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Bile acid metabolism in ascorbic acid-deficient guinea pigs.

Sterol balance techniques have been used to determine the effect of short-term ascorbic acid (AA) deprivation on bile acid excretion in the guinea pig. The effects of a brief (2-week) AA deficiency on bile acid pool sizes and the activity of the rate controlling enzyme in bile acid biosynthesis have been determined. It was found that, while food intake and body weight were not affected by the short-term AA deficiency, liver AA levels had fallen to 25% of control levels. At the same time, the rate of excretion of bile acids and the size of the bile acid pool were both reduced by about 50% in guinea pigs deficient in AA. These results were supported by a decrease in the activity of cholesterol 7 alpha-hydroxylase in the deficient animals. It is concluded that an AA deficiency will significantly impair bile acid metabolism independent of any side effects of clinical scurvy.

Animals

[Effect of an estrogen-progestin contraceptive preparation on the enzymatic acitivity of the pentosephosphate carbohydrate metabolic pathway and nucleic acid metabolic indices].

The effect of a long-term (14 days) combined introduction of mestranol and noiethinodrel in contraceptive doses on the activity of pentosophosphate routes enzymes of the carbohydrates metabolism, that of acid and basic ribonucleases and on the level of summary nucleinic acids in the uterus and liver in sexually mature female-rats was studied. It was found that the concentration of summary nucleinic acids in the tissues increases under the effect of the drug, the oxidative reactions enzymes become more active, while the activity of non-oxidative reactions enzymes of the pentosophosphate route and of acid and basic endoribonucleases in inhibited.

Animals

[Morphological and biochemical investigations of hairs in inborn errors of amino acid metabolism (author's transl)].

The influence of inborn errors of metabolism on the amino acid content, the structure and growth of human hair has been studied in patients suffering from Phenylketonuria, Cystinosis, Homocystinuria and Tyrosinosis. Examiniation of hairs under the scanning electron microscope reveals defects and abnormalities such as a plicated pattern of the cuticula in patients with Phenylketonuria and Cystinosis. The amino acid content of the hydrolized hair keratin of all patients was within normal range and did not reveal significant changes of phenylalanine, cystine, homocystine, methionine or tyrosine. Disturbance in hair growth was determined by evaluation of standardized hair root samples. The results indicate an increase in hair root atrophy with increasing severity of the disorder of amino acid metabolism.

Amino Acid Metabolism, Inborn Errors

[Alcohol induced changes of amino acid metabolism].

The effects of ethanol upon amino acid metabolism represent a complex interaction of ethanol metabolism and its products, nutritional abnormalities and pathological alterations in various organs especially the liver. The effects of chronic alcohol consumption upon amino acid absorption, digestion and transport appear largely of theoretical interest without significant impact on nitrogen balance, hepatic urea or protein synthesis or plasma amino acid patterns. Marked alterations in amino acid metabolism in the liver and other organs are observed in human alcoholics. These result in changes in plasma and tissue levels of amino acids and may explain or contribute to hepatic encephalopathy by altering levels of intermediate products such as catecholamines and neurotransmitters. Plasma amino acid changes due to ethanol may also provide a biochemical marker for the assessment of ethanol consumption in an objective fashion. Amino acid requirements in the diet may be altered in the alcoholic along with lowered protein tolerance. Administration of selected proteins or mixtures of amino acids may provide a means for maintaining nitrogen balance while avoiding or improving hepatic encephalopathy in such patients.

Alcoholism

The redox state and regulation of amino acid metabolism in man.

Traditionally, regulation of amino acid metabolism in both postabsorptive and prolonged-fasted man has been generally regarded as being hormonal in nature. In particular, insulin, and to a lesser extent glucagon, have been nominated for key roles in this process. More recently, however, reconsideration of previous studies involving insulin, glucagon, and protein meals as well as previously unreported studies (cortisol and tri-iodothyronine) from this laboratory, have suggested another means of regulating amino acid metabolism in fasting man. This new hypothesis is centered on the redox state of muscle of fasting man, which is remarkably reduced in both cytosolic and mitochondrial compartments. It was found that insulin, and to a lesser extent glucagon, when infused into fasting subjects (1) rendered muscle significantly more reduced, and (2) resulted in a diminution in urinary nitrogen excretion. In contrast, when either tri-iodothyronine or cortisol were administered to fasting individuals (1) muscle was found to become more oxidized when compared with the control period, and (2) increased urinary nitrogen excretion was observed in both cases. It was noteworthy that the ingestion of a protein meal by a nitrogen-depleted individual was followed by a dramatic change in muscle redox state (the muscle became more reduced), together with marked uptakes of a variety of amino acids. It is therefore proposed that the protein conservation evidenced by fasting man may be dependent on the reduced state of muslce tissue.

Acetoacetates

Dietary management of inborn errors of amino acid metabolism.

Individually, inborn errors of amino acid metabolism are rare. Collectively, however, they constitute a significant group of diseases whose number is constantly increasing. Their recognition is important, especially in childhood, because many of these diseases respond well to diet therapy.

Amino Acid Metabolism, Inborn Errors

[Inherited abnormalities in amino acid metabolism].

Inherited abnormalities in amino-acid metabolism, which up to a few years ago remained curiosities in the domain of the specialist, are now becoming almost of everyday significance. Improved knowledge, as a result of the combined efforts of paediatricians, genetecists and biochemists, has led to substantial progress, both clinically (diagnosis and treatment) as well as in the understanding of intermediary metabolisms and enzyme reactions. This "jigsay puzzle", the pieces of which fall gradually into place, has already resulted in spectacular results, the best example of which is that of phenylketonuria. In the past this disease inevitably led to increasing brain damage and has now become a purely biochemical disorder wince early diagnosis and appropriate diet enable the young infant to become a normal child and remain a healthy adult. These data are illustrated here.

Amino Acid Metabolism, Inborn Errors

Bile acid metabolism after jejunoileal bypass operation for obesity.

Bile acid metabolism and duodenal bacterial flora were studied in 12 obese patients before and 1-2 months after jejunoileal bypass operation, either including 37.5 cm jejunum and 12.5 cm ileum (Type I) or 12.5 cm jejunum and 37.5 cm ileum (Type III). The cholic acid pool size was unchanged after type I, but decreased after type III, bypass. The daily fractional turn-over of cholic acid increased about five times after both types of operation. The synthesis rate of cholic acid increased after both types of bypass, but more after type I than after type III. In duodenal bile the ratios of cholic to taurine conjugates increased after type I, but were unchanged after type III bypass, whereas the ratio of cholic to chenodeoxycholic acid was unchanged after both types of bypass. The bacterial flora and the occurrence of free bile acids in the fasting duodenal contents did not change after either of the two types of bypass operation. It is concluded that jejunoileal bypass results in marked disturbances in the bile acid metabolism. Surprisingly, these are most severe after bypass including the longest ileum, possibly because of insufficient stimulation of the bile acid synthesis in this type of operation.

Bile Acids and Salts

Carbohydrate and lipid metabolism during human labor: free fatty acids, glucose, insulin, and lactic acid metabolism during normal and oxytocin-induced labor for postmaturity.

This investigation was performed to study the metabolism of the major body fuels (viz. glucose and free fatty acids), insulin, and lactic acid during the stress of human labor. In addition, the role of the normal placenta in the transport of these substances between mother and the fetus was evaluated by measuring them in the mother and cord blood at delivery. To study possible alterations of this role in the placenta which had exceeded the normal period of gestation, a second comparable group of women had labor induced with oxytocin 16-18 days beyond the expected date of delivery. A dramatic twofold increase in maternal plasma free fatty acids was observed during labor. There was a lesser but definite increase in blood glucose concentrations. No rise in serum insulin levels was noted which coincided with the changes in blood glucose. Lactic acid concentrations during the course of labor were variable from baseline but at delivery, the concentrations rose to very significant levels. Free fatty acids and blood glucose levels were significantly higher in the maternal than in the fetal side. A significantly positive correlation was noted between the maternal and cord blood values except for free fatty acids in the postmature group. No significant difference, nor a correlation was found between the two compartments in the insulin nor lactic acid levels. These results suggest that during human labor free fatty acids are the principal metabolic fuel. This increase in maternal free fatty acids may serve to spare glucose as a metabolic fuel in the fetus. The mechanism responsible for the increase maternal free fatty acid mobilization remains to be determined. It is not possible to discern any consistant alteration in placental function as a consequence of prolonged gestation.

Adolescent

[Investigations of amino acid metabolism by thin layer chromatography for differentiation of Brucella (author's transl)].

The amino acid metabolism of 23 different Brucella strains was investigated for differentiation purposes. The results were evaluated by thin layer chromatography, after enzymatic incubation. The organisms (Tab. 1) were grown on Tryptose blood agar at 37 degree C for 24 or 48h. Two mg wet weight of bacteria in 0.2 ml PBS, 0.01 M, were incubated with 12.5 microng (0.025 ml) amino acid in small tubes for 16h at 37 degree C, and centrifuged for 15 min at 7500 X g. For controls, bacterial suspensions were heated for 15 min at 100 degree C to destroy enzymatic activity, and also contrifuged for 15 min at 7500 X g. Usually 4 micronl of the supernatant fluids (6 micronl for L-asparagine, and 10 micronl for L-proline) were pipetted on the thin layer plate. The tests were run in n-butanol acetic acid water, 20:5:5, with a distance of 8 cm. Amino acids were stained with ninhydrine. The tests were repeated 3-5 times with identical results. Amino acid metabolism was indicated by different staining intesities (+ to ++) in comparison to control preparations. All species could be exactly differentiated from each other, with the exception of B. suis, biotype 2, and B canis, which could not be differentiated by their amino acid metabolism. Biotyps of the same species were mostly identical. The results of these investigations could be reproduced qualitatively as well as quantitatively. The method described is recommended for routine investigations.

Amino Acids

Bile acid metabolism and fiber.

Studies in experimental animals and in humans have shown a definite interaction of dietary fiber with bile acid metabolism. In experimental animals, some types of fiber have been shown to increase bile acid excretion as well as increase pool size and turnover of bile acids. In man, increases in bile acid excretion have been observed but not consistently. Alternations in excretion and biliary bile acid levels indicate an influence of dietary fiber in bile acid metabolism. In vitro experiments have attempted to determine the nature of the fiber-bile acid interaction. Some types of fiber and some components of fiber have been shown to bind bile acids and bile salts in appreciable quantities. The capacity for various types of fiber to bind bile acids or bile salts is quite variable, and a high capacity seems to correspond with a hypocholesteremic effect. A great deal of research is still needed for elucidation of these interactions of fiber and bile acid metabolism and the resultant beneficial effects on cholesterol metabolism and the disease-related abnormalities in cholesterol metabolism.

Animals

Fatty acid metabolism in hypoxic rat liver.

Fatty acid metabolism was investigated in adult male albino rats exposed to hypobaric hypoxia at 25,000 ft simulated altitude for 6 h at 32 degrees C. Oxidation and esterification of palmitic acid-1-14C and de novo lipogenesis from acetate-1-14C were studied. Palmitic acid-1-14C oxidation in liver slices was normal while acetoacetate formation was increased. In vivo esterification of palmitic acid-1-14C to form triglycerides was increased while formation of phosphatidylcholine and phosphatidylethanolamine was observed to decrease. Decreased incorporation into plasma phosphatidylcholine with unaltered total activity in plasma triglycerides was observed. The incorporation of acetate-1-14C was observed to remain unaltered in triglycerides and phospholipids of liver with a similar pattern in the plasma indicating unaltered de novo lipogenesis. There appears to be increased esterification of fatty acids with probably impaired release of triglycerides into plasma while fatty acid biosynthesis remains unaffected.

Adrenal Glands

Probiotic supplementation improves body composition, lipid profiles, and fatty acid metabolism in combat sports athletes during the weight reduction phase.

PURPOSE: Pre-competition weight control for combat sports athletes may alter body composition and fatty acid metabolism. Probiotics have shown potential to regulate overall metabolism; however, their specific effects on fatty acid metabolism during weight control in athletes remain unclear. METHODS: Thirty-two combat sports athletes participating in the 4-week weight reduction period were assigned to either the probiotic group (Group E) or the placebo group (Group C). Body composition, lipid profiles, and fatty acid metabolism were measured before and after the 4-week weight reduction phase. RESULTS: All the athletes experienced a decrease in body weight, body mass index (BMI), body fat percentage, and muscle mass following the 4-week weight loss intervention. Notably, a more significant reduction in body fat percentage (p&#x2009;<&#x2009;0.05) was observed, along with lower levels of triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), specifically in Group E. Weight loss intervention resulted in increased levels of short-chain fatty acids (SCFAs), specifically acetic acid, propionic acid, and butyric acid. Notably, Group E exhibited higher mean values for SCFAs compared to Group C (p&#x2009;<&#x2009;0.05). Additionally, the serum levels of &#x3b3;-linolenic acid and 8,11,14-eicosatrienoic acid were significantly reduced in Group E (p&#x2009;<&#x2009;0.05). In contrast, the majority of free fatty acids (FFAs) showed significant increases, with greater magnitudes of change observed in Group C (p&#x2009;<&#x2009;0.05). CONCLUSION: Probiotic supplementation can improve body composition, enhance SCFAs levels, and decrease circulating FFAs in combat sports athletes, suggesting that probiotics may have a beneficial impact on pre-competition weight management. TRIAL REGISTRATION NUMBER: chiCTR2400079908 (Reg Date:2024-01-16).

Humans

Studies on L-ascorbic acid metabolism in rats under chronic toxicity due to organophosphorus insecticides: effects of supplementation of L-ascorbic acid in high doses.

The effects of chronic administration of two organophosphorus insecticides, parathion and malathion on the growth rate, ascorbic acid metabolism and some other nutritional and physiological parameters in rats were studied. Both parathion and malathion toxicity retarded the growth rate of rats. Inhibition of brain acetylcholinesterase was taken as an index of organophosphorus insecticide toxicity. Haemoglobin concentration of blood and organ weights were not affected under the toxic conditions. Parathion and malathion administration stimulated the activity of L-gulonolactone oxidase along with a simultaneous increase in the tissue storage and urinary excretion of vitamin C. The activities of other enzymes of ascorbic acid metabolism, dehydroascorbatase, uronolactonase, and L-gulonate dehydrogenase and decarboxylase were altered under the experimental conditions. Only minor histological changes of the liver and kidney tissues were noted under parathion and malathion toxicities. Excess intake of vitamin C under the toxic conditions was found to be very effective in counteracting the growth retardation and also the alterations produced by parathion and malathion both at the enzymatic and histological levels.

Animals

[Amino acid metabolic indices in newborn rats].

In simulated tests on rats of the 1st months of life set up for the purpose of educing causes accounting for a highly effective utilization of the milk proteins in the early post-natal perions subject to study were the amino acids metabolism rates. An investigation of the enzymes activity showed that a falling of the milk proteins utilization effectiveness proceeds against the background of an intensive inclusion of the catabolic route of the amino acids metabolism in the liver. The urea content in the urine correlated with a gradual inclusion of the enzymatic liver systems partaking in the urine formation. The amino acids metabolism with a ramified chain in the liver tissue of rats of the first days of life was found to stand low to a still greater degree than this was the case in adult animals. One of the causes responsible for a highly effective utilization of the milk proteins in the perinatal period may be due to an incomplete functioning of the catabolic route of the amino acids metabolism in the liver.

Age Factors

Integrative subtyping by bile acid metabolism identifies CLCA1/UGT2A3/ZG16 as markers of immune dysfunction and poor prognosis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the primary driver of cancer-related death and illness across the world. Despite the full-scale shift of the treatment approach for some colorectal cancer patients due to the use of immune checkpoint inhibitors (ICIs), primary resistance still poses a huge challenge to clinicians. Bile acid metabolism is involved in the pathogenesis of CRC. However, its particular function in shaping the tumor immune microenvironment (TIME) and its effect on prognosis and immune treatment response remain unclear. METHODS: Based on the transcriptome and clinical data from The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) cohort, we performed unsupervised consensus clustering and classified patients into different molecular subtypes according to bile acid metabolism. We subsequently compared overall survival (OS), immune cell infiltration levels, and differentially expressed genes among the subtypes. In addition, protein-protein interaction (PPI) network and Cox proportional hazards regression were used to identify key hub genes. Finally, the expression of these crucial hub genes was validated in the Gene Expression Omnibus (GEO) cohort and independent clinical patients. RESULTS: The bile-low group showed a significant reduction in OS time (p = 0.0049). The infiltration levels of CD8+ T cells (p < 0.05) and M1 macrophages (p < 0.01) were significantly higher in the bile-low group than in the bile-high group. We identified three key genes-CLCA1, UGT2A3, and ZG16-and found that they all were downregulated in tumor tissues across the TCGA-COAD and GEO datasets, as well as in independent clinical samples. Survival analysis showed that high CLCA1 expression was significantly associated with favorable overall survival (p < 0.001), whereas UGT2A3 (p = 0.23) and ZG16 (p = 0.17) did not reach statistical significance. The three hub genes were negatively correlated with the (TIDE) score (CLCA1: R = - 0.24, p < 0.001; UGT2A3: R = - 0.15, p = 0.0022; ZG16: R = - 0.14, p = 0.0039). CONCLUSION: Our findings suggest that bile acid metabolism could shape the TIME via key genes CLCA1, UGT2A3, and ZG16, and subsequently modify CRC prognosis and immunotherapy responses. These genes may serve as potential prognostic indicators and mechanistic mediators linking bile acid metabolism to T-cell dysfunction, offering insights for future combination strategies targeting the metabolism-barrier-immunity axis.

CLCA1