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Patients with inflammatory bowel disease (IBD) have higher incidence of extraintestinal manifestations (EIM), including liver disorders, sarcopenia, and neuroinflammation. Fermented rice bran (FRB), generated from rice bran (RB), is rich in bioactive compounds, and exhibits anti-colitis activity. However, its role in EIM prevention is still unclear. Here, for the first time, we investigated whether EIM in female C57Bl/6N mice is attenuated by FRB supplementation. EIM was induced by repeated administration of 1.5% dextran sulfate sodium (DSS) in drinking water (4 d) followed by drinking water (12 d). Mice were divided into 3 groups-control (AIN93M), 10% RB, and 10% FRB. FRB ameliorated relapsing colitis and inflammation in muscle by significantly lowering proinflammatory cytokines Tnf-α and Il-6 in serum and advanced glycation end product-specific receptor (Ager) in serum and muscle when compared with the RB and control groups. As FRB reduced aspartate aminotransferase levels and oxidative stress, it might prevent liver disorders. FRB downregulated proinflammatory cytokine and chemokine transcripts responsible for neuroinflammation in the hippocampus and upregulated mRNA expression of G protein coupled receptors (GPRs), Gpr41 and Gpr43, in small and large intestines, which may explain the FRB-mediated protective mechanism. Hence, FRB can be used as a supplement to prevent IBD-associated EIM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study was to examine the effects of dietary vitamin K (VK) 3 supplementation on immune-related substances in milk, oxidative stress indices in plasma and VK1, and menaquinone 4 (MK-4) in plasma and milk in periparturient dairy cows. Forty healthy perinatal Holstein-Friesian dairy cows were used in this study. Twenty-one animals were randomly selected and categorized into the VK3 supplemented (50 mg/day/head as VK3) group; the remaining 19 were categorized into the control group. On day 3 after calving, blood and milk were sampled, and their chemical components were determined. The VK3 supplemented group had significantly higher menaquinone 4 levels in plasma and milk on day 3 postpartum than the control group. In addition, there was a significant increase in the immunoglobulin G (IgG) level in milk. VK3 may be absorbed from the gastrointestinal tract and converted to MK-4, the biologically active form of VK, in the mammary gland and other tissues. It was thought that the increase in MK-4 level in plasma and milk induced an increase in the concentration of IgG in milk. VK3 supplementation to periparturient dairy cows may contribute to the production of colostrum with high concentrations of IgG and MK-4., (© 2022 Japanese Society of Animal Science.)

Persistent inflammatory reactions in microglial cells are strongly associated with neurodegenerative pathogenesis. Additionally, geranylgeraniol (GGOH), a plant-derived isoprenoid, has been found to improve inflammatory conditions in several animal models. It has also been observed that its chemical structure is similar to that of the side chain of menaquinone-4, which is a vitamin K 2 sub-type that suppresses inflammation in mouse-derived microglial cells. In this study, we investigated whether GGOH has a similar anti-inflammatory effect in activated microglial cells. Particularly, mouse-derived MG6 cells pre-treated with GGOH were exposed to lipopolysaccharide (LPS). Thereafter, the mRNA levels of pro-inflammatory cytokines were determined via qRT-PCR, while protein expression levels, especially the expression of NF-κB signaling cascade-related proteins, were determined via Western blot analysis. The distribution of NF-κB p65 protein was also analyzed via fluorescence microscopy. Thus, it was observed that GGOH dose-dependently suppressed the LPS-induced increase in the mRNA levels of Il-1β , Tnf-α , Il-6 , and Cox-2 . Furthermore, GGOH inhibited the phosphorylation of TAK1, IKKα/β, and NF-κB p65 proteins as well as NF-κB nuclear translocation induced by LPS while maintaining IκBα expression. We showed that GGOH, similar to menaquinone-4, could alleviate LPS-induced microglial inflammation by targeting the NF-kB signaling pathway.

Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK 1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK 2 formulations are prescribed, along with vitamin D 3 . Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.

The pregnane X receptor (PXR) is the key regulator of our defense mechanism against foreign substances such as drugs, dietary nutrients, or environmental pollutants. Because of increased health consciousness, the use of dietary supplements has gradually increased, and most of them can activate PXR. Therefore, an analysis of the interaction between drugs and nutrients is important because altered levels of drug-metabolizing enzymes or transporters can remarkably affect the efficiency of a co-administered drug. In the present study, we analyzed the effect of vitamin K-mediated PXR activation on drug metabolism-related gene expression in intestine-derived LS180 cells via gene expression studies and western blotting analyses. We demonstrated that menaquinone 4 (MK-4), along with other vitamin Ks, including vitamin K 1 , has the potential to induce MDR1 and CYP3A4 gene expression. We showed that PXR knockdown reversed MK-4-mediated stimulation of these genes, indicating the involvement of PXR in this effect. In addition, we showed that the expression of MDR1 and CYP3A4 genes increased synergistically after 24 h of rifampicin and MK-4 co-treatment. Our study thus elucidates the importance of drug-nutrient interaction mediated via PXR.

Hypogonadism, associated with low levels of testosterone synthesis, has been implicated in several diseases. Recently, the quest for natural alternatives to prevent and treat hypogonadism has gained increasing research interest. To this end, the present study explored the effect of S -allyl cysteine (SAC), a characteristic organosulfur compound in aged-garlic extract, on testosterone production. SAC was administered at 50 mg/kg body weight intraperitoneally into 7-week-old BALB/c male mice in a single-dose experiment. Plasma levels of testosterone and luteinizing hormone (LH) and testis levels of proteins involved in steroidogenesis were measured by enzymatic immunoassay and Western blot, respectively. In addition, mouse testis-derived I-10 cells were also used to investigate the effect of SAC on steroidogenesis. In the animal experiment, SAC significantly elevated testosterone levels in both the plasma and the testis without changing the LH level in plasma and increased phosphorylated protein kinase A (p-PKA) levels. Similar results were also observed in I-10 cells. The findings demonstrating the increasing effect of SAC on p-PKA and mRNA levels of Cyp11a suggest that SAC increases the testosterone level by activating the PKA pathway and could be a potential target for hypogonadism therapeutics.

The compositional analysis of volatile compounds of Nigella sativa L. seeds obtained from India and Bangladesh was carried out in this study. Apart from the proportion of volatile compounds, the chemical composition of seeds from both sources were similar. The major volatile compounds in Bangladesh seeds were p -cymene (36.35%), thymoquinone (29.77%), α-thujene (12.40%), carvacrol (2.85%), β-pinene (2.41%), limonene (1.64%), methyl linoleate (1.33%) and sabinene (1.18%), contribution of these is 87.93% of the total volatile oil. On the other hand, the major volatile compounds in Indian seeds were p -cymene (41.80%), α-thujene (13.93%), thymoquinone (10.27%), methyl linoleate (4.02%), carvacrol (3.65%), β-pinene (2.96%), d -limonene (2.11%), 4,5-epoxy-1-isopropyl-4- methyl-1-cyclohexene (1.80%), sabinene (1.50%) and 4-terpineol (1.22%); contribution of these were 83.24% of the total volatile oil. In both seeds, p -cymene, thymoquinone, and α-thujene were the major components. Importantly, N. sativa seeds of Bangladesh contained almost 3-fold thymoquinone compared to Indian seeds. In conclusion, the seeds from Bangladesh contain a higher amount of terpene ketones (29.86%) represented by thymoquinone in comparison to Indian seeds (10.61%); on the other hand, Indian seeds contained a higher amount of terpene hydrocarbons (63.18%) mainly p -cymene, compared to Bangladesh seeds (54.53%). This is the first study to report detailed compositional analysis and comparison of Nigella sativa L. seeds from Bangladesh and India., (© 2020 The Authors. Published by Elsevier Ltd.)

Testosterone plays an important role in male sexual characteristics and maturation, and decreased testosterone levels increase the risk of several diseases. Recently, onion extract rich in cysteine sulfoxides, which are amino acids unique to onions, has been reported to alleviate age-related symptoms resulting from decreased testosterone levels in males. However, the mechanism underlying the suppression of low testosterone levels by cysteine sulfoxides has not been elucidated. In this study, we found that onion extract containing cysteine sulfoxides enhanced progesterone, a precursor of testosterone, in mouse testis-derived I-10 tumor cells. Furthermore, cysteine sulfoxides activated protein kinase A (PKA) and cyclic adenosine monophosphate response element-binding protein, which are key factors in steroidogenesis. These results suggest that cysteine sulfoxides enhance steroid hormone production via activation of the PKA signaling pathway.

Type 2 diabetes mellitus is a chronic disease that is characterized by hyperglycemia, insulin resistance, and dysfunctional insulin secretion. Glycemic control remains a crucial contributor to the progression of type 2 diabetes mellitus as well as the prevention or delay in the onset of diabetes-related complications. Vitamin K is a fat-soluble vitamin that plays an important role in the regulation of the glycemic status. Supplementation of vitamin K may reduce the risk of diabetes mellitus and improve insulin sensitivity. This mini-review summarizes the recent insights into the beneficial effects of vitamin K and its possible mechanism of action on insulin sensitivity and glycemic status, thereby suppressing the progression of diabetes mellitus.

Fermented rice bran (FRB), a prospective supplement, has been proven to ameliorate certain medical conditions. However, its nutraceutical effect on muscle atrophy has never been investigated. The present study aimed to evaluate the effect of FRB on muscle atrophy in a streptozotocin (STZ)-induced diabetic rat model. Three groups of Sprague-Dawley rats, namely the control, STZ, and FRB groups, were treated as follows. The diabetic groups (STZ and FRB) were injected intraperitoneally with STZ (40 mg/kg BW), whereas the control group was injected with the vehicle. The STZ and control groups were fed the AIN93M diet, and the FRB group was fed 10% of FRB based on the AIN93M diet. The diabetic groups had reduced muscle size compared to the control group; however, these changes were alleviated in the FRB group. Moreover, the FRB group had a significantly lower expression of FBXO32/Atrogin-1 and TRIM63/MuRF1 ( p < 0.05) due to blocked NF-κB activation. In conclusion, the anti-inflammatory effect of FRB may be beneficial for ameliorating muscle atrophy in diabetic conditions.

Genomic destabilisation is associated with the induction of mutations, including those in cancer-driver genes, and subsequent clonal evolution of cells with abrogated defence systems. Such mutations are not induced when genome stability is maintained; however, the mechanisms involved in genome stability maintenance remain elusive. Here, resveratrol (and related polyphenols) is shown to enhance genome stability in mouse embryonic fibroblasts, ultimately protecting the cells against the induction of mutations in the ARF/p53 pathway. Replication stress-associated DNA double-strand breaks (DSBs) that accumulated with genomic destabilisation were effectively reduced by resveratrol treatment. In addition, resveratrol transiently stabilised the expression of histone H2AX, which is involved in DSB repair. Similar effects on the maintenance of genome stability were observed for related polyphenols. Accordingly, we propose that polyphenol consumption can contribute to the suppression of cancers that develop with genomic instability, as well as lifespan extension.

The mechanism underlying the improvement in hepatic function by liver hydrolysate (LH) after ethanol-induced hepatic injury is unclear. Therefore, we investigated the effects of LH administration on chronic ethanol-induced hepatic injury in normal rats and the mechanism underlying the improvement of its symptoms by LH. LH attenuated liver damage and reduced oxidative stress after chronic ethanol-induced hepatic injury in normal rats. LH treatment reduced hepatic injury biomarkers of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT). LH treatment also decreased levels of 8-hydroxy-deoxyguanosine (8-OHdG) as oxidative stress marker. LH may prove beneficial to prevent the liver damage of chronic ethanol, at least in part, by alleviating oxidative stress.

Rice bran (RB) is a major by-product of rice polishing and a rich source of bioactive compounds. Here, we investigated the anti-colitis effect of diet supplementation with fermented rice bran (FRB) in a murine model of ulcerative colitis. FRB was prepared by dual fermentation of RB using fungi and lactic acid bacteria. Colitis was induced in C57Bl/6N male mice ( n = 8/group) by dextran sodium sulfate (DSS). Body weight change, disease activity index (DAI), histopathology score, tissue myeloperoxidase (MPO) activity, cytokine and chemokine transcript levels, and the production of short-chain fatty acids (SCFAs) and mucin in the colonic tissue were monitored. Based on histopathology scores, DSS induced severe mucosal inflammation, with an increased loss of crypts, and inflammatory cell infiltration in the control and RB groups, but not in the FRB group. MPO activity, thiobarbituric acid-reactive substance levels, and pro-inflammatory cytokine transcript ( Tnf-α , Il-1β , Il-6 , and Il-17 ) levels were significantly higher in the control and RB groups than in the FRB group. Thus, dietary FRB attenuated intestinal inflammation owing to elevated SCFAs and tryptamine production, which might regulate tight junction barrier integrity and intestinal homeostasis. These results suggest that FRB could comprise an effective potential preventive agent for ulcerative colitis., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Purpose: The rhizome of Kaempferia parviflora (KP) is used in traditional Thai medicine. In this study, we investigated the effects of an ethanol KP extract and two of its components [5,7-dimethoxyflavone (DMF) and 5-hydroxy-3,7,3',4'-tetramethoxyflavone (TMF)] on monocyte adhesion and cellular reactive oxygen species (ROS) production in human umbilical vein endothelial cells (HUVECs), which provide an in vitro model of events relevant to the development and progression of atherosclerosis., Methods: RAW264.7 mouse macrophage-like cells were incubated with various concentrations of KP extract or polymethoxyflavonoids and stimulated with lipopolysaccharide prior to measuring nitrite levels in the culture media. Monocyte adhesion was evaluated by measuring the fluorescently labeled human monocytic leukemia THP-1 cells that is attached to tumor necrosis factor-α (TNF-α)-stimulated HUVECs. Cellular ROS production was assessed by measuring cellular antioxidant activity using pyocyanin-stimulated HUVECs., Results: KP extract and DMF reduced nitrite levels (as indicator of nitric oxide production) in LPS-stimulated RAW264.7 cells and also inhibited THP-1 cell adhesion to HUVECs. These treatments induced mRNA expression of endothelial nitric oxide synthase in TNF-α-stimulated HUVECs and downregulated that of various cell adhesion molecules, inflammatory mediators, and endothelial function-related genes. Angiotensin-converting enzyme activity was inhibited by KP extract in vitro. Furthermore, KP extract, DMF, and TMF inhibited the production of cellular ROS in pyocyanin-stimulated HUVECs., Conclusion: KP extract, DMF, and TMF showed potential anti-inflammatory and antioxidant effects in these in vitro models, properties that would inhibit the development and progression of atherosclerosis.

Background: Previous study shown that enzyme treated-rice bran effectively improved hypertension and glucose intolerance in stroke-prone spontaneously hypertensive rat (SHRSP). However, dual fermentation of rice bran's efficacy against metabolic syndrome in SHRSP is still unknown., Methods: Fermented rice bran (FRB) was prepared by dual fermentation of rice bran using fungi and lactic acid bacteria. The effect of FRB on metabolic syndrome in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated by single and chronic supplementation., Results: Dual fermentation of rice bran enriches the functional value of rice bran. Single-dose oral administration of FRB (2 g/kg body weight) reduced systolic blood pressure; however, chronic supplementation with 5 % FRB (4 weeks) significantly reduced both systolic and diastolic blood pressure. FRB supplementation improved leptin impairment and increased serum adiponectin levels and angiotensin-converting enzyme inhibitory activity. Furthermore, FRB supplementation improved glucose tolerance and insulin sensitivity as well as serum insulin levels. Lipid profiles were also improved by the regulation of 5' adenosine monophosphate-activated protein kinase activation. Moreover, supplementation with FRB reduced the expressions of hepatic transcription factors such as liver X receptor alpha, sterol regulatory element-binding protein 1c, and carbohydrate-responsive element-binding protein alpha, as well as their target genes. In conclusion, dietary supplementation with FRB may lower hypertension and alleviate metabolic syndrome., Conclusion: Metabolic syndrome was better alleviated with FRB supplementation. We therefore suggest FRB as an alternative medicine to reduce the risks of lifestyle-related diseases.

Systemic and cellular zinc homeostasis is elaborately controlled by ZIP and ZnT zinc transporters. Therefore, detailed characterization of their expression properties is of importance. Of these transporter proteins, Zip4 functions as the primarily important transporter to control systemic zinc homeostasis because of its indispensable function of zinc absorption in the small intestine. In this study, we closely investigated Zip4 protein accumulation in the rat small intestine in response to zinc status using an anti-Zip4 monoclonal antibody that we generated and contrasted this with the zinc-responsive activity of the membrane-bound alkaline phosphatase (ALP). We found that Zip4 accumulation is more rapid in response to zinc deficiency than previously thought. Accumulation increased in the jejunum as early as 1 day following a zinc-deficient diet. In the small intestine, Zip4 protein expression was higher in the jejunum than in the duodenum and was accompanied by reduction of ALP activity, suggesting that the jejunum can become zinc deficient more easily. Furthermore, by monitoring Zip4 accumulation levels and ALP activity in the duodenum and jejunum, we reasserted that zinc deficiency during lactation may transiently alter plasma glucose levels in the offspring in a sex-specific manner, without affecting homeostatic control of zinc metabolism. This confirms that zinc nutrition during lactation is extremely important for the health of the offspring. These results reveal that rapid Zip4 accumulation provides a significant conceptual advance in understanding the molecular basis of systemic zinc homeostatic control, and that properties of Zip4 protein accumulation are useful to evaluate zinc status closely., (Copyright © 2016 the American Physiological Society.)

Vitamin K is an essential nutrient for blood coagulation and bone homeostasis, and also functions in many physiological processes including inflammation and cancer progression. However, the nature and activities of its metabolites remain unclear. We report here systematic synthesis of ω-carboxylated derivatives of menaquinone (vitamin K2), including previously identified metabolites 5, K acid I (10), and K acid II (12), and evaluation of their inhibitory activity toward LPS-stimulated induction of inflammatory cytokines. These results should contribute to an improved understanding of the biochemistry and pharmacology of vitamin K., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although the aryl hydrocarbon receptor (AHR) and glucocorticoid receptor (GR) play essential roles in mammalian development, stress responses, and other physiological events, crosstalk between these receptors has been the subject of much debate. Metallothioneins are classic glucocorticoid-inducible genes that were reported to increase upon treatment with AHR agonists in rodent tissues and cultured human cells. In this study, the mechanism of human metallothionein 2A (MT2A) gene transcription activation by AHR was investigated. Cotreatment with 3-methylcholanthrene and dexamethasone, agonists of AHR and GR respectively, synergistically increased MT2A mRNA levels in HepG2 cells. MT2A induction was suppressed by RNA interference against AHR or GR. Coimmunoprecipitation experiments revealed a physical interaction between AHR and GR proteins. Moreover, chromatin immunoprecipitation assays indicated that AHR was recruited to the glucocorticoid response element in the MT2A promoter. Thus, we provide a novel mechanism whereby AHR modulates expression of human MT2A via the glucocorticoid response element and protein-protein interactions with GR., (© 2013.)

Purpose: The isoprenoid geranylgeraniol (GGOH) inhibits nuclear factor-kappa B (NF-κB) activation in the liver, yet the mechanism remains unclear. We investigated the modulation and inhibition of lipopolysaccharide (LPS)-induced NF-κB signaling in the liver of rats fed a GGOH-supplemented diet., Methods: Rats were fed a diet supplemented with or without GGOH for 10 days. Rats were then intraperitoneally injected with 0.5 mg/kg LPS or vehicle (sterilized saline) and fasted for 18 h. Plasma levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, and the liver damage indicators alanine and aspartate aminotransferases (ALT and AST) were assessed. Liver mRNA and proteins were assayed for changes in NF-κB target genes and signal transduction genes., Results: Rats fed a high-dose, GGOH-supplemented diet showed significantly lower levels of plasma inflammatory cytokines and ALT and AST activities. In the liver, GGOH significantly suppressed NF-κB activation and mRNA expression of its pro-inflammatory target genes. Furthermore, GGOH supplementation substantially suppressed mRNA expression of signal transducer genes upstream of the IκB kinase complex. Western blotting of liver extracts further demonstrated the substantial decrease in total IL-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6), leading to lower signal transduction and inhibition of NF-κB after LPS., Conclusion: A 10-day, high-dose, GGOH-supplemented diet was sufficient to inhibit LPS-induced inflammation and activation of NF-κB in rat livers. GGOH significantly modulated NF-κB signaling molecules, inhibiting its signal transduction and activation in the liver, thus protecting against liver damage.

Chronic ethanol consumption induces liver diseases, such as alcoholic hepatitis and cirrhosis. The enhancement of alcohol oxidation is important in the prevention of these liver diseases. Chronic supplementation with branched chain amino acids (BCAAs) prevents liver cirrhosis. Therefore, BCAAs may be associated with enhanced ethanol oxidation. To evaluate this hypothesis, we investigated the effect of the administration of individual BCAAs on ethanol oxidation and changes in alcohol-metabolizing enzyme activities following acute alcohol intake in rats. Blood ethanol concentrations and the activities of alcohol-metabolizing enzymes, such as alcohol dehydrogenase (ADH) and low and high Km aldehyde dehydrogenase (ALDH), were measured in the liver following acute ethanol administration in rats; the ethanol was administered 30 min after the treatment with amino acids [such as leucine (Leu), isoleucine (Ile), valine (Val) or alanine (Ala)]. Leu significantly decreased the blood ethanol concentration 1 h after ethanol administration compared to the water-treated control (C) [C 0.46 ± 0.09, Leu 0.18 ± 0.04, Ile 0.27 ± 0.09, Val 0.46 ± 0.1, Ala 0.43 ± 0.06, mean ± SEM (g/l), P < 0.05]. In addition, leucine significantly stimulated ADH activity 30 min after ethanol intake [C 0.042 ± 0.014, Leu 0.090 ± 0.016, Ile 0.042 ± 0.008, Val 0.022 ± 0.010, Ala 0.070 ± 0.016, mean ± SEM (unit/mg protein), P < 0.05] and low Km ALDH activity 15 min after ethanol intake [C 0.51 ± 0.63, Leu 3.72 ± 0.66, Ile 1.26 ± 0.89, Val: ND, Ala 1.86 ± 1.57, mean ± SEM (unit/mg protein), P < 0.05]. However, leucine and its metabolite α-keto-isocaproic acid did not enhance ethanol clearance in isolated rat hepatocytes. These results indicate that leucine accelerates ethanol oxidation by indirectly enhancing ADH and low Km ALDH activities in the liver.

The aim of the study was to investigate the effects of adenosine 5'-monophosphate (AMP) in stroke-prone spontaneously hypertensive rats (SHRSP). Male rats (10 weeks old) were divided into three groups: a control group fed an AIN-93 M diet and two others fed supplemental AMP (17.5 and 87.5 mg/kg diet) for 3 weeks. AMP effectively improved hypertension, plasma triglyceride, and HDL-cholesterol, glucose, kidney function parameters, hepatic lipid, enhances plasma nitric oxide, and plasma adiponectin accompanied by the up-regulation of mRNA expression levels of the hepatic adiponectin receptor 2. Single and chronic oral administration of AMP affected the hepatic mRNA expression levels of genes involved in β-oxidation, fatty acid synthesis, and AMP-activated protein kinase. Furthermore, a single oral dose of AMP (40 mg/kg body weight) improved hypertension and hyperglycemia in SHRSP. In conclusion, AMP displays a novel effect in ameliorating metabolic-related diseases in SHRSP and could be beneficial as a functional food.

Vitamin K is essential for blood coagulation and bone metabolism in mammals. This vitamin functions as a cofactor in the posttranslational synthesis of γ-carboxyglutamic acid (Gla) from glutamic acid residues. However, other functions of vitamin K have been reported recently. We previously found that vitamin K suppresses the inflammatory reaction induced by lipopolysaccharide (LPS) in rats and human macrophage-like THP-1 cells. In this study, we further investigated the mechanism underlying the anti-inflammatory effect of vitamin K by using cultures of LPS-treated human- and mouse-derived cells. All the vitamin K analogues analyzed in our study exhibited varied levels of anti-inflammatory activity. The isoprenyl side chain structures, except geranylgeraniol, of these analogues did not show such activity; warfarin did not interfere with this activity. The results of our study suggest that the 2-methyl-1,4-naphtoquinone ring structure contributes to express the anti-inflammatory activity, which is independent of the Gla formation activity of vitamin K. Furthermore, menaquinone-4, a form of vitamin K₂, reduced the activation of nuclear factor κB (NFκB) and inhibited the phosphorylation of IKKα/β after treatment of cells with LPS. These results clearly show that the anti-inflammatory activity of vitamin K is mediated via the inactivation of the NFκB signaling pathway., (Copyright © 2010 Elsevier Inc. All rights reserved.)

We have demonstrated previously that both acute and chronic oral administration of adenosine have novel functions such as anti-hypertensive effects and improved hyperlipidaemia in stroke-prone spontaneously hypertensive rats (SHRSP) fed a normal diet. The purpose of the present study was to investigate the effect of adenosine administration on metabolic syndrome-related parameters in SHRSP fed a high-fat diet. Six-week-old rats were divided into three groups, and were administered either water (control) or adenosine (10 or 100 mg/l) for 8 weeks. During this period, the rats had free access to a high-fat diet based on AIN-93M. The results showed that hypertension, plasma lipid, NO, insulin, glucose and urinary 8-hydroxy-2'-deoxyguanosine levels improved significantly in both adenosine groups. The mRNA expression levels of genes involved in anti-oxidative activity and adenosine receptors were also altered in the adenosine groups. Administration of adenosine also increased plasma adiponectin levels, accompanied by upregulation of mRNA expression level of adiponectin and adiponectin receptor 1 in perirenal fat and adiponectin receptor 2 in the liver. In conclusion, oral administration of adenosine is effective for improving metabolic syndrome-related parameters in SHRSP, and accordingly it may prevent the progression of the metabolic syndrome.

Feruloyl esterases hydrolyze the ester linkages of ferulic and diferulic acids present in plant cell walls. This interesting group of enzymes also has a potentially broad range of applications in the pharmaceutical and agri-food industries. An overview of the current knowledge of fungal feruloyl esterases focusing on the diverse of substrate specificity and potential applications is presented in this review. Furthermore, biological functions of ferulic acid are discussed.

In the present study, we isolated and identified an active component from the Driselase-treated fraction and investigated its effect by acute and chronic oral administration on hypertension, lipid, and glucose metabolism in stroke-prone spontaneously hypertensive rats. The active component was identified as adenosine and improves hypertension after single oral administration. Rats who were 10 weeks old were divided into control and adenosine groups and were administered water or water with adenosine (10 mg/L), respectively, for 3 weeks. Hypertension and plasma lipid, nitric oxide, insulin, leptin, adiponectin levels, and glucose metabolism were significantly improved in the adenosine group. The mRNA expression levels of genes involved in lipid and glucose metabolism were altered in the adenosine group. Single oral administration of adenosine (10 mg/kg body weight) improved hypertension and plasma triglyceride, glucose, and nitric oxide levels 2 h after administration. In conclusion, oral acute and chronic administration of adenosine are beneficial and improve the metabolic syndrome-related disease parameters.

We investigated the role of zinc in food intake regulation using rats during early-stage zinc deficiency without decreased zinc concentrations in plasma and tissues. Plasma, liver, and hypothalamic zinc concentrations were not affected in male Sprague-Dawley rats fed a zinc-deficient (Zn-Def) diet for 3 d compared with the pair-fed control group, which was fed a zinc-sufficient diet to the intake of the Zn-Def diet. Zinc sulfate at a dose of 19 micromol/kg body weight was orally or intraperitoneally (i.p.) administered to rats fed a Zn-Def diet for 3d and food intake was measured. We found that zinc stimulated food intake after oral but not i.p. administration. The mRNA expression of neuropeptide Y (NPY) and orexin in the hypothalamus significantly increased 3 h after oral but not i.p. administration of zinc. Pretreatment with an antagonist for the NPY Y(1) receptor or the orexin OX(1) receptor blocked orexigenic activity after oral administration of zinc. The stimulation of food intake by oral administration of zinc was abolished by vagotomy. Taken together, orally administered zinc may stimulate food intake via orexigenic peptides coupled to the afferent vagal stimulation in rats after short-term treatment with a Zn-Def diet.

Tocotrienol (T3), unsaturated vitamin E, has recently gained considerable attention as a potent antiangiogenic agent minimizing tumor growth, the exact intracellular mechanisms of which remain poorly understood. Because hypoxia-inducible factor-1alpha (HIF-1alpha), its downstream target vascular endothelial growth factor (VEGF), and other angiogenic factors such as interleukin-8 (IL-8) and cyclooxygenase 2 (COX-2) play critical roles in neovascularization, we tested the hypothesis that the inhibitory effect of T3 on tumor angiogenesis is via regulation of these angiogenic factors. We used 2 cancer cell lines, human colorectal adenocarcinoma cells (DLD-1) and human hepatoma cells (HepG2). T3 isomers (2 micromol/L) inhibited hypoxia-induced VEGF secretion from DLD-1, with delta-T3 showing potent inhibition. Delta-T3 suppressed hypoxia-induced VEGF and IL-8 expression in DLD-1 at both mRNA and protein levels, and we found the inhibitory mechanism of delta-T3 by reducing HIF-1alpha protein expression or increasing HIF-1alpha degradation. Also, delta-T3 (2 micromol/L) did not affect hypoxia-induced COX-2 mRNA expression; however, delta-T3 tended to suppress (P = 0.044) hypoxia-induced COX-2 protein expression, implying a possible post-transcriptional mechanism by delta-T3. Overall, our results confirmed that T3 has an inhibitory effect on angiogenic factor secretion from cancer cells and revealed the possible mechanisms, providing new information about the antiangiogenic effects of T3.

We studied the effects of a single oral administration of ferulic acid (FA) on the blood pressure (BP) and lipid profile in stroke-prone spontaneously hypertensive rats (SHRSP). Male 12-week-old SHRSP were administered FA (9.5 mg/kg of body weight) and distilled water as the control (C) (1 mL) via a gastric tube. The hypotensive effect of FA was observed at the lowest value after 2 h administration. A decrease in the angiotensin-1-converting enzyme (ACE) activity in the plasma corresponded well with the reduction of BP. Plasma total cholesterol and triglyceride levels were lower after 2 h administration. The mRNA expression of genes involved in lipid and drug metabolism was downregulated in the FA group. These results suggest that oral administration of FA appears beneficial in improving hypertension and hyperlipidemia.

Phylloquinone (vitamin K(1) = VK(1)) and the menaquinones (MK-n, or vitamin K(2) = VK(2)) are naturally occurring forms of VK. Most of the menaquinone series are synthesized by microorganisms, but we have reported that MK-4 is usual in being synthesized by the conversion of orally ingested VK(1) or MK-n in the major tissues of germfree rats and mice which lack their intestinal microflora. This result led us to deny 1960's Martius' hypothesis that described the participation of bacterial enzyme of the intestinal flora to this conversion. VK acts as a cofactor in the posttranslational synthesis of gamma-carboxyglutamic acid (Gla) from glutamic acid (Glu) residues in the nascent Gla-protein molecule. Therefore, VK is essential for blood coagulation (various clotting factors) and bone structure (as osteocalcin [OC = BGP] and matrix Gla-protein [MGP] in mammals. In addition to the liver, VK is found in the bone, brain, heart, testis, kidney, pancreas and salivary glands mainly as MK-4, and it has been reported that MK-4 itself has specific biological activities in these tissues beside Gla-protein formation. However, the physiological role of MK-4 in these organs has not been fully understood yet. Recently MK-4 has been attracted the attention of researchers due to its activities such as apoptotic activity on the osteoclast cells and leukemia cells, SXR/PXR ligand, and so on. We further review the potent important physiological role of MK-4 in the bone as well as other major tissues.

Effect of dietary supplementation of two types of rice bran fraction on blood pressure (BP), lipid profile, and glucose metabolism in stroke-prone spontaneously hypertensive rats was studied. Male 4-week-old rats were divided into one group fed the AIN-93M-based control (C) diet and two groups fed diet supplemented with 60 g/kg of Driselase and ethanol fractions (DF and EF, respectively) of rice bran. After 8 weeks feeding, the BP decreased in the DF and EF groups in comparison with the C group (p < 0.01). Plasma ACE inhibitory activity, BUN, BUN/creatinine ratio, albumin, triglyceride, and glucose levels were lower in the DF and EF groups than in the C group (p < 0.01). Plasma nitric oxide and urinary 8-hydroxy-2'-deoxyguanosine levels were lower in the DF and EF groups than in the C group (p < 0.01). Rice bran fractions appear to have a beneficial dietary component that improves hypertension, hyperlipidemia, and hyperglycemia.

Reactive oxygen species (ROS) may contribute to aging and osteoporosis resulting from marked decreases in plasma antioxidants in aged osteoporotic women. On the other hand, high-dose vitamin K2 (menaquinone-4: menatrenone, MK-4) supplementation has been reported to reduce ovariectomy-induced bone loss in rats and to decrease osteoporotic fracture in postmenopausal women. However, the mechanism by which vitamin K2 prevents osteoporosis is unclear. Recently, vitamin K2 has been suggested to preserve antioxidant activity as a novel function. Therefore, we investigated the effect of vitamin K2 on the osteoporosis of aged rats by evaluating the relationships between serum antioxidant levels and bone metabolism. Aged female rats exhibited significantly lower serum alkaline phosphatase activity and osteocalcin level, together with lower serum levels of antioxidants such as 17beta-estradiol, macrophage migration inhibitory factor (MIF) and glutathione peroxidase (GPx) activity, as compared with young female rats. On the other hand, vitamin K2 supplementation (500 mg/kg, food intake) for 98 days led to a significantly increased serum vitamin K2 level (3,045+/-915 ng/ml in the vitamin K2 supplemented group vs. 4.6+/-3.4 ng/ml in the control diet group; P<0.0001) with increased serum alkaline phosphatase activity and MIF level (P<0.05). Unexpectedly, however, it failed to increase the serum level of antioxidants such as GPx. Nor did it affect bone metabolism markers such as osteocalcin and osteopontin, which were significantly lower than in the young female rats (P<0.05). Finally, the histomorphometric properties of the proximal tibia in the femur were not altered by vitamin K2. These results suggest that high-dose vitamin K2 supplementation neither improves lowered antioxidant levels nor stimulates bone formation in aged rats.

We previously showed that alpha-eleostearic acid (alpha-ESA; 9Z11E13E-18:3) is converted to conjugated linoleic acid (CLA; 9,11-18:2) in the liver and plasma of rats that were given diets including 1% alpha-ESA for 4 wk. In this study, we investigated this phenomenon in detail. First, the chemical structure of CLA produced by alpha-ESA administration was determined. After alpha-ESA was orally administered to rats, CLA in rat liver was isolated by HPLC. The positional and geometric isomerism was determined using GC-EI/MS and (13)C-NMR, respectively, and the CLA generated in rats after alpha-ESA feeding was confirmed to be 9Z11E-CLA. Next, the concentrations of alpha-ESA and CLA were determined 0, 3, 6, and 24 h after oral administration of alpha-ESA to rats. Moreover, we also investigated whether enteric bacteria are involved in the conversion of alpha-ESA to CLA using germ-free rats. alpha-ESA was orally administered to germ-free and normal rats and alpha-ESA and CLA were detected in the organs of both groups. In addition, to confirm that this reaction was enzyme-mediated, alpha-ESA was reacted with tissue homogenates (liver, kidney, and small intestine mucous) and coenzymes (NADH, NAD(+), NADPH, and NADP(+)), and the enzyme activities were estimated from the amount of CLA produced. CLA was detected when alpha-ESA was reacted with liver, kidney, and small intestine mucous homogenates and a coenzyme (NADPH). These results indicated that alpha-ESA is converted to 9Z11E-CLA in rats by a Delta13-saturation reaction carried out by an NADPH-dependent enzyme.

We investigated the relationships among behavioral parameters, forced-swimming test parameters, and plasma and organ biotin concentrations in biotin-deficient mice. Male ddY mice were divided into four groups: early biotin deficiency group (ED group; biotin-free diet for three weeks), progressive biotin-deficiency group (PD group; biotin-free diet for seven weeks), and two age-matched control groups. The dermatological symptoms of frank biotin deficiency were observed in most mice in the PD groups (72.3%) but in only 27% of ED group mice. The liver biotin level was greatly decreased in ED and PD groups, and the plasma biotin level was also significantly decreased in the PD group, but the biotin levels were quite stable in muscle and brain. There were significant decreases in swimming time in ED and PD groups and in struggling behavior in the PD group, suggesting that biotin-deficient mice become depressed and/or fatigued without biotin deficiency being apparent in brain and muscle. One single-injection biotin administration led to a prompt recovery in swimming time. Biochemical data revealed a decrease in liver glucokinase activity and an increase in ketone bodies in both liver and plasma in biotin-deficient mice. In addition, simultaneous biotin deficiency and forced walking synergistically provoked significant increases in total ketone bodies in both plasma and liver. These results suggest that depression and/or fatigue are induced in mice by biotin deficiency.