THE EFFECTS OF AGE AND SIZE ON THE COMPANION DOG METABOLOME: ROLES OF TRYPTOPHAN AND FATTY ACID METABOLISM

Abstract Recently, the companion dog has been promoted as an ideal animal model for human aging. Dogs show an interesting phenomenon where smaller individuals are longer lived than their larger counterparts. However, many of the underlying molecular mechanisms that influence aging and longevity in the dog are unknown. To begin to uncover these physiological changes, we completed the largest metabolomics study to date in the companion dog. Here, we collected blood plasma samples from companion dogs in three in the United States for metabolomics analysis. We then looked at the effects of age and size on the metabolome to develop new hypotheses about healthy canine aging. Our most striking differences were found with regards to geographic location in the canine metabolome, in which metabolic profiles were more similar between dogs in the same city than across cities. After controlling for this location effect, we found a strong signal of amino acid metabolism, specifically tryptophan metabolism, associated with weight in the dog where metabolites in the tryptophan metabolism pathway were always higher in small, long-lived dogs. Future studies will directly investigate the role of tryptophan metabolism in model organisms.

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The Role of Gut Microbiota in Aging and Aging Related Neurodegenerative Disorders: Insights from Drosophila Model

Life ◽

10.3390/life11080855 ◽

2021 ◽

Vol 11 (8) ◽

pp. 855

Author(s):

Yan Kong ◽

Liyuan Wang ◽

Baichun Jiang

Keyword(s):

Gut Microbiota ◽

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Physiological Function ◽

Time Dependent ◽

Model Organisms ◽

Gi Tract ◽

Drosophila Model ◽

Increased Susceptibility

Aging is characterized by a time dependent impairment of physiological function and increased susceptibility to death. It is the major risk factor for neurodegeneration. Neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the main causes of dementia in the old population. Gut microbiota is a community of microorganisms colonized in the gastrointestinal (GI) tract. The alteration of gut microbiota has been proved to be associated with aging and aging related neurodegeneration. Drosophila is a powerful tool to study microbiota-mediated physiological and pathological functions. Here, we summarize the recent advances using Drosophila as model organisms to clarify the molecular mechanisms and develop a therapeutic method targeting microbiota in aging and aging-related neurodegenerative disorders.

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RIPK1-Associated Inborn Errors of Innate Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.676946 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiahui Zhang ◽

Taijie Jin ◽

Ivona Aksentijevich ◽

Qing Zhou

Keyword(s):

Immune Deficiency ◽

Molecular Mechanisms ◽

Clinical Manifestations ◽

Physiological Role ◽

Model Organisms ◽

Loss Of Function ◽

Inborn Errors ◽

Post Translational Modifications ◽

Cell Death Signaling

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is a key molecule for mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors (DRs) and pattern recognition receptors (PRRs). RIPK1 functions are regulated by multiple post-translational modifications (PTMs), including ubiquitination, phosphorylation, and the caspase-8-mediated cleavage. Dysregulation of these modifications leads to an immune deficiency or a hyperinflammatory disease in humans. Over the last decades, numerous studies on the RIPK1 function in model organisms have provided insights into the molecular mechanisms of RIPK1 role in the maintenance of immune homeostasis. However, the physiological role of RIPK1 in the regulation of cell survival and cell death signaling in humans remained elusive. Recently, RIPK1 loss-of-function (LoF) mutations and cleavage-deficient mutations have been identified in humans. This review discusses the molecular pathogenesis of RIPK1-deficiency and cleavage-resistant RIPK1 induced autoinflammatory (CRIA) disorders and summarizes the clinical manifestations of respective diseases to help with the identification of new patients.

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Longevity: epigenetic and biomolecular aspects

BioMolecular Concepts ◽

10.1515/bmc-2014-0038 ◽

2015 ◽

Vol 6 (2) ◽

pp. 105-117 ◽

Cited By ~ 12

Author(s):

Giusi Taormina ◽

Mario G. Mirisola

Keyword(s):

Simple Model ◽

Molecular Mechanisms ◽

Model Organisms ◽

Intermittent Fasting ◽

Epigenetic Mechanisms ◽

Long Term Effects ◽

Dietary Interventions ◽

Aging Theories

AbstractMany aging theories and their related molecular mechanisms have been proposed. Simple model organisms such as yeasts, worms, fruit flies and others have massively contributed to their clarification, and many genes and pathways have been associated with longevity regulation. Among them, insulin/IGF-1 plays a key and evolutionary conserved role. Interestingly, dietary interventions can modulate this pathway. Calorie restriction (CR), intermittent fasting, and protein and amino acid restriction prolong the lifespan of mammals by IGF-1 regulation. However, some recent findings support the hypothesis that the long-term effects of diet also involve epigenetic mechanisms. In this review, we describe the best characterized aging pathways and highlight the role of epigenetics in diet-mediated longevity.

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Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

Molecular Psychiatry ◽

10.1038/s41380-021-01121-1 ◽

2021 ◽

Author(s):

Yan Wei ◽

Lijia Chang ◽

Kenji Hashimoto

Keyword(s):

Psychiatric Disorders ◽

Molecular Mechanisms ◽

The United States ◽

Racemic Mixture ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Resistant Depression ◽

The Brain ◽

Related Compounds

AbstractThe discovery of robust antidepressant actions exerted by the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has been a crucial breakthrough in mood disorder research. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (arketamine) and (S)-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson & Johnson was approved in the United States of America and Europe for treatment-resistant depression. However, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. In clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like robust antidepressant actions in patients with depression, despite these compounds showing antidepressant-like effects in rodents. Thus, the rodent data do not necessarily translate to humans due to the complexity of human psychiatric disorders. Collectively, the available studies indicate that it is unlikely that NMDAR plays a major role in the antidepressant action of (R,S)-ketamine and its enantiomers, although the precise molecular mechanisms underlying antidepressant actions of (R,S)-ketamine and its enantiomers remain unclear. In this paper, we review recent findings on the molecular mechanisms underlying the antidepressant actions of (R,S)-ketamine and its potent enantiomer arketamine. Furthermore, we discuss the possible role of the brain–gut–microbiota axis and brain–spleen axis in stress-related psychiatric disorders and in the antidepressant-like action of arketamine. Finally, we discuss the potential of arketamine as a treatment for cognitive impairment in psychiatric disorders, Parkinson’s disease, osteoporosis, inflammatory bowel diseases, and stroke.

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p53 Transactivation Domain Mediates Binding and Phase Separation With poly-PR/GR

10.20944/preprints202109.0265.v1 ◽

2021 ◽

Author(s):

Sinem Usluer ◽

Emil Spreitzer ◽

Benjamin Bourgeois ◽

Tobias Madl

Keyword(s):

Phase Separation ◽

Molecular Mechanisms ◽

Hydrophobic Interactions ◽

P53 Protein ◽

Chromatin Accessibility ◽

Model Organisms ◽

Transactivation Domain ◽

Protein Levels ◽

C9orf72 Gene

Abstract: The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of poly-PR/GR dipeptide repeats which are encoded by the C9orf72 gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility which results in stabilization and enhancement of transcriptional activity of the tumor suppressor p53 in several neurodegenerative disease models. Reduction of p53 protein levels in cell and model organisms protects against neurotoxicity of poly-PR, and partially protects against neurotoxicity of poly-GR. Here, we aimed to study the detailed molecular mechanisms how p53 contributes to poly-PR/GR mediated neurodegeneration. Using a combination of biophysical techniques such as nuclear magnetic resonance (NMR) spectroscopy, fluorescence polarization, turbidity assays and differential interference contrast (DIC) microscopy, we found that p53 physically interacts with poly-PR/GR and triggers liquid-liquid phase separation of p53. We identified p53 transactivation domain 2 (TAD2) as the main binding site for PR25/GR25 and show that binding of poly-PR/GR to p53 is mediated by a network of electrostatic and/or hydrophobic interactions. Our findings might help to understand the mechanistic role of p53 in poly-PR/GR - associated neurodegeneration.

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Expression analysis of genes related to cold tolerance in Dendroctonus valens

PeerJ ◽

10.7717/peerj.10864 ◽

2021 ◽

Vol 9 ◽

pp. e10864

Author(s):

Dongfang Zhao ◽

Chunchun Zheng ◽

Fengming Shi ◽

Yabei Xu ◽

Shixiang Zong ◽

...

Keyword(s):

Cold Tolerance ◽

Expression Analysis ◽

Molecular Mechanisms ◽

Differential Expression Analysis ◽

The United States ◽

Model Organisms ◽

Large Area ◽

Illumina Hiseq ◽

Dendroctonus Valens ◽

Genes Encoding

Pine beetles are well known in North America for their widespread devastation of pine forests. However, Dendroctonus valens LeConte is an important invasive forest pest in China also. Adults and larvae of this bark beetle mainly winter at the trunks and roots of Pinus tabuliformis and Pinus sylvestris; larvae, in particular, result in pine weakness or even death. Since the species was introduced from the United States to Shanxi in 1998, its distribution has spread northward. In 2017, it invaded a large area at the junction of Liaoning, Inner Mongolia and Hebei provinces, showing strong cold tolerance. To identify genes relevant to cold tolerance and the process of overwintering, we sequenced the transcriptomes of wintering and non-wintering adult and larval D. valens using the Illumina HiSeq platform. Differential expression analysis methods for other non-model organisms were used to compare transcript abundances in adults and larvae at two time periods, followed by the identification of functions and metabolic pathways related to genes associated with cold tolerance. We detected 4,387 and 6,091 differentially expressed genes (DEGs) between sampling dates in larvae and adults, respectively, and 1,140 common DEGs, including genes encoding protein phosphatase, very long-chain fatty acids protein, cytochrome P450, and putative leucine-rich repeat-containing proteins. In a Gene Ontology (GO) enrichment analysis, 1,140 genes were assigned to 44 terms, with significant enrichment for cellulase activity, hydrolase activity, and carbohydrate metabolism. Kyoto Encyclopedia of Genes and Genomes (KEGG) classification and enrichment analyses showed that the lysosomal and purine metabolism pathways involved the most DEGs, the highly enriched terms included autophagy—animal, pentose and glucuronate interconversions and lysosomal processes. We identified 140 candidate genes associated with cold tolerance, including genes with established roles in this trait (e.g., genes encoding trehalose transporter, fructose-1,6-bisphosphatase, and trehalase). Our comparative transcriptome analysis of adult and larval D. valens in different conditions provides basic data for the discovery of key genes and molecular mechanisms underlying cold tolerance.

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Bacterial Infection in Chronic Obstructive Pulmonary Disease in 2000: a State-of-the-Art Review

Clinical Microbiology Reviews ◽

10.1128/cmr.14.2.336-363.2001 ◽

2001 ◽

Vol 14 (2) ◽

pp. 336-363 ◽

Cited By ~ 346

Author(s):

Sanjay Sethi ◽

Timothy F. Murphy

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Bacterial Infection ◽

Pulmonary Disease ◽

Molecular Mechanisms ◽

Vaccine Development ◽

Bacterial Colonization ◽

The United States ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease

SUMMARY Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. The precise role of bacterial infection in the course and pathogenesis of COPD has been a source of controversy for decades. Chronic bacterial colonization of the lower airways contributes to airway inflammation; more research is needed to test the hypothesis that this bacterial colonization accelerates the progressive decline in lung function seen in COPD (the vicious circle hypothesis). The course of COPD is characterized by intermittent exacerbations of the disease. Studies of samples obtained by bronchoscopy with the protected specimen brush, analysis of the human immune response with appropriate immunoassays, and antibiotic trials reveal that approximately half of exacerbations are caused by bacteria. Nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae are the most common causes of exacerbations, while Chlamydia pneumoniae causes a small proportion. The role of Haemophilus parainfluenzae and gram-negative bacilli remains to be established. Recent progress in studies of the molecular mechanisms of pathogenesis of infection in the human respiratory tract and in vaccine development guided by such studies promises to lead to novel ways to treat and prevent bacterial infections in COPD.

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Abstract 325: The Regulation of Endothelial Function Through Hmgcr/mevalonate Pathway Mediated Yap Activity

Circulation Research ◽

10.1161/res.127.suppl_1.325 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Chun Liu ◽

Yu Liu ◽

Christopher Chen ◽

Mo Ameen ◽

Huaxiao Yang ◽

...

Keyword(s):

Endothelial Cells ◽

Molecular Mechanisms ◽

Vascular System ◽

The United States ◽

Binding Motif ◽

Sequencing Analysis ◽

Cholesterol Lowering ◽

Mesenchymal Transition ◽

Endothelial Functions

Background: Cardiovascular diseases (CVD) are the leading cause of death in the United States. Statins, a class of hydroxy-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, have been proven to be effectively prevent and treat CVD by improving vascular functions independent of their cholesterol-lowering effect. However, the molecular mechanisms by which statins improve cardiovascular functions remain elusive. In this study, we used human induced pluripotent stem cells-derived endothelial cells (hiPSC-ECs) to explore the protective role of statins in the vascular system. Methods and Results: hiPSCs were generated from 3 healthy individuals and differentiated into endothelial cells using two different iPSC clones and two batches (4 biological replicates for each individual). hiPSC-ECs of each individual were treated with simvastatin or a vehicle control. The RNA-sequencing analysis was performed on 12 control and 12 statin-treated hiPSC-ECs. A total number of 2,580 differentially expressed genes (DEGs) were found in simvastatin-treated hiPSC-ECs. Gene enrichment analysis revealed that statin-upregulated DEGs were highly enriched in angiogenesis and anti-inflammation pathways. Interestingly, statin-downregulated DEGs were significantly enriched in epigenetic regulation and nucleosome assembly pathways, suggesting an epigenetic regulatory role of stains in vascular gene expression. To test this hypothesis, we further performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analysis on vehicle or simvastatin treated hiPSC-ECs. Transcription factor (TF) binding motif analyses of ATAC-seq peaks using HOMER revealed that YAP/TEAD binding was the most significantly downregulated TF after statin treatment. Furthermore, we observed that statin can improve endothelial functions (e.g., angiogenesis and nitric oxide production) after the YAP activity was inhibited. The ChIP-seq analysis showed that statin downregulated the expression levels of genes associated with the endothelial-to-mesenchymal transition (EndoMT) by attenuating the binding capacity of YAP. As such, simvastatin effectively rescued diabetic vascular dysfunction mainly through inhibiting EndoMT. Conclusion: We found that statins can improve endothelial functions through attenuating the chromatin accessibility of EndoMT-related genes, a process tightly regulated by the activity of YAP. These findings will provide novel insights into the protective mechanisms of statins in the cardiovascular system beyond their cholesterol-lowering effects.

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Spillover Effect of Consumer Awareness on Third Parties’ Selling Strategies and Retailers’ Platform Openness

Information Systems Research ◽

10.1287/isre.2020.0952 ◽

2020 ◽

Author(s):

Wen Song ◽

Jianqing Chen ◽

Wenli Li

Keyword(s):

Spillover Effect ◽

The United States ◽

Third Party ◽

Interesting Phenomenon ◽

The Third ◽

The Past ◽

Online Retailers ◽

The Third Party ◽

Selling Strategies

Global e-commerce sales have experienced unprecedented growth for the past years and have reached over $2 trillion annually. One interesting phenomenon along with this remarkable growth is that giant online retailers, such as Amazon.com in the United States and JD.com in China, open their platforms and allow third-party sellers to offer products there, thus inviting competition. We explore why an online retailer would open its platform and why a third-party seller would join the platform. We highlight the role of a spillover effect that, when the third-party seller joins the retailer’s platform, more consumers become aware of the third-party seller’s existence and its products which are not even listed on the retailer’s platform. We characterize how the third-party seller’s optimal selling strategies should vary with and how the retailer’s openness decision should be determined by the extent of the spillover effect and the retailer’s initial awareness advantage. Compared with the case without a spillover effect, the spillover effect makes the retailer less likely to open its platform, but it makes the third-party seller more likely to sell identical products on an open retailer platform; the spillover effect always (weakly) benefits the third-party seller, but it does not necessarily hurt the retailer.

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Protein S Protects against Podocyte Injury in Diabetic Nephropathy

Journal of the American Society of Nephrology ◽

10.1681/asn.2017030234 ◽

2018 ◽

Vol 29 (5) ◽

pp. 1397-1410 ◽

Cited By ~ 11

Author(s):

Fang Zhong ◽

Haibing Chen ◽

Yifan Xie ◽

Evren U. Azeloglu ◽

Chengguo Wei ◽

...

Keyword(s):

Diabetic Nephropathy ◽

High Glucose ◽

Molecular Mechanisms ◽

Protein S ◽

The United States ◽

Global Changes ◽

Glomerular Injury ◽

Proinflammatory Mediators

Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear.Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors. Because increased activation of Axl by the PS homolog Gas6 has been implicated in DN progression, we further examined the role of PS in DN.Results In human kidneys, glomerular PS expression was elevated in early DN but suppressed in advanced DN. However, plasma PS concentrations did not differ between patients with DN and healthy controls. A prominent increase of PS expression also colocalized with the expression of podocyte markers in early diabetic kidneys. In cultured podocytes, high-glucose treatment elevated PS expression, and PS knockdown further enhanced the high-glucose–induced apoptosis. Conversely, PS overexpression in cultured podocytes dampened the high-glucose– and TNF-α–induced expression of proinflammatory mediators. Tyro3 receptor was upregulated in response to high glucose and mediated the anti-inflammatory response of PS. Podocyte-specific PS loss resulted in accelerated DN in streptozotocin-induced diabetic mice, whereas the transient induction of PS expression in glomerular cells in vivo attenuated albuminuria and podocyte loss in diabetic OVE26 mice.Conclusions Our results support a protective role of PS against glomerular injury in DN progression.

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