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International Journal of Molecular... May 2024Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.
Topics: Humans; Amyotrophic Lateral Sclerosis; Male; Female; Middle Aged; Aged; Islet Amyloid Polypeptide; Cross-Sectional Studies; Biomarkers; Insulin; Disease Progression; Leptin; Glucagon-Like Peptide 1; C-Peptide; Ghrelin; Glucagon; Adult; Hormones
PubMed: 38791099
DOI: 10.3390/ijms25105059 -
JGH Open : An Open Access Journal of... May 2024The luminal environment is rich in macronutrients coming from our diet and resident microbial populations including their metabolites. Together, they have the capacity... (Review)
Review
The luminal environment is rich in macronutrients coming from our diet and resident microbial populations including their metabolites. Together, they have the capacity to modulate unique cell surface receptors, known as G-protein coupled receptors (GPCRs). Along the entire length of the gut epithelium, enteroendocrine cells express GPCRs to interact with luminal contents, such as GPR93 and the calcium sensing receptor to sense proteins, FFA2 and GPR84 to sense fatty acids, and SGLT1 and T1R to sense carbohydrates. Nutrient-receptor interaction causes the release of hormonal stores such as glucagon-like peptide 1, peptide YY, and cholecystokinin, which further regulate gut function. Existing data show the role of luminal components and microbial fermentation products on gut function. However, there is a lack of understanding in the mechanistic interactions between diet-derived luminal components and microbial products and nutrient-sensing receptors and downstream gastrointestinal modulation. This review summarizes current knowledge on various luminal components and describes in detail the range of nutrients and metabolites and their interaction with nutrient receptors in the gut epithelium and the emerging impact on immune cells.
PubMed: 38779131
DOI: 10.1002/jgh3.13083 -
Frontiers in Pharmacology 2024Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night.... (Review)
Review
Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.
PubMed: 38725663
DOI: 10.3389/fphar.2024.1372399 -
ACS Sensors May 2024In this work, we present the development of the first implantable aptamer-based platinum microelectrode for continuous measurement of a nonelectroactive molecule,...
In this work, we present the development of the first implantable aptamer-based platinum microelectrode for continuous measurement of a nonelectroactive molecule, neuropeptide Y (NPY). The aptamer immobilization was performed via conjugation chemistry and characterized using cyclic voltammetry before and after the surface modification. The redox label, methylene blue (MB), was attached at the end of the aptamer sequence and characterized using square wave voltammetry (SWV). NPY standard solutions in a three-electrode cell were used to test three aptamers in steady-state measurement using SWV for optimization. The aptamer with the best performance in the steady-state measurements was chosen, and continuous measurements were performed in a flow cell system using intermittent pulse amperometry. Dynamic measurements were compared against confounding and similar peptides such as pancreatic polypeptide and peptide YY, as well as somatostatin to determine the selectivity in the same modified microelectrode. Our Pt-microelectrode aptamer-based NPY biosensor provides signals 10 times higher for NPY compared to the confounding molecules. This proof-of-concept shows the first potential implantable microelectrode that is selectively sensitive to NPY concentration changes.
Topics: Neuropeptide Y; Microelectrodes; Biosensing Techniques; Platinum; Aptamers, Nucleotide; Electrochemical Techniques
PubMed: 38709872
DOI: 10.1021/acssensors.4c00449 -
Nature Communications Apr 2024Amino acid availability is monitored by animals to adapt to their nutritional environment. Beyond gustatory receptors and systemic amino acid sensors, enteroendocrine...
Amino acid availability is monitored by animals to adapt to their nutritional environment. Beyond gustatory receptors and systemic amino acid sensors, enteroendocrine cells (EECs) are believed to directly percept dietary amino acids and secrete regulatory peptides. However, the cellular machinery underlying amino acid-sensing by EECs and how EEC-derived hormones modulate feeding behavior remain elusive. Here, by developing tools to specifically manipulate EECs, we find that Drosophila neuropeptide F (NPF) from mated female EECs inhibits feeding, similar to human PYY. Mechanistically, dietary L-Glutamate acts through the metabotropic glutamate receptor mGluR to decelerate calcium oscillations in EECs, thereby causing reduced NPF secretion via dense-core vesicles. Furthermore, two dopaminergic enteric neurons expressing NPFR perceive EEC-derived NPF and relay an anorexigenic signal to the brain. Thus, our findings provide mechanistic insights into how EECs assess food quality and identify a conserved mode of action that explains how gut NPF/PYY modulates food intake.
Topics: Animals; Enteroendocrine Cells; Female; Neuropeptides; Eating; Peptide YY; Glutamic Acid; Drosophila Proteins; Drosophila melanogaster; Feeding Behavior; Receptors, Metabotropic Glutamate; Dopaminergic Neurons; Diet
PubMed: 38664401
DOI: 10.1038/s41467-024-47465-4 -
Appetite Jul 2024This was a preliminary study that examined whether appetite regulation is altered during the menstrual cycle or with oral contraceptives. Ten naturally cycling females...
This was a preliminary study that examined whether appetite regulation is altered during the menstrual cycle or with oral contraceptives. Ten naturally cycling females (NON-USERS) and nine tri-phasic oral contraceptive using females (USERS) completed experimental sessions during each menstrual phase (follicular phase: FP; ovulatory phase: OP; luteal phase: LP). Appetite perceptions and blood samples were obtained fasted, 30, 60, and 90 min post-prandial to measure acylated ghrelin, active glucagon-like peptide-1 (GLP-1), and total peptide tyrosine tyrosine (PYY). Changes were considered important if p < 0.100 and the effect size was ≥medium. There appeared to be a three-way (group x phase x time) interaction for acylated ghrelin where concentrations appeared to be greater in USERS versus NON-USERS during the OP 90-min post-prandial and during the LP fasted, and 90-min post-prandial. In USERS, ghrelin appeared to be greater 90-min post-prandial in the OP versus the FP with no other apparent differences between phases. There were no apparent differences between phases in NON-USERS. There appeared to be a three-way interaction for PYY where concentrations appeared to be greater in USERS during the FP 60-min post-prandial and during the OP 30-min post-prandial. In USERS PYY appeared to be greater 60-min post-prandial during the OP versus the LP with no other apparent differences. There were no apparent differences between phases in NON-USERS. There appeared to be no effect of group or phase on GLP-1, or appetite perceptions. These data demonstrate small effects of menstrual cycle phase and oral contraceptive use on the acylated ghrelin and total PYY response to a standardized meal, with no effects on active GLP-1 or perceived appetite, though more work with a large sample size is necessary.
Topics: Humans; Female; Ghrelin; Glucagon-Like Peptide 1; Postprandial Period; Peptide YY; Menstrual Cycle; Young Adult; Adult; Contraceptives, Oral; Appetite; Appetite Regulation; Adolescent; Fasting; Acylation
PubMed: 38636667
DOI: 10.1016/j.appet.2024.107362 -
ELife Apr 2024Revealing protein binding sites with other molecules, such as nucleic acids, peptides, or small ligands, sheds light on disease mechanism elucidation and novel drug...
Revealing protein binding sites with other molecules, such as nucleic acids, peptides, or small ligands, sheds light on disease mechanism elucidation and novel drug design. With the explosive growth of proteins in sequence databases, how to accurately and efficiently identify these binding sites from sequences becomes essential. However, current methods mostly rely on expensive multiple sequence alignments or experimental protein structures, limiting their genome-scale applications. Besides, these methods haven't fully explored the geometry of the protein structures. Here, we propose GPSite, a multi-task network for simultaneously predicting binding residues of DNA, RNA, peptide, protein, ATP, HEM, and metal ions on proteins. GPSite was trained on informative sequence embeddings and predicted structures from protein language models, while comprehensively extracting residual and relational geometric contexts in an end-to-end manner. Experiments demonstrate that GPSite substantially surpasses state-of-the-art sequence-based and structure-based approaches on various benchmark datasets, even when the structures are not well-predicted. The low computational cost of GPSite enables rapid genome-scale binding residue annotations for over 568,000 sequences, providing opportunities to unveil unexplored associations of binding sites with molecular functions, biological processes, and genetic variants. The GPSite webserver and annotation database can be freely accessed at https://bio-web1.nscc-gz.cn/app/GPSite.
Topics: Protein Binding; Deep Learning; Proteins; Binding Sites; Peptides
PubMed: 38630609
DOI: 10.7554/eLife.93695 -
Frontiers in Veterinary Science 2024This study conducted a comparison of the effects of non-protein nitrogen with different acid-base properties on feed intake, rumen fermentation, nutrient digestion and...
This study conducted a comparison of the effects of non-protein nitrogen with different acid-base properties on feed intake, rumen fermentation, nutrient digestion and antioxidant capacity in fattening Hu sheep. Sixteen fattening male sheep (31.43 ± 2.41 kg) with permanent rumen cannulas were randomly assigned to two dietary treatments: 1% urea and 1.78% ammonium chloride (NHCl, AC). A 42 days experimental period was conducted, with 14 days for adaptation and 28 days for treatment. Daily feed intake was recorded and various samples including feed, feces, rumen fluid, and blood were collected at different time points during the final week. The results indicated that the urea group had significantly higher dry matter intake, average daily gain, and gain efficiency in comparison to the AC group ( < 0.01). There was no difference in rumen pH and concentration of ammonia nitrogen between different groups ( > 0.05), but the rumen pH of urea group was higher than that of the AC group at 1 and 3 h after feeding ( < 0.05). The urea group exhibited higher concentrations of total volatile fatty acids (VFA) and individual VFAs compared to the AC group at all-time points ( < 0.01). Compared to the urea group, the intake of all nutrients decreased in the AC group ( < 0.01), but the digestibility of dry matter and organic matter increased significantly ( < 0.01), and the digestibility of CP had an increasing trend ( = 0.06) in the AC group. Additionally, the urea group had lower levels of serum glucagon-like peptide-1, peptide YY, Cl, total protein and globulin than the AC group ( < 0.05). The overall levels of HCO, superoxide dismutase, glutathione peroxidase, catalase, albumin/globulin, blood urea nitrogen and total cholesterol in the urea group increased significantly compared to the AC group ( < 0.05). It was concluded that adding urea to the high-concentrate diet resulted in increased rumen pH and improved rumen fermentation and growth performance in fattening sheep compared to NHCl addition. Furthermore, urea addition improved sheep's antioxidant capacity and maintained their acid-base balance more effectively as compared to NHCl.
PubMed: 38596467
DOI: 10.3389/fvets.2024.1381871 -
Neuropeptides Jun 2024Obesity is a critical health condition worldwide that increases the risks of comorbid chronic diseases, but it can be managed with weight loss. However, conventional... (Review)
Review
Obesity is a critical health condition worldwide that increases the risks of comorbid chronic diseases, but it can be managed with weight loss. However, conventional interventions relying on diet and exercise are inadequate for achieving and maintaining weight loss, thus there is significant market interest for pharmaceutical anti-obesity agents. For decades, receptor agonists for the gut peptide glucagon-like peptide 1 (GLP-1) featured prominently in anti-obesity medications by suppressing appetite and food reward to elicit rapid weight loss. As the neurocircuitry underlying food motivation overlaps with that for drugs of abuse, GLP-1 receptor agonism has also been shown to decrease substance use and relapse, thus its therapeutic potential may extend beyond weight management to treat addictions. However, as prolonged use of anti-obesity drugs may increase the risk of mood-related disorders like anxiety and depression, and individuals taking GLP-1-based medication commonly report feeling demotivated, the long-term safety of such drugs is an ongoing concern. Interestingly, current research now focuses on dual agonist approaches that include GLP-1 receptor agonism to enable synergistic effects on weight loss or associated functions. GLP-1 is secreted from the same intestinal cells as the anorectic gut peptide, Peptide YY (PYY), thus this review assessed the therapeutic potential and underlying neural circuits targeted by PYY when administered independently or in combination with GLP-1 to curb the appetite for food or drugs of abuse like opiates, alcohol, and nicotine. Additionally, we also reviewed animal and human studies to assess the impact, if any, for GLP-1 and/or PYY on mood-related behaviors in relation to anxiety and depression. As dual agonists targeting GLP-1 and PYY may produce synergistic effects, they can be effective at lower doses and offer an alternative approach for therapeutic benefits while mitigating undesirable side effects.
Topics: Humans; Animals; Peptide YY; Glucagon-Like Peptide 1; Anxiety; Peptide Fragments; Drug-Seeking Behavior; Obesity; Brain
PubMed: 38579490
DOI: 10.1016/j.npep.2024.102427 -
Peptides Jun 2024It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve...
It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.
Topics: Humans; Diabetes Mellitus, Type 2; Gastrectomy; Gastric Bypass; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Insulin; Peptide YY; Weight Loss
PubMed: 38552903
DOI: 10.1016/j.peptides.2024.171199