Intestinal bacterial origin of D-alanine in urine of mutant mice lacking D-amino-acid oxidase.
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ABSTRACT:
SUBMITTER: Konno R
PROVIDER: S-EPMC1131426 | biostudies-other | 1990 Jun
REPOSITORIES: biostudies-other
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Project description:Urine from mutant mice lacking D-amino-acid oxidase contained a large amount of alanine compared with that from normal mice. Urinary alanine of the mutant mice was sensitive to D-amino-acid oxidase. H.p.l.c. showed that about 94% of the urinary alanine had the D-configuration. These results suggest that D-amino-acid oxidase functions to decompose D-amino acid(s) in normal mice.
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Project description:BackgroundThyroid hormone (TH) plays a key role in the developing brain, including the cerebellum. TH deficiency induces organizational changes of the cerebellum, causing cerebellar ataxia. However, the mechanisms causing these abnormalities are poorly understood. Various animal models have been used to study the mechanism. Lacking dual oxidase (DUOX) and its maturation factor (DUOXA) are major inducers of congenital hypothyroidism. Thus, this study examined the organizational changes of the cerebellum using knockout mice of the Duoxa gene (Duoxa-/-).MethodsThe morphological, behavioral, and electrophysiological changes were analyzed in wild type (Wt) and Duoxa-deficient (Duoxa-/-) mice from postnatal day (P) 10 to P30. To detect the changes in the expression levels of presynaptic proteins, Western blot analysis was performed.ResultsThe proliferation and migration of granule cells was delayed after P15 in Duoxa-/- mice. However, these changes disappeared by P25. Although the cerebellar structure of Duoxa-/- mice was not significantly different from that of Wt mice at P25, motor coordination was impaired. It was also found that the amplitude of paired-pulse facilitation at parallel fiber-Purkinje cell synapses decreased in Duoxa-/- mice, particularly at P15. There were no differences between expression levels of presynaptic proteins regulating neurotransmitter release at P25.ConclusionsThese results indicate that the anatomical catch-up growth of the cerebellum did not normalize its function because of the disturbance of neuronal circuits by the combined effect of hypothyroidism and functional disruption of the DUOX/DUOXA complex.
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Project description:Dietary protein restriction has beneficial impacts on metabolic health. B0AT1 (SLC6A19) is the major transporter of neutral amino acids at the intestinal epithelia and absorbs the bulk of the diet-derived neutral amino acids from the intestinal lumen. It also reabsorbs neutral amino acids in the renal proximal tubules. Mice lacking B0AT1 show cellular outcomes of protein restriction, such as high FGF21 levels and low mTORC1 activity. Moreover, they have improved glucose homeostasis and resist diet-induced obesity. In this study, we investigated the relationship between protein restriction and dietary protein intake in C57Bl6/J wild-type (wt) and SLC6A19-knockout (SLC6A19ko) mice. When SLC6A19ko mice were fed diets containing 5%, 25%, or 52% of their total calories derived from protein, no differences in food intake or weight gain were observed. All essential amino acids significantly positively correlated with increasing dietary casein content in the wt mice. The SLC6A19ko mice showed reduced postprandial levels of essential amino acids in plasma, particularly following high-protein diets. Upon fasting, essential amino acids were the same in the wt and SLC6A19ko mice due to reduced amino acid catabolism. Bacterial metabolites originating from amino acid fermentation correlated with the dietary protein content, but showed a complex profile in the blood of the SLC6A19ko mice. This study highlights the potential of SLC6A19 as a knock-out or inhibition target to induce protein restriction for the treatment of metabolic disorders.
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Project description:Matrix metalloproteinases (MMPs) classically have been implicated in basement membrane destruction associated with late-stage tumor cell invasion and metastasis. However, recent studies have demonstrated that one MMP family member, matrilysin, is expressed in a high percentage of early-stage human colorectal tumors. We analyzed matrilysin expression in benign intestinal tumors from mice heterozygous for the ApcMin allele (Min/+) and found that the mRNA was induced in the majority (88%) of these adenomas. Protein was detected in the tumor cells, where, surprisingly, it was predominantly immunolocalized to the lumenal surface of dysplastic glands rather than the basement membrane or extracellular matrix. To address the role of matrilysin in Min intestinal tumorigenesis, we generated Min/+ mice deficient in this MMP by gene targeting and homologous recombination. The absence of matrilysin resulted in a reduction in mean tumor multiplicity in Min/+ animals of approximately 60% and a significant decrease in the average tumor diameter. Based on these findings, we conclude that matrilysin is a suppressor of the Min phenotype, possibly by functioning in a capacity independent of matrix degradation. These results argue for the use of MMP inhibitors in the treatment and prevention of early-stage colon cancer.
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Project description:Obesity is a risk factor for colorectal cancer. The accumulation of abdominal fat tissue causes abundant reactive oxygen species production through the activation of NADPH oxidase due to excessive insulin stimulation. The enzyme NADPH oxidase catalyzes the production of reactive oxygen species and evokes the initiation and progression of tumorigenesis. Apocynin is an NADPH oxidase inhibitor that blocks the formation of the NADPH oxidase complex (active form). In this study, we investigated the effects of apocynin on the development of azoxymethane-induced colonic aberrant crypt foci in obese KK-A(y) mice and on the development of intestinal polyps in Apc mutant Min mice. Six-week-old KK-A(y) mice were injected with azoxymethane (200 μg/mouse once per week for 3 weeks) and given 250 mg/L apocynin or 500 mg/L apocynin in their drinking water for 7 weeks. Six-week-old Min mice were also treated with 500 mg/L apocynin for 6 weeks. Treatment with apocynin reduced the number of colorectal aberrant crypt foci in KK-A(y) mice by 21% and the number of intestinal polyps in Min mice by 40% compared with untreated mice. Both groups of mice tended to show improved oxidation of serum low-density lipoprotein and 8-oxo-2'-deoxyguanosine adducts in their adipose tissues. In addition, the inducible nitric oxide synthase mRNA levels in polyp tissues decreased. Moreover, apocynin was shown to suppress nuclear factor-κB transcriptional activity in vitro. These results suggest that apocynin and other NADPH oxidase inhibitors may be effective colorectal cancer chemopreventive agents.
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