• Archives of Pharmacal Research
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• v.28 no.3
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• pp.249-268
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• 2005

Drug metabolizing enzymes (DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Most of the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and phase III transporters, which are present in abundance either at the basal unstimulated level, and/or are inducible at elevated level after exposure to xenobiotics. Recently, many important advances have been made in the mechanisms that regulate the expression of these drug metabolism genes. Various nuclear receptors including the aryl hydrocarbon receptor (AhR), orphan nuclear receptors, and nuclear factor-erythoroid 2 p45-related factor 2 (Nrf2) have been shown to be the key mediators of drug-induced changes in phase I, phase II metabolizing enzymes as well as phase III transporters involved in efflux mechanisms. For instance, the expression of CYP1 genes can be induced by AhR, which dimerizes with the AhR nuclear translocator (Arnt) , in response to many polycyclic aromatic hydrocarbon (PAHs). Similarly, the steroid family of orphan nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both heterodimerize with the ret-inoid X receptor (RXR), are shown to transcriptionally activate the promoters of CYP2B and CYP3A gene expression by xenobiotics such as phenobarbital-like compounds (CAR) and dexamethasone and rifampin-type of agents (PXR). The peroxisome proliferator activated receptor (PPAR), which is one of the first characterized members of the nuclear hormone receptor, also dimerizes with RXR and has been shown to be activated by lipid lowering agent fib rate-type of compounds leading to transcriptional activation of the promoters on CYP4A gene. CYP7A was recognized as the first target gene of the liver X receptor (LXR), in which the elimination of cholesterol depends on CYP7A. Farnesoid X receptor (FXR) was identified as a bile acid receptor, and its activation results in the inhibition of hepatic acid biosynthesis and increased transport of bile acids from intestinal lumen to the liver, and CYP7A is one of its target genes. The transcriptional activation by these receptors upon binding to the promoters located at the 5-flanking region of these GYP genes generally leads to the induction of their mRNA gene expression. The physiological and the pharmacological implications of common partner of RXR for CAR, PXR, PPAR, LXR and FXR receptors largely remain unknown and are under intense investigations. For the phase II DMEs, phase II gene inducers such as the phenolic compounds butylated hydroxyanisol (BHA), tert-butylhydroquinone (tBHQ), green tea polyphenol (GTP), (-)-epigallocatechin-3-gallate (EGCG) and the isothiocyanates (PEITC, sul­foraphane) generally appear to be electrophiles. They generally possess electrophilic-medi­ated stress response, resulting in the activation of bZIP transcription factors Nrf2 which dimerizes with Mafs and binds to the antioxidant/electrophile response element (ARE/EpRE) promoter, which is located in many phase II DMEs as well as many cellular defensive enzymes such as heme oxygenase-1 (HO-1), with the subsequent induction of the expression of these genes. Phase III transporters, for example, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptide 2 (OATP2) are expressed in many tissues such as the liver, intestine, kidney, and brain, and play crucial roles in drug absorption, distribution, and excretion. The orphan nuclear receptors PXR and GAR have been shown to be involved in the regulation of these transporters. Along with phase I and phase II enzyme induction, pretreatment with several kinds of inducers has been shown to alter the expression of phase III transporters, and alter the excretion of xenobiotics, which implies that phase III transporters may also be similarly regulated in a coordinated fashion, and provides an important mean to protect the body from xenobiotics insults. It appears that in general, exposure to phase I, phase II and phase III gene inducers may trigger cellular 'stress' response leading to the increase in their gene expression, which ultimately enhance the elimination and clearance of these xenobiotics and/or other 'cellular stresses' including harmful reactive intermediates such as reactive oxygen species (ROS), so that the body will remove the 'stress' expeditiously. Consequently, this homeostatic response of the body plays a central role in the protection of the body against 'environmental' insults such as those elicited by exposure to xenobiotics.

• Parasites, Hosts and Diseases
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• v.53 no.4
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• pp.431-438
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• 2015

In Trichinella spiralis infection, type 2 helper T (Th2) cell-related and regulatory T ($T_{reg}$) cell-related immune responses are the most important immune events. In order to clarify which Toll-like receptors (TLRs) are closely associated with these responses, we analyzed the expression of mouse TLR genes in the small intestine and muscle tissue during T. spiralis infection. In addition, the expression of several chemokine- and cytokine-encoding genes, which are related to Th2 and $T_{reg}$ cell mediated immune responses, were analyzed in mouse embryonic fibroblasts (MEFs) isolated from myeloid differentiation factor 88 (MyD88)/TIR-associated proteins (TIRAP) and Toll receptor-associated activator of interferons (TRIF) adapter protein deficient and wild type (WT) mice. The results showed significantly increased TLR4 and TLR9 gene expression in the small intestine after 2 weeks of T. spiralis infection. In the muscle, TLR1, TLR2, TLR5, and TLR9 gene expression significantly increased after 4 weeks of infection. Only the expression of the TLR4 and TLR9 genes was significantly elevated in WT MEF cells after treatment with excretory-secretory (ES) proteins. Gene expression for Th2 chemokine genes were highly enhanced by ES proteins in WT MEF cells, while this elevation was slightly reduced in MyD88/$TIRAP^{-/-}$ MEF cells, and quite substantially decreased in $TRIF^{-/-}$ MEF cells. In contrast, IL-10 and $TGF-{\beta}$ expression levels were not elevated in MyD88/$TIRAP^{-/-}$ MEF cells. In conclusion, we suggest that TLR4 and TLR9 might be closely linked to Th2 cell and $T_{reg}$ cell mediated immune responses, although additional data are needed to convincingly prove this observation.

• Journal of Pharmaceutical Investigation
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• v.37 no.6
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• pp.339-347
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• 2007

SMEDDS is mixture of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal(GI) tract. The main purpose of this work is to prepare self-microemulsifying drug delivery system(SMEDDS) for oral bioavailability enhancement of a poorly water soluble drug, atorvastatin calcium. Solubility of atorvastatin calcium was determined in various vehicles. Pseudo-ternary phase diagrams were constructed to identity the efficient self-emulsification region and particle size distributions of the resultant micro emulsions were determined using a laser diffraction sizer. Optimized formulations for in vitro dissolution and bioavailability assessment were $Capryol^{(R)}$ 90(50%), Tetraglycol(16%), and $Cremophor^{(R)}$ EL(32%). The release rate of atorvastatin from SMEDDS was significantly higher than the conventional tablet ($Lipitor^{(R)}$), 2-fold. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as atorvastatin calcium by the oral route.

• Journal of Microbiology and Biotechnology
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• v.32 no.7
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• pp.885-891
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• 2022

Plant-based protein sources such as soybean meal have low digestibility and are generally promoted accumulation of undigested proteins into the intestine by enzymatic treatments. Moreover, potential intestinal pathogens ferment undigested proteins, producing harmful substances, such as ammonia, amines and phenols, leading to an overactive immune response and diarrhea in weaned pigs. As a solution, dietary proteases hydrolyze soybean-based antinutritive factors, which negatively affect immune responses and gut microbiota. In this study, we investigated the effects of dietary proteases (PRO) in a low-crude protein (CP) commercial diet on the immune responses and gut microbiota of weaned pigs. The experimental design consisted of three dietary treatments: a commercial diet as a positive control (PC; phase1 CP = 23.71%; phase 2 CP: 22.36%), a lower CP diet than PC as negative control (NC; 0.61% less CP than PC), and NC diet supplement with 0.02% PRO. We found that PRO tended to decrease the frequency of diarrhea in the first two weeks after weaning compared with PC and NC. In addition, pigs fed PRO showed decreased TNF-α and TGF-β1 levels compared with those fed PC and NC. The PRO group had a higher relative proportion of the genus Lactobacillus and lower levels of the genus Streptococcus than the PC and NC groups. In conclusion, the addition of PRO to a low CP commercial weaned diet attenuated inflammatory responses and modified gut microbiota in weaned pigs.

• Journal of Animal Science and Technology
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• v.63 no.6
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• pp.1286-1300
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• 2021

The objective of this study was to evaluate in vitro antimicrobial and anti-biofilm activity of sodium long chain polyphosphate (SLCPP) and effect of dietary supplementation of SLCPP on growth performance, organ characteristics, blood metabolites, and intestinal microflora of broilers. Antimicrobial activities of SLCPP were observed against Escherichia coli O157:H7, Listeria monocytogenes, Salmonella enterica ser. Pullorum, Shigella sonnei, Klebsiella pneumonia, Pseudomonas aeruginosa in agar well diffusion assay. In addition, SLCPP demonstrated good anti-biofilm activity against K. pneumonia and P. aeruginosa. Furthermore, to investigate the dietary effect of SLCPP, a total of 480 1-day-old male Ross 308 broiler chicks were randomly allotted to three dietary treatment groups (4 replicates per group, 40 birds in each replicate): an antibiotic-free corn-soybean meal basal diet (NC); basal diet + enramycin 0.01% (PC); and basal diet + 0.1% SLCPP (SPP). The experiment lasted for 35 days. Results showed that birds fed with SLCPP had higher body weight (BW) and average daily gain (ADG), and lower feed conversion ratio (FCR) during the grower phase (days 7 to 21) (p < 0.05). Except for blood urea nitrogen, all other blood biochemical parameters remained unaffected by the dietary supplementation of SLCPP. Compared to the control group, lengths of the duodenum and ileum in the SPP group were significantly shorter (p < 0.05). Moreover, counts of lactic acid bacteria (LAB), total aerobes, and Streptococcus spp. in jejunum as well as LAB in cecum were increased in the SPP group than in the PC group (p < 0.05). These results suggest that dietary supplementation of SLCPP might promote the growth of broilers in their early growth phase.

• Proceedings of the Korean Aquaculture Society Conference
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• 2003.10a
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• pp.76-77
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• 2003

Olive flounder Paralichthys olivaceus larvae and early juveniles were reared for 43 days after hatching in order to observe the effects of starvation during development and metamorphosis. Morphological, histological and biochemical measurements were made to assess the nutritional condition during growth and starvation from pre-matamorphic through post-metamorphic phases. Two groups of fish were compared ; one with sufficient food supply and one under continuous starvation until death. Among morphometric analyses, both ratios of body height at anus/head height and pre-/post-anal lengths appeared to be sensitive to starvation during which substantial reduction was observed within a day of food deprivation. Histological variables as intestinal and rectal epithelial heights and gall bladder volume changed significantly with onset of starvation. The gut epithelial heights of starving fish decreased with advances in starvation, although they fluctuated during mid-metamorphic phase. In contrast, gall bladder volume increased remarkably soon after starvation. Ontogenetic changes in both gut epithelial height and gall bladder volume were evident, those associated with settlement and/or completion of metamorphosis. Abrupt decrease in the RNA/DNA ratios of starving fish were found right after onset of starvation. Even in the fed fish marked fluctuations in its ratios during metamorphosis were observed, evident by decreasing from late-metamorphic to post-metamorphic stages. These findings suggest that a combination of morphologically and histologically sensitive characteristics, and biochemical measurement could be utilized as a measure to evaluate nutritional condition related to starvation in wild olive flounder larvae and juveniles.

• Biomolecules & Therapeutics
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• v.21 no.2
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• pp.173-179
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• 2013

Objective of present study was to prepare and characterize self-nanoemulsifying drug delivery system (SNEDDS) of lutein and to evaluate its effect on bioavailability of warfarin. The SNEDDS was prepared using an oil, a surfactant, and co-surfactants with optimal composition based on pseudo-ternary phase diagram. Effect of the SNEDDS on the bioavailability of warfarin was performed using Sprague Dawley rats. Lutein was successfully formulated as SNEDDS for immediate self-emulsification and dissolution by using combination of Peceol as oil, Labrasol as surfactant, and Transcutol-HP or Lutrol-E400 as co-surfactant. Almost complete dissolution was achieved after 15 min while lutein was not detectable from the lutein powder or intra-capsule content of a commercial formulation. SNEDDS formulation of lutein affected bioavailability of warfarin, showing about 10% increase in $C_{max}$ and AUC of the drug in rats while lutein as non-SNEDDS did not alter these parameters. Although exact mechanism is not yet elucidated, it appears that surfactant and co-surfactant used for SNEDDS formulation caused disturbance in the anatomy of small intestinal microvilli, leading to permeability change of the mucosal membrane. Based on this finding, it is suggested that drugs with narrow therapeutic range such as warfarin be administered with caution to avoid undesirable drug interaction due to large amount of surfactants contained in SNEDDS.

• Journal of Korean Medical classics
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• v.13 no.2 s.17
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• pp.155-155
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• 2000

Body fluid(津液) is a general term for normal mucus in human body, including saliva, gastric juice, intestinal juice and articular fluid in joints as well as tear, running nose, sweat, etc.. The formation of Body fluid goes through two phases. First phase is digestion of food at stomach, and then evaporation and classification of energy at Triple warmer(三焦). More technically speaking, Body fluid is divided into the Jin(津) & the Aek(液). Aek is a very mild and water-like fluid, runs deep into the internal organs. Jin is a thick and sticky liquid, running shallow under the skin or in the joints of limbs. Major roles of body fluid over the body are to moisturize the internal organs, flesh, skin, etc., to soften the joints, to fill the bone marrow, and to balance Yin and Yang. This article deals with the role of body fluid and how to differentiate them, the liquid metabolism in the human body, and the formation and change of sweat, urine, tear, spit, bone marrow, etc.. The imbalance of Yin and Yang and disturbance of Triple warmer's evaporation lead into lumbago, leg weakness and edema is also explained here.

• Journal of Korean Medical classics
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• v.13 no.2 s.17
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• pp.156-171
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• 2000

Body fluid(津液) is a general term for normal mucus in human body, including saliva, gastric juice, intestinal juice and articular fluid in joints as well as tear, running nose, sweat, etc.. The formation of Body fluid goes through two phases. First phase is digestion of food at stomach, and then evaporation and classification of energy at Triple warmer(三焦). More technically speaking, Body fluid is divided into the Jin(津) & the Aek(液). Aek is a very mild and water-like fluid, runs deep into the internal organs. Jin is a thick and sticky liquid, running shallow under the skin or in the joints of limbs. Major roles of body fluid over the body are to moisturize the internal organs, flesh, skin, etc., to soften the joints, to fill the bone marrow, and to balance Yin and Yang. This article deals with the role of body fluid and how to differentiate them, the liquid metabolism in the human body, and the formation and change of sweat, urine, tear, spit, bone marrow, etc.. The imbalance of Yin and Yang and disturbance of Triple warmer's evaporation lead into lumbago, leg weakness and edema is also explained here.

• Korean Journal of Fisheries and Aquatic Sciences
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• v.45 no.4
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• pp.358-366
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• 2012

A novel neuropeptide was isolated from the skin of the conger eel Conger myriaster using hagfish Eptatretus burgeri intestine as a bioassay system. The sequence of the purified peptide was analyzed using automated amino acid sequencing and MALDI-TOF mass spectrophotometry. The molecular ion peak in the MALDI-TOF mass spectrum of the peptide was at m/z 962.89 $(M+H)^+$. The sequence of the peptide was determined to be L-P-M-L-E-T-Q-M, and was tentatively named comyrin. To investigate the complete primary structure of comyrin, comyrin-OH and comyrin-$NH_2$ were synthesized and the chemical and pharmacological properties of the synthetic peptides were compared with those of the native peptide. However, the elution time of synthetic peptides did not match that of the native peptide on the reverse-phase HPLC chromatogram. In addition, the synthetic peptides did not cause contractile activity in the intestinal smooth muscle of the hagfish. Based on these results, one possible reason for this disagreement may be the presence of a D-amino acid in comyrin.