Protein tyrosine phosphatase 1B regulates fibroblasts proliferation, motility and extracellular matrix synthesis via the MAPK/ERK signalling pathway in keloid

Liu, Qian; Wang, Qiang; Wei, Chuan‐Yuan; Wang, Lu; Yang, Yanwen; Deng, Xinyi; Liu, Jiaqi; Qi, Fazhi

doi:10.1111/exd.14443

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…Regarding molecular functions, these genes were mainly enriched in chemokine receptor binding, growth factor receptor binding, integrin binding, etc., which was consistent with previous studies [ 53 – 55 ]. KEGG analysis showed that 44 keloid-related immune genes were mainly enriched in the Jak-STAT signaling pathway, MAPK signaling pathway, TGF-β signaling pathway, and other related signaling pathways, consistent with previous studies [ 56 – 58 ]. These results suggest that 44 keloid-related immune genes may regulate these key signaling pathways during the development and progression of keloids, which needs to be further investigated.…”

Section: Discussionsupporting

confidence: 90%

Identification of novel immune-related signatures for keloid diagnosis and treatment: insights from integrated bulk RNA-seq and scRNA-seq analysis

Xiao,

Wang,

Chen

et al. 2024

Hum Genomics

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Background Keloid is a disease characterized by proliferation of fibrous tissue after the healing of skin tissue, which seriously affects the daily life of patients. However, the clinical treatment of keloids still has limitations, that is, it is not effective in controlling keloids, resulting in a high recurrence rate. Thus, it is urgent to identify new signatures to improve the diagnosis and treatment of keloids. Method Bulk RNA seq and scRNA seq data were downloaded from the GEO database. First, we used WGCNA and MEGENA to co-identify keloid/immune-related DEGs. Subsequently, we used three machine learning algorithms (Randomforest, SVM-RFE, and LASSO) to identify hub immune-related genes of keloid (KHIGs) and investigated the heterogeneous expression of KHIGs during fibroblast subpopulation differentiation using scRNA-seq. Finally, we used HE and Masson staining, quantitative reverse transcription-PCR, western blotting, immunohistochemical, and Immunofluorescent assay to investigate the dysregulated expression and the mechanism of retinoic acid in keloids. Results In the present study, we identified PTGFR, RBP5, and LIF as KHIGs and validated their diagnostic performance. Subsequently, we constructed a novel artificial neural network molecular diagnostic model based on the transcriptome pattern of KHIGs, which is expected to break through the current dilemma faced by molecular diagnosis of keloids in the clinic. Meanwhile, the constructed IG score can also effectively predict keloid risk, which provides a new strategy for keloid prevention. Additionally, we observed that KHIGs were also heterogeneously expressed in the constructed differentiation trajectories of fibroblast subtypes, which may affect the differentiation of fibroblast subtypes and thus lead to dysregulation of the immune microenvironment in keloids. Finally, we found that retinoic acid may treat or alleviate keloids by inhibiting RBP5 to differentiate pro-inflammatory fibroblasts (PIF) to mesenchymal fibroblasts (MF), which further reduces collagen secretion. Conclusion In summary, the present study provides novel immune signatures (PTGFR, RBP5, and LIF) for keloid diagnosis and treatment, and identifies retinoic acid as potential anti-keloid drugs. More importantly, we provide a new perspective for understanding the interactions between different fibroblast subtypes in keloids and the remodeling of their immune microenvironment.

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Section: Discussionsupporting

confidence: 90%

Identification of novel immune-related signatures for keloid diagnosis and treatment: insights from integrated bulk RNA-seq and scRNA-seq analysis

Xiao,

Wang,

Chen

et al. 2024

Hum Genomics

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“…Previous reports indicated that TIMP-1 suppression maybe associated with increased fbrillar collagen deposition and extensively fragmented elastic lamellae accumulation; in addition, TIMP-1 defciency was also correlated to increased tissue infammation evoking the importance of TIMP-1 in restricting extracellular matrix degradation and abnormal tissue scarring under pathological conditions [55]. PTP1B overexpression and/or overactivation has been previously reported to critically afect and downregulate the expression of both TIMP-1 and TIMP-2 in liver tissue and HSC [56,57], which correlate with our observed data, in which EMS-afected livers displayed suppressed TIMP-1 gene expression.…”

Section: Discussionmentioning

confidence: 96%

The PTP1B Inhibitor Trodusquemine (MSI-1436) Improves Glucose Uptake in Equine Metabolic Syndrome Affected Liver through Anti-Inflammatory and Antifibrotic Activity

Bourebaba,

Serwotka-Suszczak,

Bourebaba

et al. 2023

International Journal of Inflammation

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Background. Hyperactivation of protein tyrosine phosphatase (PTP1B) has been associated with several metabolic malfunctions ranging from insulin resistance, metaflammation, lipotoxicity, and hyperglycaemia. Liver metabolism failure has been proposed as a core element in underlying endocrine disorders through persistent inflammation and highly fibrotic phenotype. Methods. In this study, the outcomes of PTP1B inhibition using trodusquemine (MSI-1436) on key equine metabolic syndrome (EMS)-related alterations including inflammation, fibrosis, and glucose uptake have been analyzed in liver explants collected from EMS-affected horses using various analytical techniques, namely, flow cytometry, RT-qPCR, and Western blot. Results. PTP1B inhibition using trodusquemine resulted in decreased proinflammatory cytokines (IL-1β, TNF-α, and IL-6) release from liver and PBMC affected by EMS and regulated expression of major proinflammatory microRNAs such as miR-802 and miR-211. Moreover, MSI-1436 enhanced the anti-inflammatory profile of livers by elevating the expression of IL-10 and IL-4 and activating CD4+CD25+Foxp3+ regulatory T cells in treated PBMC. Similarly, the inhibitor attenuated fibrogenic pathways in the liver by downregulating TGF-β/NOX1/4 axis and associated MMP-2/9 overactivation. Interestingly, PTP1B inhibition ameliorated the expression of TIMP-1 and Smad7, both important antifibrotic mediators. Furthermore, application of MSI-1436 was found to augment the abundance of glycosylated Glut-2, which subsequently expanded the glucose absorption in the EMS liver, probably due to an enhanced Glut-2 stability and half-life onto the plasma cell membranes. Conclusion. Taken together, the presented data suggest that the PTP1B inhibition strategy and the use of its specific inhibitor MSI-1436 represents a promising option for the improvement of liver tissue integrity and homeostasis in the course of EMS and adds more insights for ongoing clinical trials for human MetS management.

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“…PTP1B is encoded by the protein tyrosine phosphatase non-receptor type 1 gene, which creates a 435 amino acid protein with a hydrophobic C-terminal sequence that targets PTP1B to the ER [31]. PTP1B was conventionally considered a routine treatment for diabetes [32] and obesity originally [33].…”

Section: Discussionmentioning

confidence: 99%

Role of Protein Tyrosine Phosphatase 1B Inhibitor in Early Brain Injury of Subarachnoid Hemorrhage in Mice

2023

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Clinically, early brain injury (EBI), which refers to the acute injuries to the whole brain in the phase of the first 72 h following subarachnoid hemorrhage (SAH), is intensely investigated to improve neurological and psychological function. Additionally, it will be meaningful to explore new therapeutic approaches for EBI treatment to improve the prognosis of patients with SAH. To investigate the underlying neuroprotection mechanism in vitro, the Protein tyrosine phosphatase 1B inhibitor (PTP1B-IN-1) was put in primary neurons induced by OxyHb to observe neuroapoptosis, neuroinflammation, and ER stress. Then, one hundred forty male mice were subjected to Experiment two and Experiment three. The mice in the SAH24h + PTP1B-IN-1 group were given an intraperitoneal injection of 5 mg/kg PTP1B-IN-1 30 min before anesthesia. SAH grade, neurological score, brain water content, Western blot, PCR, and Transmission Electron Microscopy (TEM) were performed to observe the underlying neuroprotection mechanism in vivo. Overall, this study suggests that PTP1B-IN-1 could ameliorate neuroapoptosis, neuroinflammation, and ER stress in vitro and in vivo by regulating the IRS-2/AKT signaling pathway, suggesting that PTP1B-IN-1 may be a candidate drug for the treatment of early brain injury after SAH.

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Protein tyrosine phosphatase 1B regulates fibroblasts proliferation, motility and extracellular matrix synthesis via the MAPK/ERK signalling pathway in keloid

Cited by 7 publications

References 36 publications

Identification of novel immune-related signatures for keloid diagnosis and treatment: insights from integrated bulk RNA-seq and scRNA-seq analysis

Identification of novel immune-related signatures for keloid diagnosis and treatment: insights from integrated bulk RNA-seq and scRNA-seq analysis

The PTP1B Inhibitor Trodusquemine (MSI-1436) Improves Glucose Uptake in Equine Metabolic Syndrome Affected Liver through Anti-Inflammatory and Antifibrotic Activity

Role of Protein Tyrosine Phosphatase 1B Inhibitor in Early Brain Injury of Subarachnoid Hemorrhage in Mice

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