Biochemical Phenomena, Metabolism, and Nutrition Commons^™

Sleep-Disordered Breathing Subtypes And Future Diet Quality In The Multi-Ethnic Study Of Atherosclerosis, Kaitlin S Potts, Cecilia Castro-Diehl, Tianyi Huang, Alexis C Wood, Jerome I Rotter, Stephen S Rich, Tamar Sofer, Susan Redline, Heming Wang

Children’s Nutrition Research Center Staff Publications

Objectives: Sleep-disordered breathing (SDB) and diet quality impact cardiometabolic disease, but few studies have examined if SDB influences diet quality. This study estimated the association between SDB subtypes (with and without sleepiness) and future diet quality in the Multi-Ethnic Study of Atherosclerosis.

Methods: Probable SDB was characterized by self-reported physician-diagnosed sleep apnea (PDSA) or habitual snoring and subtyped by presence or absence of sleepiness. A food frequency questionnaire measured diet 1.6 years before, and 7.8 years after SDB assessment. Diet quality was measured with the Alternate Healthy Eating Index-2010 (AHEI). Mean differences in AHEI at follow-up by SDB subtypes were …

Dietary Fiber Modulates Gut Microbiota And Lipid Metabolism Ameliorating Alzheimer's Pathology In 5xfad Mice, Yuhai Zhao, Christopher M. Taylor, Walter J. Lukiw, Nicolas G. Bazan

School of Graduate Studies Faculty Publications

The gut-brain axis plays a critical role in maintaining neuronal integrity and influencing the progression of Alzheimer's disease (AD). Here, we investigated how commonly consumed dietary fibers modulate gut microbiota, lipid metabolism, and AD pathology in 5xFAD mice. Male mice were fed either fiber-free (FF) or fiber-plus (FP; 1% cellulose, 2% pectin, 2% inulin) diets for five months, followed by integrated analyses of gut microbiota (16 S rRNA sequencing), fecal lipid metabolites (LC-MS/MS), and neuropathological and behavioral outcomes. FP diets markedly altered microbial composition, characterized by increases in Muribaculaceae, Ileibacterium, and Lachnospiraceae NK4A136 group and reductions in Faecalibaculum and Coriobacteriaceae …

Alcohol And Metabolic Stress Synergize To Dysregulate Mitochondrial Health And Lipid Metabolism; Evidence From A Hepatocyte Spheroid Model, Eden M. Gallegos, Kaitlin Couvillion, Drake Darden, Keishla Rodriguez-Graciani, Patricia E. Molina, Liz Simon

School of Graduate Studies Faculty Publications

Metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease frequently co-occur, manifesting as MetALD. Understanding the hepatocyte-specific effects of alcohol and metabolic stressors is critical to uncovering mechanisms of synergistic injury. This study evaluated the individual and combined effects of ethanol, sugars, and saturated/monounsaturated fats on hepatocyte lipid metabolism, oxidative stress, and mitochondrial function using a 3D human HepaRG spheroid model. HepaRG spheroids were treated with ethanol (50 mm), sugar (glucose and fructose), and fatty acids alone or in combination for 10 d. The combination of ethanol (E) and metabolic (sugar and fat, SF) stressors (ESF) synergistically increased triglyceride content …

Concerns Regarding The Standard Deviation Of Individual Responses For Assessing Treatment Response Heterogeneity, Aaron R Caldwell, David B Allison, Andrew W Brown, Gary L Gadbury, Thirupathi Reddy Mokalla, R Drew Sayer, Andrew D Vigotsky

Children’s Nutrition Research Center Staff Publications

The estimation of treatment response heterogeneity (TRH) is increasingly important as medicine moves toward personalized approaches. While various statistical methods have been proposed to quantify TRH in parallel-group trials, the standard deviation of individual responses (SDIR) has gained prominence within physiological research. This method is intended to quantify individual response variation by comparing standard deviations of change scores between intervention and control groups. We acknowledge that SDIR represents an improvement over many other flawed approaches that often involve responder counting. However, SDIR has critical limitations: 1) it cannot overcome the fundamental problem of causal inference because the correlation between potential …

Risk Score Roulette: A Cautionary Tale Of Polygenic Risk Score Reliability, Diane Xue, Elizabeth E Blue, Alexis C Wood, Jerome I Rotter, Alison E Fohner

Children’s Nutrition Research Center Staff Publications

Genetic risk prediction for Alzheimer's disease (AD) has high potential impact, yet few studies have assessed the reliability of various polygenic risk score (PRS) methods at the individual level. Here, we evaluated the reliability of AD PRS estimates among 6338 participants from the Multi-Ethnic Study of Atherosclerosis. We compared four PRS models that have been previously associated with dementia risk. Despite similar population-level performance metrics, inter-model reliability of individual-level risk assessment was low, even among individuals classified in the top and bottom deciles. These findings raise serious concerns about the downstream application of PRS for guiding interventions for AD.

Scrotal Temperature Change During Running In Naked Humans, Yasuho Takii, Makoto Fukuda, Kazuyuki Kanosue, Tamae Yoda

Children’s Nutrition Research Center Staff Publications

Male reproductive organs are functionally affected by high body temperature. This study aimed to clarify the thermoregulation mechanisms of the human scrotum during running, and experiments were conducted to investigate temperature changes in the whole body and the scrotum. Eleven male long-distance runners performed treadmill running at 60%[Formula: see text] for 60 min in an indoor environment at 27 °C and 40% relative humidity. Immediately after the start of the run, the skin temperatures in areas other than the scrotum decreased or showed a tendency to decrease. In contrast, the scrotal temperature increased immediately after the start of the run. …

Factor Structure Of Food And Physical Activity Parenting Practices Among Us Fathers By Ethnicity And Survey Language: A Cross Sectional Study, Salma M A Musaad, Louise C Mâsse, Alicia Beltran, Oriana Perez, Teresia M O'Connor

Children’s Nutrition Research Center Staff Publications

Background: Parenting practices contribute to children’s eating and physical activity behaviors, and thereby their risk of obesity and associated medical conditions. Fathers may engage in different parenting practices than mothers. The objective of this study was therefore to establish psychometrically sound tools in English and Spanish for measuring Physical Activity Parenting Practices (PAPP) and Food Parenting Practices (FPP) for Hispanic and non-Hispanic fathers of diverse races for use in future studies, such as evaluations of family-based obesity interventions targeted at fathers.

Methods: We conducted a preliminary assessment of the psychometric properties of a reduced version of the PAPP and FPP …

Rtx-303, An Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates Parp Inhibitors In Brca Mutant Tumors, Gurushankar Chandramouly, William Fried, John Gordon, Douglas Ralph, Channita Keuk, Sangeeta Kumari, Mercy Ramanjulu, William Auerbacher, Leonid Minakhin, Taylor Tredinnick, Bernadette Tiberi, George Morton, Robert Betsch, Kathy Q. Cai, Umeshkumar M Vekariya, Mrityunjay Tyagi, Tomasz Skorski, Sergey Karakashev, Neil Johnson, Wayne E. Childers, Xiaojiang S. Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like …

Fine Mapping Regulatory Variants By Characterizing Native Cpg Methylation With Nanopore Long-Read Sequencing, Yijun Tian, Shannon K. Mcdonnell, Lang Wu, Nicholas B. Larson, Liang Wang

School of Medicine Faculty Publications

5-Methylcytosine (5mC) is the most common DNA modification in the human genome. Bisulfite conversion combined with short-read sequencing captures this modification at single-nucleotide resolution but introduces PCR duplication bias and limits co-methylation analysis between distant cytosines. To resolve these limitations, we used nanopore long-read sequencing to profile human methylation and performed long-range co-methylation analysis with native DNA modification information. We analyzed the nanopore demo data in the adaptive sampling sequencing targeting the CpG islands and applied the linkage disequilibrium (LD) R to identified methylation haplotype blocks (MHBs). We found that the cancer genome exhibited significantly smaller MHBs, higher CpG density, …

Dietary Patterns For Weight And Glycemic Management In Persons With Type 1 Diabetes: A Meta-Analysis Of Clinical Trials, Daria Igudesman, Laura M Nally, Alyssa A Grimshaw, Craig G Gunderson, Elizabeth G Considine, Laura M Jacobsen, Mustafa Tosur, Peter A Gottlieb, Irl B Hirsch, Lori M Laffel, Jennifer L Sherr, Chantal Mathieu, Richard E Pratley

Children’s Nutrition Research Center Staff Publications

Background: Medical nutrition therapy is fundamental for managing glycemia and weight in type 1 diabetes, yet dietary guidance specific to this population and relevant subgroups is lacking.

Purpose: We synthesized the interventional literature investigating diet patterns for glycemic and weight management in youth and adults with type 1 diabetes, with attention to interindividual variation that suggests the need for precision approaches. The protocol was prospectively registered (CRD42024519941).

Data sources: AMED, CINAHL, Cochrane Library, Ovid MEDLINE, Ovid Embase, Google Scholar, and Web of Science Core Collection were searched from January 2011 to June 2024.

Study selection: Clinical trials ≥4 weeks with …

Effectiveness Of Vitamin D3 In Facilitating The Therapeutic Progression Of Healing Diabetic Foot Ulcers, Fatemeh Nouri, Sara Aghaei, Gülüzar Özbolat, Yusuf Döğüş, Mahdi Mirhamidi, Reza Rahimi Barghani, Amin Daemi

Chulalongkorn Medical Journal

Background: Today’s, diabetes and its complications have afflicted a large population all over the world, so that it is estimated that its prevalence in all age groups will reach from 2.8% in 2000 to 4.4% in 2030. It is well known that vitamin D may cause rapid wound healing and anti-inflammatory.

Objective: Regarding the importance of the quality of life of diabetic patients and the improvement of chronic diabetic foot ulcers, this paper aims to investigate the efficacy of vitamin D3 on the healing of diabetic foot ulcers. The present research is conducted as a randomized controlled trial.

Methods: …

Associations Among Human Milk Polyunsaturated Fatty Acids And Infant Sleep Patterns: A Cross-Sectional Study, Ana M Palacios, Dominick J Lemas, Bridget E Young, Erik Parker, Stephanie Dickinson, Nandi Marshall, Kelly L Sullivan, Haley Wilt, Michelle I Cardel, David B Allison

Children’s Nutrition Research Center Staff Publications

Background: Infant sleep is critical for cognitive, emotional, and long-term health outcomes. Although diet-sleep relationships are established, limited research has explored how polyunsaturated fatty acids (PUFAs) in human milk (HM) relate to infant sleep.

Objectives: This study aims to examine associations between PUFAs in HM and sleep patterns in 2-mo-old infants exclusively fed with HM.

Methods: This cross-sectional secondary analysis used data from a lactation cookie trial involving 131 parents of healthy, term infants. Participants provided a fasting HM sample and completed sociodemographic and Brief Infant Sleep Questionnaire surveys. Multivariate linear models were adjusted for infant sex assigned at birth, …

Repeated Withdrawal Of A Glpr Agonist Induces Hyperleptinemia And Deteriorates Metabolic Health In Obese Aging Um-Het3 Mice, Nisi Jiang, Jiyuan Yin, Noah Lawrence, Jieyi Meng, Laurence T Maeyens, Ziying Xu, Xin Li, Mbolle Ekane, Ariana Chaudhary, Pengju Cao, Guannan Li, Carolina Solis-Herrera, Yi Zhu, Shangang Zhao

Children’s Nutrition Research Center Staff Publications

GLP-1-based therapy is highly effective in combating aging-associated metabolic diseases. However, the metabolic effects of frequent withdrawal from this therapy in aged, obese mice have not been previously studied. In this study, aged obese UM-HET3 mice were assigned to three groups: Group 1 received no liraglutide treatment (Lira OFF); Group 2 underwent 3 cycles of treatment followed by withdrawal (Lira ON/OFF); and Group 3 remained on continuous treatment (Lira ON). As expected, mice in Group 3 showed reduced body weight and food intake, along with improved metabolic health. In contrast, mice in Group 2 developed hyperleptinemia and visceral fat expansion, …

Liver-Specific Expression Of Hiv-1 Viral Protein R Causes Hepatic Steatosis And Glucose Intolerance In Male Mice, Neeti Agarwal, Pradip Saha, Claudia E Ramirez Bustamante, Sean M Hartig, Mark A Herman, Ashok Balasubramanyam, Jordan E Lake

Faculty, Staff and Students Publications

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized in people with HIV (PWH), with both HIV and antiretroviral therapy contributing to liver damage and glucose intolerance. However, the role of viral proteins derived from reservoirs in this process remains unclear.

Methods: Adeno-associated virus (AAV) constructs encoding a control protein or HIV-1 viral protein R (Vpr) driven by the thyroxine-binding globulin promoter were administered to male mice (n = 5 per group) fed regular chow or a high-fat diet (HFD). Young adult mice underwent intraperitoneal glucose tolerance testing and magnetic resonance imaging, followed by euthanasia. Liver and adipose tissues …

Comparison Of Authentic Urine N-Ethylpentedrone Metabolites To Predicted In Silico And In Vitro Human Hepatocyte Metabolism, Gloria Daziani, Omayema Taoussi, Diletta Berardinelli, Giulia Bambagiotti, Marilyn A. Huestis, Francesco P. Busardò, Jeremy Carlier

Institute of Emerging Health Professions Faculty Papers

Synthetic cathinones are the second most common class of substances belonging to the category of new psychoactive substances (NPS). N-ethylpentedrone (NEPD) self-administration was reported, making it important to elucidate its metabolic pathway to improve its detection. NEPD is often taken together with other substances; confidently identifying its intake is important for accurate toxicological analysis and understanding its toxicity. NEPD metabolism was studied following incubation with human hepatocytes and analysis by liquid chromatography-high-resolution mass spectrometry paired with Compound Discoverer software (Thermo Fisher Scientific). Prediction of possible metabolites was performed with the online software GLORYx. In vivo NEPD metabolism was evaluated by …

Mt1-Mmp Inhibition Rejuvenates Ageing Brain And Rescues Cognitive Deficits In Obesity, Pallavi Asthana, Liguo Li, Lin Lu, Jiayan Wu, Shuo Zhang, Ningning Li, Sheung Kin Ken Wong, Susma Gurung, Yijing Zhang, Yuwan Lin, Yufeng Peng, Zongtang Xu, Kui Ming Chan, Lixiang Zhai, Aiping Lyu, Zhao-Xiang Bian, Xin Ge, Ashok Iyaswamy, Min Li, Ya Su, Zhongjun Zhou, Pingyi Xu, Hoi Leong Xavier Wong

The Brown Foundation: Institute of Molecular Medicine

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the …

Amino Acids And Cart Distinguish A-Β+ Ketosis-Prone Diabetes From Type 1 And Type 2 Diabetes During Hyperglycemic Crises, Farook Jahoor, Jean W Hsu, Kelly R Keene, W Frank Peacock, Xiaofang Huang, Danielle Guffey, Jinyoung Byun, Rasmus Bennet, Ake Lernmark, Mustafa Tosur, Ashok Balasubramanyam

Children’s Nutrition Research Center Staff Publications

Context: When clinically stable, patients with A-β+ ketosis-prone diabetes (KPD) manifest unique markers of amino acid metabolism. Biomarkers differentiating KPD from type 1 (T1D) and type 2 diabetes (T2D) during hyperglycemic crises would accelerate diagnosis and management.

Objective: Compare serum metabolomics of KPD, T1D, and T2D patients during hyperglycemic crises, and utilize classification and regression tree (CART) modeling to distinguish these forms of diabetes.

Methods: At an urban hospital emergency center, adults with KPD, T1D, and T2D during hyperglycemic crises with or without diabetic ketoacidosis (DKA), and healthy controls, underwent comparisons of serum metabolite and hormonal profiles and CART analyses. …

The Role Of Ceramides As Biomarkers And Therapeutic Targets For Cardiometabolic Disease And Its Intersection With Cellular Aging, Youssef Moustafa Shalaby

Thesis/ Dissertation Defenses

Ceramides (Cer), a subclass of sphingolipids with potent bioactive properties, have gained recognition as key players in the pathogenesis of cardiometabolic diseases (CMD). They modulate critical cellular functions such as apoptosis, inflammation, insulin signaling, and oxidative stress. This dissertation explores the dual role of Cer as both early diagnostic markers and therapeutic targets, bridging clinical insights with mechanistic understanding through a combination of human and experimental studies.

A highly sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify intracellular levels of specific Cer species, including CerC16:0, CerC18:0, CerC22:0, CerC24:0, and CerC24:1. This method was translated into …

Integrated Systems Biology Identifies Disruptions In Mitochondrial Function And Metabolism As Key Contributors To Hfpef, Andrew A. Gibb, Kyle Lapenna, Ryan B. Gaspar, Nadina R. Latchman, Yinfei Tan, Carmen Choya-Foces, Jake E. Doiron, Zhen Li, Huijing Xia, Michael P. Lazaropoulos, Mariell Conwell, Thomas E. Sharp, Traci T. Goodchild, David J. Lefer, John W. Elrod

School of Graduate Studies Faculty Publications

Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases. The ZSF1-obese rat model recapitulates clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and diastolic dysfunction. We utilized a systems-biology approach to define the metabolic and transcriptional signatures to gain mechanistic insight into pathways contributing to HFpEF development. Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14 weeks of age for extensive physiological phenotyping and left ventricle (LV) tissue harvesting for unbiased-metabolomics, RNA-sequencing, and mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes …

A Consensus Guide To Preclinical Indirect Calorimetry Experiments, Alexander S Banks, David B Allison, Thierry Alquier, Ansarullah, Steven N Austad, Johan Auwerx, Julio E Ayala, Joseph A Baur, Stefania Carobbio, Gary A Churchill, Morten Dall, Rafael De Cabo, Jose Donato, Nathalia R V Dragano, Carol F Elias, Anthony W Ferrante, Brian N Finck, Jose E Galgani, Zachary Gerhart-Hines, Laurie J Goodyear, Justin L Grobe, Rana K Gupta, Kirk M Habegger, Sean M Hartig, Andrea L Hevener, Steven B Heymsfield, Corey D Holman, Martin Hrabě De Angelis, David E James, Lawrence Kazak, Jae Bum Kim, Martin Klingenspor, Xingxing Kong, Sander Kooijman, Louise Lantier, K C Kent Lloyd, James C Lo, Irfan J Lodhi, Paul S Maclean, Owen P Mcguinness, Gema Medina-Gómez, Raghavendra G Mirmira, Christopher D Morrison, Gregory J Morton, Timo D Müller, Yoshihiro Ogawa, David Pajuelo-Reguera, Matthew J Potthoff, Nathan Qi, Marc L Reitman, Patrick C N Rensen, Jan Rozman, Jennifer M Rutkowsky, Kei Sakamoto, Philipp E Scherer, Gary J Schwartz, Radislav Sedlacek, Mohammed Selloum, Saame Raza Shaikh, Shuai Chen, Gerald I Shulman, Vojtěch Škop, Alexander A Soukas, John R Speakman, Bruce M Spiegelman, Gregory R Steinberg, Katrin J Svensson, John P Thyfault, Tony Tiganis, Paul M Titchenell, Nigel Turner, Licio A Velloso, Antonio Vidal-Puig, Christopher S Ward, Ashley S Williams, Christian Wolfrum, Allison W Xu, Ying Xu, Juleen R Zierath, International Indirect Calorimetry Consensus Committee (Iiccc)

Children’s Nutrition Research Center Staff Publications

Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data …