Lobeglitazone attenuates fibrosis in corneal fibroblasts by interrupting TGF-beta-mediated Smad signaling

Nuwormegbe, Selikem Abla; Park, Na-Young; Kim, Sun Woong

doi:10.1007/s00417-021-05370-2

Cited by 6 publications

(5 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One study previously demonstrated that murine corneal fibrosis was regulated in part by TGF-β1/SMAD2 activation [ 99 ]. Nuwormegbe et al, 2021 [ 100 ], revealed that TGF-β1-induced fibrosis was suppressed via SMAD3 signal inhibition in the human cornea. This finding was substantiated by another group, which reported that SMAD3 overexpression enhanced TGF-β1-induced fibroblasts to myofibroblast differentiation in HCFs [ 101 ].…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea

Nicholas,

Basu,

Mandal

et al. 2024

IJMS

View full text Add to dashboard Cite

Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-β) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-β and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-β1 (β1), 1 μM sphingosine-1-phosphate (S1P), and 5 μM Sphingosine kinase inhibitor 2 (I2). Five groups were tested: (1) control (no treatment); rescue groups; (2) β1/S1P; (3) β1/I2; prevention groups; (4) S1P/β1; and (5) I2/β1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-β signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-β binding proteins (LTBPs), TGF-β receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I2 prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I2 prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I2 treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-β receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I2 as a novel therapy for corneal fibrosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea

Nicholas,

Basu,

Mandal

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

“…Lobeglitazone also inhibited the transcription of nicotinamide adenine dinucleotide phosphate oxidase (Nox) 4 and the production of reactive oxygen species (ROS) produced by TGF-β1. The results concluded that lobeglitazone has a beneficial therapeutic effect on corneal scarring [20].…”

Section: Corneal Fibroblastsmentioning

confidence: 91%

Lobeglitazone and Its Therapeutic Benefits: A Review

2023

Cureus

View full text Add to dashboard Cite

Lobeglitazone is a newer oral hypoglycemic agent that has been tested in type 2 diabetes mellitus (T2DM). We aim to conduct a narrative review to find out the therapeutic benefits of lobeglitazone in patients with T2DM. We scientifically searched the electronic database of PubMed from inception until September 12, 2023, using Medical Subject Heading (MeSH) keywords. Additionally, we searched for pre-clinical trials related to lobeglitazone. We retrieved all available results of phase 1 to phase 3 studies of lobeglitazone in T2DM. Subsequently, we reviewed the results narratively. Three double-blind, randomized, placebocontrolled studies and a phase 3 trial of lobeglitazone showed that 0.5 mg daily dose exhibits effective therapeutic activity in glycemic, lipid, and hepatic control, and is also used as a secondary treatment in nonalcoholic fatty liver disease. Lobeglitazone exhibits as much antidiabetic activity as other thiazolidinediones such as pioglitazone and rosiglitazone. Side effects of lobeglitazone included peripheral edema, weight gain, and bone mineral density, which did not require hospitalization for these effects. This article highlights the pharmacological, pre-clinical, clinical, and safety pharmacology of novel thiazolidinedione lobeglitazone.

show abstract

“…Erlotinib and gefitinib are examples of TKIs that have been studied for their effects on EGFR and their interaction with TGF-β signaling in various cellular contexts [182]. Their potential in modulating corneal fibrosis remains an area of active research [183][184][185]. Dual inhibitors targeting both the TGF-β and EGFR pathways simultaneously represent another exciting avenue [186,187].…”

Section: Therapeutic Targets For Tgf-β Signaling Based Therapiesmentioning

confidence: 99%

TGF-β-Based Therapies for Treating Ocular Surface Disorders

Ogata,

Verma,

Coulson-Thomas

et al. 2024

Cells

View full text Add to dashboard Cite

The cornea is continuously exposed to injuries, ranging from minor scratches to deep traumas. An effective healing mechanism is crucial for the cornea to restore its structure and function following major and minor insults. Transforming Growth Factor-Beta (TGF-β), a versatile signaling molecule that coordinates various cell responses, has a central role in corneal wound healing. Upon corneal injury, TGF-β is rapidly released into the extracellular environment, triggering cell migration and proliferation, the differentiation of keratocytes into myofibroblasts, and the initiation of the repair process. TGF-β-mediated processes are essential for wound closure; however, excessive levels of TGF-β can lead to fibrosis and scarring, causing impaired vision. Three primary isoforms of TGF-β exist—TGF-β1, TGF-β2, and TGF-β3. Although TGF-β isoforms share many structural and functional similarities, they present distinct roles in corneal regeneration, which adds an additional layer of complexity to understand the role of TGF-β in corneal wound healing. Further, aberrant TGF-β activity has been linked to various corneal pathologies, such as scarring and Peter’s Anomaly. Thus, understanding the molecular and cellular mechanisms by which TGF-β1-3 regulate corneal wound healing will enable the development of potential therapeutic interventions targeting the key molecule in this process. Herein, we summarize the multifaceted roles of TGF-β in corneal wound healing, dissecting its mechanisms of action and interactions with other molecules, and outline its role in corneal pathogenesis.

show abstract

Lobeglitazone attenuates fibrosis in corneal fibroblasts by interrupting TGF-beta-mediated Smad signaling

Cited by 6 publications

References 51 publications

Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea

Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea

Lobeglitazone and Its Therapeutic Benefits: A Review

TGF-β-Based Therapies for Treating Ocular Surface Disorders

Contact Info

Product

Resources

About