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Molecular Metabolism Jun 2024Interleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated...
OBJECTIVE
Interleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease due to its involvement in multiple cellular pathways and observed hepatoprotective effects. The short serum half-life of IL-22 has previously limited its use in clinical applications; however, the development of mRNA-lipid nanoparticle (LNP) technology offers a novel therapeutic approach that uses a host-generated IL-22 fusion protein. In the present study, the effects of administration of an mRNA-LNP encoding IL-22 on metabolic disease parameters was investigated in various mouse models.
METHODS
C57BL/6NCrl mice were used to confirm mouse serum albumin (MSA)-IL-22 protein expression prior to assessments in C57BL/6NTac and CETP/ApoB transgenic mouse models of metabolic disease. Mice were fed either regular chow or a modified amylin liver nonalcoholic steatohepatitis-inducing diet prior to receiving either LNP-encapsulated MSA-IL-22 or MSA mRNA via intravenous or intramuscular injection. Metabolic markers were monitored for the duration of the experiments, and postmortem histology assessment and analysis of metabolic gene expression pathways were performed.
RESULTS
MSA-IL-22 was detectable for ≥8 days following administration. Improvements in body weight, lipid metabolism, glucose metabolism, and lipogenic and fibrotic marker gene expression in the liver were observed in the MSA-IL-22-treated mice, and these effects were shown to be durable.
CONCLUSIONS
These results support the application of mRNA-encoded IL-22 as a promising treatment strategy for metabolic syndrome and associated comorbidities in human populations.
PubMed: 38871178
DOI: 10.1016/j.molmet.2024.101965 -
American Journal of Physiology.... Jun 2024Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects...
Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, glucose control, and insulin action. However, how the metabolic benefits are maintained after long-lasting treatment is unknown. This study investigates the long-term anti-obesity and anti-diabetic treatment efficacy of the DACRA KBP-336 alone and combined with the GLP-1 analog semaglutide. Zucker diabetic Sprague Dawley (ZDSD) rats with obesity and diabetes received KBP-336 (4.5 nmol/kg Q3D), semaglutide (50 nmol/kg Q3D), or the combination for 7 months, and the treatment impact on body weight, food intake, glucose control, and insulin action was evaluated. Furthermore, serum levels of the cardiac fibrosis biomarker endotrophin were evaluated. KBP-336, semaglutide and the combination lowered body weight significantly compared to the vehicle, with the combination inducing a larger and more sustained weight loss than either monotherapy. All treatments resulted in reduced fasting blood glucose levels and HbA1c levels, and improved glucose tolerance compared to vehicle-treated rats. Further, all treatments protected against lost insulin secretory capacity and improved insulin action. Serum levels of endotrophin were significantly lowered by KBP-336 compared to vehicle. This study shows the benefit of combining KBP-336 and semaglutide to obtain significant and sustained weight loss and improved glucose control. Further, KBP-336-driven reductions in circulating endotrophin indicate a clear reduction in the risk of complications. Altogether, KBP-336 is a promising candidate for the treatment of obesity and type 2 diabetes both alone and in combination with GLP-1 analogs.
PubMed: 38864815
DOI: 10.1152/ajpendo.00092.2024 -
Anatomia, Histologia, Embryologia Jul 2024In this study, we investigated amylin-like substance distribution in the pancreas of Japanese quail (Coturnix japonica) using a specific anti-rat amylin serum. We...
In this study, we investigated amylin-like substance distribution in the pancreas of Japanese quail (Coturnix japonica) using a specific anti-rat amylin serum. We detected amylin-immunoreactive cells dispersed in the pancreatic extra-islet region but not in the islet region. The synthetic rat amylin-containing serum pre-absorption abolished the staining profile. Almost all amylin-immunoreactive cells were immuno-positive for peptide YY (PYY). In addition, certain amylin-immunoreactive cells stained immuno-positive for glucagon. Amylin and PYY co-secreted from the extra-islet cells might participate in the insulin and glucagon release regulation in the pancreas and food intake modulation through the central nervous system.
Topics: Animals; Peptide YY; Islet Amyloid Polypeptide; Coturnix; Glucagon; Pancreas; Immunohistochemistry; Islets of Langerhans; Male; Rats
PubMed: 38864153
DOI: 10.1111/ahe.13074 -
British Journal of Pharmacology Jun 2024Only limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH). Glabridin, a promising anti-obesity candidate, has only limited...
BACKGROUND AND PURPOSE
Only limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH). Glabridin, a promising anti-obesity candidate, has only limited druggability due to its low in vivo chemical stability and bioavailability. Therefore, we developed vutiglabridin (VUTI), which is based on a glabridin backbone, and investigated its mechanism of action in treating NASH in animal models.
EXPERIMENTAL APPROACH
Anti-NASH effects of VUTI were determined in in vitro fatty liver models, spheroids of primary human hepatocytes and L02 normal liver cell lines. To identify VUTI possible cellular target/s, biotin-labelled VUTI was synthesized and underwent chemical proteomic analysis. Further, the evaluation of VUTI therapeutic efficacy was carried out using an amylin-NASH and high-fat (HF) diet-induced obese (DIO) mouse models. This was carried out using transcriptomic, lipidomic and proteomic analyses of the livers from the amylin-NASH mouse model.
KEY RESULTS
VUTI treatment markedly reduces hepatic steatosis, fibrosis and inflammation by promoting lipid catabolism, activating autophagy and improving mitochondrial dysfunction, all of which are hallmarks of effective NASH treatment. The cellular target of VUTI was identified as paraoxonase 2 (PON2), a newly proposed protein target for the treatment of NASH, VUTI enhanced PON2 activity. The results using PON2 knockdown cells demonstrated that PON2 is important for VUTI- activation of autophagy, promoting mitochondrial function, decreasing oxidative stress and alleviating lipid accumulation under lipotoxic condition.
CONCLUSION AND IMPLICATIONS
Our data demonstrated that VUTI is a promising therapeutic for NASH. Targeting PON2 may be important for improving liver function in various immune-metabolic diseases including NASH.
PubMed: 38852992
DOI: 10.1111/bph.16438 -
Small (Weinheim An Der Bergstrasse,... Jun 2024Accurate construction of artificial nano-chaperones' structure is crucial for precise regulation of protein conformational transformation, facilitating effective...
Accurate construction of artificial nano-chaperones' structure is crucial for precise regulation of protein conformational transformation, facilitating effective treatment of proteopathy. However, how the ligand-anchors of nano-chaperones affect the spatial conformational changes in proteins remains unclear, limiting the development of efficient nano-chaperones. In this study, three types of gold nanoparticles (AuNPs) with different core/ligands interface anchor structures (Au─NH─R, Au─S─R, and Au─C≡C─R, R = benzoic acid) are synthesized as an ideal model to investigate the effect of interfacial anchors on Aβ and amylin fibrillization. Computational results revealed that the distinct interfacial anchors imparted diverse distributions of electrostatic potential on the nanointerface and core/ligands bond strength of AuNPs, leading to differential interactions with amyloid peptides. Experimental results demonstrated that all three types of AuNPs exhibit site-specific inhibitory effects on Aβ fibrillization due to preferential binding. For amylin, amino-anchored AuNPs demonstrate strong adsorption to multiple sites on amylin and effectively inhibit fibrillization. Conversely, thiol- and alkyne-anchored AuNPs adsorb at the head region of amylin, promoting folding and fibrillization. This study not only provided molecular insights into how core/ligands interfacial anchors of nanomaterials induce spatial conformational changes in amyloid peptides but also offered guidance for precisely engineering artificial-chaperones' nanointerfaces to regulate the conformational transformation of proteins.
PubMed: 38829034
DOI: 10.1002/smll.202312046 -
ENeuro Jun 2024Amylin, a pancreatic hormone that is cosecreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely...
Amylin, a pancreatic hormone that is cosecreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely throughout the brain and are coexpressed on mesolimbic dopamine neurons. Activation of amylin receptors is known to reduce food intake, but the neurochemical mechanisms behind this remain to be elucidated. Amylin receptor activation in the ventral tegmental area (VTA), a key dopaminergic nucleus in the mesolimbic reward system, has a potent ability to suppress intake of palatable fat and sugar solutions. Although previous work has demonstrated that VTA amylin receptor activation can dampen mesolimbic dopamine signaling elicited by random delivery of sucrose, whether this is also the case for fat remains unknown. Herein we tested the hypothesis that amylin receptor activation in the VTA of male rats would attenuate dopamine signaling in the nucleus accumbens core in response to random intraoral delivery of either fat or sugar solutions. Results show that fat solution produces a greater potentiation of accumbens dopamine than an isocaloric sucrose solution. Moreover, activation of VTA amylin receptors elicits a more robust suppression of accumbens dopamine signaling in response to fat solution than to sucrose. Taken together these results shed new light on the amylin system as a therapeutic target for obesity and emphasize the reinforcing nature of high-fat/high-sugar diets.
Topics: Animals; Ventral Tegmental Area; Male; Dopamine; Nucleus Accumbens; Receptors, Islet Amyloid Polypeptide; Rats, Sprague-Dawley; Dietary Fats; Signal Transduction; Amylin Receptor Agonists; Rats; Sucrose
PubMed: 38806231
DOI: 10.1523/ENEURO.0133-24.2024 -
Biomedicine & Pharmacotherapy =... Jul 2024Type 1 diabetes (T1D) is a chronic autoimmune condition that affects millions of people worldwide. Insulin pumps or injections are the standard treatment options for... (Review)
Review
Type 1 diabetes (T1D) is a chronic autoimmune condition that affects millions of people worldwide. Insulin pumps or injections are the standard treatment options for this condition. This article provides a comprehensive overview of the several type 1 diabetes treatment options, focusing on oral insulin. The article is divided into parts that include immune-focused treatments, antigen vaccination, cell-directed interventions, cytokine-directed interventions, and non-immunomodulatory adjuvant therapy. Under the section on non-immunomodulatory adjunctive treatment, the benefits and drawbacks of medications such as metformin, amylin, sodium-glucose cotransporter inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 Ras), and verapamil are discussed. The article also discusses the advantages of oral insulin, including increased patient compliance and more dependable and regular blood sugar control. However, several variables, including the enzymatic and physical barriers of the digestive system, impair the administration of insulin via the mouth. Researchers have looked at a few ways to get over these challenges, such as changing the structure of the insulin molecule, improving absorption with the use of absorption enhancers or nanoparticles, and taking oral insulin together with other medications. Even with great advancements in the use of these treatment strategies, T1D still needs improvement in the therapeutic difficulties. Future studies in these areas should focus on creating tailored immunological treatments, looking into combination medications, and refining oral insulin formulations in an attempt to better control Type 1 Diabetes. The ultimate objective is to create accurate, customized strategies that will enhance glycemic management and the quality of life for individuals with the condition.
Topics: Humans; Diabetes Mellitus, Type 1; Insulin; Administration, Oral; Hypoglycemic Agents; Animals
PubMed: 38805967
DOI: 10.1016/j.biopha.2024.116808 -
Cell Biochemistry and Biophysics May 2024The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aβ), α-synuclein, mutant Huntingtin Protein (mHTT) and...
The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aβ), α-synuclein, mutant Huntingtin Protein (mHTT) and islet amyloid polypeptide (IAPP) among others are associated with disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Type 2 Diabetes (T2D), respectively. The dissolution of mature fibrils and toxic amyloidogenic intermediates, including oligomers, continues to be the pinnacle in the treatment of neurodegenerative disorders. Yet, methods to effectively and quantitatively report on the interconversion between amyloid monomers, oligomers and mature fibrils fall short. Here we describe a simplified method that implements the use of gel electrophoresis to address the transformation between soluble monomeric amyloid proteins and mature amyloid fibrils. The technique implements an optimized but well-known, simple, inexpensive, and quantitative assessment previously used to assess the oligomerization of amyloid monomers and subsequent amyloid fibrils. This method facilitates the screening of small molecules that disintegrate oligomers and fibrils into monomers, dimers, and trimers and/or retain amyloid proteins in their monomeric forms. Most importantly, our optimized method diminishes existing barriers associated with existing (alternative) techniques to evaluate fibril formation and intervention.
PubMed: 38802601
DOI: 10.1007/s12013-024-01293-x -
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