Targeted removal of leukemia cells from the circulating system by whole-body magnetic hyperthermia in mice.

Until now, magnetic hyperthermia was used to remove solid tumors by targeting magnetic nanoparticles (MNPs) to tumor sites. In this study, leukemia cells in the bloodstream were directly removed by whole-body hyperthermia, using leukemia cell-specific MNPs. An epithelial cellular adhesion molecule (EpCAM) antibody was immobilized on the surface of MNPs (EpCAM-MNPs) to introduce the specificity of MNPs to leukemia cells. The viability of THP1 cells (human monocytic leukemia cells) was decreased to 40.8% of that in control samples by hyperthermia using EpCAM-MNPs. In AKR mice, an animal model of lymphoblastic leukemia, the number of leukemia cells was measured following the intravenous injection of EpCAM-MNPs and subsequent whole-body hyperthermia treatment. The result showed that the leukemia cell number was also decreased to 43.8% of that without the treatment of hyperthermia, determined by Leishman staining of leukemia cells. To support the results, simulation analysis of heat transfer from MNPs to leukemia cells was performed using COMSOL Multiphysics simulation software. The surface temperature of leukemia cells adhered to EpCAM-MNPs was predicted to be increased to 82 °C, whereas the temperature of free cells without adhered MNPs was predicted to be 38 °C. Taken together, leukemia cells were selectively removed by magnetic hyperthermia from the bloodstream, because EpCAM-modified magnetic particles were specifically attached to leukemia cell surfaces. This approach has the potential to remove metastatic cancer cells, and pathogenic bacteria and viruses floating in the bloodstream.

FMO3 and its metabolite TMAO contribute to the formation of gallstones.

Trimethylamine-N-oxide (TMAO) is a metabolite derived from trimethylamine (TMA), which is first produced by gut microbiota and then oxidized by flavin-containing monooxygenase 3 (FMO3) in the liver. TMAO may contribute to the development of diseases such as atherosclerosis because of its role in regulating lipid metabolism. In this study, we found that high plasma TMAO levels were positively associated with the presence of gallstone disease in humans. We further found increased hepatic FMO3 expression and elevated plasma TMAO level in a gallstone-susceptible strain of mice C57BL/6J fed a lithogenic diet (LD), but not in a gallstone-resistant strain of mice AKR/J. Dietary supplementation of TMAO or its precursor choline increased hepatic FMO3 expression and plasma TMAO levels and induced hepatic canalicular cholesterol transporters ATP binding cassette (Abc) g5 and g8 expression in mice. Up-regulation of ABCG5 and ABCG8 expression was observed in hepatocytes incubated with TMAO in vitro. Additionally, in AKR/J mice fed a LD supplemented with 0.3% TMAO, the incidence of gallstones rose up to 70% compared with 0% in AKR/J mice fed only a LD. This was associated with increased hepatic Abcg5 and g8 expression induced by TMAO. Our study demonstrated TMAO could be associated with increased hepatic Abcg5/g8 expression, biliary cholesterol hypersecretion and gallstone formation.

Preventive Effects of Fermented Brown Rice and Rice Bran on Spontaneous Lymphomagenesis in AKR/NSlc Female Mice

Fermented brown rice and rice bran with Aspergillus oryzae (FBRA) is known to possess potentials to prevent chemical carcinogenesis in multiple organs of rodents. In the present study, possible chemopreventive effect of FBRA against spontaneous occurrence of lymphomas was examined using female AKR/NSlc mice. Four-week-old female AKR/ NSlc mice were divided into three groups, and fed diets containing FBRA for 26 weeks at a dose level 0% (Group 1), 5% (Group 2) or 10% (Group 3). At the termination of experiment, the incidence of thymic malignant lymphoma of Group 3 was significantly lower than of Group 1 (p < 0.05). The average number of apoptotic cells of the thymic lymphoma of Group 3 was significantly larger than that of Group 1 (p < 0.05). In addition, the incidences of malignant lymphoma arising from body surface and abdominal lymph nodes, and the frequencies of lymphoma cell invasion to liver, kidney, spleen, and ovary of Group 3 were relatively lower than those of Group 1. These results indicate that FBRA inhibits spontaneous development of the lymphoma in female AKR/NSc mice and the inhibition of lymphomagenesis may relate to the induction of apoptosis by exposure of FBRA, suggesting that FBRA could be a protective agent against development of human lymphoma.

High-fat diet induced isoform changes of the Parkinson's disease protein DJ-1.

Genetic and environmental factors mediate via different physiological and molecular processes a shifted energy balance leading to overweight and obesity. To get insights into the underlying processes involved in energy intake and weight gain, we compared hypothalamic tissue of mice kept on a high-fat or control diet for 10 days by a proteomic approach. Using two-dimensional difference gel electrophoresis in combination with LC-MS/MS, we observed significant abundance changes in 15 protein spots. One isoform of the protein DJ-1 was elevated in the high-fat diet group in three different mouse strains SWR/J, C57BL/6N, and AKR/J analyzed. Large-scale validation of DJ-1 isoforms in individual samples and tissues confirmed a shift in the pattern of DJ-1 isoforms toward more acidic isoforms in several brain and peripheral tissues after feeding a high-fat diet for 10 days. The identification of oxidation of cysteine 106 as well as 2-succinyl modification of the same residue by mass spectrometry not only explains the isoelectric shift of DJ-1 but also links our results to similar shifts of DJ-1 observed in neurodegenerative disease states under oxidative stress. We hypothesize that DJ-1 is a common physiological sensor involved in both nutrition-induced effects and neurodegenerative disease states.

[Serotonin and dopamine brain metabolism in mice with different predisposition to catalepsy].

Catalepsy usually is caused by imbalance of dopamine (DA) and serotonin (5-HT) systems of brain. The aim of our work was to verify if this imbalance plays an important role in the mechanism of hereditary catalepsy in mice. Maintenance of DA, 5-HT and their main metabolites--5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, homovanilic acid was determined in cortex, hypothalamus, hippocampus, striatum, substantia nigra and nuclei raphes in catalepsy-resistant AKR/J mice strain and catalepsy-prone CBA/LacJ mice strain and recombinant mice AKR/J.CBA-D13Mit76 (D13) strain. The latest strain was selected by transferring of a fragment of the chromosome 13 from CBA/LacJ carrying the main gene of hereditary catalepsy to AKR/J genome. There were no interstrain differences in concentration of biogenic amines and their metabolites in all brain regions. As a result of our work the hypothesis about the important role of 5-HT and/or DA systems of brain in the mechanism of hereditary catalepsy in mice was denied.

The retinoic acid receptor agonist Am80 increases mucosal inflammation in an IL-6 dependent manner during Trichuris muris infection.

PURPOSE: Vitamin A metabolites, such as all-trans-retinoic acid (RA) that act through the nuclear receptor; retinoic acid receptor (RAR), have been shown to polarise T cells towards Th2, and to be important in resistance to helminth infections. Co-incidentally, people harbouring intestinal parasites are often supplemented with vitamin A, as both vitamin A deficiency and parasite infections often occur in the same regions of the globe. However, the impact of vitamin A supplementation on gut inflammation caused by intestinal parasites is not yet completely understood. METHODS: Here, we use Trichuris muris, a helminth parasite that buries into the large intestine of mice causing mucosal inflammation, as a model of both human trichuriasis and IBD, treat with an RARα/ß agonist (Am80) and quantify the ensuing pathological changes in the gut. RESULTS: Critically, we show, for the first time, that rather than playing an anti-inflammatory role, Am80 actually exacerbates helminth-driven inflammation, demonstrated by an increased colonic crypt length and a significant CD4(+) T cell infiltrate. Further, we established that the Am80-driven crypt hyperplasia and CD4(+) T cell infiltrate were dependent on IL-6, as both were absent in Am80-treated IL-6 knock-out mice. CONCLUSIONS: This study presents novel data showing a pro-inflammatory role of RAR ligands in T. muris infection, and implies an undesirable effect for the administration of vitamin A during chronic helminth infection.

[Effects of stress on corticosterone level, expression of c-Fos gene and serotonin turnover in brain in mice with genetic predisposition to catalepsy].

Freezing or catalepsy is a passive-defensive reaction to stress. The participation of brain serotonin (5-HT) in the regulation of catalepsy was shown. The major gene of predisposition to catalepsy in CBA strain was localized in a 59-70 cM fragment of chromosome 13. This fragment was transferred from the CBA strain to genome of AKR non-cataleptic strain and created AKR. CBA-D13Mit76 (D13) congenic strain. The aim of the study was to compare the effects of acute stress (restriction, 1 h) on corticosterone level in plasma, the expression of c-Fos gene (neuromarker of stress) and serotonin metabolism in the brain in AKR catalepsy-resistant strain and congenic D13 catalepsy-prone strain. The level of corticosterone was significantly lower (p < 0.001) in the stressed D13 mice compared with the stressed AKR mice. Acute stress led to increased expression of c-Fos gene in the hypothalamus and midbrain in mice of both strains. Stress increased (p < 0.05) serotonin turnover in midbrain in D13 mice, but not in AKR. Thus, the fragment of chromosome 13, containing the major gene of catalepsy, participates in the regulation of hormonal response and serotonin turnover to acute stress.

Antioxidant α-tocopherol checks lymphoma promotion via regulation of expression of protein kinase C-α and c-Myc genes and glycolytic metabolism.

Overproduction of reactive oxygen species (ROS) due to environmental challenge or metabolic imbalance leads to oxidative stress, causing overactivation of a number of oncogenes that promote cancer development. Therefore, antioxidants should be able to check cancer growth by modulating oncogene activity. The requirement of high energy during unlimited cell proliferation is fulfilled by the switching of cancerous cells to a fast glycolytic pathway bypassing the oxygen dependent respiratory pathway. Almost all cancers exhibit a high expression of lactate dehydrogenase A (LDH-A) to ensure a high energy supply. The present study focused on modulating redox-sensitive oncogenes such as protein kinase C (PKC) and c-Myc by treatment of lymphoma bearing mice with the antioxidant α-tocopherol, the most active component of vitamin E. Further, the impact of α-tocopherol on LDH activity was tested. The results showed down-regulation of expression of stress-activated genes PKC-α, c-Myc and LDH-A by α-tocopherol in cancerous mice. α-Tocopherol contributes to the check of cell proliferation by decreasing the activity of LDH-A.

α-Tocopherol attenuates NF-κB activation and pro-inflammatory cytokine IL-6 secretion in cancer-bearing mice.

Cancer development and progression are closely associated with inflammation. NF-κB (nuclear factor κB) provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of malignant cells to resist tumour surveillance mechanisms. NF-κB might also regulate tumour angiogenesis and invasiveness and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches. ROS (reactive oxygen species) initiate inflammation by up-regulation of pro-inflammatory cytokines and therefore antioxidants provide a major defence against inflammation. α-Tocopherol is a lipid-soluble antioxidant. In addition to decreasing lipid peroxidation, α-tocopherol may exert intracellular effects. Hence, the aim of this study was to test the effect of α-tocopherol supplementation in cancer prevention via suppression of NF-κB-mediated pro-inflammatory cytokines. α-Tocopherol treatment significantly down-regulates expression, synthesis as well as secretion of pro-inflammatory cytokine IL-6 (interleukin-6) in cancerous mice. It also suppresses NF-κB binding to IL-6 promoter in liver leading to decreased secretion of IL-6 in serum. The regulation of the signalling pathway by α-tocopherol is found apart from its antioxidant capacity to reduce lipid peroxidation. Thus, the present study provides evidence for the hypothesis that besides the powerful free radical scavenging effects, α-tocopherol has genomic effects in down-regulation of pro-inflammatory cytokine and cancer prevention via the NF-κB-dependent pathway.

The effect of fenugreek on the gene expression of arachidonic acid metabolizing enzymes.

The main bioactive compounds of Trigonella foenum graecum L. (fenugreek) seeds are protodioscin, trigoneoside, diosgenin and yamogenin, which have anticarcinogenic potency through inhibition of cell proliferation and inhibition of prostaglandin synthesis. The effect of fenugreek on ALOX and COX genes was examined in AKR/J H-2(k) mice exposed to dimethylbenz[α]anthracene (DMBA), a potent carcinogen. The expression pattern of these genes was determined by detecting the mRNA expression in various tissues (the lungs, liver, spleen and the kidneys) in four groups of mice. Two groups were fed with normal and two of them with fenugreek containing nutriment. Each group divided into DMBA treated and control groups. Mice were autopsied on day 7 after DMBA treatment for mRNA isolation. Fenugreek consumption itself did not change gene expression compared with the control group. DMBA could increase the expression of ALOX12, ALOX15, ALOX5 genes mainly in all organs. Fenugreek consumption was generally protective in each organ in a different manner. DMBA treatment increased COX2 gene expression, but fenugreek was protective in all tissues examined. In COX1 gene, the fenugreek diet could suppress the expression, except for spleen, independently from carcinogen exposure. Therefore by inhibiting the arachidonic acid metabolism fenugreek may prevent tumorigenesis.

[Changes in fatty acid composition in the brain and liver in aging mice of high cancer risk AKR strain and effect of savory essential oil administration on leukemic process].

Age-related alterations of fatty acid composition in liver and brain of AKR mice was investigated. The effect of savory essential oil (Satureja hortensis L.), added with drinking water on fatty acid composition in these organs and the processes of lipid peroxidation in erythrocytes were estimated. It was found that during aging the percentage of saturated fatty acids and polyunsaturated fatty acids decreased while monounsaturated fatty acids increased. The development of leukemia was accompanied by the increase of saturated and polyunsaturated fatty acids percentage and a decrease of monounsaturated fatty acids amount. In the liver aging caused the increase in the percentage of saturated fatty acids, the decrease of monounsaturated fatty acids, while the amount of polyunsaturated fatty acids was not changed. Leukemia (after 8 month) was accompanied by the increase of percentage of monounsaturated fatty acids and the decrease in the amount of oleinic and docosohexaenic acids. The intake of savory essential oil was accompanied by intensification of polyunsaturated fatty acids synthesis in mice liver and reduction of lipid peroxidation products content.

Differential effects of sucrose and fructose on dietary obesity in four mouse strains.

We examined sugar-induced obesity in mouse strains polymorphic for Tas1r3, a gene that codes for the T1R3 sugar taste receptor. The T1R3 receptor in the FVB and B6 strains has a higher affinity for sugars than that in the AKR and 129P3 strains. In Experiment 1, mice had 40days of access to lab chow plus water, sucrose (10 or 34%), or fructose (10 or 34%) solutions. The strains consumed more of the sucrose than isocaloric fructose solutions. The pattern of strain differences in caloric intake from the 10% sugar solutions was FVB>129P3=B6>AKR; and that from the 34% sugar solutions was FVB>129P3>B6>/=AKR. Despite consuming more sugar calories, the FVB mice resisted obesity altogether. The AKR and 129P3 mice became obese exclusively on the 34% sucrose diet, while the B6 mice did so on the 34% sucrose and 34% fructose diets. In Experiment 2, we compared total caloric intake from diets containing chow versus chow plus 34% sucrose. All strains consumed between 11 and 25% more calories from the sucrose-supplemented diet. In Experiment 3, we compared the oral acceptability of the sucrose and fructose solutions, using lick tests. All strains licked more avidly for the 10% sucrose solutions. The results indicate that in mice (a) Tas1r3 genotype does not predict sugar-induced hyperphagia or obesity; (b) sucrose solutions stimulate higher daily intakes than isocaloric fructose solutions; and (c) susceptibility to sugar-induced obesity varies with strain, sugar concentration and sugar type.

Lemon grass (Cymbopogon citratus) ameliorates murine spontaneous ileitis by decreasing lymphocyte recruitment to the inflamed intestine.

OBJECTIVE: Aberrant leukocyte migration has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Lemon grass is a natural herb that contains citral, which suppresses lymphocyte expression of gut homing molecules by inhibiting retinoic acid formation. We therefore hypothesized that lemon grass intake could ameliorate excess migration of leukocytes to the inflamed intestine in chronic ileitis. METHODS: Migration of fluorescence-labeled T cells to microvessels in the ileal mucosa of SAMP1/Yit mice was monitored using intravital microscopy. In some mice, lemon grass solution was administered for two weeks. For evaluation of the effects on chronic ileitis, mice were treated with lemon grass for 26 weeks. RESULTS: Surface expression of beta7 and CCR9 on T lymphocytes was stronger in SAMP1/Yit mice than in AKR/J mice. Lemon grass treatment attenuated the surface expression of beta7-integrin and CCR9. The number of adherent lymphocytes to microvessels in chronic inflamed ileum was significantly few when lymphocytes were isolated from lemon grass treated mice. Long-term lemon grass treatment improved ileitis in SAMP1/Yit mice, which was assessed by body weight, histological changes and the infiltration of beta7-positive cells. CONCLUSION: Lemon grass ameliorated ileitis through decreasing lymphocyte migration by inhibiting beta7-expression, suggesting its therapeutic usefulness for IBD.

Phenotypic alterations of dendritic cells are involved in suppressive activity of trichosanthin-induced CD8+CD28- regulatory T cells.

The nature and differentiation of regulatory CD8(+)CD28(-) T cells are poorly understood. In this study, we demonstrate that native Ag trichosanthin (Tk), a highly purified linear peptide isolated from a Chinese medicinal herb, is able to induce strong suppression of OVA-specific lymphoproliferation at low concentrations via activation of IL-4/IL-10-secreting CD8(+)CD28(-) regulatory T cells (Tregs). To elucidate the underlying mechanisms, we firstly identified two types of mouse inbred strains, high susceptible (HS) and low susceptible, for the Tk-related suppression. They are H-2(d) (or H-2(b)) and H-2(k), respectively. The suppression is evoked only if bone marrow-derived dendritic cells (BDCs) instead of purified T cells are treated with Tk in an OVA-specific T-BDC interaction. Moreover, a special pattern of cytokine/transcription factors (IL-4(+)IL-10(+)IFN-gamma(-)Gata3(+)T-bet(-)) during suppressed OVA-specific T cell proliferation was observed in HS C57BL/6 but not in low-susceptible C3H/He mice. Consistently, the percentage of CD8(+)CD28(-) Tregs preferentially expanded from 5.5 to 26.1% in the presence of Tk, an occurrence that was also detected only in HS C57BL/6 mice. These expanded Tregs were able to induce a strong inhibition of one-way MLCs, which indicated that the Tk-induced hyporeaction and the activation of CD8(+)CD28(-) Tregs might be under the influence of different genetic backgrounds. Additionally, obvious alterations of phenotypic parameters of BDCs after Tk stimulation were also identified, including enhanced production of IL-10, decreased secretion of IL-12, and detection of Jagged1, a Notch ligand on BDCs. Collectively, our data suggest that the changed APC-related factors are essential, at least in part, for the activation and differentiation of Tk-induced CD8(+)CD28(-) Tregs.

The traditional Chinese herbal formula ASHMI inhibits allergic lung inflammation in antigen-sensitized and antigen-challenged aged mice.

BACKGROUND: Although asthma is typically characterized as a childhood disease, it can develop later in life. Older asthmatic patients may be at increased risk for corticosteroid adverse effects. We developed a novel traditional Chinese medicine to treat asthma called antiasthma simplified herbal medicine intervention (ASHMI). Herbal products may offer safer adjunctive treatment for older asthmatic patients. OBJECTIVE: To investigate the effects of ASHMI on characteristics of allergic asthma in an aged mouse model of asthma. METHODS: BALB/c mice (6 weeks old [young] and 6, 12, and 18 months old [aged]) received ASHMI treatment before and during intraperitoneal ovalbumin sensitization and intratracheal challenges. The control groups were untreated, age-matched, ovalbumin-sensitized and ovalbumin-challenged mice (ovalbumin mice) and naive mice. After the final antigen challenge, airway pressure (defined as the time-integrated change in peak airway pressure) after acetylcholine provocation was measured, representing airway hyperresponsiveness, and bronchoalveolar lavage fluid, sera, lung tissues for histologic analysis, messenger RNA, and collagen were collected. RESULTS: Mean time-integrated change in peak airway pressure values in 6-week-old and 6-, 12-, and 18-month-old ASHMI ovalbumin mice were significantly reduced compared with those of age-matched, nontreated ovalbumin mice. Bronchoalveolar lavage fluid eosinophil numbers were significantly lower in all ASHMI ovalbumin mice. Treatment with ASHMI of young and aged ovalbumin mice resulted in significantly decreased lung inflammation, detected via hematoxylin-eosin staining; airway mucous cell metaplasia, determined by means of periodic acid-Schiff staining; and messenger RNA copy numbers of the mucin gene MUC5AC. Levels of ovalbumin specific IgE and the T(H)2 cytokines interleukin 4 (IL-4), IL-5, and IL-13 in lung and splenocyte cultures were reduced. Interferon gamma secretion was increased. Treatment with ASHMI reduced collagen production. CONCLUSION: Treatment with ASHMI reduces several features of asthma in aged antigen-sensitized and antigen-challenged mice.

Genome-wide microarray analysis of brain gene expression in mice on a short-term high iron diet.

The effects of systemic iron overload on the brain are unclear. Microarray analysis of brain gene expression in mice following short-term iron supplementation revealed altered expression of 287 genes, although most changes were small. Transcripts for the iron storage protein ferritin light chain increased 20% (p=0.002) and transcripts for iron regulatory protein 1, which negatively regulates ferritin translation, decreased 28% (p=0.048). There were expression changes for genes involved in important brain functions such as neurotransmission and nitric oxide signaling, which is dependent on iron. Few changes related to reactive oxygen species, inflammation or apoptosis, however expression changes were observed for genes causatively linked to neurological disorders, including Charcot-Marie-Tooth disease, neuronal ceroid lipofuscinosis and mucolipidosis. The latter involve intralysosomal lipofuscin build-up that may reflect lysosomal iron accumulation. The findings suggest that high iron intake may cause subtle brain effects of clinical relevance in some circumstances.

Mice lacking cannabinoid CB1-, CB2-receptors or both receptors show increased susceptibility to trinitrobenzene sulfonic acid (TNBS)-induced colitis.

This study was performed to assess whether mice lacking the cannabinoid receptor CB1, CB2 or both receptors show increased susceptibility to TNBS colitis in comparison to wildtype mice. Previously, activation of CB1 and CB2 receptors showed attenuation of TNBS colitis in mice. The aim of the study was to investigate the susceptibility of three mouse strains CB1-, CB2- and CB1+2 double knockout mice in the model of TNBS colitis. The different knockout mice were given each a single enema with TNBS 7 mg, volume 150 microl (in 50% ethanol solution) on day 1. Control group (C57BL/6 mice) received the same concentration of TNBS enema and each strain received vehicle application of 150 microl 50% ethanol solution. After a 3-day period, the animals were sacrificed and their colon excised. A scoring system was used to describe macroscopical and histological changes. Messenger RNA-expression of TNF-alpha and IL-1beta as pro-inflammatory markers was measured by RT-PCR. All three knockout strains showed increased susceptibility to TNBS colitis quantified by macroscopical and histological scoring systems and pro-inflammatory cytokine expression in comparison to the TNBS control group (wild type C57BL/6 animals). Mice lacking the CB1-, CB2-receptor or both receptors showed aggravation of inflammation in the model of TNBS colitis. Lacking of both cannabinoid receptors did not result in potentiation of colitis severity compared to lacking of each CB1 or CB2, respectively. These results suggest that the endocannabinoid system may have tonic inhibitory effects on inflammatory responses in the colon.

Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice.

Trodusquemine (MSI-1436) causes rapid and reversible weight loss in genetic models of obesity. To better predict the potential effects of trodusquemine in the clinic, we investigated the effects of trodusquemine treatment in a murine model of diet-induced obesity (DIO). Trodusquemine suppressed appetite, reduced body weight (BW) in a fat-specific manner, and improved plasma insulin and leptin levels in mice. Screening assays revealed that trodusquemine selectively inhibited protein-tyrosine phosphatase 1B (PTP1B), a key enzyme regulating insulin and leptin signaling. Trodusquemine significantly enhanced insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) beta and STAT3, direct targets of PTP1B, in HepG2 cells in vitro and/or hypothalamic tissue in vivo. These data establish trodusquemine as an effective central and peripheral PTP1B inhibitor with the potential to elicit noncachectic fat-specific weight loss and improve insulin and leptin levels.

Omega-3 polyunsaturated fatty acids ameliorate the severity of ileitis in the senescence accelerated mice (SAM)P1/Yit mice model.

Clinical studies using omega-3 polyunsaturated fatty acids (omega3-PUFA) to Crohn's disease (CD) are conflicting. Beneficial effects of dietary omega3-PUFA intake in various experimental inflammatory bowel disease (IBD) models have been reported. However, animal models of large intestinal inflammation have been used in all previous studies, and the effect of omega3 fat in an animal model of small intestinal inflammation has not been reported. We hypothesized that the effects of omega3 fat are different between large and small intestine. The aim of this study was to determine whether the direct effect of omega3 fat is beneficial for small intestinal inflammation. Senescence accelerated mice (SAM)P1/Yit mice showed remarkable inflammation of the terminal ileum spontaneously. The numbers of F4/80-positive monocyte-macrophage cells as well as beta7-integrin-positive lymphocytes in the intestinal mucosa were increased significantly compared with those in the control mice (AKR-J mice). The area of mucosal addressin cell adhesion molecule-1 (MAdCAM-1)-positive vessels was also increased. The degree of expression levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6 and interferon (IFN)-gamma mRNA were increased significantly compared with those in the control mice. The feeding of two different kinds of omega3 fat (fish-oil-rich and perilla-oil-rich diets) for 16 weeks to SAMP1/Yit mice ameliorated inflammation of the terminal ileum significantly. In both the omega3-fat-rich diet groups, enhanced infiltration of F4/80-positive monocytes/macrophages in intestinal mucosa of SAMP1/Yit mice cells and the increased levels of MCP-1, IL-6 and IFN-gamma mRNA expression were ameliorated significantly compared with those in the control diet group. The results suggest that omega3 fat is beneficial for small intestinal inflammation by inhibition of monocyte recruitment to inflamed intestinal mucosa.

Mifepristone treatment improves length and quality of survival of mice with spontaneous leukemia.

BACKGROUND: Mifepristone was found to suppress expression of the progesterone-induced blocking factor (PIBF). Progesterone-induced blocking factor suppresses natural killer cell activity. The objective of the present study was to determine if treatment of mice with spontaneous murine lymphocyte leukemia with the progesterone receptor antagonist mifepristone could improve length and quality of life. MATERIALS AND METHODS: Sixty-one mice were gavaged with mifepristone and 33 controls with olive oil. Quality of life was determined by body conditioning score (BCS). Treatment was initiated when the mice were 6 months old. RESULTS: Within 2 weeks of therapy only 11.4% of the mifepristone treated mice died vs. about 50% of controls. The BCS was 5 (highest quality) in 82% of treated mice vs. 11% of controls after 2 weeks of therapy. CONCLUSION: Mifepristone therapy should be further evaluated for treating leukemia and lymphoma.