bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence of Prolonged Orocecal Transit Time and Small Intestinal Bacterial Overgrowth in Acromegalic Patients
Authors: Resmini Eugenia , Parodi Andrea , Savarino Vincenzo , Greco Alfredo , Rebora Alberto , Minuto Francesco , Ferone Diego 
Published: April 2007

Abstract
Context: Gastrointestinal abnormalities in acromegaly include dolichomegacolon, slow colonic transit, and increased prevalence of colonic polyps. Conversely, no data are available on the small intestine.
Objective: The aim of the study was to investigate the orocecal transit time (OCTT) and the presence of small intestinal bacterial overgrowth (SIBO).
Patients: A total of 41 acromegalic patients and 30 sex- and age-matched control subjects entered the study. Acromegalic patients were classified according to the medical treatment with somatostatin analogs as “treated” (n = 22) and “untreated” (n = 19), whereas according to the disease control, as “controlled” (n = 17), “uncontrolled” (n = 10), and “partially controlled” (n = 14). Patients and controls completed a questionnaire and underwent a standardized 10-g lactulose hydrogen breath test to determine the OCTT and presence of SIBO. SIBO-positive patients underwent eradication with rifaximine.
Results: An increased prevalence of SIBO (18 of 41 vs. 1 of 30; P &lt; 0.0001) and a significantly delayed OCTT (169.53 ± 8.15 vs. 107.25 ± 6.56 min; P &lt; 0.0001) were evidenced in patients compared with controls. No significant statistical differences were found between “treated” or “untreated” patients positive for SIBO or between “controlled,” “partially controlled,” and “uncontrolled” patients. OCTT was significantly delayed in “treated” vs. “untreated” patients (183.21 ± 9.01 and 158.89 ± 6.38, respectively; P = 0.02) and in patients compared with controls (105.75 ± 6.34; P &lt; 0.0001). Rifaximine eradicated SIBO in more than 50% of patients who underwent treatment.
Conclusions: These data demonstrate for the first time that SIBO occurs more frequently in acromegalic patients, however, it can be successfully treated by a specific antibiotic. Medical therapy with somatostatin analogs does not affect SIBO prevalence. OCTT resulted significantly prolonged in both “treated” and “untreated” patients, suggesting that acromegaly determines per se an impairment of the intestinal motility. Indeed, disease control seems irrelevant on the delayed OCTT, suggesting that this alteration might be an irreversible complication of acromegaly, probably related to an autonomic intestinal disorder, as we have previously demonstrated at the cardiac level.
Transforming Growth Factor β Is a Critical Regulator of Adult Human Islet Plasticity
Authors: Hanley Stephen , Rosenberg Lawrence 
Published: April 2007

AbstractTissue plasticity is well documented in the context of pancreatic regeneration and carcinogenesis, with recent reports implicating dedifferentiated islet cells both as endocrine progenitors and as the cell(s) of origin in pancreatic adenocarcinoma. Accordingly, it is noteworthy that accumulating evidence suggests that TGFβ signaling is essential to pancreatic endocrine development and maintenance, whereas its loss is associated with the progression to pancreatic adenocarcinoma. The aim of this study was to examine the role of TGFβ in an in vitro model of islet morphogenetic plasticity. Human islets were embedded in a collagen gel and cultured under conditions that induced transformation into duct-like epithelial structures (DLS). Addition of TGFβ caused a dose-dependent decrease in DLS formation. Although it was demonstrated that collagen-embedded islets secrete low levels of TGFβ, antibody-mediated neutralization of this endogenously released TGFβ improved DLS formation rates, suggesting local TGFβ concentrations may in fact be higher. Time course studies indicated that TGFβ signaling was associated with an increase in ERK and p38 MAPK phosphorylation, although inhibitor-based studies were consistent with an islet endocrine-stabilizing effect mediated by p38 alone. Localization of TGFβ signaling molecules suggested that the action of TGFβ is directly on the β-cell to inhibit apoptosis and thus stabilize endocrine phenotype.
pH-Sensitive liposomes-principle and application in cancer therapy
Authors: Karanth H , Murthy R S R 
Published: April 2007

AbstractThe purpose of this review is to provide an insight into the different aspects of pH-sensitive liposomes. The review consists of 6 parts: the first introduces different types of medications made in liposomal drug delivery to overcome several drawbacks; the second elaborates the development of pH-sensitive liposomes; the third explains diverse mechanisms associated with the endocytosis and the cytosolic delivery of the drugs through pH-sensitive liposomes; the fourth describes the role and importance of pH-sensitive lipid dioleoylphosphatidylethanolamine (DOPE) and research carried on it; the fifth explains successful strategies used so far using the mechanism of pH sensitivity for fusogenic activity; the final part is a compilation of research that has played a significant role in emphasizing the success of pH-sensitive liposomes as an efficient drug delivery system in the treatment of malignant tumours. pH-Sensitive liposomes have been extensively studied in recent years as an amicable alternative to conventional liposomes in effectively targeting and accumulating anti-cancer drugs in tumours. This research suggests that pH-sensitive liposomes are more efficient in delivering anti-cancer drugs than conventional and long-circulating liposomes due to their fusogenic property. Research focused on the clinical and therapeutic side of pH-sensitive liposomes would enable their commercial utility in cancer treatment.
Synthesis and evaluation of ampicillin-conjugated gum arabic microspheres for sustained release
Authors: Nishi K K , Antony M , Jayakrishnan A 
Published: April 2007

Abstract
Ampicillin was conjugated to periodate-oxidized gum arabic (GA), a branched polysaccharide, to form the imino conjugate of the drug and the polysaccharide. The water-soluble conjugate was dispersed by sonication in a mixture of toluene and liquid paraffin in the presence of a non-ionic surfactant as droplet stabilizer and fabricated into microspheres by heat denaturation at 80°C to obtain spheres less than 2 μm in diameter. These microspheres did not undergo dissolution in water on prolonged incubation. In-vitro release of ampicillin into phosphate buffer from the microspheres was slow and sustained with a cumulative release between 10 and 25% of the drug content in 10 days depending on the degree of oxidation of GA and the drug payload. Release into simulated gastric fluid was faster due to faster hydrolysis of the drug-GA bond in the acid medium, but when the medium was changed to intestinal fluid, the release was slowed down. Ampicillin released was functionally active and inhibited the growth of S. aureus and E. coli in cultures, although not as actively as free ampicillin. The microspheres underwent slow biodegradation on prolonged incubation in aqueous media. These studies show that ampicillin conjugated with oxidized GA and fabricated into microspheres possesses sustained-release characteristics for prolonged periods.
Pharmacokinetic modelling of pentoxifylline and lisofylline after oral and intravenous administration in mice
Authors: Wyska Elzbieta , Szymura-Oleksiak Joanna , Pȩkala Elżbieta , Obruśnik Anna 
Published: April 2007

AbstractThe aim of this study was to develop pharmacokinetic models for pentoxifylline (PTX) and the R(-)-enantiomer of the PTX metabolite 1, lisofylline (LSF), in order to identify some factors influencing the absorption of these compounds from the intestines and to clarify mechanisms involved in their non-linear pharmacokinetics. Serum samples were collected after oral and intravenous administration of PTX and LSF to male CD-1 mice at two different doses. In addition, both compounds under investigation were coadministered with a modulator of drug transporters, verapamil, and an inhibitor of cytochrome P450 (CYP) 3A4, ketoconazole. Pharmacokinetic analysis revealed that a one-compartment model with Michaelis-Menten type absorption and elimination best described the pharmacokinetics of PTX, whereas the LSF concentration-time data were adequately fitted to a two-compartment model with a first-order absorption and Michaelis-Menten type elimination process. Both coadministered compounds significantly decreased the area under the concentration-time curve from 0 to 60 min calculated for PTX and increased the value of this parameter for LSF. The results of this study indirectly suggest that saturation of drug transport across intestinal cells and elimination from the central compartment may be responsible for the non-linear pharmacokinetics of PTX, whereas in the case of LSF, the dose dependency in the pharmacokinetics is solely related to the elimination from the central compartment. It seems that the observed changes in PTX and LSF concentrations after coadministration with verapamil and ketoconazole may be clinically significant, especially after chronic treatment, however further studies are necessary to assess the importance of these interactions in humans.
Transport and metabolism of MitoQ10, a mitochondria-targeted antioxidant, in Caco-2 cell monolayers
Authors: Li Yan , Fawcett J Paul , Zhang Hu , Tucker Ian G 
Published: April 2007

AbstractMitoquinone (MitoQ10 mesylate) is a mitochondria-targeted antioxidant formulated for oral administration in the treatment of neurodegenerative diseases. We have investigated the absorption and metabolism of MitoQ10 in Caco-2 cell monolayers. The intracellular accumulation of MitoQ10 was 18–41% of the total amount of MitoQ10 added. Some of the intracellular MitoQ10 was reduced to mitoquinol and subsequently metabolized to glucuronide and sulfate conjugates. Transport of MitoQ10 was polarized with the apparent permeability (Papp) from basolateral (BL) to apical (AP) (PappBL→AP) being &gt;2.5-fold the Papp from apical to basolateral (PappAP→BL). In the presence of 4% bovine serum albumin on the basolateral side, the PappAP→BL value increased 7-fold compared with control. The PappBL→AP value decreased by 26, 31 and 61% in the presence of verapamil 100 μM, ciclosporin 10 and 30 μM, respectively, whereas the PappAP→BL value increased 71% in the presence of ciclosporin 30 μM. Apical efflux of mitoquinol sulfate and mitoquinol glucuronide conjugates was significantly decreased by ciclosporin 30 μM and the breast cancer receptor protein (BCRP) inhibitor, reserpine 25 μM, respectively. These results suggested that the bioavailability of MitoQ10 may be limited by intracellular metabolism and the action of P-glycoprotein and BCRP. However, the dramatic increase in absorptive Papp in the presence of bovine serum albumin on the receiver side suggests these barrier functions may be less significant in-vivo.
Site-specific bidirectional efflux of 2,4-dinitrophenyl-S-glutathione, a substrate of multidrug resistance-associated proteins, in rat intestine and Caco-2 cells
Authors: Yokooji Tomoharu , Murakami Teruo , Yumoto Ryoko , Nagai Junya , Takano Mikihisa 
Published: April 2007

AbstractThe site-specific function of multidrug-resistance-associated proteins (MRPs), especially MRP2 and MRP3, was examined in rat intestine and human colon adenocarcinoma (Caco-2) cells. The MRP function was evaluated pharmacokinetically by measuring the efflux transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG), an MRP substrate, after application of 1-chloro-2,4-dinitrobenzene (CDNB), a precursor of DNP-SG. The expression of rat and human MRP2 and MRP3 was analysed by Western blotting. The rat jejunum exhibited a higher apical MRP2 and a lower basolateral MRP3 expression than ileum. In accordance with the expression level, DNP-SG efflux to the mucosal surface was significantly greater in jejunum, while serosal efflux was greater in ileum. Site-specific bidirectional efflux of DNP-SG was also observed in in-vivo studies, in which portal and femoral plasma levels and biliary excretion rate of DNP-SG were significantly higher when CDNB was administered to ileum. Caco-2 cells also showed a bidirectional efflux of DNP-SG. Probenecid, an MRP inhibitor, significantly suppressed the mucosal efflux in jejunum and serosal efflux in ileum. In contrast, probenecid significantly suppressed both apical and basolateral efflux of DNP-SG in Caco-2 cells, though the inhibition was of small magnitude. In conclusion, the efflux of DNP-SG from enterocytes mediated by MRPs exhibited a significant regional difference in rat intestine, indicating possible variability in intestinal bioavailabilities of MRP substrates, depending on their absorption sites along the intestine.
Protective action of 9-hydroxypinoresinol against oxidative damage in brain of mice challenged with kainic acid
Authors: Cui Hui Song , Sok Dai-Eun , Min Byung Sun , Kim Mee Ree 
Published: April 2007

Abstract
The neuroprotective effect of 9-hydroxypinoresinol was examined in mice challenged with kainic acid (KA), a potent central nervous system excitotoxin. For this purpose, mice were administered intraperitoneally with 9-hydroxypinoresinol before KA injection. A remarkable neuroprotective effect was observed with a single dose of 9-hydroxypinoresinol (30 mg kg−1) 24 h before KA challenge. Furthermore, 9-hydroxypinoresinol (20 mg kg−1) administered for 3 days before KA challenge reduced the mortality (60%) induced by KA to zero, and alleviated behavioural signs of KA neurotoxicity. Additionally, pretreatment with 9-hydroxypinoresinol (20 mg kg−1) prevented the decrease in the levels of total glutathione (GSH) and thiobarbituric acid reactive substances (P &lt;0.05). GSH peroxidase activity in brain tissue was restored to control levels, although GSH reductase activity and GSH S-transferase activity were not affected. Such a protective action was also observed even with a lower dose (10 mg kg−1) of 9-hydroxypinoresinol administered for 3 days, albeit to a lesser extent. From the results, it is proposed that 9-hydroxypinoresinol exerts a potent neuroprotective effect mainly by preventing oxidative stress in brain tissue of mice challenged with KA.
Amides fromPiper nigrumL. with dissimilar effects on melanocyte proliferation in-vitro
Authors: Lin Zhixiu , Liao Yonghong , Venkatasamy Radhakrishnan , Hider Robert C , Soumyanath Amala 
Published: April 2007

AbstractMelanocyte proliferation stimulants are of interest as potential treatments for the depigmentary skin disorder, vitiligo. Piper nigrum L. (Piperaceae) fruit (black pepper) water extract and its main alkaloid, piperine (1), promote melanocyte proliferation in-vitro. A crude chloroform extract of P. nigrum containing piperine was more stimulatory than an equivalent concentration of the pure compound, suggesting the presence of other active components. Piperine (1), guineensine (2), pipericide (3), N-feruloyltyramine (4) and N-isobutyl-2E, 4E-dodecadienamide (5) were isolated from the chloroform extract. Their activity was compared with piperine and with commercial piperlongumine (6) and safrole (7), and synthetically prepared piperettine (8), piperlonguminine (9) and 1-(3, 4-methylenedioxyphenyl)-decane (10). Compounds 6–10 either occur in P. nigrum or are structurally related. Compounds 1, 2, 3, 8 and 9 stimulated melanocyte proliferation, whereas 4, 5, 6, 7 and 10 did not. Comparison of structures suggests that the methylenedioxyphenyl function is essential for melanocyte stimulatory activity. Only those compounds also possessing an amide group were active, although the amino component of the amide group and chain linking it to the methylenedioxyphenyl group can vary. P. nigrum, therefore, contains several amides with the ability to stimulate melanocyte proliferation. This finding supports the traditional use of P. nigrum extracts in vitiligo and provides new lead compounds for drug development for this disease.
Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase
Authors: McNally Virginia A , Rajabi Mehdi , Gbaj Abdul , Stratford Ian J , Edwards Philip N , Douglas Kenneth T , Bryce Richard A , Jaffar Mohammed , Freeman Sally 
Published: April 2007

Abstract
A series of novel imidazolyluracil conjugates were rationally designed and synthesised to probe the active site constraints of the angiogenic enzyme, thymidine phosphorylase (TP, E.C. 2.4.2.4). The lead compound in the series, 15d, showed good binding in the active site of human TP with an inhibition in the low μM range. The absence of a methylene bridge between the uracil and the imidazolyl sub-units (series 16) decreased potency (up to 3-fold). Modelling suggested that active site residues Arg202, Ser217 and His116 are important for inhibitor binding.
Hypothermic effects of hops are antagonized with the competitive melatonin receptor antagonist luzindole in mice
Authors: Butterweck Veronika , Brattstroem Axel , Grundmann Oliver , Koetter Uwe 
Published: April 2007

Abstract
Hops (Humulus lupulus, Cannabinaceae) has been used in traditional European medicine as a mild sedative for the treatment of anxiety, nervousness, and insomnia. However, there has been little information available about the underlying sleep inducing mechanism of hops. We have investigated the effects of a hops extract on the rectal body temperature in mice. Hops extract (250 mg kg−1) significantly decreased body temperature in male BL6/C57J mice (ΔT −0.75 ± 0.07°C) 2 h after oral administration. The effects of the plant extract were comparable with melatonin (50 mg kg−1; ΔT −0.66 ± 0.06°C; 2 h after i.p. injection). The hypothermic effects of melatonin and hops extract were antagonized with the competitive melatonin receptor antagonist luzindole. Thus, our data suggests that the hypothermic-and therefore the sleep-inducing-effects of hops extract are possibly mediated through activation of melatonin receptors.
Antioxidant and anticancer activity of 3‘-formyl-4’, 6‘-dihydroxy-2’-methoxy-5‘-methylchalcone and (2S)-8-formyl-5-hydroxy-7-methoxy-6-methylflavanone
Authors: Ye Chun-Lin , Liu Yu , Wei Dong-Zhi 
Published: April 2007

Abstract
Two new flavonoids - 3′-formyl-4′,6′-dihydroxy-2′-methoxy-5′-methylchalcone (FMC) and (2S)-8-formyl-5-hydroxy-7-methoxy-6-methylflavanone (FMF) - isolated from the buds of Cleistocalyx operculatus, were investigated for their antioxidant and anticancer activity. Total antioxidant activity and reducing ability were measured. 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and superoxide anion radical scavenging assays were carried out to evaluate the antioxidant potential of the two compounds. The antioxidant activity of the two compounds increased in a concentration-dependent manner. FMC and FMF at a concentration of 500 μM inhibited lipid peroxidation by 64.3 ± 2.5% and 60.3 ± 2.3%, respectively, an antioxidant activity approximately similar to that of 500 μM α-tocopherol (66.3 ± 2.5%). Similarly, the effect of FMC and FMF on reducing power increased in a concentration-dependent manner. In DPPH radical scavenging assays, the IC50 values of FMC and FMF were 50.2 ± 2.8 μM and 75.8 ± 2.5 μM, respectively. Moreover, FMC and FMF scavenged the superoxide generated by the phenazine methosulfate (PMS)/reduced β-nicotinamide adenine dinucleotide (NADH) nitroblue tetrazolium (NBT) system, with IC50 values of 56.3 ± 2.3 μM and 317.5 ± 2.9 μM, respectively. The anticancer activity of the two compounds were determined in five human cancer cell lines, SMMC-7721 (liver cancer), 8898 (pancreatic cancer), K562 (chronic leukaemia), HeLa (tumour of cervix uteri) and 95-D (high metastic lung carcinoma). FMC and FMF showed broad-spectrum anticancer activity against all the human cancer cell lines tested. The results obtained in the current study indicate that the two flavonoids could be a potential source of natural antioxidant and anticancer agents. To our knowledge, this is the first report on bioactivity of FMC and FMF.
Suppression of the NF-kB signalling pathway by ergolide, sesquiterpene lactone, in HeLa cells
Authors: Chun Jae Kwang , Seo Dong-Wan , Ahn Seong Hoon , Park Jae Hyun , You Jueng-Soo , Lee Chang-Hee , Lee Jae Cheol , Kim Yong Kee , Han Jeung-Whan 
Published: April 2007

AbstractWe have previously reported that ergolide, a sesquiterpene lactone isolated from Inula britannica, suppresses inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression by inhibiting nuclear factor-kB (NF-kB) in RAW 264.7 macrophages. In this study, we show that ergolide suppresses the DNA binding activity of NF-kB and nuclear translocation of NF-kB p65 subunit, leading to the inhibition of NF-kB-dependent gene transcription in 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated HeLa cells. We also show that ergolide decreases the degradation and phosphorylation of IkB, an inhibitory protein of NF-kB, and this effect is accompanied by a simultaneous reduction of IkB kinase (IKK) activity. However, ergolide does not inhibit in-vitro IKK activity directly, suggesting the possible involvement of upstream IKK kinases in the regulation of NF-kB activation. Furthermore, ergolide-mediated protein kinase Cα (PKCα) inhibition is involved in reduction of NF-kB inhibition, as demonstrated by the observation that dominant negative PKCα, but not p44/42 MAPK and p38 MAPK, inhibits TPA-stimulated reporter gene expression. Taken together, our results suggest that ergolide suppresses NF-kB activation through the inhibition of PKCα-IKK activity, providing insight for PKCα as a molecular target for anti-inflammatory drugs.
Cytochrome P450 inhibitory action of Echinacea preparations differs widely and co-varies with alkylamide content
Authors: Modarai M , Gertsch J , Suter A , Heinrich M , Kortenkamp A 
Published: April 2007

AbstractEchinacea preparations are one of the best selling herbal medicinal products with a well established therapeutic use in the prophylaxis of upper respiratory tract infections. Their consumption is increasing, but information about their ability to inhibit cytochrome P450 enzymes (CYP) is fragmentary. The picture is further complicated by a lack of phytochemical characterization of previously tested preparations. Due to its well characterized immunomodulatory activity, the standardized Swiss registered Echinacea purpurea (L.) Moench Echinaforce extract was selected for detailed study. With the single baculovirus-expressed CYP isoforms 1A2, 2C19, 2D9 and 3A4, inhibitory actions were measured by monitoring fluorescent metabolites derived from enzyme substrates (supersome assay). The Echinaforce extract induced mild inhibition of all these isoforms, with CYP 3A4 being the most, and CYP 2D6 the least sensitive enzyme. To assess whether CYP inhibition might be a general feature of Echinacea preparations, an additional nine commercially available preparations were screened using CYP 3A4. All tested preparations were able to inhibit CYP 3A4, but inhibitory potencies (expressed as median inhibitory concentration, IC50) varied by a factor of 150. The alkylamides are thought to be responsible for the immunomodulatory activity of Echinacea, and so the concentration of 2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and total alkylamide content were determined in all preparations, and the latter was found to be associated with their CYP 3A4 inhibitory potency. The chemically pure alkylamides dodeca-2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and dodeca-2E,4E-dieonoic acid isobutylamide (2) showed inhibitory activity on CYP 2C19, 2D6 and 3A4. However, unlike the Echinaforce extract, the alkylamides did not induce CYP 1A2 inhibition. Thus, other, as yet unidentified constituents also contribute to the overall weak inhibitory effects seen with Echinacea preparations in-vitro.