The PTP1B selective inhibitor MSI-1436 mitigates Tunicamycin-induced ER stress in human hepatocarcinoma cell line through XBP1 splicing modulation

Bourebaba, Lynda; Komakula, Sai Santosh Babu; Weiß, Christine; Adrar, Nabil; Marycz, Krzysztof

doi:10.1371/journal.pone.0278566

Cited by 3 publications

(4 citation statements)

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“…Noteworthy, incubation of EMS liver explants with MSI-1436 resulted in a further decreased expression of total XBP1 mRNA and spliced XBP1 level. This outcome is in agreement with our recently published data, showing the ability of MSI-1436 to blockade XBP1 splicing in a model pf tunicamycin-indued ER stress in HepG2 cell line ( 77 ). These findings additionally suggest that the mechanisms underlying XBP1 functional outputs under metabolic ER stress differ from other proteostatic perturbators and seemingly encompass more intricate and interconnected molecular events, and the implication of unrelated external influences leading to either increased or decreased IRE1α-XBP1 axis activation ( 78 ).…”

Section: Discussionsupporting

confidence: 93%

The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses

et al. 2023

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BackgroundEquine 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.MethodsLiver 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.ResultsClinical 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. ConclusionPresented 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.

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Section: Discussionsupporting

confidence: 93%

The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses

et al. 2023

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“…Previous studies have shown that the deletion of PTP1B in mice also improves mitochondrial integrity by suppressing ER stressmediated overexpression of Pink1 and Parkin, supporting the therapeutic potential of PTP1B inhibitors for the restoration or enhancement of mitochondrial biogenesis [98]. Another study showed induction of PINK1 and a reduction in PARKIN levels after MSI-1436 pretreatment in a human hepatocarcinoma cell line [5]. However, this contradiction with our results could be attributed to a cell type-dependent effect.…”

Section: Discussioncontrasting

confidence: 89%

“…Hepatocytes are the primary cell type in the liver, constituting up to 80% of all hepatic cells. These cells perform diverse functions, including the detoxification of metabolites, regulation of glucose and lipid metabolism, synthesis of serum proteins, and secretion of bile [3][4][5][6]. Non-alcoholic fatty liver disease (NAFLD), a prevalent chronic liver disorder, is characterized by abnormal accumulation of triglycerides and other lipids in the liver.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, it enhances the survival of hepatocellular carcinoma cell lines exposed to stressed conditions induced by palmitate/oleate. This protective effect is achieved by reducing lipoapoptosis, improving mitochondrial dynamics, and attenuating oxidative and endoplasmic reticulum stress [5,26]. Additionally, MSI-1436 has been shown to enhance the differentiation of adipose-derived progenitor stem cells from EMS by modulating endoplasmic reticulum stress, apoptosis, and oxidative stress [29].…”

Section: Introductionmentioning

confidence: 99%

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Trodusquemine (MSI-1436) Restores Metabolic Flexibility and Mitochondrial Dynamics in Insulin-Resistant Equine Hepatic Progenitor Cells (HPCs)

Qasem,

Dąbrowska,

Króliczewski

et al. 2024

Cells

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Equine metabolic syndrome (EMS) is a significant global health concern in veterinary medicine. There is increasing interest in utilizing molecular agents to modulate hepatocyte function for potential clinical applications. Recent studies have shown promising results in inhibiting protein tyrosine phosphatase (PTP1B) to maintain cell function in various models. In this study, we investigated the effects of the inhibitor Trodusquemine (MSI-1436) on equine hepatic progenitor cells (HPCs) under lipotoxic conditions. We examined proliferative activity, glucose uptake, and mitochondrial morphogenesis. Our study found that MSI-1436 promotes HPC entry into the cell cycle and protects them from palmitate-induced apoptosis by regulating mitochondrial dynamics and biogenesis. MSI-1436 also increases glucose uptake and protects HPCs from palmitate-induced stress by reorganizing the cells’ morphological architecture. Furthermore, our findings suggest that MSI-1436 enhances 2-NBDG uptake by increasing the expression of SIRT1, which is associated with liver insulin sensitivity. It also promotes mitochondrial dynamics by modulating mitochondria quantity and morphotype as well as increasing the expression of PINK1, MFN1, and MFN2. Our study provides evidence that MSI-1436 has a positive impact on equine hepatic progenitor cells, indicating its potential therapeutic value in treating EMS and insulin dysregulation.

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Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine

Maccari

Ottanà

2023

IJMS

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Protein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic events, thus providing a useful tool for the discovery of novel therapeutic agents. The search for allosteric PTP1B inhibitors can represent a successful strategy to identify drug-like candidates by offering the opportunity to overcome some issues related to catalytic site-directed inhibitors, which have so far hampered the development of drugs targeting this enzyme. In this context, trodusquemine (MSI-1436), a natural aminosterol that acts as a non-competitive PTP1B inhibitor, appears to be a milestone. Initially discovered as a broad-spectrum antimicrobial agent, trodusquemine exhibited a variety of unexpected properties, ranging from antidiabetic and anti-obesity activities to effects useful to counteract cancer and neurodegeneration, which prompted its evaluation in several preclinical and clinical studies. In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure–activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors.

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The PTP1B selective inhibitor MSI-1436 mitigates Tunicamycin-induced ER stress in human hepatocarcinoma cell line through XBP1 splicing modulation

Cited by 3 publications

References 61 publications

The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses

The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses

Trodusquemine (MSI-1436) Restores Metabolic Flexibility and Mitochondrial Dynamics in Insulin-Resistant Equine Hepatic Progenitor Cells (HPCs)

Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine

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