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Manfred Lautenschlager - One of the best experts on this subject based on the ideXlab platform.
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intestinal formation of trans crocetin from saffron extract crocus sativus l and in vitro permeation through intestinal and blood brain barrier
Phytomedicine, 2015Co-Authors: Manfred Lautenschlager, Sabine Huwel, Martina Dufer, Kristina Riehemann, Hans-joachim Galla, S Brandt, Jandirk Sendker, Andreas HenselAbstract:Abstract Aims : Extracts of saffron ( Crocus sativus L.) have traditionally been used against depressions. Recent preclinical and clinical investigations have rationalized this traditional use. Tran s-crocetin, a saffron metabolite originating from the Crocin apocarotenoids, has been shown to exert strong NMDA receptor affinity and is thought to be responsible for the CNS activity of saffron. Pharmacokinetic properties of the main constituents from saffron have only been described to a limited extent. Therefore the present in vitro study aimed to determine if Crocin-1 and trans- crocetin are able to pass the intestinal barrier and to penetrate the blood brain barrier (BBB). Additionally, the intestinal conversion of glycosylated Crocins to the lipophilic crocetin had to be investigated. Experiments with Caco-2 cells and two different porcine BBB systems were conducted. Further on, potential intestinal metabolism of saffron extract was investigated by ex vivo experiments with murine intestine. Methodology: In vitro Caco-2 monolayer cell culture was used for investigation of intestinal permeation of Crocin-1 and trans -crocetin. In vitro models of porcine brain capillary endothelial cells (BCEC) and blood cerebrospinal fluid barrier (BCSFB) were used for monitoring permeation characteristics of trans -crocetin through the blood brain barrier (BBB). Intestine tissue and feces homogenates from mice served for metabolism experiments. Results : Crocin-1, even at high concentrations (1000 µM) does not penetrate Caco-2 monolayers in relevant amounts. In contrast, trans -crocetin permeates in a concentration-independent manner (10–114 µM) the intestinal barrier by transcellular passage with about 32% of the substrate being transported within 2 h and a permeation coefficient of P app 25.7 × 10 − 6 ± 6.23 × 10 − 6 cm/s. Trans -crocetin serves as substrate for pGP efflux pump. Trans -crocetin permeates BBB with a slow but constant velocity over a 29 h period (BCEC system: P app 1.48 × 10 − 6 ± 0.12 × 10 − 6 cm/s; BCSFB system P app 3.85 × 10 − 6 ± 0.21 × 10 − 6 cm/s). Conversion of glycosylated Crocins from saffron extract to trans -crocetin occurs mainly by intestinal cells, rather than by microbiological fermentation in the colon. Conclusion : The here described in vitro studies have shown that Crocins from saffron are probably not bioavailable in the systemic compartment after oral application. On the other side the investigations clearly have pointed out that Crocins get hydrolyzed in the intestine to the deglycosylated trans- crocetin, which subsequently is absorbed by passive transcellular diffusion to a high extend and within a short time interval over the intestinal barrier. Crocetin will penetrate in a quite slow process the blood brain barrier to reach the CNS. The intestinal deglycosylation of different Crocins in the intestine is mainly due to enzymatic processes in the epithelial cells and only to a very minor extent due to deglycosylation by the fecal microbiome. On the other side the fecal bacteria degrade the apocarotenoid backbone to smaller alkyl units, which do not show any more the typical UV absorbance of Crocins. As previous studies have shown strong NMDA receptor affinity and channel opening activity of trans -crocetin the use of saffron for CNS disorders seems to be justified from the pharmacokinetic and pharmacodynamic background.
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effective isolation protocol for secondary metabolites from saffron semi preparative scale preparation of Crocin 1 and trans crocetin
Fitoterapia, 2014Co-Authors: Manfred Lautenschlager, Jandirk Sendker, Matthias Lechtenberg, A HenselAbstract:Abstract Extracts from saffron, the dried stigmata from Crocus sativus L. are recognized as valuable tools for pharmaceutical development in neuroprotection and antidepressive therapy. One major lead compound is Crocin-1 (1), which gets metabolized to the C20-dicarboxylic acid trans-crocetin (2) being responsible for potential NMDA-antagonistic effects in the central nervous system. Neither Crocin-1 nor crocetin are commercially available in sufficient quality and to a reasonable price. The following protocol describes effective methods to obtain both compounds from an EtOH–water extract (2:8) in good yields (about 43% related to the starting material). Crocin-1 (purity > 90%) can be obtained from the extract by means of partition chromatography (FCPC) in a single run without fractionation of the mobile phase by using only the stationary phase and in yields of about 48%, related to the saffron extract. Trans-crocetin can be obtained from the EtOH–water extract by enzymatic deglycosylation of Crocins using commercially available cheap glycosidase mixtures as e.g. Rohm Enzyme® or RohamentCL®. Further polishing can be achieved by flash chromatography on MCI® stationary phase with yields between 6 and 11%. The protocols described provide effective isolation of Crocin-1 and trans-crocetin reference compounds for further preclinical and analytical studies with saffron extracts.
Jandirk Sendker - One of the best experts on this subject based on the ideXlab platform.
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intestinal formation of trans crocetin from saffron extract crocus sativus l and in vitro permeation through intestinal and blood brain barrier
Phytomedicine, 2015Co-Authors: Manfred Lautenschlager, Sabine Huwel, Martina Dufer, Kristina Riehemann, Hans-joachim Galla, S Brandt, Jandirk Sendker, Andreas HenselAbstract:Abstract Aims : Extracts of saffron ( Crocus sativus L.) have traditionally been used against depressions. Recent preclinical and clinical investigations have rationalized this traditional use. Tran s-crocetin, a saffron metabolite originating from the Crocin apocarotenoids, has been shown to exert strong NMDA receptor affinity and is thought to be responsible for the CNS activity of saffron. Pharmacokinetic properties of the main constituents from saffron have only been described to a limited extent. Therefore the present in vitro study aimed to determine if Crocin-1 and trans- crocetin are able to pass the intestinal barrier and to penetrate the blood brain barrier (BBB). Additionally, the intestinal conversion of glycosylated Crocins to the lipophilic crocetin had to be investigated. Experiments with Caco-2 cells and two different porcine BBB systems were conducted. Further on, potential intestinal metabolism of saffron extract was investigated by ex vivo experiments with murine intestine. Methodology: In vitro Caco-2 monolayer cell culture was used for investigation of intestinal permeation of Crocin-1 and trans -crocetin. In vitro models of porcine brain capillary endothelial cells (BCEC) and blood cerebrospinal fluid barrier (BCSFB) were used for monitoring permeation characteristics of trans -crocetin through the blood brain barrier (BBB). Intestine tissue and feces homogenates from mice served for metabolism experiments. Results : Crocin-1, even at high concentrations (1000 µM) does not penetrate Caco-2 monolayers in relevant amounts. In contrast, trans -crocetin permeates in a concentration-independent manner (10–114 µM) the intestinal barrier by transcellular passage with about 32% of the substrate being transported within 2 h and a permeation coefficient of P app 25.7 × 10 − 6 ± 6.23 × 10 − 6 cm/s. Trans -crocetin serves as substrate for pGP efflux pump. Trans -crocetin permeates BBB with a slow but constant velocity over a 29 h period (BCEC system: P app 1.48 × 10 − 6 ± 0.12 × 10 − 6 cm/s; BCSFB system P app 3.85 × 10 − 6 ± 0.21 × 10 − 6 cm/s). Conversion of glycosylated Crocins from saffron extract to trans -crocetin occurs mainly by intestinal cells, rather than by microbiological fermentation in the colon. Conclusion : The here described in vitro studies have shown that Crocins from saffron are probably not bioavailable in the systemic compartment after oral application. On the other side the investigations clearly have pointed out that Crocins get hydrolyzed in the intestine to the deglycosylated trans- crocetin, which subsequently is absorbed by passive transcellular diffusion to a high extend and within a short time interval over the intestinal barrier. Crocetin will penetrate in a quite slow process the blood brain barrier to reach the CNS. The intestinal deglycosylation of different Crocins in the intestine is mainly due to enzymatic processes in the epithelial cells and only to a very minor extent due to deglycosylation by the fecal microbiome. On the other side the fecal bacteria degrade the apocarotenoid backbone to smaller alkyl units, which do not show any more the typical UV absorbance of Crocins. As previous studies have shown strong NMDA receptor affinity and channel opening activity of trans -crocetin the use of saffron for CNS disorders seems to be justified from the pharmacokinetic and pharmacodynamic background.
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effective isolation protocol for secondary metabolites from saffron semi preparative scale preparation of Crocin 1 and trans crocetin
Fitoterapia, 2014Co-Authors: Manfred Lautenschlager, Jandirk Sendker, Matthias Lechtenberg, A HenselAbstract:Abstract Extracts from saffron, the dried stigmata from Crocus sativus L. are recognized as valuable tools for pharmaceutical development in neuroprotection and antidepressive therapy. One major lead compound is Crocin-1 (1), which gets metabolized to the C20-dicarboxylic acid trans-crocetin (2) being responsible for potential NMDA-antagonistic effects in the central nervous system. Neither Crocin-1 nor crocetin are commercially available in sufficient quality and to a reasonable price. The following protocol describes effective methods to obtain both compounds from an EtOH–water extract (2:8) in good yields (about 43% related to the starting material). Crocin-1 (purity > 90%) can be obtained from the extract by means of partition chromatography (FCPC) in a single run without fractionation of the mobile phase by using only the stationary phase and in yields of about 48%, related to the saffron extract. Trans-crocetin can be obtained from the EtOH–water extract by enzymatic deglycosylation of Crocins using commercially available cheap glycosidase mixtures as e.g. Rohm Enzyme® or RohamentCL®. Further polishing can be achieved by flash chromatography on MCI® stationary phase with yields between 6 and 11%. The protocols described provide effective isolation of Crocin-1 and trans-crocetin reference compounds for further preclinical and analytical studies with saffron extracts.
Damian Garciaolmo - One of the best experts on this subject based on the ideXlab platform.
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effects of long term treatment of colon adenocarcinoma with Crocin a carotenoid from saffron crocus sativus l an experimental study in the rat
Nutrition and Cancer, 1999Co-Authors: Hans H Riese, Julio Escribano, Jesus Ontanon, J A Fernandez, M Atienzar, Damian GarciaolmoAbstract:We used an experimental model in the rat to examine the effects of long-term treatment with Crocin, a glycosylated carotenoid from the stigmas of the saffron crocus, on colon cancer. BD-IX rats were divided into four groups: Groups G1 and G2, designated "cancer groups," were used to study the effects of Crocin on the progression of colon cancer, and Groups G3 and G4, designated "toxicity groups," were used to study the effects of the treatment on metabolic processes and the parenchyma. DHD/K12-PROb cells were injected subcutaneously into the chest of Group G1 and G2 animals. From 1 to 13 weeks after inoculation, animals in Groups G2 and G4 received a weekly injection of Crocin (400 mg/kg body wt s.c.). Animals in Groups G1 and G3 received no treatment. In addition, lines of animal and human colon adenocarcinoma cells (DHD/K12-PROb and HT-29) were used to perform assays in vitro to examine the cytotoxicity of Crocin. Life span was extended and tumor growth was slower in Crocin-treated female rats, but no significant antitumor effect was found in male rats. Acute tubular necrosis was found in all kidney samples from Crocin-treated animals, but slight signs of nephrotoxicity were found by biochemical analysis of the serum. In assays in vitro, Crocin had a potent cytotoxic effect on human and animal adenocarcinoma cells (HT-29 and DHD/K12-PROb cells, 50% lethal dose = 0.4 and 1.0 mM, respectively). Treated cells exhibited a remarkable loss of cytoplasm and wide cytoplasmic vacuole-like areas. In conclusion, long-term treatment with Crocin enhances survival selectively in female rats with colon cancer without major toxic effects. The effects of Crocin might be related to its strong cytotoxic effect on cultured tumor cells.
A Hensel - One of the best experts on this subject based on the ideXlab platform.
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effective isolation protocol for secondary metabolites from saffron semi preparative scale preparation of Crocin 1 and trans crocetin
Fitoterapia, 2014Co-Authors: Manfred Lautenschlager, Jandirk Sendker, Matthias Lechtenberg, A HenselAbstract:Abstract Extracts from saffron, the dried stigmata from Crocus sativus L. are recognized as valuable tools for pharmaceutical development in neuroprotection and antidepressive therapy. One major lead compound is Crocin-1 (1), which gets metabolized to the C20-dicarboxylic acid trans-crocetin (2) being responsible for potential NMDA-antagonistic effects in the central nervous system. Neither Crocin-1 nor crocetin are commercially available in sufficient quality and to a reasonable price. The following protocol describes effective methods to obtain both compounds from an EtOH–water extract (2:8) in good yields (about 43% related to the starting material). Crocin-1 (purity > 90%) can be obtained from the extract by means of partition chromatography (FCPC) in a single run without fractionation of the mobile phase by using only the stationary phase and in yields of about 48%, related to the saffron extract. Trans-crocetin can be obtained from the EtOH–water extract by enzymatic deglycosylation of Crocins using commercially available cheap glycosidase mixtures as e.g. Rohm Enzyme® or RohamentCL®. Further polishing can be achieved by flash chromatography on MCI® stationary phase with yields between 6 and 11%. The protocols described provide effective isolation of Crocin-1 and trans-crocetin reference compounds for further preclinical and analytical studies with saffron extracts.
Yukihiro Shoyama - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotective Activities of Saffron and Crocin.
Advances in neurobiology, 2016Co-Authors: Shinji Soeda, Kosuke Aritake, Yoshihiro Urade, Hiroshi Sato, Yukihiro ShoyamaAbstract:We first considered that saffron is really safety food because it has a long-use history. The neuroprotective activities of saffron and its major constituent, Crocin, are separately discussed in vitro and in vivo. We reviewed the inhibitory activities of Crocin against PC-12 cell apoptosis. The oxidative stress decreased the cellular levels of glutathione (GSH) which is an inhibitor of neutral sphingomyelinase (N-SMase). Therefore, the level of GSH was assayed by the addition of Crocin resulted in the activation of glutathione reductase (GR). It became evident that Crocin treatment prevents the N-SMase activation resulting in the decrease of ceramide release. From these evidences we summarized the role of Crocin for neuronal cell death. We used the ethanol-blocking assay system for learning and memory activities. The effect of saffron and Crocin on improving ethanol-induced impairment of learning behaviors of mice in passive avoidance tasks has been clear. Further, we did make clear that saffron and Crocin prevent the inhibitory effect of ethanol on long-term potentiation (LTP) in the dentate gyrus. Finally we found that 100 mg/kg of Crocin gave non-rapid eye movement sleep (non-REM sleep) although mice were started to be active during night time.
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dietary Crocin inhibits colitis and colitis associated colorectal carcinogenesis in male icr mice
Evidence-based Complementary and Alternative Medicine, 2012Co-Authors: Kunihiro Kawabata, Yukihiro Shoyama, Nguyen Huu Tung, Shigeyuki Sugie, Takayuki Mori, Takuji TanakaAbstract:A natural carotenoid Crocin is contained in saffron and gardenia flowers (crocuses and gardenias) and is used as a food colorant. This study reports the potential inhibitory effects of Crocin against inflammation-associated mouse colon carcinogenesis and chemically induced colitis in male ICR mice. In the first experiment, dietary Crocin significantly inhibited the development of colonic adenocarcinomas induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) in mice by week 18. Crocin feeding also suppressed the proliferation and immunohistochemical expression of nuclear factor- (NF-) κB but increased the NF-E2-related factor 2 (Nrf2) expression, in adenocarcinoma cells. In the second experiment, dietary feeding with Crocin for 4 weeks was able to inhibit DSS-induced colitis and decrease the mRNA expression of tumor necrosis factor α, interleukin- (IL-) 1β, IL-6, interferon γ, NF-κB, cyclooxygenase-2, and inducible nitric oxide synthase in the colorectal mucosa and increased the Nrf2 mRNA expression. Our results suggest that dietary Crocin suppresses chemically induced colitis and colitis-related colon carcinogenesis in mice, at least partly by inhibiting inflammation and the mRNA expression of certain proinflammatory cytokines and inducible inflammatory enzymes. Therefore, Crocin is a candidate for the prevention of colitis and inflammation-associated colon carcinogenesis.
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Promising Pharmacological Actions of Crocin in Crocus Sativus on the Central Nervous System
Studies in natural products chemistry, 2007Co-Authors: Shinji Soeda, Takashi Ochiai, Hiroshi Shimeno, Hiroyuki Tanaka, Hiroshi Saito, Minoru Sugiura, Futoshi Taura, Satoshi Morimoto, Yukihiro ShoyamaAbstract:ABSTRACT: Information on clinically available activities in both peripheral and neuronal systems of Crocin in saffron has been accumulated. The LTP-blocking effect of ethanol was significantly improved by oral-, intravenous-, and intracerebroventricular-administration of Crocin, respectively. We investigated the effects of ethanol and Crocin on synaptic potentials mediated by N-methyl-D-aspartate (NMDA) receptors in the dentate gyrus of rat hippocampal slices. Crocin alone did not affect synaptic potentials mediated by non-NMDA or NMDA receptors. Crocin did not affect the inhibition of non-NMDA response by 100 mM ethanol, but significantly blocked the inhibition of NMDA response by 10-50 mM ethanol. We performed whole-cell patch recording with primary cultured rat hippocampal neurons, and confirmed that Crocin blocked ethanol inhibition of inward currents evoked by the application of NMDA. We also demonstrated that Crocin suppresses the effect of tumor necrosis factor (TNF)-α on neuronally differentiated PC-12 cells. The modulating effects of Crocin on the expression of Bcl-2 family proteins led to a marked reduction of a TNF-α-induced release of cytochrome c from the mitochondoria. Crocin also blocked the cyotochrome c-induced activation of caspase-3. We found that Crocin inhibited the effect of daunorubicin as well. The present paper focuses on the pharmacological actions of Crocin on the central nervous system and reviews briefly the findings of such studies on the prevention of neuronal programmed cell death (apoptosis).
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Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo.
Biochimica et Biophysica Acta, 2006Co-Authors: Takashi Ochiai, Hiroshi Shimeno, Akihisa Toda, Reiko Eyanagi, Michihiro Fujiwara, Katsunori Iwasaki, Hiroyuki Tanaka, Kenichi Mishima, Yukihiro Shoyama, Shinji SoedaAbstract:Abstract Crocus sativus L. (saffron) has been used as a spice for flavoring and coloring food preparations, and in Chinese traditional medicine as an anodyne or tranquilizer. Our previous study demonstrated that Crocin, a carotenoid pigment of saffron, can suppress the serum deprivation-induced death of PC12 cells by increasing glutathione (GSH) synthesis and thus inhibiting neutral sphingomyelinase (nSMase) activity and ceramide formation. The carotenoid pigments of saffron consist of crocetin di-(β- d -glucosyl)-ester [diCrocin], crocetin-(β- d -gentiobiosyl)-(β- d -glucosyl)-ester [triCrocin] and crocetin-di-(β- d -gentiobiosyl)-ester [Crocin]. Saffron also contains picroCrocin, the substance causing saffron's bitter taste. In this study, to confirm whether neuroprotective effects of saffron are caused solely by Crocin, we examined the antioxidant and GSH-synthetic activities of these Crocins in PC12 cells under serum-free and hypoxic conditions. Measurements of cell viability, peroxidized membrane lipids and caspase-3 activity showed that the rank order of the neuroprotective potency at a concentration of 10 μM was Crocin > triCrocin > diCrocin and picroCrocin (the latter two Crocins had a little or no potency). In addition, we show that among these saffron's constituents, Crocin most effectively promotes mRNA expression of γ-glutamylcysteinyl synthase (γ-GCS), which contributes to GSH synthesis as the rate-limiting enzyme, and that the carotenoid can significantly reduce infarcted areas caused by occlusion of the middle cerebral artery (MCA) in mice.
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Crocin prevents the death of rat pheochromyctoma pc 12 cells by its antioxidant effects stronger than those of α tocopherol
Neuroscience Letters, 2004Co-Authors: Takashi Ochiai, Shinji Soeda, Hiroyuki Tanaka, Yukihiro Shoyama, Shigekazu Ohno, Hiroshi ShimenoAbstract:Crocin is a pharmacologically active component of Crocus sativus L. (saffron) used in traditional Chinese medicine. We report here the effects of Crocin on neuronally differentiated pheochromocytoma (PC-12) cells deprived of serum/glucose. Depriving the PC-12 cells of serum/glucose caused peroxidation of their cell membrane lipids and decreased intercellular superoxide dismutase (SOD) activity. Treating the PC-12 cells with 10 μM Crocin inhibited the formation of peroxidized lipids, partly restored the SOD activity, and maintained the neuron's morphology. These antioxidant effects of Crocin were more effective than those of α-tocopherol at the same concentration. Crocin also suppressed the activation of caspase-8 caused by serum/glucose deprivation. These results together with our previous data suggest that Crocin is a unique and potent antioxidant that combats oxidative stress in neurons.