Suppression of STAT3 signaling promotes cellular reprogramming into insulin-producing cells induced by defined transcription factors

Miura, Masaki; Miyatsuka, Takeshi; Katahira, Takehiro; Sasaki, Shugo; Suzuki, Luka; Himuro, Miwa; Nishida, Yuya; Fujitani, Yoshio; Matsuoka, Taka‐aki; Watada, Hirotaka

doi:10.1016/j.ebiom.2018.09.035

Cited by 11 publications

(15 citation statements)

References 32 publications

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“…STAT3 signalling has been demonstrated to be essential for human pancreas development and endocrine differentiation (17). We observed almost complete STAT3 inactivation in the first stages of stem cells reprogrammed into β-like cells, in line with published data (64). STAT3 is a target of PDX1 (51), binds to the Neurog3 promoter (65) and is involved in the activation of NEUROG3 in differentiating human embryonic stem cells (66).…”

Section: Discussionsupporting

confidence: 89%

STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and Its Deficiency Induces Glucose Intolerance in Obesity

et al. 2021

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Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in βcells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese and diabetic subjects. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

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Section: Discussionsupporting

confidence: 89%

STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and Its Deficiency Induces Glucose Intolerance in Obesity

et al. 2021

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“…16 Signal transducer and activator of transcription (STAT3) has been proved to be involved in cell differentiation of the nervous system. 17 The STAT3 signaling pathway has been identified as a critical participant in neuroinflammation, and its activation has been found in the spinal dorsal horn of both spinal cord injury and neuropathic pain models. 18 The current study has shown that miR-7a could affect neuropathic pain development via the STAT3 signaling pathway by regulating NEFL based on the rat model of SNL, which offers a better understanding for the underlying molecular mechanisms in neuropathic pain progression.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligationviathe neurofilament light polypeptide-dependent signal transducer and activator of transcription signaling pathway

et al. 2019

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Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs have been recently linked to many diseases, including neuropathic pain. However, the role of miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation rat model. After establishment of spinal nerve ligation rat models, rats were infected with adeno-associated virus-neurofilament light polypeptide, adeno-associated virus-miR-7a or treated with metformin. The paw withdrawal threshold and paw withdrawal latency were assessed afterward, and the expression of miR-7a and neurofilament light polypeptide as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of neurofilament light polypeptide on neuropathic pain was detected using plasmid overexpressing neurofilament light polypeptide. Spinal nerve ligation rat model exhibited upregulation of neurofilament light polypeptide but downregulation of miR-7a. In addition, neurofilament light polypeptide accumulation or miR-7a inhibition decreased paw withdrawal threshold and paw withdrawal latency. Then, neurofilament light polypeptide accumulation or miR-7a inhibition was observed to increase the phosphorylation level of signal transducer and activator of transcription. miR-7a was found to directly target neurofilament light polypeptide and downregulate neurofilament light polypeptide. In addition, inhibiting the signal transducer and activator of transcription signaling pathway was also revealed to increase paw withdrawal threshold and paw withdrawal latency. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the signal transducer and activator of transcription signaling pathway by repressing neurofilament light polypeptide. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.

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“…STAT3 has a role in cell differentiation in various systems including immune and endocrine systems. However recent studies showed that STAT3 suppression together with Pdx1 expression increased the number of β-cells ( Miura et al, 2018 ). Caffeic acid (TP15), t -ferulic acid (TP18), 4α-[(β-D-glucopyranosyloxy)methyl]-5α-(2-hydroxyethyl)-3-methylcyclopent-2-en-1-one (TP22), 5α-[2-(β-D-glucopyranosyloxy)ethyl]-4α-hydroxymethyl-3-methylcyclopent-2-en-1-one (TP23), and teupolin VIII (TP29) showed interaction with the target STAT3 ( Table S5 ).…”

Section: Discussionmentioning

confidence: 99%

Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L. in the treatment of type 2 diabetes mellitus

Kutluay

Diker

2020

PeerJ

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Background Type 2 diabetes mellitus (T2DM) is a metabolic disease affecting a huge population worldwide. Teucrium polium L. has been used as a folk medicine for the treatment of T2DM in Anatolia, Turkey. The antihyperglycemic effect of the plant was reported previously. However, there was no detailed study on the underlying molecular mechanisms. In this study, we generated a research plan to clarify the active constituents of the extract and uncover the molecular mechanisms using network pharmacology analysis. Methods For this purpose, we composed a dataset of 126 compounds for the phytochemical profile of the aerial parts of T. polium. Drug-likeness of the compounds was evaluated, and 52 compounds were selected for further investigation. A total of 252 T2DM related targets hit by selected compounds were subjected to DAVID database. Results The KEGG pathway analysis showed enrichment for the TNF signaling pathway, insulin resistance, the HIF-1 signaling pathway, apoptosis, the PI3K-AKT signaling pathway, the FOXO signaling pathway, the insulin signaling pathway, and type 2 diabetes mellitus which are related to T2DM . AKT1, IL6, STAT3, TP53, INS, and VEGFA were found to be key targets in protein-protein interaction. Besides these key targets, with this study the role of GSK3β, GLUT4, and PDX1 were also discussed through literature and considered as important targets in the antidiabetic effect of T. polium. Various compounds of T. polium were shown to interact with the key targets activating PI3K-AKT and insulin signaling pathways. Conclusions According to these findings, mainly phenolic compounds were identified as the active components and IRS1/PI3K/AKT signaling and insulin resistance were identified as the main pathways regulated by T. polium. This study reveals the relationship of the compounds in T. polium with the targets of T2DM in human. Our findings suggested the use of T. polium as an effective herbal drug in the treatment of T2DM and provides new insights for further research on the antidiabetic effect of T. polium.

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Suppression of STAT3 signaling promotes cellular reprogramming into insulin-producing cells induced by defined transcription factors

Cited by 11 publications

References 32 publications

STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and Its Deficiency Induces Glucose Intolerance in Obesity

STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and Its Deficiency Induces Glucose Intolerance in Obesity

MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligationviathe neurofilament light polypeptide-dependent signal transducer and activator of transcription signaling pathway

Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L. in the treatment of type 2 diabetes mellitus

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