections of nicotine. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in the appetitive effects of nicotine and morphine and in the sensitized locomotor stimulant effects of nicotine and morphine or MK-801.
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The purpose of this study was to investigate the mechanism by which cadmium (Cd2+) crosses the intestinal epithelium using a Caco-2 cell model. Experimentation was designed to determine which of several possible pathways of transport are operative. These pathways include passive diffusion, transport via a calcium pathway, sulfhydryl-mediated transport, and carrier-mediated (active transport and/or facilitated diffusion) transport. To examine the diffusion pathway the effect of various apical cadmium concentrations on the amount of cadmium transported was tested. The effects of verapamil, calcium, and 1,25(OH)2 vitamin D3 (vit. D3) on Cd2+ transport were examined to investigate the possible existence of a calcium transport pathway. N-Ethylmaleimide, a sulfhydryl group blocker, was used to determine whether Cd2+ transport is sulfhydryl-mediated. Active transport was evaluated by examining the effect of 2,4-dinitrophenol, a metabolic inhibitor, on the transport of Cd2+. These studies indicated that: (1) a portion of the overall transport of Cd2+ can be attributed to diffusion, (2) stimulation of calcium binding protein transcription by vit. D3 enhances Cd2+ transport, and (3) the transport process for Cd2+ has both sulfhydryl-mediated and carrier-mediated components.
A total of 119 patients with primary renal disease, blood pressure > 130/85 mmHg, proteinuria > 1 g/day, and creatinine clearance > or = 50 ml/min.
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Mahuang decoction, Ephedra combined with Cassia twig, Bitter apricot kernel and Prepared licorice, has been widely used as a multi-herb prescription in traditional Chinese medicine (TCM). Many modern pharmacological studies have shown that the compatibility application of these four herbs has promising therapeutic effects on respiratory infection, acute glomerulonephritis and chronic renal failure. However, the underlying principles for governing the formulation of Mahuang decoction remain unknown. In this study, we used a Caco-2 cell monolayer model to explicate the possible compatibility mechanism of Mahuang decoction from the perspective of intestinal absorption.
We studied the effects of streptozotocin-induced diabetes on the cardiac repolarisation time (Q-T interval) in Sprague-Dawley rats during a 4-day period of hyperglycaemia and a subsequent 4-day period of normoglycaemia. The Q-T interval was also evaluated in isolated hearts of non-diabetic rats, in condition of high glucose concentration.
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Male New Zealand albino rabbits (2-2.5 kg) were employed in these studies. Animals were kept under anesthesia and a concentric microdialysis probe was implanted in the vitreous humor and a linear probe in the anterior chamber. Isotonic phosphate buffered saline was perfused through the probes, and samples were collected every 20 minutes over a period of 10 hours. Quinidine was administered both systemically (5 mg/kg bodyweight) and intravitreally (5.68 microg and 0.568 microg). Inhibition experiments were performed in vivo in the presence of verapamil, which is a known P-gp inhibitor.
The most frequent drawback of doxorubicin is the onset of drug resistance, due to the active efflux through P-glycoprotein (Pgp). Recently formulations of liposome-encapsulated doxorubicin have been approved for the treatment of tumors resistant to conventional anticancer drugs, but the molecular basis of their efficacy is not known. To clarify by which mechanisms the liposome-encapsulated doxorubicin is effective in drug-resistant cancer cells, we analyzed the effects of doxorubicin and doxorubicin-containing anionic liposomal nanoparticles ("Lipodox") on the drug-sensitive human colon cancer HT29 cells and on the drug-resistant HT29-dx cells. Interestingly, we did not detect any difference in drug accumulation and toxicity between free doxorubicin and Lipodox in HT29 cells, but Lipodox was significantly more effective than doxorubicin in HT29-dx cells, which are rich in Pgp. This effect was lost in HT29-dx cells silenced for Pgp and acquired by HT29 cells overexpressing Pgp. Lipodox was less extruded by Pgp than doxorubicin and inhibited the pump activity. This inhibition was due to a double effect: the liposome shell per se altered the composition of rafts in resistant cells and decreased the lipid raft-associated amount of Pgp, and the doxorubicin-loaded liposomes directly impaired transport and ATPase activity of Pgp. The efficacy of Lipodox was not increased by verapamil and cyclosporin A and was underwent interference by colchicine. Binding assays revealed that Lipodox competed with verapamil for binding Pgp and hampered the interaction of colchicine with this transporter. Site-directed mutagenesis experiments demonstrated that glycine 185 is a critical residue for the direct inhibitory effect of Lipodox on Pgp. Our work describes novel properties of liposomal doxorubicin, investigating the molecular bases that make this formulation an inhibitor of Pgp activity and a vehicle particularly indicated against drug-resistant tumors.
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The results showed that basal P-gp ATPase activity was increased by CJY with half-maximal activity concentration (Km) of 2.9±0.3 μM and the maximal ATPase activity velocity (Vmax) of 265±21 nM · min-1 · mg-1. Kinetic studies on ATPase activity showed the effects of Verapamil (Ver) on CJY-stimulated, CJX1 on Ver-stimulated, and CJX1 on CJY-stimulated P-gp ATPase activity were all non-competitive inhibition, indicating that these substrates can simultaneously but independently bind to diverse sites on P-gp. The combined effects of CJY with Ver, and CJY with CJX1 show that mixtures of both drugs at these fixed-ratios displayed synergistic interactions.
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To investigate whether down-regulation of P-glycoprotein (P-gp) is correlated to resistance to cisplatin and VP-16 in four histopathological subtype cell lines of lung cancer (SK-MES-1, SPCA-1, NCI-H-460 and NCI-H-446).
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The aim of this study was to evaluate the effectiveness of the treatment with 4-aminopyridine (4-AP, potassium channel inhibitor) and Bay K 8644 (calcium channel activator) in experimentally evoked verapamil poisoning in rats and to compare the results of this treatment with the effectiveness of widely accepted methods (adrenaline, calcium compounds). The experiment was carried out on male and female Wistar rats which were divided into 4 experimental (A, B, C, D) and a control (K) groups. Rats were anesthetized and the abdominal aorta was cannulated for mean arterial pressure and heart rate measurements while caudal vein was cannulated for drug administration. All animals were infused with verapamil (150 mg/kg/h) until 50% reduction of mean arterial pressure and/or heart rate was observed. After verapamil, control animals were given 0.9% NaCl solution and the other groups received 687.5 mg/kg/h of calcium glucolactobionicum (group A), 0.3 mg/kg/h of adrenaline (group B), 2 mg/kg/h of 4-AP (group C) or 2 mg/kg/h of Bay K 8644 (group D). The mean blood pressure and heart rate was checked and ECG was recorded every 10 min. A statistically significant decrease in mortality compared with the control group was observed in animals treated with adrenaline (p < or = 0.05), Bay K 8644 (p < or = 0.01) and 4-AP (p < or = 0.005). The treatment of experimentally evoked poisoning in rats using 4-AP or Bay K 8644 resulted in fast receding of poisoning symptoms: increase in blood pressure and heart rate, receding of bradyarrhythmia and return of sinus rhythm. The results of the study suggest the usefulness of 4-AP and Bay K 8644 in the treatment of verapamil poisoning.
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Apical efflux of 3 is associated with P-gp and MRP, but the efflux of 4 involves P-gp and/or MRP. The computational approach used in this study provided the basis for P-gp substrates of compounds 3 and 4 from their electron donor subunits spatial separation.
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The combination of turbidometry and long light path fiber optic UV spectroscopy offers accurate, almost real-time exposure determination in a wide range of concentrations with little effort, affordable instrumentation, and no delay for data reporting. For research compounds with challenging physicochemical properties this method provides valuable data to support the validity of the measurements.
Development of biochemical modulators and application of the same with anticancer drugs is a current approach of modern cancer chemotherapy. We report the effect of two novel hydroxamic acid derivatives, viz. oxaly bis (N-phenyl) hydroxamic acid (OBPHA) and succinyl bis (N-phenyl) hydroxamic acid (SBPHA) on doxorubicin sensitivity and on P-glycoprotein (P-gp) in acetyl amino fluorene (AAF) induced preneoplastic hepatocytes in vitro. OBPHA increases doxorubicin sensitivity in AAF induced preneoplastic hepatocytes compared to normal hepatocytes. SBPHA, with an additional -CH(2)-CH(2)- group than OBPHA does not modulate the sensitivity of doxorubicin. The mechanism of action of OBPHA and SBPHA and their in vivo toxicity on male Swiss mice has been studied. OBPHA in combination with doxorubicin (i.e. OBPHA+doxorubicin) has higher antitumour activity compared to doxorubicin alone group; in consequence, OBPHA may decrease the dose related side effect of doxorubicin.
We believe this case illustrates that avoiding the use of drugs that are cytochrome P450 3A4 and/or P-glycoprotein substrates reduces the risk of rhabdomyolysis caused by 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors.
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In the cortical collecting duct of the rat two Ca(2+)-dependent K+ channels have been described so far. In the luminal membrane a maxi K+ channel with a single channel conductance of 139 +/- 3 pS in excised membrane patches (n = 91) at 0 mV clamp voltage and asymmetrical KCl-concentrations in pipette and bath was found, while in the basolateral membrane an intermediate conductance K+ channel (85 +/- 1 pS, n = 53) and a small K+ channel (28 +/- 2 pS, n = 15) was described. All these K+ channels had similar pharmacological properties since all could be blocked by the K+ channel inhibitors Ba2+, TEA+, and charybdotoxin. Verapamil, known as a L-type Ca2+ channel blocker, was also capable of inhibiting these K+ channels. While the maxi K+ channel from the luminal membrane was upregulated by intracellular Ca2+ (EC50: 5 microM), the small and the intermediate K+ channel from the basolateral membrane were downregulated (IC50: 10 microM). When the cytosolic Ca(2+)-activity was in the physiological range below 1 microM the activity of the maxi K+ channel was low and regulated via intracellular pH and ATP. Furthermore, when CCD cells were strongly depolarized and under hypoosmotic stress, Ca2+ rose and activated this K+ channel, indicating that this channel is involved in volume regulation. Like the maxi K+ channel the intermediate conductance K+ channel from the basolateral membrane was also sensitive to intracellular changes of pH where acidic pH inhibited while alkaline pH activated this channel. But unlike the K+ channels from the luminal membrane the K+ channel from the basolateral membrane is not regulated by ATP up to 5 mM. The activity of the K+ channels from the basolateral membrane decreased steadily after excision of the membrane. This decrease could be prevented by applying cGMP and MgATP to the bath and thus, activating a membrane-bound cGMP-dependent protein kinase (PKG). The activation of the PKG could be reversed by its specific inhibitor KT5823 (1 microM). Due to the opposite regulation via intracellular Ca2+ and the involvement of different protein kinases a specific and independent regulation of K+ secretion and Na+ reabsorption is possible in the CCD of the rat.