The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Hsing-wen Sung - One of the best experts on this subject based on the ideXlab platform.
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a novel ph sensitive hydrogel composed of n o carboxymethyl chitosan and alginate cross linked by Genipin for protein drug delivery
Journal of Controlled Release, 2004Co-Authors: Sung Ching Chen, Yuhsin Lin, Hsing-wen SungAbstract:A novel pH-sensitive hydrogel system composed of a water-soluble chitosan derivative (N,O-carboxymethyl chitosan, NOCC) and alginate blended with Genipin was developed for controlling protein drug delivery. Genipin, a naturally occurring cross-linking agent, is significantly less cytotoxic than glutaraldehyde and may provide a less extent of cross-linking to form a semiinterpenetrating polymeric network (semi-IPN) within the developed hydrogel system. The drug-loading process used in the study was simple and mild. All procedures used were performed in aqueous medium at neutral environment. In the study, preparation of the NOCC/alginate-based hydrogels was reported. Swelling characteristics of these hydrogels as a function of pH values were investigated. Additionally, release profiles of a model protein drug (bovine serum albumin, BSA) from test hydrogels were studied in simulated gastric and intestinal media. The semi-IPN formation of the Genipin-cross-linked NOCC/alginate hydrogel was confirmed by means of the scanning electron microscopy-energy dispersive X-ray spectrometer (SEM-EDS) and the ninhydrin assays. The percentage of decrease of free amino groups and cross-linking density for the NOCC/alginate hydrogel cross-linked with 0.75 mM Genipin were 18% and 26 mol/m(3), respectively. At pH 1.2, the swelling ratio of the Genipin-cross-linked NOCC/alginate hydrogel was limited (2.5) due to formation of hydrogen bonds between NOCC and alginate. At pH 7.4, the carboxylic acid groups on the Genipin-cross-linked NOCC/alginate hydrogel became progressively ionized. In this case, the hydrogel swelled more significantly (6.5) due to a large swelling force created by the electrostatic repulsion between the ionized acid groups. The amount of BSA released at pH 1.2 was relatively low (20%), while that released at pH 7.4 increased significantly (80%). The results clearly suggested that the Genipin-cross-linked NOCC/alginate hydrogel could be a suitable polymeric carrier for site-specific protein drug delivery in the intestine.
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Genipin crosslinked gelatin microspheres as a drug carrier for intramuscular administration in vitro and in vivo studies
Journal of Biomedical Materials Research Part A, 2003Co-Authors: Huangchien Liang, Wenhsiang Chang, Kojung Lin, Hsing-wen SungAbstract:Gelatin microspheres have been widely evaluated as a drug carrier. Nevertheless, gelatin dissolves rather rapidly in aqueous environments, making the use of the polymer difficult for the production of long-term delivery systems. This adverse aspect requires the use of a crosslinking agent in forming nonsoluble networks in microspheres. However, the use of crosslinking agents such as formaldehyde and glutaraldehyde can lead to toxic side effects owing to residual crosslinkers. In an attempt to overcome this problem, a naturally occurring crosslinking agent (Genipin) was used to crosslink gelatin microspheres as a biodegradable drug-delivery system for intramuscular administration. Glutaraldehyde was used as a control. In the in vitro study, the morphology, dynamic swelling, and antienzymatic degradation of test microspheres were evaluated. In the in vivo study, the biocompatibility and degradability of test microspheres were implanted in the skeletal muscle of a rat model via intramuscular injection. The results obtained in the study suggested that crosslinking of gelatin microspheres with glutaraldehyde or Genipin may produce distinct crosslinking structures. The water transport mechanism in both the glutaraldehyde- and Genipin-crosslinked gelatin microspheres exhibit anomalous behavior ranging from Fickian to Case-II extremes. The increase of the swelling diameter for the Genipin-crosslinked microspheres was significantly less than that observed for the glutaraldehyde-crosslinked microspheres. In the animal study, it was found that the degree in inflammatory reaction for tissues implanted with the Genipin-crosslinked microspheres was significantly less than that implanted with the glutaraldehyde-crosslinked microspheres. Additionally, the degradation rate of the Genipin-crosslinked microspheres was significantly slower than their glutaraldehyde-crosslinked counterparts. These results indicated that the Genipin-crosslinked gelatin microspheres may be used as a long-acting drug carrier for intramuscular administration. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 65A: 271–282, 2003
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Genipin crosslinked gelatin microspheres as a drug carrier for intramuscular administration in vitro and in vivo studies
Journal of Biomedical Materials Research Part A, 2003Co-Authors: Huangchien Liang, Wenhsiang Chang, Kojung Lin, Hsing-wen SungAbstract:Gelatin microspheres have been widely evaluated as a drug carrier. Nevertheless, gelatin dissolves rather rapidly in aqueous environments, making the use of the polymer difficult for the production of long-term delivery systems. This adverse aspect requires the use of a crosslinking agent in forming nonsoluble networks in microspheres. However, the use of crosslinking agents such as formaldehyde and glutaraldehyde can lead to toxic side effects owing to residual crosslinkers. In an attempt to overcome this problem, a naturally occurring crosslinking agent (Genipin) was used to crosslink gelatin microspheres as a biodegradable drug-delivery system for intramuscular administration. Glutaraldehyde was used as a control. In the in vitro study, the morphology, dynamic swelling, and antienzymatic degradation of test microspheres were evaluated. In the in vivo study, the biocompatibility and degradability of test microspheres were implanted in the skeletal muscle of a rat model via intramuscular injection. The results obtained in the study suggested that crosslinking of gelatin microspheres with glutaraldehyde or Genipin may produce distinct crosslinking structures. The water transport mechanism in both the glutaraldehyde- and Genipin-crosslinked gelatin microspheres exhibit anomalous behavior ranging from Fickian to Case-II extremes. The increase of the swelling diameter for the Genipin-crosslinked microspheres was significantly less than that observed for the glutaraldehyde-crosslinked microspheres. In the animal study, it was found that the degree in inflammatory reaction for tissues implanted with the Genipin-crosslinked microspheres was significantly less than that implanted with the glutaraldehyde-crosslinked microspheres. Additionally, the degradation rate of the Genipin-crosslinked microspheres was significantly slower than their glutaraldehyde-crosslinked counterparts. These results indicated that the Genipin-crosslinked gelatin microspheres may be used as a long-acting drug carrier for intramuscular administration.
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crosslinking of biological tissues using Genipin and or carbodiimide
Journal of Biomedical Materials Research Part A, 2003Co-Authors: Hsing-wen Sung, Wenhisang Chang, Meng-horng LeeAbstract:The study was to investigate the crosslinking characteristics, mechanical properties, and resistance against enzymatic degradation of biological tissues after fixation with Genipin (a naturally occurring crosslinking agent) and/or carbodiimide. Fresh tissue was used as a control. It was found that both Genipin and carbodiimide are effective crosslinking agents for tissue fixation and Genipin crosslinking is comparatively slower than carbodiimide crosslinking. Additionally, tissue fixation in Genipin and/or carbodiimide may produce distinct crosslinking structures. Carbodiimide may form intrahelical and interhelical crosslinks within or between tropocollagen molecules, whereas Genipin may further introduce intermicrofibrillar crosslinks between adjacent collagen microfibrils. The stability (denaturation temperature and resistance against enzymatic degradation) of the fixed tissue is mainly determined by its intrahelical and interhelical crosslinks. In contrast, intermicrofibrillar crosslinks significantly affect the mechanical properties (tissue shrinkage during fixation, tensile strength, strain at break, and ruptured pattern) of the fixed tissue. Moreover, the degree of enzymatic degradation of the fixed tissue may be influenced by three factors: the availability, to the enzyme, of recognizable cleavage sites, the degree of crosslinking, and the extent of helical integrity of tropocollagen molecules in tissue. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 64A: 427–438, 2003
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crosslinking of biological tissues using Genipin and or carbodiimide
Journal of Biomedical Materials Research Part A, 2003Co-Authors: Hsing-wen Sung, Wenhisang Chang, Meng-horng LeeAbstract:The study was to investigate the crosslinking characteristics, mechanical properties, and resistance against enzymatic degradation of biological tissues after fixation with Genipin (a naturally occurring crosslinking agent) and/or carbodiimide. Fresh tissue was used as a control. It was found that both Genipin and carbodiimide are effective crosslinking agents for tissue fixation and Genipin crosslinking is comparatively slower than carbodiimide crosslinking. Additionally, tissue fixation in Genipin and/or carbodiimide may produce distinct crosslinking structures. Carbodiimide may form intrahelical and interhelical crosslinks within or between tropocollagen molecules, whereas Genipin may further introduce intermicrofibrillar crosslinks between adjacent collagen microfibrils. The stability (denaturation temperature and resistance against enzymatic degradation) of the fixed tissue is mainly determined by its intrahelical and interhelical crosslinks. In contrast, intermicrofibrillar crosslinks significantly affect the mechanical properties (tissue shrinkage during fixation, tensile strength, strain at break, and ruptured pattern) of the fixed tissue. Moreover, the degree of enzymatic degradation of the fixed tissue may be influenced by three factors: the availability, to the enzyme, of recognizable cleavage sites, the degree of crosslinking, and the extent of helical integrity of tropocollagen molecules in tissue.
Byungchul Kim - One of the best experts on this subject based on the ideXlab platform.
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Genipin up regulates heme oxygenase 1 via pi3 kinase jnk1 2 nrf2 signaling pathway to enhance the anti inflammatory capacity in raw264 7 macrophages
Archives of Biochemistry and Biophysics, 2011Co-Authors: Wookwang Jeon, Byungchul Kim, Heyyoung HongAbstract:Abstract Genipin, an aglycon of geniposide, has been reported to exhibit diverse pharmacological functions such as antitumor and anti-inflammatory effects. This study aimed to elucidate the anti-inflammatory mechanism of Genipin, focusing particularly on the role of heme oxygenase-1 (HO-1), a potent anti-inflammatory enzyme. In RAW264.7 cells, Genipin increased HO-1 expression and its enzyme activity via a NF-E2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway. These effects were significantly inhibited by exposure to the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, or by expression of a dominant negative mutant of PI 3-kinase. Additional experiments showed that the activation of c-Jun NH 2 -terminal kinase 1/2 (JNK1/2) is required for Genipin-induced phosphorylation and nuclear translocation of Nrf2 and antioxidant response element (ARE)-driven induction of HO-1, and acts as a downstream effector of PI 3-kinase. Furthermore, functional significance of HO-1 induction was revealed by Genipin-mediated inhibition of lipopolysaccharide-stimulated inducible nitric oxide synthase expression or cyclooxygenase-2 promoter activity, the response was reversed by the blocking of HO-1 protein synthesis or HO-1 enzyme activity. Therefore, identification of PI 3-kinase-JNK1/2-Nrf2-linked signaling cascade in Genipin-mediated HO-1 expression defines the signaling event that could participate in Genipin-mediated anti-inflammatory response.
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mixed lineage kinase 3 connects reactive oxygen species to c jun nh2 terminal kinase induced mitochondrial apoptosis in Genipin treated pc3 human prostate cancer cells
Biochemical and Biophysical Research Communications, 2007Co-Authors: Hyeyoung Hong, Byungchul KimAbstract:It has been reported that Genipin, the aglycone of geniposide, induces apoptotic cell death in human hepatoma cells via a NADPH oxidase-reactive oxygen species (ROS)-c-Jun NH(2)-terminal kinase (JNK)-dependent activation of mitochondrial pathway. This continuing work aimed to define that mixed lineage kinase 3 (MLK3) is a key mediator, which connect between ROS and JNK in Genipin-induced cell death signaling. In PC3 human prostate cancer cells, Genipin stimulated MLK3 activity in concentration- and time-dependent manner. The PC3 cells stably transfected with dominant-negative form of MLK3 was less susceptible to population of the sub-G1 apoptotic cells, activation of caspase, collapse of mitochondrial membrane potential, and release of cytochrome c triggered by Genipin, suggesting a crucial role of MLK3 in Genipin signaling to apoptotic cell death. Diphenyleneiodonium (DPI), a specific inhibitor of NADPH oxidase, markedly inhibited ROS generation and MLK3 phosphorylation in the Genipin-treated cells. Pretreatment with SP0600125, a specific inhibitor of JNK but neither U0126, a specific inhibitor of MEK1/2 nor PD169316, a specific inhibitor of p38 suppressed Genipin-induced apoptotic cell death. Notably, both the phosphorylation of JNK and induction of c-Jun induced by Genipin were markedly inhibited in PC3-EGFP-MLK3 (K144R) cells expressing a dominant-negative MLK3 mutant. Taken together, our observations suggest Genipin signaling to apoptosis of PC3 cells is mediated via activation of ROS-dependent MLK3, which leads to downstream activation of JNK.
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Genipin induced apoptosis in hepatoma cells is mediated by reactive oxygen species c jun nh2 terminal kinase dependent activation of mitochondrial pathway
Biochemical Pharmacology, 2005Co-Authors: Byungchul Kim, Eun-hee Park, Honggyum Kim, Sin Ae Lee, Seunghwan Lim, Seong Jin Kim, Chang Jin LimAbstract:Genipin, the aglycone of geniposide, exhibits anti-inflammatory and anti-angiogenic activities. Here we demonstrate that Genipin induces apoptotic cell death in FaO rat hepatoma cells and human hepatocarcinoma Hep3B cells, detected by morphological cellular changes, caspase activation and release of cytochrome c. During Genipin-induced apoptosis, reactive oxygen species (ROS) level was elevated, and N-acetyl-l-cysteine (NAC) and glutathione (GSH) suppressed activation of caspase-3, -7 and -9. Stress-activated protein kinase/c-Jun NH2-terminal kinase 1/2(SAPK/JNK1/2) but neither MEK1/2 nor p38 MAPK was activated in Genipin-treated hepatoma cells. SP600125, an SAPK/JNK1/2 inhibitor, markedly suppressed apoptotic cell death in the Genipin-treated cells. The FaO cells stably transfected with a dominant-negative c-Jun, TAM67, was less susceptible to apoptotic cell death triggered by Genipin. Diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, inhibited ROS generation, apoptotic cell death, caspase-3 activation and JNK activation. Consistently, the stable expression of Nox1-C, a C-terminal region of Nox1 unable to generate ROS, blocked the formation of TUNEL-positive apoptotic cells, and activation of caspase-3 and JNK in FaO cells treated with Genipin. Our observations imply that Genipin signaling to apoptosis of hepatoma cells is mediated via NADPH oxidase-dependent generation of ROS, which leads to downstream of JNK.
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Antiinflammatory effects of Genipin, an active principle of gardenia.
European journal of pharmacology, 2004Co-Authors: Hye-jin Koo, Byungchul Kim, Chang Jin Lim, Yun Seon Song, Hee-jeong Kim, Yong-ha Lee, Sung-min Hong, Su-jung Kim, Changbae Jin, Eun-hee ParkAbstract:Genipin, the aglycone of geniposide, is metabolically produced from the geniposide in body tissues. The purpose of this study is to clarify some pharmacological actions of Genipin. Genipin showed concentration-dependent inhibition on lipid peroxidation induced by Fe++/ascorbate in rat brain homogenate. Genipin exhibited significant topical antiinflammatory effect shown as an inhibition of croton oil-induced ear edema in mice. Nitric oxide (NO) synthesis by inducible nitric oxide synthase (iNOS) is increased in inflammatory diseases and leads to cellular injury. Genipin concentration-dependently (50-300 microM) inhibited NO production and iNOS expression upon stimulation by lipopolysaccharide/interferon-gamma (IFN-gamma) in RAW 264.7, a murine macrophage cell line. Genipin markedly blocked lipopolysaccharide-evoked degradation of inhibitor-kappaB-beta (IkappaB-beta), indicating that it exhibits inhibitory effect on NO production through the inhibition of nuclear factor-kappaB (NF-kappaB) activation. It was also shown to contain potent antiangiogenic activity in a dose-dependent manner, which was detected by chick embryo chorioallantoic membrane assay. In summary, we demonstrate that Genipin possesses antiinflammatory and is a specific hydroxyl radical scavenger. Its antiangiogenic and NO production-inhibitory properties are also presented.
Huangchien Liang - One of the best experts on this subject based on the ideXlab platform.
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Genipin crosslinked gelatin microspheres as a drug carrier for intramuscular administration in vitro and in vivo studies
Journal of Biomedical Materials Research Part A, 2003Co-Authors: Huangchien Liang, Wenhsiang Chang, Kojung Lin, Hsing-wen SungAbstract:Gelatin microspheres have been widely evaluated as a drug carrier. Nevertheless, gelatin dissolves rather rapidly in aqueous environments, making the use of the polymer difficult for the production of long-term delivery systems. This adverse aspect requires the use of a crosslinking agent in forming nonsoluble networks in microspheres. However, the use of crosslinking agents such as formaldehyde and glutaraldehyde can lead to toxic side effects owing to residual crosslinkers. In an attempt to overcome this problem, a naturally occurring crosslinking agent (Genipin) was used to crosslink gelatin microspheres as a biodegradable drug-delivery system for intramuscular administration. Glutaraldehyde was used as a control. In the in vitro study, the morphology, dynamic swelling, and antienzymatic degradation of test microspheres were evaluated. In the in vivo study, the biocompatibility and degradability of test microspheres were implanted in the skeletal muscle of a rat model via intramuscular injection. The results obtained in the study suggested that crosslinking of gelatin microspheres with glutaraldehyde or Genipin may produce distinct crosslinking structures. The water transport mechanism in both the glutaraldehyde- and Genipin-crosslinked gelatin microspheres exhibit anomalous behavior ranging from Fickian to Case-II extremes. The increase of the swelling diameter for the Genipin-crosslinked microspheres was significantly less than that observed for the glutaraldehyde-crosslinked microspheres. In the animal study, it was found that the degree in inflammatory reaction for tissues implanted with the Genipin-crosslinked microspheres was significantly less than that implanted with the glutaraldehyde-crosslinked microspheres. Additionally, the degradation rate of the Genipin-crosslinked microspheres was significantly slower than their glutaraldehyde-crosslinked counterparts. These results indicated that the Genipin-crosslinked gelatin microspheres may be used as a long-acting drug carrier for intramuscular administration. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 65A: 271–282, 2003
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Genipin crosslinked gelatin microspheres as a drug carrier for intramuscular administration in vitro and in vivo studies
Journal of Biomedical Materials Research Part A, 2003Co-Authors: Huangchien Liang, Wenhsiang Chang, Kojung Lin, Hsing-wen SungAbstract:Gelatin microspheres have been widely evaluated as a drug carrier. Nevertheless, gelatin dissolves rather rapidly in aqueous environments, making the use of the polymer difficult for the production of long-term delivery systems. This adverse aspect requires the use of a crosslinking agent in forming nonsoluble networks in microspheres. However, the use of crosslinking agents such as formaldehyde and glutaraldehyde can lead to toxic side effects owing to residual crosslinkers. In an attempt to overcome this problem, a naturally occurring crosslinking agent (Genipin) was used to crosslink gelatin microspheres as a biodegradable drug-delivery system for intramuscular administration. Glutaraldehyde was used as a control. In the in vitro study, the morphology, dynamic swelling, and antienzymatic degradation of test microspheres were evaluated. In the in vivo study, the biocompatibility and degradability of test microspheres were implanted in the skeletal muscle of a rat model via intramuscular injection. The results obtained in the study suggested that crosslinking of gelatin microspheres with glutaraldehyde or Genipin may produce distinct crosslinking structures. The water transport mechanism in both the glutaraldehyde- and Genipin-crosslinked gelatin microspheres exhibit anomalous behavior ranging from Fickian to Case-II extremes. The increase of the swelling diameter for the Genipin-crosslinked microspheres was significantly less than that observed for the glutaraldehyde-crosslinked microspheres. In the animal study, it was found that the degree in inflammatory reaction for tissues implanted with the Genipin-crosslinked microspheres was significantly less than that implanted with the glutaraldehyde-crosslinked microspheres. Additionally, the degradation rate of the Genipin-crosslinked microspheres was significantly slower than their glutaraldehyde-crosslinked counterparts. These results indicated that the Genipin-crosslinked gelatin microspheres may be used as a long-acting drug carrier for intramuscular administration.
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in vivo evaluation of cellular and acellular bovine pericardia fixed with a naturally occurring crosslinking agent Genipin
Biomaterials, 2002Co-Authors: Yen Chang, Huangchien Liang, Chenchi Tsai, Hsing-wen SungAbstract:Abstract A cell extraction process was employed in the study to remove the cellular components from bovine pericardium, leaving a framework of largely insoluble collagen and elastin. It was hypothesized in the literature that this process may decrease the antigenic load (or increase the biocompatibility) within the material. Additionally, acellular tissues may provide a natural microenvironment for host-cell migration to regenerate the tissue. The study was to evaluate the biocompatibility of cellular and acellular bovine pericardia fixed with a naturally occurring crosslinking agent (Genipin) implanted subcutaneously in a growing rat model. Additionally, the tissue regeneration rate in the Genipin-fixed acellular tissue was investigated. The glutaraldehyde-fixed counterparts were used as controls. The results indicated that the degrees in inflammatory reaction for the Genipin-fixed cellular and acellular tissues were significantly less than their glutaraldehyde-fixed counterparts. Additionally, it was noted that the inflammatory reactions for the glutaraldehyde-fixed cellular and acellular tissues lasted much longer than their Genipin-fixed counterparts. The tissue regeneration rate for the Genipin-fixed acellular tissue was significantly faster than its glutaraldehyde-fixed counterpart. The calcium content of each studied group, analyzed by atomic absorption, did not change significantly until at the 52nd week, postoperatively. The differences in calcium content between the cellular and acellular tissues were insignificant for both the glutaraldehyde- and Genipin-fixed groups throughout the entire course of the study. In summary, the biocompatibility of the Genipin-fixed cellular and acellular tissues was superior to their glutaraldehyde-fixed counterparts. The Genipin-fixed acellular tissue provided a better microenvironment for tissue regeneration than its glutaraldehyde-fixed counterpart, due to its low cytotoxicity. These results suggested that the Genipin-fixed acellular tissue might be used as a tissue-engineering matrix in the clinical applications.
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in vitro evaluation of a chitosan membrane cross linked with Genipin
Journal of Biomaterials Science-polymer Edition, 2001Co-Authors: Yu-chiun Tan, Huangchien Liang, Rong-nan Huang, Hsing-wen SungAbstract:The study was to evaluate the characteristics of a chitosan membrane cross-linked with a naturally-occurring cross-linking reagent, Genipin. This newly-developed Genipin-cross-linked chitosan membrane may be used as an implantable drug-delivery system. The chitosan membrane without cross-linking (fresh) and the glutaraldehyde-cross-linked chitosan membrane were used as controls. The characteristics of test chitosan membranes evaluated were their cross-linking degree, swelling ratio, mechanical properties. antimicrobial activity, cytotoxicity, and degradability. It was found that cross-linking of chitosan membrane using Genipin increased its ultimate tensile strength but significantly reduced its strain-at-fracture and swelling ratio. There was no significant difference in antimicrobial activity between the Genipin-cross-linked chitosan membrane and its fresh counterpart. Additionally, the results showed that the Genipin-cross-linked chitosan membrane had a significantly less cytotoxicity and a slower degradation rate compared to the glutaraldehyde-cross-linked membrane. These results suggested that the Genipin-cross-linked chitosan membrane may be a promising carrier for fabricating an implantable drug-delivery system. The drug-release characteristics of the Genipin-cross-linked chitosan membrane are currently under investigation.
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in vitro evaluation of the genotoxicity of a naturally occurring crosslinking agent Genipin for biologic tissue fixation
Journal of Biomedical Materials Research, 2000Co-Authors: Chenchi Tsai, Rong-nan Huang, Hsing-wen Sung, Huangchien LiangAbstract:The objective of the present study was to evaluate in vitro, using Chinese hamster ovary (CHO-K1) cells, the genotoxicity of Genipin, a naturally occurring crosslinking agent. Glutaraldehyde, the most commonly used crosslinking agent for biologic tissue fixation, was employed as a reference chemical. The selected procedures for this evaluation were the micronucleus (MN) and sister chromatid exchange (SCE) assays with or without the addition of a metabolic activation system (S9 mix). Before starting the genotoxicity assays, the maximum noncytotoxic amounts of glutaraldehyde and Genipin were determined using the MTT assay. The results obtained in the MTT assay revealed that the cytotoxicity of Genipin was significantly lower than that of glutaraldehyde with or without S9 mix. The frequencies of MN observed in the cases drugged with varying concentrations of glutaraldehyde or Genipin were not statistically different from those seen in the negative controls (blank) in the presence or absence of S9 mix. However, it was noted that glutaraldehyde significantly inhibited the cell-cycle progression while the cells drugged with Genipin did not result in cell-cycle delay. In the SCE assay, the numbers of SCE per cell observed in the cases drugged with varying concentrations of glutaraldehyde were significantly greater than those found in the negative controls with or without S9 mix. Nevertheless, these numbers were still low compared to the numbers of SCE induced by the strong mutagens used as our positive control substances. This suggests that glutaraldehyde may produce a weakly clastogenic response in CHO-K1 cells. In contrast, the numbers of SCE per cell obtained in the cases drugged with Genipin were comparable to those observed in the negative controls in those that were except drugged with the highest dose (50 ppm). This suggests that Genipin does not cause clastogenic response in CHO-K1 cells provided its concentration is lower than 50 ppm. In conclusion, as far as cytotoxicity and genotoxicity are concerned, Genipin is a promising crosslinking agent for biologic tissue fixation.
Sun Mee Lee - One of the best experts on this subject based on the ideXlab platform.
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Genipin protects d galactosamine and lipopolysaccharide induced hepatic injury through suppression of the necroptosis mediated inflammasome signaling
European Journal of Pharmacology, 2017Co-Authors: Minjong Seo, Seok-joo Kim, Jeongmin Hong, Sun Mee LeeAbstract:Acute liver failure (ALF) is a life-threatening syndrome resulting from massive inflammation and hepatocyte death. Necroptosis, a programmed cell death controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, has been shown to play an important role in regulating inflammation via crosstalk between other intracellular signaling. The inflammasome is a major intracellular multiprotein that induces inflammatory responses by mediating immune cell infiltration, thus potentiating injury. Genipin, a major active compound of the gardenia fruit, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. This study investigated the hepatoprotective mechanisms of Genipin on d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced ALF, particularly focusing on interaction between necroptosis and inflammasome. Mice were given an intraperitoneal injection of Genipin (25, 50, and 100mg/kg) or necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.8mg/kg) 1h prior to GalN (800mg/kg)/LPS (40μg/kg) injection and were killed 3h after GalN/LPS injection. Genipin improved the survival rate and attenuated increases in serum aminotransferase activities and inflammatory cytokines after GalN/LPS injection. Genipin reduced GalN/LPS-induced increases in RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome complex, similar to the effects of Nec-1. GalN/LPS significantly increased serum levels of high-mobility group box 1 and interleukin (IL)-33, which were attenuated by Genipin and Nec-1. Moreover, similar to Nec-1, Genipin attenuated GalN/LPS-induced increases in the protein expression levels of NLRP3, ASC, and caspase-1, inflammasome components, and levels of liver and serum IL-1β. Taken together, our findings suggest that Genipin ameliorates GalN/LPS-induced hepatocellular damage by suppressing necroptosis-mediated inflammasome signaling.
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Genipin protects the liver from ischemia reperfusion injury by modulating mitochondrial quality control
Toxicology and Applied Pharmacology, 2017Co-Authors: Junkyu Shi, Sun Mee LeeAbstract:Abstract Hepatic ischemia and reperfusion (IR) injury is closely linked to oxidative mitochondrial damage. Since mitochondrial quality control (QC) plays a pivotal role in the recovery of impaired mitochondrial function, mitochondrial QC has emerged as a potential therapeutic target. Genipin, an iridoid compound from Gardenia jasminoides , has been showed antioxidant and anti-inflammatory properties. In this study, we investigated the hepatoprotective mechanism of Genipin against IR-induced hepatic injury, particularly focusing on mitochondrial QC. Male C57BL/6 mice underwent liver ischemia for 60 min, followed by reperfusion for 6 h. Genipin (100 mg/kg, i.p.) or vehicle (10% Tween 80 in saline) was administrated to mice 1 h before ischemia. Liver and blood samples were collected 6 h after reperfusion. Hepatic IR increased hepatocellular oxidative damage and induced mitochondrial dysfunction. These phenomena were ameliorated by Genipin. Hepatic IR also increased the level of mitochondrial fission, such as dynamin-related protein 1 and the level of PINK1 protein expression. In contrast, hepatic IR decreased the levels of mitochondrial biogenesis related proteins (e.g., peroxisome proliferator-activated receptor gamma coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A), mitophagy related proteins (e.g., Parkin), and fusion related protein (e.g., mitofusin 2). Furthermore, hepatic IR decreased the levels of sirtuin1 protein and phosphorylation of AMP-activated protein kinase. Genipin alleviated these IR-induced changes. These data indicate that Genipin protects against IR-induced hepatic injury via regulating mitochondrial QC. (225/250).
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protective effects of geniposide and Genipin against hepatic ischemia reperfusion injury in mice
Biomolecules & Therapeutics, 2013Co-Authors: Joon Ki Kim, Hyo Yeon Kim, Sun Mee LeeAbstract:Geniposide is an active product extracted from the gardenia fruit, and is one of the most widely used herbal preparations for liver disorders. This study examined the cytoprotective properties of geniposide and its metabolite, Genipin, against hepatic ischemia/reperfusion (I/R) injury. C57BL/6 mice were subjected to 60 min of ischemia followed by 6 h of reperfusion. Geniposide (100 mg/kg) and Genipin (50 mg/kg) were administered orally 30 min before ischemia. In the I/R mice, the levels of serum alanine aminotransferase and hepatic lipid peroxidation were elevated, whereas hepatic glutathione/glutathione disulfide ratio was decreased. These changes were attenuated by geniposide and Genipin administration. On the other hand, increased hepatic heme oxygenase-1 protein expression was potentiated by geniposide and Genipin administration. The increased levels of tBid, cytochrome c protein expression and caspase-3 activity were attenuated by geniposide and Genipin. Increased apoptotic cells in the I/R mice were also significantly reduced by geniposide and Genipin treatment. Our results suggest that geniposide and Genipin offer significant hepatoprotection against I/R injury by reducing oxidative stress and apoptosis.
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Genipin attenuates sepsis by inhibiting Toll-like receptor signaling.
Molecular medicine (Cambridge Mass.), 2012Co-Authors: Tae-hoon Kim, Seong-jin Yoon, Sun Mee LeeAbstract:The pathogenesis of sepsis is characterized by overwhelming inflammatory responses that lead to tissue damage and organ failure. Toll-like receptor (TLR) signaling is crucial for induction of hyperinflammatory responses and tissue injury during sepsis. Genipin, an aglycon of geniposide, has antiinflammatory and antimicrobial activities. The purpose of this study was to test the hypothesis that Genipin reduces multiple organ dysfunction and mortality during sepsis through inhibition of TLR signaling. Male ICR were subjected to sepsis by cecal ligation and puncture (CLP) or endotoxemia by lipopolysaccharide (LPS). Various doses of Genipin (1),2.5 and 5 mg/kg) or a vehicle were administered intravenously immediately after CLP or intraperitoneally after LPS treatment. In another set of survival tests, mice were treated with 2.5 mg/kg of Genipin 0 and 24 h after CLP. Genipin was found to improve survival and to attenuate multiple organ dysfunction. Genipin attenuated production of proinflammatory cytokines and release of high-mobility group box 1 (HMGB1). Genipin prevented TLR2 and TLR4, myeloid differentiation factor 88 and the Toll/interleukin-1 receptor domain-containing adaptor protein, inducing interferon-β overexpression. Phosphorylation of mitogen-activated protein kinases and interferon regulatory factor 3 and translocation of nuclear factor (NF)-κB were prevented by Genipin. Moreover, Genipin attenuated increases in serum tumor necrosis factor-α and HMGB1 in LPS-induced endotoxemia. Pam3CSK4- and LPS-mediated production of nitrites and proinflammatory cytokines was suppressed by Genipin in RAW264.7 cells. Genipin attenuated mortality and organ injuries during sepsis through interference with TLR signaling. Therefore, Genipin might be useful as a potential therapeutic agent for treatment of sepsis.
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Genipin protects lipopolysaccharide-induced apoptotic liver damage in D-galactosamine-sensitized mice.
European journal of pharmacology, 2010Co-Authors: Seok-joo Kim, Joon Ki Kim, Dong-ung Lee, Jong-hwan Kwak, Sun Mee LeeAbstract:This study examined the effects of Genipin, isolated from Gardenia jasminoides Ellis, on d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatic apoptosis and liver failure. Mice were given an intraperitoneal injection of Genipin (25, 50, 100 and 200mg/kg) 1h before GalN (700mg/kg)/LPS (10microg/kg) administration. The survival rate of the Genipin group was significantly higher than that of the control. Genipin markedly reduced the increases in serum aminotransferase activities and lipid peroxidation. The glutathione content decreased in GalN/LPS group, and this decrease was attenuated by Genipin. Increases in serum tumor necrosis factor-alpha (TNF-alpha), which were observed in GalN/LPS-treated mice, were significantly reduced by Genipin. Genipin attenuated the GalN/LPS-induced apoptosis of hepatocytes, as estimated by the caspase-3 and -8 activity assay, TNF-R1 associated death domain (TRADD) protein measurement and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method. Moreover, increased cytosolic cytochrome c protein was reduced by Genipin. After 3h of GalN/LPS injection, nuclear phosphorylated c-Jun (p-c-Jun) level was significantly increased, whereas it was attenuated by Genipin. Also, the increased nuclear level of nuclear factor-kappaB and the decreased cytosolic level of IkappaB-alpha protein were significantly attenuated by Genipin. Our results suggest that Genipin offers marked hepatoprotection against damage induced by GalN/LPS related with its antioxidative, anti-apoptotic activities, and inhibition of NF-kappaB nuclear translocation and nuclear p-c-Jun expression.
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Genipin crosslinked gelatin microspheres as a drug carrier for intramuscular administration in vitro and in vivo studies
Journal of Biomedical Materials Research Part A, 2003Co-Authors: Huangchien Liang, Wenhsiang Chang, Kojung Lin, Hsing-wen SungAbstract:Gelatin microspheres have been widely evaluated as a drug carrier. Nevertheless, gelatin dissolves rather rapidly in aqueous environments, making the use of the polymer difficult for the production of long-term delivery systems. This adverse aspect requires the use of a crosslinking agent in forming nonsoluble networks in microspheres. However, the use of crosslinking agents such as formaldehyde and glutaraldehyde can lead to toxic side effects owing to residual crosslinkers. In an attempt to overcome this problem, a naturally occurring crosslinking agent (Genipin) was used to crosslink gelatin microspheres as a biodegradable drug-delivery system for intramuscular administration. Glutaraldehyde was used as a control. In the in vitro study, the morphology, dynamic swelling, and antienzymatic degradation of test microspheres were evaluated. In the in vivo study, the biocompatibility and degradability of test microspheres were implanted in the skeletal muscle of a rat model via intramuscular injection. The results obtained in the study suggested that crosslinking of gelatin microspheres with glutaraldehyde or Genipin may produce distinct crosslinking structures. The water transport mechanism in both the glutaraldehyde- and Genipin-crosslinked gelatin microspheres exhibit anomalous behavior ranging from Fickian to Case-II extremes. The increase of the swelling diameter for the Genipin-crosslinked microspheres was significantly less than that observed for the glutaraldehyde-crosslinked microspheres. In the animal study, it was found that the degree in inflammatory reaction for tissues implanted with the Genipin-crosslinked microspheres was significantly less than that implanted with the glutaraldehyde-crosslinked microspheres. Additionally, the degradation rate of the Genipin-crosslinked microspheres was significantly slower than their glutaraldehyde-crosslinked counterparts. These results indicated that the Genipin-crosslinked gelatin microspheres may be used as a long-acting drug carrier for intramuscular administration. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 65A: 271–282, 2003
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Genipin crosslinked gelatin microspheres as a drug carrier for intramuscular administration in vitro and in vivo studies
Journal of Biomedical Materials Research Part A, 2003Co-Authors: Huangchien Liang, Wenhsiang Chang, Kojung Lin, Hsing-wen SungAbstract:Gelatin microspheres have been widely evaluated as a drug carrier. Nevertheless, gelatin dissolves rather rapidly in aqueous environments, making the use of the polymer difficult for the production of long-term delivery systems. This adverse aspect requires the use of a crosslinking agent in forming nonsoluble networks in microspheres. However, the use of crosslinking agents such as formaldehyde and glutaraldehyde can lead to toxic side effects owing to residual crosslinkers. In an attempt to overcome this problem, a naturally occurring crosslinking agent (Genipin) was used to crosslink gelatin microspheres as a biodegradable drug-delivery system for intramuscular administration. Glutaraldehyde was used as a control. In the in vitro study, the morphology, dynamic swelling, and antienzymatic degradation of test microspheres were evaluated. In the in vivo study, the biocompatibility and degradability of test microspheres were implanted in the skeletal muscle of a rat model via intramuscular injection. The results obtained in the study suggested that crosslinking of gelatin microspheres with glutaraldehyde or Genipin may produce distinct crosslinking structures. The water transport mechanism in both the glutaraldehyde- and Genipin-crosslinked gelatin microspheres exhibit anomalous behavior ranging from Fickian to Case-II extremes. The increase of the swelling diameter for the Genipin-crosslinked microspheres was significantly less than that observed for the glutaraldehyde-crosslinked microspheres. In the animal study, it was found that the degree in inflammatory reaction for tissues implanted with the Genipin-crosslinked microspheres was significantly less than that implanted with the glutaraldehyde-crosslinked microspheres. Additionally, the degradation rate of the Genipin-crosslinked microspheres was significantly slower than their glutaraldehyde-crosslinked counterparts. These results indicated that the Genipin-crosslinked gelatin microspheres may be used as a long-acting drug carrier for intramuscular administration.
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A Genipin-crosslinked gelatin membrane as wound-dressing material: in vitro and in vivo studies.
Journal of biomaterials science. Polymer edition, 2003Co-Authors: Wenhsiang Chang, Yen Chang, Po-hong Lai, Hsing-wen SungAbstract:A naturally occurring crosslinking agent (Genipin) was used in this study to crosslink gelatin hydrogel to develop a wound-dressing membrane. The study was to investigate the in vitro characteristics of the Genipin-crosslinked gelatin membrane. The glutaraldehyde-crosslinked counterpart, at a similar crosslinking degree, was used as control. Additionally, an in vivo experiment was undertaken to study the wound healings covered with the glutaraldehyde- and Genipin-crosslinked dressings in a rat model. The in vitro results obtained suggested that crosslinking of gelatin membranes with glutaraldehyde or Genipin may produce distinct crosslinking structures. The differences in crosslinking structure can significantly affect the mechanical property, water-vapor-transmission rate, swelling ratio, degradation against enzyme and cellular compatibility of the crosslinked membranes. In the in vivo study, it was found that the degree of inflammatory reaction for the wound treated with the Genipin-crosslinked dressing was significantly less severe than that covered with the glutaraldehyde-crosslinked dressing throughout the entire course of the study. Additionally, the healing rate for the wound treated with the Genipin-crosslinked dressing was notably faster than its glutaraldehyde-crosslinked counterpart.
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In vitro surface characterization of a biological patch fixed with a naturally occurring crosslinking agent.
Biomaterials, 2000Co-Authors: Hsing-wen Sung, Chiun Nan Chen, Rong-nan Huang, Jer-chen Hsu, Wenhsiang ChangAbstract:The study was designed to characterize the surface properties (including water contact angle, surface tension, protein adsorption, platelet adhesion, and cellular compatibility) of a biological patch fixed with Genipin, a naturally occurring crosslinking agent. Fresh and glutaraldehyde-fixed counterparts were used as controls. It was found that both glutaraldehyde and Genipin are effective crosslinking agents for biological tissue fixation. Fixation of biological tissue with glutaraldehyde or Genipin significantly increased its hydrophilicity and surface tension and reduced its mol ratio of adsorbed fibrinogen to adsorbed albumin as well as the amount of adhered platelet. There were no significant differences in hydrophilicity, surface tension, the mole ratio of adsorbed fibrinogen to adsorbed albumin, and the amount of platelet adhesion between the glutaraldehyde- and Genipin-fixed tissues. However, the cellular compatibilities of fresh and the Genipin-fixed tissues were significantly superior to the glutaraldehyde-fixed tissue.