Abstract  Iron accumulation in the brain has been associated to the pathogenesis of neurodegenerative disorders. We have previously demonstrated that iron overload in the neonatal period results in severe and persistent memory deficits in adult rats. Alterations in histone acetylation have been associated with memory deficits in models of neurological disorders. Here we examine histone acetylation in the brain and the effects of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) on memory in the neonatal iron overload model in rats. Rats received vehicle or 30.0-mg/kg Fe⁺² orally at postnatal days 12-14. When animals reached adulthood, they were given training in either novel object recognition or inhibitory avoidance. Histone acetylation in the dorsal hippocampus and the effects of NaB were examined in separate sets of rats. Iron overload led to a reduction in H3 lysine 9 acetylation in the hippocampus, without affecting the acetylation of other H3 and H4 lysine residues. A single systemic injection of NaB (1.2 g/kg) immediately after training ameliorated iron-induced memory impairments. The results suggest that a reduction in H3K9 acetylation might play a role in iron-induced memory impairment and support the view that HDACis can rescue memory dysfunction in models of brain disorders.

Abstract  AIM: The effect of combining sodium butyrate (NaB), a histone deacetylase inhibitor, and 7-hydroxy-staurosporine (UCN-01) on cytotoxicity in human cervical carcinoma cells was evaluated.

MATERIALS AND METHODS: HeLa and CaSki cells were treated using NaB alone or in combination with staurosporine (STS) or its analog UCN-01. Cytotoxicity was determined by flow cytometry and morphological assays. Apoptotic pathways were characterized by Western blotting and immunostaining. CaSki cells were also xenografted into nude mice to assess the in vivo effects of NaB/UCN-01 combination.

RESULTS: Treatment with NaB and STS or UCN-01 resulted in enhanced apoptosis of cancer cells. Apoptosis involved mitochondrial pathways and overexpression of p53 and p73. In concordance, co-treatment modulated some p53/p73 downstream targets such as p21, BAX, BCL-2 and BCL-X(L), leading to increased caspase-3 and poly(ADP-ribose) polymerase cleavage. In vivo, NaB/UCN-01 combination exerted a substantial tumour growth suppression effect compared with single treatment.

CONCLUSION: UCN-01 was shown to be a potentiator of NaB therapy for cervical cancer cells.

Abstract  Sodium butyrate (NaB), a potent histone deacetylase inhibitor, induces cell cycle arrest and apoptosis in malignant cells. We investigated the effects on cellular proliferation in vitro when combining NaB with antineoplastic drugs commonly used to treat leukemias. Our results demonstrate that NaB increases the cytotoxic effects of cytarabine and etoposide, but not of bleomycin, doxorubicin, vincristine or methotrexate. These data suggest that NaB is a promising adjuvant therapeutic agent for the treatment of lymphoblastic leukemias, and provides a basis for further studies in this field.

Abstract  Microbial coinfection has great impact on the course of disease progression of HIV-1 and the development of AIDS-related deaths. In fact, progression of AIDS development is more rapid in individuals with concomitant infections. Although it is well known that immunosuppression due to HIV-1 infection leads to AIDS-associated opportunistic infections, it has also become apparent that opportunistic infection often promotes the disease progression of HIV-1 infection by enhancing viral transmission or replication, or by modulating host immune responses. We have focused on such microbial interaction between HIV-1 and butyrate- producing anaerobic bacteria and explored the effects of these bacterial culture supernatants containing butyric acid in upregulating HIV-1 gene expression and thus inducing viral replication from the latently infected cells. Since butyric acid inhibits histone deacetylases, these findings suggest that the HIV latency is maintained in 'recessive' chromatin, where histone proteins are largely deacetylated, and that concomitant infection of butyrate-producing bacteria could obviously be a risk factor for HIV-1 reactivation in infected individuals, and might contribute to AIDS progression. Moreover, it is possible that therapeutic elimination of such bacterial infection could conceivably prevent the clinical development of AIDS and its epidemiological transmission. Widespread epidemiological surveys are warranted in order to elucidate the role of concomitant infection of such bacteria.

Abstract  While conservation of ATP is often a desirable trait for microbial production of chemicals, we demonstrate that additional consumption of ATP may be beneficial to drive product formation in a nonnatural pathway. Although production of 1-butanol by the fermentative coenzyme A (CoA)-dependent pathway using the reversal of β-oxidation exists in nature and has been demonstrated in various organisms, the first step of the pathway, condensation of two molecules of acetyl-CoA to acetoacetyl-CoA, is thermodynamically unfavorable. Here, we show that artificially engineered ATP consumption through a pathway modification can drive this reaction forward and enables for the first time the direct photosynthetic production of 1-butanol from cyanobacteria Synechococcus elongatus PCC 7942. We further demonstrated that substitution of bifunctional aldehyde/alcohol dehydrogenase (AdhE2) with separate butyraldehyde dehydrogenase (Bldh) and NADPH-dependent alcohol dehydrogenase (YqhD) increased 1-butanol production by 4-fold. These results demonstrated the importance of ATP and cofactor driving forces as a design principle to alter metabolic flux.

Abstract  An Escherichia coli strain was engineered to synthesize 1-hexanol from glucose by extending the coenzyme A (CoA)-dependent 1-butanol synthesis reaction sequence catalyzed by exogenous enzymes. The C4-acyl-CoA intermediates were first synthesized via acetyl-CoA acetyltransferase (AtoB), 3-hydroxybutyryl-CoA dehydrogenase (Hbd), crotonase (Crt), and trans-enoyl-CoA reductase (Ter) from various organisms. The butyryl-CoA synthesized was further extended to hexanoyl-CoA via β-ketothiolase (BktB), Hbd, Crt, and Ter. Finally, hexanoyl-CoA was reduced to yield 1-hexanol by aldehyde/alcohol dehydrogenase (AdhE2). Enzyme activities for the C6 intermediates were confirmed by assays using HPLC and GC. 1-Hexanol was secreted to the fermentation medium under anaerobic conditions. Furthermore, co-expressing formate dehydrogenase (Fdh) from Candida boidinii increased the 1-hexanol titer. This demonstration of 1-hexanol production by extending the 1-butanol pathway provides the possibility to produce other medium chain length alcohols using the same strategy.

Abstract  Short days induce winter-like adaptations in small mammals such as Siberian hamsters (Phodopus sungorus (Pallas, 1773)). Specifically, hamsters adjust food consumption, metabolic processes, and immune function to optimize energetic needs and promote winter survival. One potentially inexpensive behavioral adaptation to increase survival is avoidance of infection. We tested the hypothesis that photoperiod affects avoidance of potentially infected food. In experiment 1, hamsters were weaned into either short or long days with ad libitum food. Three weeks later, hamsters were presented with either skim milk treated with butyric acid (2%), a bacterial product that serves as a potent cue of spoilage, or unadulterated skim milk; consumption was measured. After milk presentation, blood samples were obtained to assess cortisol. In experiment 2, skim-milk consumption was again assessed after 3 weeks in either short or long days. In experiment 3, we tested the hypothesis that food avoidance was due to photoperiod-induced differential neophobia. Short-day hamsters increased milk consumption, which was blocked by butyric acid. Short days increased cortisol concentrations; neither food restriction nor butyric acid affected cortisol concentrations. Photoperiod did not alter neophobic responses. These experiments suggest that short-day hamsters avoid food treated with butyric acid possibly as an adaptive trait to avoid costly winter infections.

Abstract  The present study was to investigate the effects of dietary microencapsulated sodium butyrate (SB) and acute pre-slaughter stress, mimicked by subcutaneous corticosterone (CORT) administration, on BW, carcass characteristics, muscle antioxidant status, and meat quality of broiler chickens. A total of 120 1-d-old broiler chickens were fed a control diet (without SB) or a 0.4-g microencapsulated SB/kg diet. On 42 d, half of the birds from each treatment were given 1 single subcutaneous injection of CORT (4 mg/kg of BW in corn oil) to mimic acute stress, whereas the other half were injected with the same amount of corn oil (sham control). Three hours later, BW loss was determined and breast meat samples were collected. The results showed that the BW of the CORT-challenged groups lost much more than the sham control group (P < 0.001), whereas it was alleviated by the dietary microencapsulated SB (P < 0.05). Meanwhile, the catalase activity was decreased and malondialdehyde level was increased by the stress (P < 0.05), and the microencapsulated-SB diet significantly inhibited this effect (P < 0.05). Lower pH values and higher yellowness values were also observed in CORT-challenged chickens (P < 0.05), and the microencapsulated-SB diet treatment partially exerted a preventive effect. Microencapsulated SB significantly decreased the contents of saturated fatty acids and C18:0 (P < 0.01 and P < 0.001), and increased C20:0 and C20:4 contents. However, the effect of the stress treatment on fatty acid composition was insignificant (P > 0.05). In addition, diet and stress did not significantly influence carcass characteristics and the chemical composition of breast meat (P > 0.05). These results suggest that microencapsulated SB was favorable for chickens in the presence of stress, which may be partially ascribed to the ability of SB to decrease catabolism and oxidative injury of tissues.

Abstract  The short-chain fatty acids acetate, propionate, and butyrate are produced by colonic bacterial fermentation of carbohydrates. Butyrate is important in the regulation of the colonocyte cell cycle and gut motility and may also reduce the risk of large bowel cancer. We have shown that dietary butyrylated starch can deliver butyrate to the large bowel in a sustained manner. We hypothesized that ingestion of butyrylated starch increases large bowel butyrate levels and decreases colonic contractility. Groups of male Sprague-Dawley rats (n = 8) were fed AIN-93G-based diet containing a highly digestible low-amylose maize starch (LAMS) control or 5% or 10% butyrylated LAMS (LAMSB) for 10 days. We found that cecal but not colonic tissue weight as well as cecal and distal colonic digesta weights and fecal output were higher in LAMSB fed rats. Butyrylated LAMS lowered digesta pH throughout the large bowel. Cecal, proximal, and distal colonic butyrate pools and portal venous butyrate concentrations were higher in rats fed LAMSB. Electrically stimulated and receptor-dependent carbachol and prostaglandin E(2)-induced isotonic contractions were lower in isolated intact sections of proximal colon (P < .05) but not the terminal ileum after 10% LAMSB ingestion. These results demonstrated that elevation of butyrate levels in the large bowel of the rat correlated with reduction of contractile activity of the colonic musculature, which may assist in the reabsorption of water and minerals.

Abstract  Butyrate is an inhibitor of histone deacetylase (HDAC) and has been extensively evaluated as a chemoprevention agent for colon cancer. We recently showed that mutations in the adenomatous polyposis coli (APC) gene confer resistance to HDAC inhibitor-induced apoptosis in colon cancers. Here, we show that APC mutation rendered colon cancer cells resistant to butyrate-induced apoptosis due to the failure of butyrate to down-regulate survivin in these cells. Another cancer-preventive agent, 3,3'-diindolylmethane (DIM), was identified to be able to down-regulate survivin in colon cancers expressing mutant APC. DIM inhibited survivin mRNA expression and promoted survivin protein degradation through inhibition of p34(cdc2)-cyclin B1-mediated survivin Thr(34) phosphorylation. Pretreatment with DIM enhanced butyrate-induced apoptosis in colon cancer cells expressing mutant APC. DIM/butyrate combination treatment induced the expression of proapoptotic Bax and Bak proteins, triggered Bax dimerization/activation, and caused release of cytochrome c and Smac proteins from mitochondria. Whereas overexpression of survivin blocked DIM/butyrate-induced apoptosis, knocking down of survivin by small interfering RNA increased butyrate-induced apoptosis in colon cancer cells. We further showed that DIM was able to down-regulate survivin and enhance the effects of butyrate in apoptosis induction and prevention of familial adenomatous polyposis in APC(min/+) mice. Thus, the combination of DIM and butyrate is potentially an effective strategy for the prevention of colon cancer.

Abstract  Produced by dietary fiber, butyrate is a potential chemopreventive agent against colon cancer. It stimulates proliferation of normal colonic epithelial cells but induces growth inhibition, differentiation, apoptosis, or a combination of effects in colon carcinoma cells. In this study, we used cDNA membrane arrays and real-time reverse transcriptase-polymerase chain reaction to identify stress genes that were differentially regulated by sodium butyrate (NaB) in HT 29 human colon carcinoma cells. The results indicated that a group of heat shock protein (hsp) genes were upregulated by 3 mM NaB within the first 24 hours of exposure. Because the transcription of hsp genes is under the control of heat shock factors (HSFs), we measured the effects of overexpressed HSF-1 on the responses of HT 29 cells to NaB. Overexpression of HSF-1 inhibited NaB-induced differentiation as measured by alkaline phosphatase activity and carcinoembryonic antigen expression. These results suggest that increased expression of HSFs and Hsps might render colon carcinoma cells resistant to the chemopreventive effects of butyrate.

Abstract  An experiment was designed to evaluate the effects of 3 different additives on the gastrointestinal microbiota of early-weaned pigs. Early-weaned (18 to 22 d; n = 32) pigs (6.0 +/- 0.10 kg of BW) from 8 litters were randomly distributed into 8 pens. Each pen was assigned 1 of 4 dietary treatments: a prestarter or control diet, the control diet with 0.04% avilamycin (AB), with 0.3% sodium butyrate, or with 0.03% plant extract mixture (XT; standardized mixture with 5% (wt/wt) carvacrol extracted from Origanum spp., 3% cinnamaldehyde extracted from Cinnamonum spp., and 2% capsicum oleoresin from Capsicum annum). At the end of the experimental period, 8 pigs per treatment were killed, and samples of their intestinal content were taken. The total bacterial load along the gastrointestinal tract (GIT; stomach, jejunum, cecum, and distal colon) and the lactobacilli and enterobacteria in the jejunum and cecum were measured by quantitative PCR. The total microbial counts along the GIT did not differ among the diets, but there was an increase in the lactobacilli:enterobacteria ratio in the cecum of the piglets on the XT diet (P = 0.003). Restriction fragment length polymorphism of the PCR-amplified V3, V4, and V5 regions of the 16S rDNA gene showed changes in the structure of the microbial community in the jejunum. Dendrograms grouped animals by diets; control with 0.3% sodium butyrate was the treatment that promoted the biggest changes in the microbial ecosystem, followed by AB and then XT. Biodiversity increased when using additives compared with the control diet (P = 0.002). Microbial metabolic activity along the hindgut was studied using the concentration of purine bases and carbohydrase activities. Different patterns for purine bases were observed between diets (diet x intestinal section, P = 0.01). The control diet reached a maximum purine base concentration at the end of the colon, whereas that of the AB diet was reached at the cecum. We could not detect any cellulase or xylanase activities in animals of this age. Appreciable amylase and amylopectinase activities were found, but they did not differ between diets. The results suggest that the effects of avilamycin, butyrate, or the plant extract would not be related to a reduction in the number of total bacteria inhabiting different sections of the GIT but rather to changes in the ecological structure and metabolic activity of the microbial community.

Abstract  Sodium butyrate as a histone deacetylase inhibitor is known to exhibit anti-cancer effects via the differentiation and apoptosis of various carcinoma cells. However, the mechanism by which sodium butyrate induces apoptosis and the involvement of telomerase activity during apoptosis is not completely understood. To investigate the underlying pathways, sodium butyrate's potential to induce apoptosis in human leukemic U937 cells and its effects on telomerase activity were investigated. Exposure of U937 cells to sodium butyrate resulted in growth inhibition and induction of apoptosis in a dose-dependent manner as measured by hemocytometer counts, fluorescence microscopy, agarose gel electrophoresis and flow cytometry analysis. The increase in apoptosis was associated with the up-regulation in pro-apoptotic Bax expression, and down-regulation of anti-apoptotic Bcl-2 and Bcl-XL. Sodium butyrate treatment also inhibited the levels of cIAP family members and induced the activation of caspase-3. Furthermore, sodium butyrate markedly inhibited the activity of telomerase and the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively down-regulated by sodium butyrate. Taken together, it is suggested that sodium butyrate can be a promising chemopreventive agent for leukemic cells and changes in Bcl-2 family expressions, as well as telomerase activity may, play critical roles in sodium butyrate-induced apoptosis in U937 cells.

Abstract  We explored in humans concentration-detection functions for the odor of the homologous n-alcohols ethanol, 1-butanol, 1-hexanol, and 1-octanol. These functions serve to establish structure-activity relationships, and reflect the pharmacology of the olfactory sense at the behavioral level. We tested groups of 14 to 17 subjects (half of them females), averaging 31 to 35 years old. An 8-station vapor delivery device (VDD8) presented the stimulus under a three-alternative forced-choice procedure against carbon-filtered air. The VDD8 was built to meet the demands of typical human sniffs in a short-term (<5 s) olfactory detection task, and to accurately control odorant generation, delivery, and stability. Actual stimulus concentration was quantified by gas chromatography before and during testing. The functions obtained were log normally distributed and were accurately modeled by a sigmoid (logistic) function, both at the group and at the individual level. Sensitivity to ethanol was the lowest and to 1-octanol the highest. Functions became steeper with increasing carbon chain length. For all alcohols the concentration detected halfway between chance and perfect detection (threshold) was at the ppb (or nM) level. Females were slightly more sensitive than males. Intersubject variability across participants was between one and two orders of magnitude. The present odor thresholds were lower than many reported in the past but their relative pattern across alcohols paralleled that in our earlier data and in compilation studies. A previously described quantitative structure-activity relationship for odor potency holds promise to model thresholds that, like those obtained here, best reflect the intrinsic sensitivity of human olfaction.

Abstract  Introduction: Short chain fatty acids (SCFA) acetate, propionate and butyrate are the major anions produced by the bacterial fermentation of dietary fiber (DF) in colon. Recently, butyrate has been recently studied because is important to maintain colonic functions and because it has been related with a protective effect in colorectal cancer, which is mainly, explained by its potential to regulate gene expression by inhibiting enzyme histone-deacetylase (HDAC). Several investigationsshown that SCFAreceptor GPR43 is involved insignal transduction mechanisms once they bind to ligands such as butyrate to generate different physiological effects in colonocytes. Objective: Determine if dietary fiber consumption from nopal (Opuntia ficus I.) containing a ratio of soluble-insoluble fiber 40/60, has a direct influence on the quantitative expression of butyrate-specific receptor GPR43. Methods: Wistar rats were fed with four different diets formulated at different concentrations of dietary fiber of 0, 5, 15 and 25% of dietary fiber from opuntia, respectively. Results and discussion: The results shown an increase in the expression of GPR43 (93.1%) when rats was fed with a 5% fiber diet, using beta-actin as a reference gene. The results of this investigation will contribute to determinate the relation of diet with intestinal health for the purpose of expanding the knowledge of butyric acid on colonic functions. (Nutr Hosp. 2011;26:1052-1058) DOI: 10.3305/nh.2011.26.5.5054

Abstract  BACKGROUND: In ulcerative colitis (UC) butyrate metabolism is impaired due to a defect in the butyrate oxidation pathway and/or transport. In the present study we correlated butyrate uptake and oxidation to the gene expression of the butyrate transporter SLC16A1 and the enzymes involved in butyrate oxidation (ACSM3, ACADS, ECHS1, HSD17B10, and ACAT2) in UC and controls.

METHODS: Colonic mucosal biopsies were collected during endoscopy of 88 UC patients and 20 controls with normal colonoscopy. Butyrate uptake and oxidation was measured by incubating biopsies with (14) C-labeled Na-butyrate. To assess gene expression, total RNA from biopsies was used for quantitative reverse-transcription polymerase chain reaction (qRT-PCR). In 20 UC patients, gene expression was reassessed after treatment with infliximab.

RESULTS: Butyrate uptake and oxidation were significantly decreased in UC versus controls (P < 0.001 for both). Butyrate oxidation remained significantly reduced in UC after correction for butyrate uptake (P < 0.001), suggesting that the butyrate oxidation pathway itself is also affected. Also, the mucosal gene expression of SLC16A1, ACSM3, ACADS, ECHS1, HSD17B10, and ACAT2 was significantly decreased in UC as compared with controls (P < 0.001 for all). In a subgroup of patients (n = 20), the gene expression was reassessed after infliximab therapy. In responders to therapy, a significant increase in gene expression was observed. Nevertheless, only ACSM3 mRNA levels returned to control values after therapy in the responders groups.

CONCLUSIONS: The deficiency in the colonic butyrate metabolism in UC is initiated at the gene expression level and is the result of a decreased expression of SLC16A1 and enzymes in the β-oxidation pathway of butyrate.

Abstract  The objective of this study was the evaluation of the inclusion of calcium propionate, sodium butyrate and sodium monensin in the starter concentrate on ruminal parameters and forestomach development in dairy calves. Fifteen newborn Holstein calves were rumen cannulated and housed in individual stalls until ten weeks old, with free access to water, fed 4 liters of milk per day. split in two meals, and starter concentrate ad libitum containing sodium butyrate (0.15%), sodium monensin (30 m) or calcium propionate (0.15%). Starting at the fourth week of life, before and 2 hours after the morning feeding, ruminal fluid samples were taken weekly to determine the pH, short-chain fatty acids and ammonia-N. After 10 weeks, the animals were slaughtered to assess the forestomach growth. The rumen pH was affected by sampling time and the additives used in the starter concentrate. The total short-chain fatty acids concentration and each fatty acid concentration, were was not affected by the additives. However, except for molar concentration of acetic acid, all rumen fermentation parameters were affected by sampling time. The total forestomach weight and the average weight of each compartment and the maximum reticulum-rumen capacity were not affected by additives Supplied in the starter concentrate. No significant effects of the additives were observed on the height, width and number of papillae of the ruminal epithelium. The inclusion of these additives in starter concentrate had no effect on most of the ruminal parameters and forestomach development in suckling calves.

Abstract  In milk-fed calves, the effects of sodium-butyrate (Na-butyrate) to replace flavomycin on growth performance and some mechanisms involved were studied. Pancreatic and intestinal morphology, digestive enzyme activities, plasma gut regulatory peptide concentrations, and expression of their receptors in the gastrointestinal tract were measured. Gastrointestinal tract defense systems were examined by measuring protein levels of 2 heat-shock proteins (HSP27 and HSP70). The calves were randomly allocated into 2 groups fed the same basic diet with flavomycin as an antimicrobial growth promoter or with Na-butyrate (3 g/kg of dry matter). Sodium-butyrate disappeared quickly in the upper gut and was not found in circulating blood. Supplementation with Na-butyrate enhanced growth rate and improved feed conversion into body weight gain compared with the flavomycin group. Supplementation with Na-butyrate was likely associated with an improvement in efficacy of the gastrointestinal tract digestive capacities expressed by enhanced production of digestive enzymes and increased absorptive capacities in the upper small intestine. The effects could have been controlled by insulin-like growth factor-1 but probably not by any of the cholecystokinin/gastrin peptide family. Concentrations of HSP27 and HSP70 were increased in stomach and colon of calves receiving Na-butyrate, thereby assuring protection of cells with intensive metabolism (chaperone function). In conclusion, beneficial effects of Na-butyrate on maturation of gastrointestinal functions were shown in milk-fed calves and may be applied to young mammals of other species.

Abstract  Sodium butyrate (NaBu) is known to exhibit anti-cancer effects via the differentiation and apoptosis of various carcinoma cells. However, the mechanism by which NaBu induces apoptosis and the involvement of protein kinases during apoptosis is not completely understood. To investigate the underlying pathways, we performed cell culture experiments in androgen-independent human prostate cancer (DU145 cells) focusing on various protein kinases. NaBu causes concentration-dependent cell detachment and growth inhibition. Exposure of DU145 cells to NaBu for 24 h caused a strong apoptotic effect with 26% nuclear fragmentation and condensation. In addition, NaBu induced caspase-3 and poly-ADP ribose polymerase cleavage and up-regulation of bax, suggesting that mitochondrial damage is involved in NaBu-induced caspase-dependent apoptosis. Interestingly, NaBu stimulated p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) activation, but not extracellular signal-regulated kinase 1/2 activation during apoptosis. Furthermore, NaBu up-regulated total protein levels and phospho forms of MAPK kinase 3 (MKK3) and MAPK kinase 4 (MKK4) as the upstream kinases of p38 MAPK and JNK independently of oxidative stress. Taken together, it is suggested that NaBu can be a promising chemopreventive agent for prostate cancer and the p38 MAPK and JNK pathways have critical roles in NaBu-induced apoptosis in DU145 cells.

Abstract  2,4,5-trimethyl-3-thiazoline (TMT), a component of fox feces, is a widely used odorant to induce innate fear behavior in rats and mice. However, based on the slight acrid smell it was argued that the observed behavioral effects are a result of the aversive and not of the fear-inducing properties of TMT. In the present study, we tried to directly compare the aversive and fear-inducing properties of TMT with those of the aversive control odor butyric acid. We first identified concentrations of butyric acid and TMT that induce similar amounts of avoidance behavior in rats, indicating that these concentrations have similar aversive properties. In a second experiment, these two concentrations were then tested for their ability to induce freezing, a species-specific defensive response. Only TMT but not butyric acid induced freezing in the rats. This supports the hypothesis that TMT indeed has specific fear-inducing properties and that the observed behavioral effects could not simply be reduced to the aversive properties of TMT.

Abstract  Our previous study has revealed that providing dry feeds increased the plasma concentration of antidiuretic hormone (ADH) in suckling calves, leading to altered water balance. To examine whether ketone bodies formed from ruminal fermentation-derived butyrate induced ADH secretion in suckling calves, the effects of intraruminal administration of butyrate on plasma concentration of ADH and ketone bodies, plasma and urine osmolality, and urine volume were examined. Six male Holstein calves aged 4 wk were used. Three levels of butyrate (0 g, 22 g and 44 g) were intraruminally administrated in a 3 x 3 Latin square design, and blood plasma and urine were analyzed. Plasma concentration of ketone bodies was increased by intraruminal administration of butyrate within 15 min in a dose-dependent manner, and the elevation of plasma levels continued until 4 h. Plasma concentration of ADH was also increased by the butyrate treatment, and it was higher in the 44 g butyrate group than in the 22 g butyrate group from 15 min to 2 h. The duration of the elevated plasma concentration of ADH was shorter than that of plasma concentration of ketone bodies. The relationship between plasma concentrations of ADH and those of ketone bodies was statistically significant, although the relationship was weaker. In accordance with the elevation of plasma ADH levels, the butyrate treatment resulted in the decreases in urine volume and increases in urine osmolality. Plasma osmolality was not different among the groups. The present results suggest that ruminal butyrate-derived ketone bodies are at least partly responsible for ADH secretion in suckling calves fed with dry feeds, and that the secreted ADH decreases urine volume through the increase in urine osmolality. (c) 2006 Elsevier B.V. All rights reserved.

Abstract  In the healthy adult brain, neurogenesis normally occurs in the subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Cerebral ischemia enhances neurogenesis in neurogenic and non-neurogenic regions of the ischemic brain of adult rodents. This study demonstrated that post-insult treatment with a histone deacetylase inhibitor, sodium butyrate (SB), stimulated the incorporation of bromo-2'-deoxyuridine (BrdU) in the SVZ, DG, striatum, and frontal cortex in the ischemic brain of rats subjected to permanent cerebral ischemia. SB treatment also increased the number of cells expressing polysialic acid-neural cell adhesion molecule, nestin, glial fibrillary acidic protein, phospho-cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) in various brain regions after cerebral ischemia. Furthermore, extensive co-localization of BrdU and polysialic acid-neural cell adhesion molecule was observed in multiple regions after ischemia, and SB treatment up-regulated protein levels of BDNF, phospho-CREB, and glial fibrillary acidic protein. Intraventricular injection of K252a, a tyrosine kinase B receptor antagonist, markedly reduced SB-induced cell proliferation detected by BrdU and Ki67 in the ipsilateral SVZ, DG, and other brain regions, blocked SB-induced nestin expression and CREB activation, and attenuated the long-lasting behavioral benefits of SB. Together, these results suggest that histone deacetylase inhibitor-induced cell proliferation, migration and differentiation require BDNF-tyrosine kinase B signaling and may contribute to long-term beneficial effects of SB after ischemic injury.