Enhanced preference for dried bonito dashi by prior experience with dashi and various taste substances in mice.

Dried bonito dashi, a complex mixture of sour, bitter, and umami substances as well as over 400 odorants, is the most widely used Japanese fish broth that enhances palatability of various dishes. Recent studies have suggested that prior experience with dried bonito dashi produces strong enhancement of subsequent intake and preference for dried bonito dashi. The present study investigated taste substances in dried bonito dashi that enhance subsequent dashi preference by its prior exposure. Male C57BL/6N mice were initially exposed for 10 days to (1) dried bonito dashi, (2) a chemical mixture of taste substances identified in dried bonito dashi (artificially reconstituted dashi), or (3) individual chemical solutions such as NaCl, monosodium l-glutamate (MSG), inosine 5'-monophosphate (IMP), lactic acid, histidine, and glucose. Intakes of 0.01-100% dried bonito dashi with water were then measured using ascending concentration series of 2-day two-bottle choice tests. Prior exposure to 1-100% dashi enhanced subsequent dashi preference in a concentration-dependent manner and the greatest effects were attained with 10-100% dashi exposure. Exposure to the reconstituted dashi also enhanced subsequent dashi preference. Among individual chemical solutions, 0.1% IMP produced modest enhancement of subsequent dashi preference, but neither NaCl, MSG, histidine, lactic acid, nor glucose did. These results suggest that IMP is at least a key substance that produces experience-based enhancement of dried bonito dashi preference.

Supplementation effects of a kokumi substance, γ-Glu-Val-Gly, on the ingestion of basic taste solutions in rats.

In addition to the well-accepted taste receptors corresponding to the 6 basic taste qualities, sweet, salty, sour, bitter, umami, and fatty, another type of taste receptor, calcium-sensing receptor (CaSR), is located in taste bud cells. CaSR is called the kokumi receptor because its agonists induce koku (or kokumi), a Japanese word meaning the enhancement of flavor characteristics, such as thickness, mouthfulness, and continuity. Kokumi is an important factor in enhancing food palatability. γ-Glu-Val-Gly (EVG) is the most potent agonist of CaSR, which induces a strong kokumi flavor. However, no behavioral studies have been documented in animals using EVG. Here, we show that EVG at low concentrations that do not elicit a taste of its own enhances preferences for umami, fat, and sweet taste solutions in rats. An increased preference for inosine monophosphate (IMP) and Intralipos was the most dominant effect. NPS-2143, an antagonist of CaSR, abolished the additive effect of EVG on IMP and Intralipos solutions. These effects of EVG on taste stimuli are thought to occur in the oral cavity, because the effects of EVG were confirmed in a brief exposure test. The additive effects on IMP and Intralipos remained after the transection of the chorda tympani, indicating that these effects also occur in the palate and/or posterior part of the tongue. Moreover, the additive effects of EVG were verified in electrophysiological taste nerve responses. These results may partially provide the underlying mechanisms for EVG to induce kokumi flavor in humans.

Effects of inosine monophosphate and exercise training on neuronal nitric oxide synthase in the mouse brain.

Recently, the purine nucleoside inosine has been demonstrated to have several neuroprotective effects. Similarly, exercise training has well-known beneficial effects on mental health and cognitive function. Neuronal nitric oxide synthase (nNOS) is a key neuronal messenger in several brain regions, and the downregulation of nNOS has been shown to improve brain function. However, whether inosine and exercise training have combined effects on nNOS pathway-related proteins in the brain remains unknown. We found, for the first time, that inosine monophosphate (IMP), which is a precursor of inosine, decreases nNOS levels in the ventral hippocampus (vHp) and the cerebellum (Ce), but not in the dorsal hippocampus (dHp). In the vHp, the phosphorylation of cAMP response element-binding protein (CREB) was also upregulated, which negatively correlated with nNOS protein levels. In the cerebral cortex (Cx), no significant activation of the nNOS pathway was observed. In the dHp, vHp, Cx, and Ce, no interactions between the effects of IMP and exercise on nNOS protein and CREB phosphorylation levels were observed. The phosphorylation of nNOS was regulated by the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Although IMP induced minor changes in Akt phosphorylation, nNOS phosphorylation was unchanged by either IMP or exercise. In conclusion, in the vHp, which is associated with emotional behavior, IMP decreased nNOS levels and activated CREB, suggesting that IMP can elicit anxiolytic effects.

Identification of Phosphate-Containing Compounds as New Inhibitors of 14-3-3/c-Abl Protein-Protein Interaction.

The 14-3-3/c-Abl protein-protein interaction (PPI) is related to carcinogenesis and in particular to pathogenesis of chronic myeloid leukemia (CML). Previous studies have demonstrated that molecules able to disrupt this interaction improve the nuclear translocation of c-Abl, inducing apoptosis in leukemia cells. Through an X-ray crystallography screening program, we have identified two phosphate-containing compounds, inosine monophosphate (IMP) and pyridoxal phosphate (PLP), as binders of human 14-3-3σ, by targeting the protein amphipathic groove. Interestingly, they also act as weak inhibitors of the 14-3-3/c-Abl PPI, demonstrated by NMR, SPR, and FP data. A 37-compound library of PLP and IMP analogues was investigated using a FP assay, leading to the identification of three further molecules acting as weak inhibitors of the 14-3-3/c-Abl complex formation. The antiproliferative activity of IMP, PLP, and the three derivatives was tested against K-562 cells, showing that the parent compounds had the most pronounced effect on tumor cells. PLP and IMP were also effective in promoting the c-Abl nuclear translocation in c-Abl overexpressing cells. Further, these compounds demonstrated low cytotoxicity on human Hs27 fibroblasts. In conclusion, our data suggest that 14-3-3σ targeting compounds represent promising hits for further development of drugs against c-Abl-dependent cancers.

Fishmeal replacement by soya protein concentrate with inosine monophosphate supplementation influences growth, digestibility, immunity, blood health, and stress resistance of red sea bream, Pagrus major.

We assessed the effects of fishmeal (FM) replacement by soy protein concentrate (SPC) with inosine monophosphate (IMP) supplementation on growth, digestibility, immunity, blood health, and stress resistance of red sea bream, Pagrus major. FM protein of a FM-based control diet (FM100) was replaced with 25 (FM75), 50 (FM50), 75 (FM25), and 100% (FM0) by SPC protein, and each replacement group was supplemented with 0.4% IMP to formulate five experimental diets. Each diet was randomly allocated to triplicate groups of fish (4.8 g) for 56 days. Results demonstrated that fish fed diet groups FM50 and FM75 had significantly the highest final weight, weight gain, specific growth rate, and feed intake. Meanwhile, in comparison to the control, growth performance and feed utilization did not significantly differ with the 75% FM-replaced diet group by SPC with IMP supplementation. Apparent digestibility coefficient of dry matter, protein, and lipid also followed a similar trend. All growth, feed utilization, and digestibility parameters were significantly lower in the FM0 diet group. Triglyceride level was increased (P < 0.05) with the increasing replacement level and it was significantly highest in the FM0 diet group. The fish fed diet groups FM100 and FM50 showed the best condition of oxidative and freshwater stress resistance, respectively. Meanwhile, the groups with up to 75% FM-replaced diet also showed acceptable stress resistance status. Overall, enhanced innate immune responses were observed in the entire FM replaced with IMP-supplemented diet groups in comparison to the control. Considering SGR as a model, the regression analysis determined that 71.7% FM protein could be replaced by SPC protein with IMP supplementation in diets for the growth of red sea bream.

Inosine Monophosphate Dehydrogenase Pharmacogenetics in Hematopoietic Cell Transplantation Patients.

We evaluated inosine monophosphate dehydrogenase (IMPDH) 1 and IMPDH2 pharmacogenetics in 247 recipient-donor pairs after nonmyeloablative hematopoietic cell transplant (HCT). Patients were conditioned with total body irradiation + fludarabine and received grafts from related or unrelated donors (10% HLA mismatch), with postgraft immunosuppression of mycophenolate mofetil (MMF) with a calcineurin inhibitor. Recipient and donor IMPDH genotypes (rs11706052, rs2278294, rs2278293) were not associated with day 28 T cell chimerism, acute graft-versus-host disease (GVHD), disease relapse, cytomegalovirus reactivation, nonrelapse mortality, or overall survival. Recipient IMPDH1 rs2278293 genotype was associated with a lower incidence of chronic GVHD (hazard ratio, .72; P = .008) in nonmyeloablative HCT recipients. Additional studies are needed to confirm these results with the goal of identifying predictive biomarkers to MMF that lower GVHD.

Short-term perception of and conditioned taste aversion to umami taste, and oral expression patterns of umami taste receptors in chickens.

Umami taste is one of the five basic tastes (sweet, umami, bitter, sour, and salty), and is elicited by l-glutamate salts and 5'-ribonucleotides. In chickens, the elucidation of the umami taste sense is an important step in the production of new feedstuff for the animal industry. Although previous studies found that chickens show a preference for umami compounds in long-term behavioral tests, there are limitations to our understanding of the role of the umami taste sense in chicken oral tissues because the long-term tests partly reflected post-ingestive effects. Here, we performed a short-term test and observed agonists of chicken umami taste receptor, l-alanine and l-serine, affected the solution intakes of chickens. Using this method, we found that chickens could respond to umami solutions containing monosodium l-glutamate (MSG) + inosine 5'-monophosphate (IMP) within 5 min. We also demonstrated that chickens were successfully conditioned to avoid umami solution by the conditioned taste aversion test. It is noted that conditioning to umami solution was generalized to salty and sweet solutions. Thus, chickens may perceive umami taste as a salty- and sweet-like taste. In addition, we found that umami taste receptor candidates were differentially expressed in different regions of the chicken oral tissues. Taken together, the present results strongly suggest that chickens have a sense of umami taste and have umami taste receptors in their oral tissue.

Taste sensitivity to a mixture of monosodium glutamate and inosine 5'-monophosphate by mice lacking both subunits of the T1R1+T1R3 amino acid receptor.

The taste of l-glutamate and its synergism with 5'-ribonucleotides is thought to be primarily mediated through the T1R1+T1R3 heterodimer in some mammals, including rodents and humans. While knockout (KO) mice lacking either receptor subunit show impaired sensitivity to a range of monosodium glutamate (MSG) concentrations mixed with 2.5 mM inosine 5'-monophosphate (IMP) in amiloride, wild-type (WT) controls can detect this IMP concentration, hindering direct comparison between genotypes. Moreover, some residual sensitivity persists in the KO group, suggesting that the remaining subunit could maintain a limited degree of function. Here, C57BL/6J, 129X1/SvJ, and T1R1+T1R3 double KO mice ( n = 16 each to start the experiment) were trained in a two-response operant task in gustometers and then tested for their ability to discriminate 100 µM amiloride from MSG (starting with 0.6 M) and IMP (starting with 2.5 mM) in amiloride (MSG+I+A). Testing continued with successive dilutions of both MSG and IMP (in amiloride). The two WT strains were similarly sensitive to MSG+I+A ( P > 0.8). KO mice, however, were significantly impaired relative to either WT strain ( P < 0.01), although they were able to detect the highest concentrations. Thus, normal detectability of MSG+I+A requires an intact T1R1+T1R3 receptor, without regard for allelic variation in the T1R3 gene between the WT strains. Nevertheless, residual sensitivity by the T1R1+T1R3 KO mice demonstrates that a T1R-independent mechanism can contribute to the detectability of high concentrations of this prototypical umami compound stimulus.

A mutant of phosphomannomutase1 retains full enzymatic activity, but is not activated by IMP: Possible implications for the disease PMM2-CDG.

The most frequent disorder of glycosylation, PMM2-CDG, is caused by a deficiency of phosphomannomutase activity. In humans two paralogous enzymes exist, both of them require mannose 1,6-bis-phosphate or glucose 1,6-bis-phosphate as activators, but only phospho-mannomutase1 hydrolyzes bis-phosphate hexoses. Mutations in the gene encoding phosphomannomutase2 are responsible for PMM2-CDG. Although not directly causative of the disease, the role of the paralogous enzyme in the disease should be clarified. Phosphomannomutase1 could have a beneficial effect, contributing to mannose 6-phosphate isomerization, or a detrimental effect, hydrolyzing the bis-phosphate hexose activator. A pivotal role in regulating mannose-1phosphate production and ultimately protein glycosylation might be played by inosine monophosphate that enhances the phosphatase activity of phosphomannomutase1. In this paper we analyzed human phosphomannomutases by conventional enzymatic assays as well as by novel techniques such as 31P-NMR and thermal shift assay. We characterized a triple mutant of phospomannomutase1 that retains mutase and phosphatase activity, but is unable to bind inosine monophosphate.

Characterization of AICAR transformylase/IMP cyclohydrolase (ATIC) from Staphylococcus lugdunensis.

The 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/inosine monophosphate (IMP) cyclohydrolase (ATIC) catalyzes final two steps of purine nucleotide de novo biosynthetic pathway. This study reports the characterization of ATIC from Staphylococcus lugdunensis (SlugATIC). Apart from kinetic analysis and a detailed biophysical characterization of SlugATIC, the role of ATIC in cell proliferation has been demonstrated for the first time. The purified recombinant SlugATIC and its truncated domains exist mainly in dimeric form was revealed in gel-filtration and glutaraldehyde cross-linking studies. The two activities reside on separate domains was demonstrated in kinetic analysis of SlugATIC and reconstituted truncated N-terminal IMP cyclohydrolase (IMPCHase) and C-terminal AICAR transformylase (AICAR TFase) domains. Site-directed mutagenesis showed that Lys255 and His256 are the key catalytic residues, while Asn415 substantially contributes to AICAR TFase activity in SlugATIC. The differential scanning calorimetry (DSC) analysis revealed a molten globule-like structure for independent N-terminal domain as compared with a relatively stable conformational state in full-length SlugATIC signifying the importance of covalently linked domains. Unlike reported crystal structures, the DSC studies revealed significant conformational changes on binding of leading ligand to AICAR TFase domain in SlugATIC. The cell proliferation activity of SlugATIC was observed where it promoted proliferation and viability of NIH 3T3 and RIN-5F cells, exhibited in vitro wound healing in NIH 3T3 fibroblast cells, and rescued RIN-5F cells from the cytotoxic effects of palmitic acid and high glucose. The results suggest that ATIC, an important drug target, can also be exploited for its cell proliferative properties.

An Examination of the Role of L-Glutamate and Inosine 5'-Monophosphate in Hedonic Taste-Guided Behavior by Mice Lacking the T1R1 + T1R3 Receptor.

The heterodimeric T1R1 + T1R3 receptor is considered critical for normal signaling of L-glutamate and 5'-ribonucleotides in the oral cavity. However, some taste-guided responsiveness remains in mice lacking one subunit of the receptor, suggesting that other receptors are sufficient to support some behaviors. Here, mice lacking both receptor subunits (KO) and wild-type (WT, both n = 13) mice were tested in a battery of behavioral tests. Mice were trained and tested in gustometers with a concentration series of Maltrin-580, a maltodextrin, in a brief-access test (10-s trials) as a positive control. Similar tests followed with monosodium glutamate (MSG) with and without the ribonucleotide inosine 5'-monophosphate (IMP), but always in the presence of the epithelial sodium channel blocker amiloride (A). Brief-access tests were repeated following short-term (30-min) and long-term (48-h) exposures to MSG + A + IMP and were also conducted with sodium gluconate replacing MSG. Finally, progressive ratio tests were conducted with Maltrin-580 or MSG + A + IMP, to assess appetitive behavior while minimizing satiation. Overall, MSG generated little concentration-dependent responding in either food-restricted WT or KO mice, even in combination with IMP. However, KO mice licked less to the amino acid stimuli, a measure of consummatory behavior in the brief-access tests. In contrast, both groups initiated a similar number of trials and had a similar breakpoint in the progressive ratio task, both measures of appetitive (approach) behavior. Collectively, these results suggest that while the T1R1 + T1R3 receptor is necessary for consummatory responding to MSG (+IMP), other receptors are sufficient to maintain appetitive responding to this "umami" stimulus complex in food-restricted mice.

Uric acid ameliorates indomethacin-induced enteropathy in mice through its antioxidant activity.

BACKGROUND AND AIM: Uric acid is excreted from blood into the intestinal lumen, yet the roles of uric acid in intestinal diseases remain to be elucidated. The study aimed to determine whether uric acid could reduce end points associated with nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. METHODS: A mouse model of NSAID-induced enteropathy was generated by administering indomethacin intraperitoneally to 8-week-old male C57BL/6 mice, and then vehicle or uric acid was administered orally. A group of mice treated with indomethacin was also concurrently administered inosinic acid, a uric acid precursor, and potassium oxonate, an inhibitor of uric acid metabolism, intraperitoneally. For in vitro analysis, Caco-2 cells treated with indomethacin were incubated in the presence or absence of uric acid. RESULTS: Oral administration of uric acid ameliorated NSAID-induced enteropathy in mice even though serum uric acid levels did not increase. Intraperitoneal administration of inosinic acid and potassium oxonate significantly elevated serum uric acid levels and ameliorated NSAID-induced enteropathy in mice. Both oral uric acid treatment and intraperitoneal treatment with inosinic acid and potassium oxonate significantly decreased lipid peroxidation in the ileum of mice with NSAID-induced enteropathy. Treatment with uric acid protected Caco-2 cells from indomethacin-induced oxidative stress, lipid peroxidation, and cytotoxicity. CONCLUSIONS: Uric acid within the intestinal lumen and in serum had a protective effect against NSAID-induced enteropathy in mice, through its antioxidant activity. Uric acid could be a promising therapeutic target for NSAID-induced enteropathy.

Inosine-5'-monophosphate is a candidate agent to resolve rigor mortis of skeletal muscle.

The object of the present study was to reveal the action of inosine-5'-monophosphate (IMP) toward myofibrils in postmortem muscles. IMP solubilized isolated actomyosin within a narrow range of KCl concentration, 0.19-0.20 mol/L, because of the dissociation of actomyosin into actin and myosin, but it did not solubilize the proteins in myofibrils with 0.2 mol/L KCl. However, IMP could solubilize both proteins in myofibrils with 0.2 mol/L KCl in the presence of 1 m mol/L pyrophosphate or 1.0-3.3 m mol/L adenosine-5'-diphosphate (ADP). Thus, we presumed that pyrophosphate and ADP released thin filaments composed of actin, and thick filaments composed of myosin from restraints of myofibrils, and then both filaments were solubilized through the IMP-induced dissociation of actomyosin. Thus, we concluded that IMP is a candidate agent to resolve rigor mortis because of its ability to break the association between thick and thin filaments.

Structural Basis for the Specificity of Human NUDT16 and Its Regulation by Inosine Monophosphate.

Human NUDT16 is a member of the NUDIX hydrolase superfamily. After having been initially described as an mRNA decapping enzyme, recent studies conferred it a role as an "housecleaning" enzyme specialized in the removal of hazardous (deoxy)inosine diphosphate from the nucleotide pool. Here we present the crystal structure of human NUDT16 both in its apo-form and in complex with its product inosine monophosphate (IMP). NUDT16 appears as a dimer whose formation generates a positively charged trench to accommodate substrate-binding. Complementation of the structural data with detailed enzymatic and biophysical studies revealed the determinants of substrate recognition and particularly the importance of the substituents in position 2 and 6 on the purine ring. The affinity for the IMP product, harboring a carbonyl in position 6 on the base, compared to purine monophosphates lacking a H-bond acceptor in this position, implies a catalytic cycle whose rate is primarily regulated by the product-release step. Finally, we have also characterized a phenomenon of inhibition by the product of the reaction, IMP, which might exclude non-deleterious nucleotides from NUDT16-mediated hydrolysis regardless of their cellular concentration. Taken together, this study details structural and regulatory mechanisms explaining how substrates are selected for hydrolysis by human NUDT16.

Dried bonito dashi: taste qualities evaluated using conditioned taste aversion methods in wild-type and T1R1 knockout mice.

The primary taste of dried bonito dashi is thought to be umami, elicited by inosine 5'-monphosphate (IMP) and L-amino acids. The present study compared the taste qualities of 25% dashi with 5 basic tastes and amino acids using conditioned taste aversion methods. Although wild-type C57BL/6J mice with compromised olfactory systems generalized an aversion of dashi to all 5 basic tastes, generalization was greater to sucrose (sweet), citric acid (sour), and quinine (bitter) than to NaCl (salty) or monosodium L-glutamate (umami) with amiloride. At neutral pH (6.5-6.9), the aversion generalized to l-histidine, L-alanine, L-proline, glycine, L-aspartic acid, L-serine, and monosodium L-glutamate, all mixed with IMP. Lowering pH of the test solutions to 5.7-5.8 (matching dashi) with HCl decreased generalization to some amino acids. However, adding lactic acid to test solutions with the same pH increased generalization to 5'-inosine monophosphate, L-leucine, L-phenylalanine, L-valine, L-arginine, and taurine but eliminated generalization to L-histidine. T1R1 knockout mice readily learned the aversion to dashi and generalized the aversion to sucrose, citric acid, and quinine but not to NaCl, glutamate, or any amino acid. These results suggest that dashi elicits a complex taste in mice that is more than umami, and deleting T1R1 receptor altered but did not eliminate their ability to taste dashi. In addition, lactic acid may alter or modulate taste transduction or cell-to-cell signaling.

The importance of the presence of a 5'-ribonucleotide and the contribution of the T1R1 + T1R3 heterodimer and an additional low-affinity receptor in the taste detection of L-glutamate as assessed psychophysically.

The molecular receptors underlying the purported "umami" taste quality commonly associated with l-glutamate have been controversial. Evidence supports the involvement of the T1R1 + T1R3 heterodimer, a GPCR broadly tuned to l-amino acids, but variants of two mGluRs expressed in taste buds have also been implicated. Using a rigorous psychophysical taste-testing paradigm, we demonstrated impaired, if not eliminated, detection of MSG in WT and T1R1, T1R2, T1R3, and T1R2 + T1R3 KO mice when the contribution of sodium was minimized by the epithelial sodium channel blocker amiloride. When inosine 5'-monophosphate (IMP), a ribonucleotide that potentiates the l-glutamate signal through the T1R1 + T1R3 heterodimer, was added, the WT and T1R2 KO mice were able to detect the compound stimulus across all MSG (+amiloride) concentrations due, in part, to the taste of IMP. In contrast, mice lacking T1R1 or T1R3 could not detect IMP alone, yet some were able to detect MSG + amiloride + IMP, but only at the higher MSG concentrations. Interestingly, the sensitivity of T1R1 KO mice to another l-amino acid, lysine, was unimpaired, suggesting that some l-amino acids can be detected through T1R1 + T1R3-independent receptors without sensitivity loss. Given that IMP is not thought to affect mGluRs, behavioral detection of l-glutamate appears to require the contribution of the T1R1 + T1R3 receptor. However, the partial competence observed in some T1R1 and T1R3 KO mice when MSG + amiloride + IMP was tested suggests that a T1R1 or T1R3 homodimer or an unidentified protein, perhaps in conjunction with T1R1 or T1R3, can serve as a low-affinity taste receptor for l-glutamate in the presence of IMP.

Decline of umami preference in aged rats.

The effects of aging on the umami sensation were compared between the preference and neural responses from the greater superficial petrosal nerve (GSP innervating the soft palate) and the chorda tympani nerve (CT innervating the fungiform papillae) in the Sprague Dawley rat. A two-bottle preference test revealed that younger rats (5-12 weeks) preferred significantly 0.001 M 5'-inosine monophosphate (IMP), 0.01 M mono sodium glutamate (MSG), and binary mixtures of 0.001 M IMP+0.01 M MSG than deionized water. However, aged rats (21-22 months) showed no significant preference to these umami solutions compared to deionized water. Among the other four basic taste stimuli, there were no significant differences in preference between young and aged rats. Regardless of the age of the rat, neural responses from the GSP and CT produced robust integrated responses to all three umami solutions used in the two-bottle tests. These results indicate that the lack of preference to umami in aged rats is a central nervous system phenomenon and suggests that the loss of preference to umami taste in aged rats is caused by homeostatic changes in the brain incurred by aging.

Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil.

A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.

IMP improves water-holding capacity, physical and sensory properties of heat-induced gels from porcine meat.

Water-holding capacity (WHC) of heat-induced pork gels was examined. The heat-induced gels were obtained from meat homogenates prepared by adding nine volumes of 0.3-0.5 mol/L NaCl solutions containing 9-36 mmol/L disodium inosine-5'-monophosphate (IMP) or 9 mmol/L tetrapotassium pyrophosphate (KPP) to minced pork. IMP at 36 mmol/L enhanced the WHC to the same level as attained by KPP. Physical and sensory properties of heat-induced gels were also examined. The heat-induced gels were prepared from porcine meat homogenates containing 0.3 mol/L NaCl and 9-36 mmol/L IMP or 9 mmol/L KPP. IMP at 36 mmol/L enhanced the values of hardness, cohesiveness, gumminess and springiness, measured with a Tensipresser, and several organoleptic scores to the same level as the score attained by KPP. Thus, it is concluded that IMP is expected to be a practical substitute for pyrophosphates to improve the quality of sausages.