MicroRNA-195-3p promotes hepatic stellate cell activation and liver fibrosis by suppressing PTEN expression

Wang, Ao; Bu, Fang-tian; Li, Juanjuan; Zhang, Yafei; Jia, Peng-cheng; You, Hongmei; Wang, Sha; Wu, Yuanyuan; Zhu, Sai; Huang, Cheng; Li, Jun

doi:10.1016/j.toxlet.2021.11.014

Cited by 15 publications

(7 citation statements)

References 44 publications

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“…MiR-21 downregulates PTEN expression by binding to its mRNA which inhibits translation and promotes PTEN mRNA degradation. Decreased PTEN expression is associated with the progression of liver, lung, and kidney fibrosis, and the extent of organ fibrosis is positively correlated with the degree of PTEN downregulation [64,65]. This connection is further evidenced by studies like the one showing exacerbated renal collagen production, ECM deposition, and myofibroblast differentiation in Angiotensin II (AngII)-induced hypertension in mice with myeloid PTEN deficiency.…”

Section: Discussionmentioning

confidence: 90%

Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance

Trivedi,

Bose,

Saha

et al. 2023

Cells

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Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.

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Section: Discussionmentioning

confidence: 90%

Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance

Trivedi,

Bose,

Saha

et al. 2023

Cells

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“…Arsenite modulates PTEN-seduced M2 polarization in macrophages through miR-21, which is tied up with HSCs stimulation [106] . Ascending levels of miR-195-3p quelled PTEN expression, a negative regulator of the PI3K/Akt/mTOR signal to LF, on chromosome 10, thereby promoting HSCs activation and proliferation [107] . MiR-1297, the target gene of PTEN, promotes the HSCs stimulation by the PTEN/PI3K/AKT pathway and accelerates LF progress [108] .…”

Section: Notch Signaling Pathway Acts On Hscs Through Other Signaling...mentioning

confidence: 99%

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

Zheng

Yang

Luo

et al. 2022

Preprint

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Liver fibrosis (LF) is a trauma repair process carried out by the liver in response to various acute and chronic liver injuries, featured by excessive proliferation as well as abnormal dismissal of extracellular matrix as the main pathological features, and its continuous development will deteriorate into cirrhosis, liver cancer as well as other illnesses. The occurrence of LF is closely related to Hepatic stellate cells (HSCs) stimulation, and intervention in HSCs proliferation is expected to reverse LF. Plant-based small molecule drugs have anti-LF effects, and their mechanisms of action are related to anti-inflammation, anti-oxidative stress, as well as inhibition of abnormal accumulation of extracellular matrix. Consequently, new agents for HSCs will be required to furnish a possible curative response. Small-molecule natural products might be attractive for LF therapy. That is because they not only have the effect against HSCs, but also have excellent qualities such as low toxic side effects and easy availability from the perspective of safety and cost. In this review, we provide an updated review of the signal transduction pathways involved in HSCs and small-molecule natural products targeting HSCs reported in the past 3 years at home and abroad, with the aim of providing new ideas for the development of plant-based small molecule drugs targeting HSCs to reverse LF.

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“…According to previous reports, repression of HSCs by epigenetic drug can reduce ECM deposition and attenuate liver fibrosis 5,6 . Although abnormal gene expressions involved in HSCs activation have been found in liver fibrosis, therapeutic methods for effective anti‐hepatic fibrosis are not enough 7 . Thus, it is necessary to identify underlying mechanisms of liver fibrosis and find more new methods for liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

LncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway attenuated ferroptosis and contributed to liver fibrosis

Li,

Zou,

Jin

et al. 2024

Environmental Toxicology

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Liver fibrosis is an invertible pathophysiologic process featured by excessive accumulation of extracellular matrix (ECM) which injures liver cells and activates hepatic stellate cells (HSCs). Besides, inducing ferroptosis in activated HSCs can alleviate liver fibrosis. LncRNAs modulate ferroptosis in activated HSCs and ECM deposition in liver fibrosis. However, the role of lncRNA FRMD6‐AS1 in liver fibrosis is not discovered. In this study, lncRNA FRMD6‐AS1 was dramatically up‐regulated in activated HSCs. Knockdown of FRMD6‐AS1 markedly increased iron ion, ROS and MDA levels, decreased GSH level, SLC7A11 and GPX4 protein expressions in activated HSCs. In addition, HSCs activation markers α‐SMA and COL1α1 expressions were up‐regulated in activated HSCs; knockdown of FRMD6‐AS1 markedly down‐regulated α‐SMA and COL1α1 expressions in HSCs. Besides, lncRNA FRMD6‐AS1 could interact with miR‐491‐5p, and negatively modulate miR‐491‐5p expression. USP13 was a target of miR‐491‐5p, and could be negatively modulated by miR‐491‐5p. Moreover, FRMD6‐AS1 knockdown increased iron ion and ROS levels, decreased SLC7A11 and GPX4 protein expressions, facilitated HSCs viability, and up‐regulated α‐SMA and COL1α1 expressions via miR‐491‐5p/USP13 pathway. Finally, FRMD6‐AS1 knockdown restored liver tissue structure and abrogated fibrosis in livers in a CCL4 liver fibrosis mouse model. Hence, lncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway repressed ferroptosis, promoted ECM deposition and facilitated liver fibrosis in vitro and in vivo models.

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MicroRNA-195-3p promotes hepatic stellate cell activation and liver fibrosis by suppressing PTEN expression

Cited by 15 publications

References 44 publications

Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance

Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

LncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway attenuated ferroptosis and contributed to liver fibrosis

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