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Nutrients Mar 2024Lactose intolerance, which affects about 65-75% of the world's population, is caused by a genetic post-weaning deficiency of lactase, the enzyme required to digest the... (Review)
Review
Lactose intolerance, which affects about 65-75% of the world's population, is caused by a genetic post-weaning deficiency of lactase, the enzyme required to digest the milk sugar lactose, called lactase non-persistence. Symptoms of lactose intolerance include abdominal pain, bloating and diarrhea. Genetic variations, namely lactase persistence, allow some individuals to metabolize lactose effectively post-weaning, a trait thought to be an evolutionary adaptation to dairy consumption. Although lactase non-persistence cannot be altered by diet, prebiotic strategies, including the consumption of galactooligosaccharides (GOSs) and possibly low levels of lactose itself, may shift the microbiome and mitigate symptoms of lactose consumption. This review discusses the etiology of lactose intolerance and the efficacy of prebiotic approaches like GOSs and low-dose lactose in symptom management.
Topics: Humans; Lactose Intolerance; Lactose; Lactase; Abdominal Pain; Biological Evolution; Prebiotics
PubMed: 38613035
DOI: 10.3390/nu16071002 -
Proceedings of the National Academy of... Aug 2023Trehalose plays a crucial role in the survival and virulence of the deadly human pathogen (). The type I ATP-binding cassette (ABC) transporter LpqY-SugABC is the sole...
Trehalose plays a crucial role in the survival and virulence of the deadly human pathogen (). The type I ATP-binding cassette (ABC) transporter LpqY-SugABC is the sole pathway for trehalose to enter . The substrate-binding protein, LpqY, which forms a stable complex with the translocator SugABC, recognizes and captures trehalose and its analogues in the periplasmic space, but the precise molecular mechanism for this process is still not well understood. This study reports a 3.02-Å cryoelectron microscopy structure of trehalose-bound LpqY-SugABC in the pretranslocation state, a crystal structure of LpqY in a closed form with trehalose bound and five crystal structures of LpqY in complex with different trehalose analogues. These structures, accompanied by substrate-stimulated ATPase activity data, reveal how LpqY recognizes and binds trehalose and its analogues, and highlight the flexibility in the substrate binding pocket of LpqY. These data provide critical insights into the design of trehalose analogues that could serve as potential molecular probe tools or as anti-TB drugs.
Topics: Humans; Cryoelectron Microscopy; Mycobacterium tuberculosis; Trehalose; ATP-Binding Cassette Transporters; Molecular Probes
PubMed: 37603751
DOI: 10.1073/pnas.2307625120 -
The Journal of Nutrition Jul 2023Elevated serum erythritol concentration is a predictive biomarker of diabetes and cardiovascular incidence and complications. Erythritol is synthesized endogenously from...
BACKGROUND
Elevated serum erythritol concentration is a predictive biomarker of diabetes and cardiovascular incidence and complications. Erythritol is synthesized endogenously from glucose, but little is known regarding the origin of elevated circulating erythritol in vivo.
OBJECTIVES
In vitro evidence indicates that intracellular erythritol is elevated by high-glucose cell culture conditions and that final step of erythritol synthesis is catalyzed by the enzymes sorbitol dehydrogenase (SORD) and alcohol dehydrogenase (ADH) 1. The purpose of this study was to determine whether dietary intake and/or diet-induced obesity affect erythritol synthesis in mice and whether this relationship is modified by the loss of the enzymes SORD or ADH1.
METHODS
First, 8-wk-old male Sord, Sord, Adh1, and Adh1 mice were fed either low-fat diet (LFD) with 10% fat-derived calories or diet-induced obesity high-fat diet (HFD) with 60% fat-derived calories for 8 wk. Plasma and tissue erythritol concentrations were measured using gas chromatography-mass spectrometry. Second, male wild-type 8-wk-old C57BL/6J mice were fed LFD or HFD with plain drinking water or 30% sucrose water for 8 wk. Blood glucose and plasma and urinary erythritol concentrations were measured in nonfasted and fasted samples. Tissue erythritol was measured after killing. Finally, male Sord and Sord mice were fed LFD with 30% sucrose water for 2 wk; then, nonfasted plasma, urine, and tissue erythritol concentrations were quantified.
RESULTS
Plasma and tissue erythritol concentrations were not affected by loss of Sord or Adh1 in mice fed LFD or HFD. In wild-type mice, consumption of 30% sucrose water significantly elevated plasma and urinary erythritol concentrations on both LFD-fed and HFD-fed mice compared with that of plain water. Sord genotype did not affect plasma or urinary erythritol concentration in response to sucrose feeding, but Sord mice had reduced kidney erythritol content compared with wild-type littermates in response to sucrose.
CONCLUSIONS
Sucrose intake, not HFD, elevates erythritol synthesis and excretion in mice. Loss of ADH1 or SORD does not significantly affect erythritol concentration in mice.
Topics: Mice; Male; Animals; Dietary Fats; Erythritol; Mice, Inbred C57BL; Obesity; Diet, High-Fat; Glucose; Sucrose
PubMed: 37245661
DOI: 10.1016/j.tjnut.2023.05.022 -
Acta Biomaterialia Sep 2023Decellularized lung scaffolds and hydrogels are increasingly being utilized in ex vivo lung bioengineering. However, the lung is a regionally heterogenous organ with...
Decellularized lung scaffolds and hydrogels are increasingly being utilized in ex vivo lung bioengineering. However, the lung is a regionally heterogenous organ with proximal and distal airway and vascular compartments of different structures and functions that may be altered as part of disease pathogenesis. We previously described decellularized normal whole human lung extracellular matrix (ECM) glycosaminoglycan (GAG) composition and functional ability to bind matrix-associated growth factors. We now determine differential GAG composition and function in airway, vascular, and alveolar-enriched regions of decellularized lungs obtained from normal, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) patients. Significant differences were observed in heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA) content and CS/HS compositions between both different lung regions and between normal and diseased lungs. Surface plasmon resonance demonstrated that HS and CS from decellularized normal and COPD lungs similarly bound fibroblast growth factor 2, but that binding was decreased in decellularized IPF lungs. Binding of transforming growth factor β to CS was similar in all three groups but binding to HS was decreased in IPF compared to normal and COPD lungs. In addition, cytokines dissociate faster from the IPF GAGs than their counterparts. The differences in cytokine binding features of IPF GAGs may result from different disaccharide compositions. The purified HS from IPF lung is less sulfated than that from other lungs, and the CS from IPF contains more 6-O-sulfated disaccharide. These observations provide further information for understanding functional roles of ECM GAGs in lung function and disease. STATEMENT OF SIGNIFICANCE: Lung transplantation remains limited due to donor organ availability and need for life-long immunosuppressive medication. One solution, the ex vivo bioengineering of lungs via de- and recellularization has not yet led to a fully functional organ. Notably, the role of glycosaminoglycans (GAGs) remaining in decellularized lung scaffolds is poorly understood despite their important effects on cell behaviors. We have previously investigated residual GAG content of native and decellularized lungs and their respective functionality, and role during scaffold recellularization. We now present a detailed characterization of GAG and GAG chain content and function in different anatomical regions of normal diseased human lungs. These are novel and important observations that further expand knowledge about functional GAG roles in lung biology and disease.
Topics: Humans; Glycosaminoglycans; Lung; Chondroitin Sulfates; Pulmonary Disease, Chronic Obstructive; Extracellular Matrix; Disaccharides
PubMed: 37433361
DOI: 10.1016/j.actbio.2023.06.043 -
Chemical Senses Jan 2024Although studies have shown that olfaction may contribute to the perception of tastant, literature is scarce or circumstantial, especially in humans. This study aims to...
Although studies have shown that olfaction may contribute to the perception of tastant, literature is scarce or circumstantial, especially in humans. This study aims to (i) explore whether humans can perceive solutions of basic prototypical tastants through orthonasal and retronasal olfaction and (ii) to examine what volatile odor compounds (VOCs) underlie this ability. Solutions of 5 basic tastants (sucrose, sodium chloride, citric acid, monosodium glutamate [MSG], quinine) dissolved in water, and 2 fatty acids (oleic and linoleic acid) dissolved in mineral oil were prepared. Triangle discrimination tests were performed (n = 41 in duplicate) to assess whether the tastant solutions can be distinguished from blanks (solvents) through ortho- and retronasal olfaction. Participants were able to distinguish all tastant solutions from blank through orthonasal olfaction. Only sucrose, sodium chloride, oleic acid, and linoleic acid were distinguished from blank by retronasal olfaction. Ethyl dichloroacetate, methylene chloride, and/or acetone were identified in the headspace of sucrose, MSG, and quinine solutions but not in the headspace of water, sodium chloride, and citric acid solutions. Fat oxidation compounds such as alcohols and aldehydes were detected in the headspace of the oleic and linoleic acid solutions but not the mineral oil. We conclude that prototypical tastant solutions can be discriminated from water and fatty acid solutions from mineral oil through orthonasal olfaction. Differences in the volatile headspace composition between blanks and tastant solutions may have facilitated the olfactory discrimination. These findings can have methodological implications for future studies assessing gustatory perception using these prototypical taste compounds.
Topics: Humans; Smell; Sodium Chloride; Sodium Glutamate; Quinine; Mineral Oil; Taste; Water; Sucrose; Citric Acid; Linoleic Acids
PubMed: 38175732
DOI: 10.1093/chemse/bjad054 -
Nature Communications Nov 2023Maize kernels are complex biological systems composed of three genetic sources, namely maternal tissues, progeny embryos, and progeny endosperms. The lack of gene...
Maize kernels are complex biological systems composed of three genetic sources, namely maternal tissues, progeny embryos, and progeny endosperms. The lack of gene expression profiles with spatial information has limited the understanding of the specific functions of each cell population, and hindered the exploration of superior genes in kernels. In our study, we conduct microscopic sectioning and spatial transcriptomics analysis during the grain filling stage of maize kernels. This enables us to visualize the expression patterns of all genes through electronical RNA in situ hybridization, and identify 11 cell populations and 332 molecular marker genes. Furthermore, we systematically elucidate the spatial storage mechanisms of the three major substances in maize kernels: starch, protein, and oil. These findings provide valuable insights into the functional genes that control agronomic traits in maize kernels.
Topics: Transcriptome; Zea mays; Phloem; In Situ Hybridization; Sucrose
PubMed: 37938556
DOI: 10.1038/s41467-023-43006-7 -
Experimental & Molecular Medicine Jul 2023Nonalcoholic fatty liver disease (NAFLD) is a serious metabolic disorder characterized by excess fat accumulation in the liver. Over the past decade, NAFLD prevalence...
Nonalcoholic fatty liver disease (NAFLD) is a serious metabolic disorder characterized by excess fat accumulation in the liver. Over the past decade, NAFLD prevalence and incidence have risen globally. There are currently no effective licensed drugs for its treatment. Thus, further study is required to identify new targets for NAFLD prevention and treatment. In this study, we fed C57BL6/J mice one of three diets, a standard chow diet, high-sucrose diet, or high-fat diet, and then characterized them. The mice fed a high-sucrose diet had more severely compacted macrovesicular and microvesicular lipid droplets than those in the other groups. Mouse liver transcriptome analysis identified lymphocyte antigen 6 family member D (Ly6d) as a key regulator of hepatic steatosis and the inflammatory response. Data from the Genotype-Tissue Expression project database showed that individuals with high liver Ly6d expression had more severe NAFLD histology than those with low liver Ly6d expression. In AML12 mouse hepatocytes, Ly6d overexpression increased lipid accumulation, while Ly6d knockdown decreased lipid accumulation. Inhibition of Ly6d ameliorated hepatic steatosis in a diet-induced NAFLD mouse model. Western blot analysis showed that Ly6d phosphorylated and activated ATP citrate lyase, which is a key enzyme in de novo lipogenesis. In addition, RNA- and ATAC-sequencing analyses revealed that Ly6d drives NAFLD progression by causing genetic and epigenetic changes. In conclusion, Ly6d is responsible for the regulation of lipid metabolism, and inhibiting Ly6d can prevent diet-induced steatosis in the liver. These findings highlight Ly6d as a novel therapeutic target for NAFLD.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Liver; Inflammation; Lipid Metabolism; Diet, High-Fat; Lipids; Sucrose; Mice, Inbred C57BL
PubMed: 37394588
DOI: 10.1038/s12276-023-01033-w -
Inflammatory Bowel Diseases Nov 2023While artificial sweeteners are deemed safe, preclinical studies indicate that artificial sweeteners contribute to gastrointestinal inflammation. Little is known about...
BACKGROUND
While artificial sweeteners are deemed safe, preclinical studies indicate that artificial sweeteners contribute to gastrointestinal inflammation. Little is known about patients' perceptions and consumption of artificial sweeteners in inflammatory bowel disease (IBD). We surveyed the consumption frequency and beliefs of IBD patients and control participants regarding artificial sweeteners.
METHODS
We surveyed 130 individuals (IBD patients, n = 93; control/non-IBD participants, n = 37) among our tertiary hospital population to determine consumption frequency and beliefs regarding artificial sweeteners (Splenda/sucralose, Stevia/stevia, NutraSweet/Equal/aspartame). A 14-question questionnaire surveyed the frequency of 9 dietary habits, preferences, and beliefs on health benefits of commercial artificial sweeteners, using the following as positive and negative control questions: table sugar, water, fruits/vegetables, and coconut-oil, among others.
RESULTS
Despite the similarity in yes/no consumption data, artificial sweeteners (Q4 t test P = .023) and diet (low calorie) foods/drinks (Q4 t test P = .023) were consumed more frequently by patients with IBD than by control participants, while no difference in preference for water instead of juices/sodas was observed between IBD patients and control participants. Conversely, patients with IBD consumed table sugar less frequently than control participants (Q1 t test-P = .09), in agreement with their reporting of sugary foods as cause of symptoms (P < .01). A positive correlation was observed between artificial sweeteners and fresh fruits/vegetables among the first 31 IBD patients (Spearman P = .017) and confirmed with 62 new IBD patients (r = 0.232; 95% CI, 0.02-0.43; P = .031), indicating that artificial sweeteners are deemed a healthy habit in IBD. Excluding fresh fruits/vegetables, multivariate analyses to develop surrogate principal component analysis indexes of healthy habits confirmed that artificial sweeteners consumption follows healthy preferences among our IBD patients (adjusted P < .0001).
CONCLUSIONS
Consumption of artificial sweeteners correlated with healthy habits, suggesting that our IBD population deemed artificial sweeteners as healthy and/or had preferences for naturally or artificially sweetened flavors and products.
Topics: Humans; Sweetening Agents; Dietary Sucrose; Vegetables; Fruit; Inflammatory Bowel Diseases; Diet; Water
PubMed: 36680556
DOI: 10.1093/ibd/izac272 -
American Journal of Physiology.... Dec 2023Duchenne muscular dystrophy (DMD), a progressive muscle disease caused by the absence of functional dystrophin protein, is associated with multiple cellular,...
Duchenne muscular dystrophy (DMD), a progressive muscle disease caused by the absence of functional dystrophin protein, is associated with multiple cellular, physiological, and metabolic dysfunctions. As an added complication to the primary insult, obesity/insulin resistance (O/IR) is frequently reported in patients with DMD; however, how IR impacts disease severity is unknown. We hypothesized a high-fat, high-sucrose diet (HFHSD) would induce O/IR, exacerbate disease severity, and cause metabolic alterations in dystrophic mice. To test this hypothesis, we treated 7-wk-old mdx (disease model) and C57 mice with a control diet (CD) or an HFHSD for 15 wk. The HFHSD induced insulin resistance, glucose intolerance, and hyperglycemia in C57 and mdx mice. Of note, mdx mice on CD were also insulin resistant. In addition, visceral adipose tissue weights were increased with HFHSD in C57 and mdx mice though differed by genotype. Serum creatine kinase activity and histopathological analyses using Masson's trichrome staining in the diaphragm indicated muscle damage was driven by dystrophin deficiency but was not augmented by diet. In addition, markers of inflammatory signaling, mitochondrial abundance, and autophagy were impacted by disease but not diet. Despite this, in addition to disease signatures in CD-fed mice, metabolomic and lipidomic analyses demonstrated a HFHSD caused some common changes in C57 and mdx mice and some unique signatures of O/IR within the context of dystrophin deficiency. In total, these data revealed that in mdx mice, 15 wk of HFHSD did not overtly exacerbate muscle injury but further impaired the metabolic status of dystrophic muscle.
Topics: Humans; Animals; Mice; Mice, Inbred mdx; Dystrophin; Muscle, Skeletal; Sucrose; Insulin Resistance; Muscular Dystrophy, Duchenne; Diet, High-Fat; Disease Models, Animal
PubMed: 37811713
DOI: 10.1152/ajpregu.00246.2022 -
Journal of Medical Toxicology :... Jul 2023Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration.
METHODS
We used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test.
RESULTS
Out of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism.
CONCLUSIONS
This multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury.
Topics: Humans; Acetaminophen; Alanine Transaminase; Genome-Wide Association Study; Maltose; Multiomics; Chemical and Drug Induced Liver Injury; Urea
PubMed: 37231244
DOI: 10.1007/s13181-023-00951-5