Hyperactivation of Wnt/β-catenin and Jak/Stat3 pathways in human and zebrafish foetal growth restriction models: Implications for pharmacological rescue

Risato, Giovanni; Celeghin, Rudy; Casas, Raquel Brañas; Dinarello, Alberto; Zuppardo, Alessandro; Vettori, Andrea; Pilichou, Kalliopi; Thiene, Gaetano; Basso, Cristina; Argenton, Francesco; Visentin, Silvia; Cosmi, Erich; Tiso, Natascia; Beffagna, Giorgia

doi:10.3389/fcell.2022.943127

Cited by 7 publications

(4 citation statements)

References 72 publications

(90 reference statements)

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“…Zebrafish is an in vivo model in which the pathophysiological roles of HIF1α and JAK/STAT signalling have been extensively studied [ 9 , 34 , 38 – 46 ]. Thus, it appeared as a valid platform to analyze the STAT3-HIF1α crosstalk and the physiological implications of this interplay between transcription factors.…”

Section: Resultsmentioning

confidence: 99%

STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

et al. 2023

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STAT3 and HIF1α are two fundamental transcription factors involved in many merging processes, like angiogenesis, metabolism, and cell differentiation. Notably, under pathological conditions, the two factors have been shown to interact genetically, but both the molecular mechanisms underlying such interactions and their relevance under physiological conditions remain unclear. In mouse embryonic stem cells (ESCs) we manage to determine the specific subset of hypoxia-induced genes that need STAT3 to be properly transcribed and, among them, fundamental genes like Vegfa, Hk1, Hk2, Pfkp and Hilpda are worth mentioning. Unexpectedly, we also demonstrated that the absence of STAT3 does not affect the expression of Hif1α mRNA nor the stabilization of HIF1α protein, but the STAT3-driven regulation of the hypoxia-dependent subset of gene could rely on the physical interaction between STAT3 and HIF1α. To further elucidate the physiological roles of this STAT3 non-canonical nuclear activity, we used a CRISPR/Cas9 zebrafish stat3 knock-out line. Notably, hypoxia-related fluorescence of the hypoxia zebrafish reporter line (HRE:mCherry) cannot be induced when Stat3 is not active and, while Stat3 Y705 phosphorylation seems to have a pivotal role in this process, S727 does not affect the Stat3-dependent hypoxia response. Hypoxia is fundamental for vascularization, angiogenesis and immune cells mobilization; all processes that, surprisingly, cannot be induced by low oxygen levels when Stat3 is genetically ablated. All in all, here we report the specific STAT3/HIF1α-dependent subset of genes in vitro and, for the first time with an in vivo model, we determined some of the physiological roles of STAT3-hypoxia crosstalk.

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Section: Resultsmentioning

confidence: 99%

STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

et al. 2023

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“…We found that the Wnt/ β ‐catenin pathway was activated in IUGR suckling piglets, whereas B. subtilis supplementation made the activity of the Wnt/ β ‐catenin pathway return to normal level. On the basis of a previous study, hyperactivation of the Wnt/ β ‐catenin pathway appeared in human and zebrafish IUGR models 36 . There was a study reporting that Bacillus siamensis suppressed the expression of β ‐catenin in human embryonic kidney 293 cells 37 .…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of a previous study, hyperactivation of the Wnt/⊎-catenin pathway appeared in human and zebrafish IUGR models. 36 There was a study reporting that Bacillus siamensis suppressed the expression of ⊎-catenin in human embryonic kidney 293 cells. 37 These findings showed that the increased proliferation level of intestinal epithelial cells was attributed to the increased proliferation level of intestinal stem cells in IUGR suckling piglets.…”

Section: Discussionmentioning

confidence: 99%

Bacillus subtilis alleviates excessive apoptosis of intestinal epithelial cells in intrauterine growth restriction suckling piglets via the members of Bcl‐2 and caspase families

Xie,

Yun,

et al. 2024

J Sci Food Agric

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BackgroundThe intestine is a barrier resisting various stress responses. Intrauterine growth restriction (IUGR) can cause the damage of intestinal barrier via destroying the balance of intestinal epithelial cells' proliferation and apoptosis. Bacillus subtilis has been reported to regulate intestinal epithelial cells' proliferation and apoptosis. Thus, the purpose of the current study was to determine if B. subtilis could regulate intestinal epithelial cells' proliferation and apoptosis in intrauterine growth restriction suckling piglets.ResultsCompared with normal birth weight group, IUGR group showed greater mean optical density values of Ki‐67 positive cells in the ileal crypt (P < 0.05). IUGR resulted in higher ability of proliferation and apoptosis of intestinal epithelial cells, by up‐regulation of the mRNA or proteins expression of leucine rich repeat containing G protein coupled receptor 5, Caspase‐3, Caspase‐7, β‐catenin, cyclinD1, B‐cell lymphoma‐2 associated agonist of cell death, and BCL2 associated X (P < 0.05), and down‐regulation of the mRNA or protein expression of B‐cell lymphoma‐2 and B‐cell lymphoma‐2‐like 1 (P < 0.05). However, B. subtilis supplementation decreased the mRNA or proteins expression of leucine rich repeat containing G protein coupled receptor 5, SPARC related modular calcium binding 2, tumor necrosis factor receptor superfamily member 19, cyclinD1, Caspase‐7, β‐catenin, B‐cell lymphoma‐2 associated agonist of cell death, and Caspase‐3 (P < 0.05), and increased the mRNA expression of B‐cell lymphoma‐2 (P < 0.05).ConclusionIUGR led to excessive apoptosis of intestinal epithelial cells, which induced compensatory proliferation. However, B. subtilis treatment prevented intestinal epithelial cells of IUGR suckling piglets from excessive apoptosis.This article is protected by copyright. All rights reserved.

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“…Multiple compound or heterozygous mutations were proven to entail a more severe prognosis [55]. The disease was reproduced in transgenic mice [56,57] (Figure 24) and in zebrafish [58][59][60]. However, electrical instability was found in the absence of a pathological substrate [61].…”

Section: Arrhythmogenic Cardiomyopathy: a Genetically Determined Hear...mentioning

confidence: 99%

Desmosomal Arrhythmogenic Cardiomyopathy: The Story Telling of a Genetically Determined Heart Muscle Disease

et al. 2023

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The history of arrhythmogenic cardiomyopathy (AC) as a genetically determined desmosomal disease started since the original discovery by Lancisi in a four-generation family, published in 1728. Contemporary history at the University of Padua started with Dalla Volta, who haemodynamically investigated patients with “auricularization” of the right ventricle, and with Nava, who confirmed familiarity. The contemporary knowledge advances consisted of (a) AC as a heart muscle disease with peculiar electrical instability of the right ventricle; (b) the finding of pathological substrates, in keeping with a myocardial dystrophy; (c) the inclusion of AC in the cardiomyopathies classification; (d) AC as the main cause of sudden death in athletes; (e) the discovery of the culprit genes coding proteins of the intercalated disc (desmosome); (f) progression in clinical diagnosis with specific ECG abnormalities, angiocardiography, endomyocardial biopsy, 2D echocardiography, electron anatomic mapping and cardiac magnetic resonance; (g) the discovery of left ventricular AC; (h) prevention of SCD with the invention and application of the lifesaving implantable cardioverter defibrillator and external defibrillator scattered in public places and playgrounds as well as the ineligibility for competitive sport activity for AC patients; (i) genetic screening of the proband family to unmask asymptomatic carriers. Nondesmosomal ACs, with a phenotype overlapping desmosomal AC, are also treated, including genetics: Transmembrane protein 43, SCN5A, Desmin, Phospholamban, Lamin A/C, Filamin C, Cadherin 2, Tight junction protein 1.

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Hyperactivation of Wnt/β-catenin and Jak/Stat3 pathways in human and zebrafish foetal growth restriction models: Implications for pharmacological rescue

Cited by 7 publications

References 72 publications

STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

Bacillus subtilis alleviates excessive apoptosis of intestinal epithelial cells in intrauterine growth restriction suckling piglets via the members of Bcl‐2 and caspase families

Desmosomal Arrhythmogenic Cardiomyopathy: The Story Telling of a Genetically Determined Heart Muscle Disease

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