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81.
S Khom B Strommer J Ramharter T Schwarz C Schwarzer T Erker GF Ecker J Mulzer S Hering 《British journal of pharmacology》2010,161(1):65-78
BACKGROUND AND PURPOSE
Subunit-specific modulators of γ-aminobutyric acid (GABA) type A (GABAA) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic acid (VA) was recently identified as a β2/3 subunit-specific modulator of GABAA receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABAA receptor modulators and to gain insight into the structure–activity relation of this molecule.EXPERIMENTAL APPROACH
The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABAA receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (IGABA) through GABAA receptors (EC50) and efficacies (maximal stimulation of IGABA) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test.KEY RESULTS
Valerenic acid amide (VA-A) displayed the highest efficacy (more than twofold greater IGABA enhancement than VA) and highest potency (EC50= 13.7 ± 2.3 µM) on α1β3 receptors. Higher efficacy and potency of VA-A were also observed on α1β2γ2s and α3β3γ2s receptors. Anxiolytic effects were most pronounced for VA-A.CONCLUSIONS AND IMPLICATIONS
Valerenic acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting β3 subunit containing GABAA receptors for development of anxiolytics. 相似文献82.
83.
Almac E Aksu U Bezemer R Jong W Kandil A Yuruk K Demirci-Tansel C Ince C 《Resuscitation》2012,83(9):1166-1172
IntroductionFluid resuscitation therapy is the initial step of treatment for hemorrhagic shock. In the present study we aimed to investigate the acute effects of acetate-balanced colloid and crystalloid resuscitation on renal oxygenation in a rat model of hemorrhagic shock. We hypothesized that acetate-balanced solutions would be superior in correcting impaired renal perfusion and oxygenation after severe hemorrhage compared to unbalanced solutions.MethodsIn anesthetized, mechanically ventilated rats, hemorrhagic shock was induced by withdrawing blood from the femoral artery until mean arterial pressure (MAP) was reduced to 30 mmHg. One hour later, animals were resuscitated with either hydroxyethyl starch (HES, 130/0.42 kDa) dissolved in saline (HES-NaCl; n = 6) or a acetate-balanced Ringer's solution (HES-RA; n = 6), as well as with acetated Ringer's solution (RA; n = 6) or 0.9% NaCl alone (NaCl; n = 6) until a target MAP of 80 mmHg was reached. Oxygen tension in the renal cortex (CμPO2), outer medulla (MμPO2), and renal vein were measured using phosphorimetry.ResultsHemorrhagic shock (MAP = 30 mmHg) significantly decreased renal oxygenation and oxygen consumption. Restoring the MAP to 80 mmHg required 24.8 ± 1.7 ml of NaCl, 21.7 ± 1.4 ml of RA, 5.9 ± 0.5 ml of HES-NaCl (p < 0.05 vs. NaCl and RA), and 6.0 ± 0.4 ml of HES-RA (p < 0.05 vs. NaCl and RA). NaCl, RA, and HES-NaCl resuscitation led to hyperchloremic acidosis, while HES-RA resuscitation did not. Only HES-RA resuscitation could restore renal blood flow back to ~85% of baseline level (from 1.9 ± 0.1 ml/min during shock to 5.1 ml ± 0.2 ml/min 60 min after HES-RA resuscitation) which was associated with an improved renal oxygenation (CμPO2 increased from 24 ± 2 mmHg during shock to 50 ± 2 mmHg 60 min after HES-RA resuscitation) albeit not to baseline level. At the end of the protocol, creatinine clearance was decreased in all groups with no differences between the different resuscitation groups.ConclusionWhile resuscitation with the NaCl and RA (crystalloid solutions) and the HES-NaCl (unbalanced colloid solution) led to hyperchloremic acidosis, resuscitation with the HES-RA (acetate-balanced colloid solution) did not. The HES-RA was furthermore the only fluid restoring renal blood flow back to ~85% of baseline level and most prominently improved renal microvascular oxygenation. 相似文献
84.
85.
Mandy van Gulijk Bob Belderbos Daphne Dumoulin Robin Cornelissen Koen Bezemer Larissa Klaase Floris Dammeijer Joachim Aerts 《International journal of cancer. Journal international du cancer》2023,152(7):1438-1443
Immunotherapy with anti-PD1/PD-L1 is effective in only a subgroup of patients with malignant pleural mesothelioma (MPM). We investigated the efficacy of a combination of anti-PD1/PD-L1 and dendritic cell (DC) therapy to optimally induce effective anti-tumor immunity in MPM in both humans and mice. Data of nine MPM patients treated with DC therapy and sequential anti-PD1 treatment were collected and analyzed for progression-free survival (PFS) and overall survival (OS). Survival and T-cell responses were monitored in AC29 mesothelioma-bearing mice treated concurrently with the combination therapy; additionally, the role of the tumor-draining lymph node (TDLN) was investigated. The combination therapy resulted in a median OS and PFS of 17.7 and 8.0 months, respectively. Grade 3 to 4 treatment-related adverse events had not been reported. Survival of the mesothelioma-bearing mice treated with the combination therapy was longer than that of untreated mice, and coincided with improved T-cell activation in peripheral blood and less T-cell exhaustion in end stage tumors. Comparable results were obtained when solely the TDLN was targeted. We concluded that this combination therapy is safe and shows promising OS and PFS. The murine data support that PD-L1 treatment may reinvigorate the T-cell responses induced by DC therapy, which may primarily be the result of TDLN targeting. 相似文献
86.
87.
A review of the recent literature regarding malignant transformation of oral lichen planus. 总被引:11,自引:0,他引:11
E H van der Meij K P Schepman L E Smeele J E van der Wal P D Bezemer I van der Waal 《Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics》1999,88(3):307-310
On the basis of a literature review of the period 1950-1976, Krutchkoff et al questioned the possible premalignant nature of oral lichen planus. Their criticism was largely based on insufficiencies of data in support of the initial diagnoses of the condition. In this article, a review of the literature from the period 1977-1999 has been described; the criteria used were those of Krutchkoff et al. Thirty-three (34%) of 98 reported cases were accepted as having sufficiently documented evidence of malignant transformation of oral lichen planus. Although this percentage is somewhat higher than the percentage reported by Krutchkoff et al, there apparently remains a need for uniformly accepted criteria to establish a firm diagnosis of oral lichen planus. Only when such criteria are available will it be possible to conduct long-term prospective studies on the suggested possible premalignant nature of oral lichen planus. 相似文献
88.
J M Bezemer D W Grijpma P J Dijkstra C A van Blitterswijk J Feijen 《Journal of controlled release》2000,66(2-3):307-320
Protein-containing films and microspheres, based on poly(ethylene glycol)-poly(butylene terephthalate) (PEG-PBT) multiblock copolymers, were prepared from water-in-oil (w/o) emulsions. The properties of the matrices could be controlled by the water-to-polymer ratio (w/p) in the w/o emulsion. A linear increase in water uptake of the matrices was observed with increasing emulsion w/p. This could be explained by an increase in the number of dispersed water-rich domains in the polymer matrix. At low volume fraction of the dispersed phase (epsilon), lysozyme release was mainly dependent on the permeability of the swollen polymer bulk. Above a critical volume fraction (the percolation threshold epsilon(c)), the dispersed water-rich phase formed an interconnected network, which largely enhanced the permeability of the matrix. Determination of the permeability of PEG-PBT matrices for vitamin B(12) as a function of epsilon confirmed the formation of such an interconnected network. This interconnected network could be used to achieve controlled release of a large protein (bovine serum albumin, BSA) from PEG-PBT films and microspheres. Due to its hydrodynamic diameter, BSA was screened by the polymer network when epsilon was low. However above epsilon(c), the fraction released BSA increased with increasing volume fraction of the dispersed phase. A very rapid BSA release could be obtained, with the majority of the incorporated BSA released within 1 day, as well as a slow and continuous release, lasting for over 150 days. When BSA-containing microspheres were prepared with a volume fraction just below the percolation threshold, a delayed release was observed. This was attributed to the effect of polymer degradation on matrix permeability. 相似文献
89.
90.
Wang Minjiao Qian Yifeng Zhao Hanjiang Zhu Min Yu Hongbo Shen Steve GF. 《Clinical oral investigations》2022,26(12):7083-7093
Clinical Oral Investigations - To evaluate postoperative mandibular stability and condylar changes in patients with mandibular hypoplasia and preoperative condylar resorption (CR) undergoing... 相似文献