Biological Transporters as Targets for New Drug Design

Wang, Hui Po; Wang, Chun Li

doi:10.1016/s1878-3317(09)60008-5

Cited by 7 publications

(6 citation statements)

References 90 publications

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“…In addition, we have shown that CS-ZPV complex increases IL 10 levels, an established anti-inflammatory cytokine. This result is in accordance with data from the literature, where authors suggest that IL-10 inhibits pro-inflammatory cytokines and increases wound healing (Wang and Wang, 2009).…”

Section: Discussionsupporting

confidence: 93%

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Chitosan Membrane Modified With a New Zinc(II)-Vanillin Complex Improves Skin Wound Healing in Diabetic Rats

et al. 2019

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The treatment of chronic wounds is considered a public health problem. When the condition affects at-risk groups such as those with diabetics, it becomes a great clinical challenge. In this work, we evaluated the healing effects of a new zinc complex, [Zn(phen)(van)2], identified as ZPV, which was synthesized, characterized and associated with chitosan (CS) membranes and tested on cutaneous wounds of diabetic rats. Chitosan membranes were modified by Schiff base reaction with the complex under two experimental conditions (14 and 21 days), resulting in membranes with concentrations of complex equal to 0.736 μmol cm-2 (CS-ZPV1) and 1.22 μmol cm-2 (CS-ZPV2). Release assays in aqueous medium indicated that the membranes release the complex gradually when exposed to an aqueous medium. Diabetes was inducted in Wistar rats using 40 mg/kg (i.v.) streptozotocin. On the 7th day after diabetic induction, a circular excision on the skin (1.0 cm) was performed with a punch. The lesions were treated with the pure chitosan membrane and the membrane associated with the zinc-vanillin complex in two different doses. Skin samples were subjected to macroscopic and histopathological analyses, cytokine (TNF-α, IL-1β, and IL-10) quantification and reverse transcriptase polymerase chain reaction (TGF-β and VEGF) assays. The analyses showed a decrease in wound size, reepithelialization, angiogenic stimulus, collagen deposition, and reduced levels of TNF-α and IL-1β as well as increased IL-10 and gene expression of TGF-β and VEGF. The evaluated parameters suggest that CS-ZPV in the two concentrations tested may be effective in the treatment of chronic wounds.

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Section: Discussionsupporting

confidence: 93%

“…There is a growing interest in the development of selective drug delivery systems (Wang and Wang, 2009). In this context, bioabsorbable polymers, such as chitosan, have received special attention in the biomedical area.…”

Section: Introductionmentioning

confidence: 99%

Chitosan Membrane Modified With a New Zinc(II)-Vanillin Complex Improves Skin Wound Healing in Diabetic Rats

et al. 2019

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“…We previously reported a kinetic study on the BBMV uptake of d -phenylglycine-α-methyldopa. The uptake of this dipeptide was also significantly inhibited by typical PepT1 substrate [ 22 ]. The high value of Michaelis-Menten kinetic parameter (Vmax/Km) in comparison to that of passive diffusion (Kd) at low concentrations suggested that PepT1 dominates the transport of the d -phenylglycine-containing dipeptide through the intestine.…”

Section: Discussionmentioning

confidence: 99%

“…We therefore synthesized a series of d -phenylglycine-containing di- and tripeptide derivatives as dopamine prodrug [22]. Rationale behind the design of these compounds was that the oral bioavailability of l -dopa might be improved due to the affinity of d -phenylglycine to PepT1.…”

Section: Introductionmentioning

confidence: 99%

“…Based on the thought that d -phenylglycine is the common moiety in the molecules of PepT1-mediated orally absorbable amino-β-lactams [ 21 ], we thought that this moiety might be useful as a seeing-eye dog for guiding l -dopa to transport through the intestine via PepT1. We therefore synthesized a series of d -phenylglycine-containing di- and tripeptide derivatives as dopamine prodrug [ 22 ]. Rationale behind the design of these compounds was that the oral bioavailability of l -dopa might be improved due to the affinity of d -phenylglycine to PepT1.…”

Section: Introductionmentioning

confidence: 99%

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Evidence of d-phenylglycine as delivering tool for improving l-dopa absorption

Wang

Yang

Lu³

et al. 2010

J Biomed Sci

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Backgroundl-Dopa has been used for Parkinson's disease management for a long time. However, its wide variety in the rate and the extent of absorption remained challenge in designing suitable therapeutic regime. We report here a design of using d-phenylglycine to guard l-dopa for better absorption in the intestine via intestinal peptide transporter I (PepT1).Methodsd-Phenylglycine was chemically attached on l-dopa to form d-phenylglycine-l-dopa as a dipeptide prodrug of l-dopa. The cross-membrane transport of this dipeptide and l-dopa via PepT1 was compared in brush-boarder membrane vesicle (BBMV) prepared from rat intestine. The intestinal absorption was compared by in situ jejunal perfusion in rats. The pharmacokinetics after i.v. and p.o. administration of both compounds were also compared in Wistar rats. The striatal dopamine released after i.v. administration of d-phenylglycine-l-dopa was collected by brain microdialysis and monitored by HPLC. Anti-Parkinsonism effect was determined by counting the rotation of 6-OHDA-treated unilateral striatal lesioned rats elicited rotation with (+)-methamphetamine (MA).ResultsThe BBMV uptake of d-phenylglycine-l-dopa was inhibited by Gly-Pro, Gly-Phe and cephradine, the typical PepT1 substrates, but not by amino acids Phe or l-dopa. The cross-membrane permeability (Pm*) determined in rat jejunal perfusion of d-phenylglycine-l-dopa was higher than that of l-dopa (2.58 ± 0.14 vs. 0.94 ± 0.10). The oral bioavailability of d-phenylglycine-l-dopa was 31.7 times higher than that of l-dopa in rats. A sustained releasing profile of striatal dopamine was demonstrated after i. v. injection of d-phenylglycine-l-dopa (50 mg/kg), indicated that d-phenylglycine-l-dopa might be a prodrug of dopamine. d-Phenylglycine-l-dopa was more efficient than l-dopa in lowering the rotation of unilateral striatal lesioned rats (19.1 ± 1.7% vs. 9.9 ± 1.4%).ConclusionThe BBMV uptake studies indicated that d-phenylglycine facilitated the transport of l-dopa through the intestinal PepT1 transporter. The higher jejunal permeability and the improved systemic bioavailability of d-phenylglycine-l-dopa in comparison to that of l-dopa suggested that d-phenylglycine is an effective delivery tool for improving the oral absorption of drugs like l-dopa with unsatisfactory pharmacokinetics. The gradual release of dopamine in brain striatum rendered this dipeptide as a potential dopamine sustained-releasing prodrug.

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In Vivo Inhibition of Trans-Plasma Membrane Electron Transport by Antiviral Drugs in Grapevine

et al. 2013

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Electrophysiological techniques were applied to investigate the action of antiviral drugs during trans-plasma events in in vivo grapevine cells infected by GLRaV-1 and GLRaV-3. Carbon fiber microelectrodes and redox-sensitive dyes were used to measure trans-plasma membrane electron transport (t-PMET) activity in healthy and infected samples treated with ribavirin, tiazofurin and oseltamivir. Each drug caused a reduction in oxidation current (expressed as Δ[Fe(2+)]) in healthy samples, indicating t-PMET inhibition. In almost all infected samples, the effect of drugs on t-PMET activity was significantly lower, suggesting that higher content of NADH in infected plants can interfere with t-PMET inhibition caused by drugs. Moreover, virus-infected samples exhibited elevated t-PMET activity compared to healthy samples. Analogous effects were observed by dye tests. Considering the effects of drugs on trans-plasma membrane potential, tests showed the activity of a proton pump during drug treatments with no significant difference with regard to health status.

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Biological Transporters as Targets for New Drug Design

Cited by 7 publications

References 90 publications

Chitosan Membrane Modified With a New Zinc(II)-Vanillin Complex Improves Skin Wound Healing in Diabetic Rats

Chitosan Membrane Modified With a New Zinc(II)-Vanillin Complex Improves Skin Wound Healing in Diabetic Rats

Evidence of d-phenylglycine as delivering tool for improving l-dopa absorption

In Vivo Inhibition of Trans-Plasma Membrane Electron Transport by Antiviral Drugs in Grapevine

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