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Infection and Immunity Sep 1989Inbred strain 2 guinea pigs were vaccinated with Mycobacterium bovis BCG or were left unvaccinated. They were maintained for 6 weeks on defined, isocaloric diets...
Inbred strain 2 guinea pigs were vaccinated with Mycobacterium bovis BCG or were left unvaccinated. They were maintained for 6 weeks on defined, isocaloric diets containing either 30% (control animals) or 10% (animals receiving low protein) ovalbumin as the sole protein source. Animals were challenged by the respiratory route with a low dose of virulent M. tuberculosis H37Rv and killed 4 weeks later. Protein-malnourished animals were not protected by previous vaccination with BCG. Lymphocytes isolated from various tissues were tested in vitro for proliferative responses to mitogen (concanavalin A) and antigen (purified protein derivative [PPD]), production of interleukin-2 (IL-2), and response to exogenous recombinant IL-2 (rIL-2). Protein-malnourished guinea pigs responded only weakly to PPD skin tests, and their blood and lymph node lymphocytes exhibited impaired proliferation when cultured with PPD in vitro. IL-2 levels were consistently low in cultures of stimulated blood and spleen lymphocytes from protein-deprived animals. BCG vaccination of nutritionally normal guinea pigs, on the other hand, induced significantly more IL-2 production by PPD- and concanavalin A-stimulated lymphocytes. The addition of exogenous mouse rIL-2 (40 and 80 U/ml) in vitro to PPD-stimulated blood and lymph node cells from nonvaccinated, protein-deprived guinea pigs resulted in no improvement of the proliferative response. Previous vaccination of malnourished guinea pigs did not consistently enhance the response of PPD-stimulated lymphocytes to added rIL-2. Dietary protein deficiency and BCG vaccination appear to modulate antigen-driven cellular immunity in animals with tuberculosis by altering the production of, and the response to, IL-2 by PPD-stimulated lymphocytes.
Topics: Animals; BCG Vaccine; Cells, Cultured; Dietary Proteins; Female; Guinea Pigs; Hypersensitivity, Delayed; Immunity, Innate; Interleukin-2; Lymphocyte Activation; Male; Protein Deficiency; Recombinant Proteins; Tuberculin; Tuberculosis, Pulmonary
PubMed: 2788135
DOI: 10.1128/iai.57.9.2606-2611.1989 -
Asia Pacific Journal of Clinical... 2020Lean body mass (LBM) agglomerates the bulk of nitrogen (N)-containing molecules following well-identified age and sex evolutionary patterns best appraised in clinical... (Review)
Review
Lean body mass (LBM) agglomerates the bulk of nitrogen (N)-containing molecules following well-identified age and sex evolutionary patterns best appraised in clinical practice using the serial measurement of plasma transthyretin (TTR). Methionine (Met), the sole essential amino acid bearing a sulfur (S) atom, presides at the initiation of protein synthesis while maintaining stable body tissue S:N molar ratios of approximately 1:14.5. In protein- depleted states, N- and Met-deficiencies operate as limiting factors for LBM protein synthesis and accretion, causing growth retardation and subnormal TTR plasma values. In inflammatory disorders, LBM is subjected to cytokine-induced tissue breakdown reflecting the S:N ratio found in healthy tissues whereas the liver secretion of TTR declines in proportion. Both malnutrition and inflammation are characterized by stepwise LBM downsizing and reduced bioavailability of Met body stores setting in motion molecular mechanisms safeguarding Met homeostasis at the expense of augmented homocysteine (Hcy) values in biological fluids. Divergent TTR and Hcy alterations indicate that rising Hcy values measured in plasma and cerebrospinal fluid should be regarded as the dark side of efficient compensatory processes. As a result, the neuroprotective activities normally exerted by TTR are weakened, whereas the oxidative burden generated by supranormal Hcy concentrations are strengthened. The combination of protein malnutrition and inflammatory disorders of any cause maximizes the risk of incurable neurodegenerative effects.
Topics: Alzheimer Disease; Energy Metabolism; Humans; Inflammation; Protein Deficiency
PubMed: 32990603
DOI: 10.6133/apjcn.202009_29(3).0002 -
FASEB Journal : Official Publication of... Mar 2019Levels of augmenter of liver regeneration (ALR), a multifunctional protein, are reduced in steatohepatitis. ALR depletion from ALR /Alb-Cre [ALR-L-knockout (KO)] mouse...
Levels of augmenter of liver regeneration (ALR), a multifunctional protein, are reduced in steatohepatitis. ALR depletion from ALR /Alb-Cre [ALR-L-knockout (KO)] mouse causes robust steatosis and apoptosis of hepatocytes, and pericellular fibrosis between 1 and 2 wk postbirth. Steatosis regresses by 4 wk upon reappearance of ALR-expressing hepatocytes. We investigated mechanisms of ALR depletion-induced steatosis. ALR-L-KO mice (1-, 2-, and 4 wk old) and Adeno-Cre-transfected ALR hepatocytes were used for in vivo and in vitro studies. ALR depletion from hepatocytes in vivo downregulated peroxisome proliferator-activated receptor (PPAR)-α, carnitine palmitoyl transferase I (CPT1)a, peroxisomal membrane protein 70 (PMP70) (modest down-regulation), and acyl-CoA oxidase 1 (ACOX1). The markedly up-regulated (20X) novel microRNA-540 (miR-540) was identified to target PPARα, PMP70, ACOX1, and CPT1a. ALR depletion from primary hepatocytes increased oxidative stress, miR-540 expression, and steatosis and down-regulated PPARα, ACOX1, PMP70, and CPT1a expression. Anti-miR-540 mitigated ALR depletion-induced steatosis and prevented loss of PPARα, ACOX1, PMP70, and CPT1a expression. Antioxidant N-acetylcysteine and recombinant ALR (rALR) both inhibited ALR depletion-induced miR-540 expression and lipid accumulation in hepatocytes. Finally, treatment of ALR-L-KO mice with rALR between 1 and 2 wk prevented miR-540 expression, and arrested steatosis and fibrosis. We conclude that ALR deficiency-mediated oxidative stress induces generation of miR-540, which promotes steatosis by dysregulating peroxisomal and mitochondrial lipid homeostasis.-Kumar, S., Rani, R., Karns, R., Gandhi, C. R. Augmenter of liver regeneration protein deficiency promotes hepatic steatosis by inducing oxidative stress and microRNA-540 expression.
Topics: Animals; Apoptosis; Endoplasmic Reticulum; Fatty Liver; Female; Hepatocytes; Humans; Liver; Liver Regeneration; Mice; Mice, Knockout; MicroRNAs; Mitochondria; Oxidative Stress; PPAR alpha; Protein Deficiency; Up-Regulation
PubMed: 30540918
DOI: 10.1096/fj.201802015R -
American Journal of Medical Genetics.... Jan 2022D-bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality....
D-bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency. Loss-of-function variants typically result in no residual enzyme activity; however, splice variants may result in protein with residual function. We describe a full-term newborn presenting with hypotonia, seizures, and unexplained hypoglycemia, who was later found to have rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed RNA from the patient's father with RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three amino acids from the new reading frame. This RNA-seq analysis was correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble vitamin deficiencies to reduce complications.
Topics: Exons; Hearing Loss, Sensorineural; Humans; Hypoglycemia; Infant, Newborn; Peroxisomal Multifunctional Protein-2; Protein Deficiency
PubMed: 34623748
DOI: 10.1002/ajmg.a.62520 -
Deutsches Arzteblatt International Sep 2011Failure to thrive impairs children's weight gain and growth, their defenses against infection, and their psychomotor and intellectual development. (Review)
Review
BACKGROUND
Failure to thrive impairs children's weight gain and growth, their defenses against infection, and their psychomotor and intellectual development.
METHODS
This paper is a review of pertinent articles that were published from 1995 to October 2010 and contained the terms "failure to thrive", "underweight", "malnutrition", "malabsorption", "maldigestion" and "refeeding syndrome". The articles were retrieved by a search in the PubMed and Cochrane Library databases.
RESULTS
In developed countries, failure to thrive is usually due to an underlying disease. The degree of malnutrition is assessed with anthropometric techniques. For each patient, the underlying disease must be identified and the mechanism of failure to thrive understood, so that proper medical and nutritional treatment can be provided. Nutritional treatment involves either giving more food, or else raising the caloric density of the patient's food. Liquid formulas can be given as a supplement to normal meals or as balanced or unbalanced tube feeds; they can be given orally, through a nasogastric tube, or through a gastrostomy tube. Severely malnourished children with poor oral intake should be treated with parenteral nutrition. To avoid refeeding syndrome in severely malnourished children, food intake should be increased slowly at first, and phosphate, magnesium, and potassium supplements should be given.
CONCLUSION
The proper treatment of failure to thrive in childhood consists of treatment of the underlying illness, combined with nutritional treatment that addresses the mechanism of the accompanying failure to thrive.
Topics: Adolescent; Algorithms; Child; Child, Preschool; Dietary Supplements; Energy Intake; Enteral Nutrition; Failure to Thrive; Humans; Infant; Parenteral Nutrition, Total; Protein-Energy Malnutrition; Refeeding Syndrome
PubMed: 22025931
DOI: 10.3238/arztebl.2011.0642 -
The American Journal of Clinical... Nov 2016Environmental enteropathy, which is linked to undernutrition and chronic infections, affects the physical and mental growth of children in developing areas worldwide....
BACKGROUND
Environmental enteropathy, which is linked to undernutrition and chronic infections, affects the physical and mental growth of children in developing areas worldwide. Key to understanding how these factors combine to shape developmental outcomes is to first understand the effects of nutritional deficiencies on the mammalian system including the effect on the gut microbiota.
OBJECTIVE
We dissected the nutritional components of environmental enteropathy by analyzing the specific metabolic and gut-microbiota changes that occur in weaned-mouse models of zinc or protein deficiency compared with well-nourished controls.
DESIGN
With the use of a H nuclear magnetic resonance spectroscopy-based metabolic profiling approach with matching 16S microbiota analyses, the metabolic consequences and specific effects on the fecal microbiota of protein and zinc deficiency were probed independently in a murine model.
RESULTS
We showed considerable shifts within the intestinal microbiota 14-24 d postweaning in mice that were maintained on a normal diet (including increases in Proteobacteria and striking decreases in Bacterioidetes). Although the zinc-deficient microbiota were comparable to the age-matched, well-nourished profile, the protein-restricted microbiota remained closer in composition to the weaned enterotype with retention of Bacteroidetes. Striking increases in Verrucomicrobia (predominantly Akkermansia muciniphila) were observed in both well-nourished and protein-deficient mice 14 d postweaning. We showed that protein malnutrition impaired growth and had major metabolic consequences (much more than with zinc deficiency) that included altered energy, polyamine, and purine and pyrimidine metabolism. Consistent with major changes in the gut microbiota, reductions in microbial proteolysis and increases in microbial dietary choline processing were observed.
CONCLUSIONS
These findings are consistent with metabolic alterations that we previously observed in malnourished children. The results show that we can model the metabolic consequences of malnutrition in the mouse to help dissect relevant pathways involved in the effects of undernutrition and their contribution to environmental enteric dysfunction.
Topics: Animals; DNA, Bacterial; Diet; Dietary Proteins; Feces; Gastrointestinal Microbiome; Gastrointestinal Tract; Lipocalin-2; Male; Malnutrition; Metabolomics; Mice; Mice, Inbred C57BL; Peroxidase; Protein Deficiency; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Weaning; Zinc
PubMed: 27733402
DOI: 10.3945/ajcn.116.131797 -
Nestle Nutrition Institute Workshop... 2013One-carbon metabolism, or methyl transfer, is critical for metabolism in all cells, is involved in the synthesis of purines, pyrimidines, in the methylation of numerous... (Review)
Review
One-carbon metabolism, or methyl transfer, is critical for metabolism in all cells, is involved in the synthesis of purines, pyrimidines, in the methylation of numerous substrates, proteins, DNA and RNA, and in the expression of a number of genes. Serine is the primary endogenous methyl donor to the one carbon pool. Perturbations in methyl transfer due to nutrient and hormonal changes can have profound effect on cell function, growth and proliferation. It is postulated that at critical stages in development, nutrient and environmental influences by their effect on methyl transfer can impair fetal growth, reprogram metabolism and cause long-term morbidity in the offspring. The potential for their effects is underscored by the unique gestation-related changes in methyl transfer in healthy women, the late expression of transsulfuration cascade in the fetus and the unique metabolism of glycine and serine in the fetus. Dietary protein restriction in animal models and protein malnutrition in humans causes remarkable changes in the methyl transfer in vivo. Although the specific consequences of perturbation in maternal and fetal methyl transfer remain to be determined, a profound influence is suggested by the demonstrated relationship between maternal folate and B12 insufficiency and metabolic programming.
Topics: Amino Acids; Animals; Carbon; DNA Methylation; Dietary Proteins; Female; Fetal Development; Fetal Growth Retardation; Fetus; Humans; Methylation; Nutritional Status; Pregnancy; Prenatal Nutritional Physiological Phenomena; Protein Deficiency; Vitamin B Deficiency
PubMed: 23887111
DOI: 10.1159/000348459 -
Frontiers in Immunology 2022Malnutrition refers to inadequate energy and/or nutrient intake. Malnutrition exhibits a bidirectional relationship with infections whereby malnutrition increases risk... (Review)
Review
Malnutrition refers to inadequate energy and/or nutrient intake. Malnutrition exhibits a bidirectional relationship with infections whereby malnutrition increases risk of infections that further aggravates malnutrition. Severe malnutrition (SM) is the main cause of secondary immune deficiency and mortality among children in developing countries. SM can manifest as marasmus (non-edematous), observed most often (68.6% of all malnutrition cases), kwashiorkor (edematous), detected in 23.8% of cases, and marasmic kwashiorkor, identified in ~7.6% of SM cases. Marasmus and kwashiorkor occur due to calorie-energy and protein-calorie deficiency (PCD), respectively. Kwashiorkor and marasmic kwashiorkor present with reduced protein levels, protein catabolism rates, and altered levels of micronutrients leading to uncontrolled oxidative stress, exhaustion of anaerobic commensals, and proliferation of pathobionts. Due to these alterations, kwashiorkor children present with profoundly impaired immune function, compromised intestinal barrier, and secondary micronutrient deficiencies. Kwashiorkor-induced alterations contribute to growth stunting and reduced efficacy of oral vaccines. SM is treated with antibiotics and ready-to-use therapeutic foods with variable efficacy. Kwashiorkor has been extensively investigated in gnotobiotic (Gn) mice and piglet models to understand its multiple immediate and long-term effects on children health. Due to numerous physiological and immunological similarities between pigs and humans, pig represents a highly relevant model to study kwashiorkor pathophysiology and immunology. Here we summarize the impact of kwashiorkor on children's health, immunity, and gut functions and review the relevant findings from human and animal studies. We also discuss the reciprocal interactions between PCD and rotavirus-a highly prevalent enteric childhood pathogen due to which pathogenesis and immunity are affected by childhood SM.
Topics: Animals; Child; Germ-Free Life; Humans; Kwashiorkor; Malnutrition; Mice; Protein-Energy Malnutrition; Rotavirus; Swine
PubMed: 35585989
DOI: 10.3389/fimmu.2022.826268 -
Scientific Reports Oct 2020Recent research suggests that protein deficiency symptoms are influenced by the intestinal microbiota. We investigated the influence of low protein diet on composition...
Recent research suggests that protein deficiency symptoms are influenced by the intestinal microbiota. We investigated the influence of low protein diet on composition of the intestinal microbiota through animal experiments. Specific pathogen-free (SPF) mice were fed one of four diets (3, 6, 9, or 12% protein) for 4 weeks (n = 5 per diet). Mice fed the 3% protein diet showed protein deficiency symptoms such as weight loss and low level of blood urea nitrogen concentration in their serum. The intestinal microbiota of mice in the 3% and 12% protein diet groups at day 0, 7, 14, 21 and 28 were investigated by 16S rRNA gene sequencing, which revealed differences in the microbiota. In the 3% protein diet group, a greater abundance of urease producing bacterial species was detected across the duration of the study. In the 12% diet protein group, increases of abundance of Streptococcaceae and Clostridiales families was detected. These results suggest that protein deficiency may be associated with shifts in intestinal microbiota.
Topics: Animals; Bacterial Proteins; Clostridiales; Diet, Protein-Restricted; Disease Models, Animal; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred BALB C; Nutritional Status; Protein Deficiency; RNA, Ribosomal, 16S; Specific Pathogen-Free Organisms; Streptococcaceae; Urease
PubMed: 33051527
DOI: 10.1038/s41598-020-74122-9 -
CMAJ : Canadian Medical Association... Aug 2005Malnutrition, with its 2 constituents of protein-energy malnutrition and micronutrient deficiencies, continues to be a major health burden in developing countries. It is... (Review)
Review
Malnutrition, with its 2 constituents of protein-energy malnutrition and micronutrient deficiencies, continues to be a major health burden in developing countries. It is globally the most important risk factor for illness and death, with hundreds of millions of pregnant women and young children particularly affected. Apart from marasmus and kwashiorkor (the 2 forms of protein- energy malnutrition), deficiencies in iron, iodine, vitamin A and zinc are the main manifestations of malnutrition in developing countries. In these communities, a high prevalence of poor diet and infectious disease regularly unites into a vicious circle. Although treatment protocols for severe malnutrition have in recent years become more efficient, most patients (especially in rural areas) have little or no access to formal health services and are never seen in such settings. Interventions to prevent protein- energy malnutrition range from promoting breast-feeding to food supplementation schemes, whereas micronutrient deficiencies would best be addressed through food-based strategies such as dietary diversification through home gardens and small livestock. The fortification of salt with iodine has been a global success story, but other micronutrient supplementation schemes have yet to reach vulnerable populations sufficiently. To be effective, all such interventions require accompanying nutrition-education campaigns and health interventions. To achieve the hunger- and malnutrition-related Millennium Development Goals, we need to address poverty, which is clearly associated with the insecure supply of food and nutrition.
Topics: Cost of Illness; Developing Countries; Food, Fortified; Health Promotion; Humans; Incidence; Micronutrients; Patient Education as Topic; Poverty; Protein-Energy Malnutrition; Public Health; Rural Population
PubMed: 16076825
DOI: 10.1503/cmaj.050342