msi-1436 and Inflammation

msi-1436 has been researched along with Inflammation* in 2 studies

Other Studies

2 other study(ies) available for msi-1436 and Inflammation

ArticleYear
The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses.
    Frontiers in endocrinology, 2023, Volume: 14

    Equine metabolic syndrome (EMS) is a multifactorial pathology gathering insulin resistance, low-grade inflammation and past or chronic laminitis. Among the several molecular mechanisms underlying EMS pathogenesis, increased negative insulin signalling regulation mediated by protein tyrosine phosphatase 1 B (PTP1B) has emerged as a critical axis in the development of liver insulin resistance and general metabolic distress associated to increased ER stress, inflammation and disrupted autophagy. Thus, the use of PTP1B selective inhibitors such as MSI-1436 might be considered as a golden therapeutic tool for the proper management of EMS and associated conditions. Therefore, the present investigation aimed at verifying the clinical efficacy of MSI-1436 systemic administration on liver metabolic balance, insulin sensitivity and inflammatory status in EMS affected horses. Moreover, the impact of MSI-1436 treatment on liver autophagy machinery and associated ER stress in liver tissue has been analysed.. Liver explants isolated from healthy and EMS horses have been treated with MSI-1436 prior to gene and protein expression analysis of main markers mediating ER stress, mitophagy and autophagy. Furthermore, EMS horses have been intravenously treated with a single dose of MSI-1436, and evaluated for their metabolic and inflammatory status.. Clinical application of MSI-1436 to EMS horses restored proper adiponectin levels and attenuated the typical hyperinsulinemia and hyperglycemia. Moreover, administration of MSI-1436 further reduced the circulating levels of key pro-inflammatory mediators including IL-1β, TNF-α and TGF-β and triggered the Tregs cells activation. At the molecular level, PTP1B inhibition resulted in a noticeable mitigation of liver ER stress, improvement of mitochondrial dynamics and consequently, a regulation of autophagic response. Similarly, short-term ex vivo treatment of EMS liver explants with trodusquemine (MSI-1436) substantially enhanced autophagy by upregulating the levels of HSC70 and Beclin-1 at both mRNA and protein level. Moreover, the PTP1B inhibitor potentiated mitophagy and associated expression of MFN2 and PINK1. Interestingly, inhibition of PTP1B resulted in potent attenuation of ER stress key mediators' expression namely, CHOP, ATF6, HSPA5 and XBP1.. Presented findings shed for the first time promising new insights in the development of an MSI-1436-based therapy for proper equine metabolic syndrome intervention and may additionally find potential translational application to human metabolic syndrome treatment.

    Topics: Animals; Autophagy; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Horses; Humans; Inflammation; Insulin Resistance; Liver; Metabolic Syndrome

2023
Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid β-Associated Alzheimer's Disease in Mice.
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020, 02-12, Volume: 40, Issue:7

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, resulting in the progressive decline of cognitive function in patients. Familial forms of AD are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Inflammation and amyloidosis from amyloid β (Aβ) aggregates are implicated in neuron loss and cognitive decline. Inflammation activates the protein-tyrosine phosphatase 1B (PTP1B), and this could suppress many signaling pathways that activate glycogen synthase kinase 3β (GSK3β) implicated in neurodegeneration. However, the significance of PTP1B in AD pathology remains unclear. Here, we show that pharmacological inhibition of PTP1B with trodusquemine or selective ablation of PTP1B in neurons prevents hippocampal neuron loss and spatial memory deficits in a transgenic AD mouse model with Aβ pathology (hAPP-J20 mice of both sexes). Intriguingly, while systemic inhibition of PTP1B reduced inflammation in the hippocampus, neuronal PTP1B ablation did not. These results dissociate inflammation from neuronal loss and cognitive decline and demonstrate that neuronal PTP1B hastens neurodegeneration and cognitive decline in this model of AD. The protective effect of PTP1B inhibition or ablation coincides with the restoration of GSK3β inhibition. Neuronal ablation of PTP1B did not affect cerebral amyloid levels or plaque numbers, but reduced Aβ plaque size in the hippocampus. In summary, our preclinical study suggests that targeting PTP1B may be a new strategy to intervene in the progression of AD.

    Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholestanes; Disease Models, Animal; Female; Glycogen Synthase Kinase 3 beta; Hippocampus; Humans; Inflammation; Insulin Resistance; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Peptide Fragments; Plaque, Amyloid; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Recombinant Proteins; Spatial Memory; Spermine

2020