p62-Nrf2 Regulatory Loop Mediates the Anti-Pulmonary Fibrosis Effect of Bergenin

Zeng, Qian; Zhou, Tingting; Zhao, Feiyan; Xiong, Dayan; He, Bin; Hua, Qingzhong; Ma, Lin; Deng, Lang; Sang, Xiaoxue; Xie, Weixi; Chen, Jia; Wang, Zun; Ren, Lu; Luo, Ziqiang; Huang, Xiaoting; Liu, Wei; Tang, Siyuan

doi:10.3390/antiox11020307

Cited by 16 publications

(8 citation statements)

References 56 publications

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“…Furthermore, the in vivo study employed with SQSTM1 cKO mice confirmed that SQSTM1 in tubular cells played a critical role in the protective effect of Cana on renal fibrosis. Notably, SQSTM1 can contribute to the regulation of fibrotic process via the vitamin D receptor or NRF2 pathway, which are independent autophagy programs ( 65 , 66 ). Thus, the role of SQSTM1 in regulating the protective effects of Cana in renal fibrosis may be either dependent or independent of the autophagy pathways.…”

Section: Discussionmentioning

confidence: 99%

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

Yang

Ling

et al. 2023

Front. Immunol.

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The dysregulation of autophagy contributes to renal fibrosis. N6-Methyladenosine (m6A) RNA modification is a critical mediator of autophagy. Our previous studies have reported that the disorder of the PPARα/fatty acid oxidation (FAO) axis in renal tubular cells is suppressed by STAT6, which is involved in the regulation of renal fibrotic processes. Here, we found that canagliflozin significantly upregulates SQSTM1/P62, promoting PPARα-mediated FAO by inducing autophagy-dependent STAT6 degradation both in TGF-β1-treated HK2 cells and in unilateral ureteral occlusion (UUO) and ischemia–reperfusion (I/R) renal fibrosis mouse models. Knockdown of P62/SQSTM1 led to the impairment autophagic flux and the dysregulation of the STAT6/PPARα axis, which was confirmed by SQSTM1/P62cKO mice with UUO treatment along with bioinformatics analysis. Furthermore, SQSTM1/P62 deficiency in renal tubular cells inhibited canagliflozin’s effects that prevent FAO disorder in renal tubular cells and renal fibrosis. Mechanistically, the level of m6A eraser FTO, which interacted with SQSTM1 mRNA, decreased in the renal tubular cells both in vitro and in vivo after canagliflozin administration. Decrease in FTO stabilized SQSTM1 mRNA, which induced autophagosome formation. Collectively, this study uncovered a previously unrecognized function of canagliflozin in FTO in the autophagy modulation through the regulation of SQSTM1 mRNA stability in the renal tubular STAT6/PPARα/FAO axis and renal fibrosis.

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Section: Discussionmentioning

confidence: 99%

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

Yang

Ling

et al. 2023

Front. Immunol.

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“…Nrf2 is the master activator for most of the antioxidant enzymes, and its expression was lower in the fibroblasts and myofibroblasts of patients with IPF [ 29 ]. Bergenin improve pulmonary fibrosis by inducing the activation of Nrf2 to relieve oxidative stress and reduce the deposition of the extracellular matrix [ 30 ]. Some studies indicated that CA showed good capability against oxidative stress [ 31 ], which protected cells from injury.…”

Section: Discussionmentioning

confidence: 99%

Calycosin Ameliorates Bleomycin-Induced Pulmonary Fibrosis via Suppressing Oxidative Stress, Apoptosis, and Enhancing Autophagy

Liu

Xiao-xu

Wan

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Calycosin (CA) is a flavonoid extracted from the root of Astragalus membranaceus and has antioxidant, anti-inflammation, and antiapoptosis properties. The objective of this study was to investigate the efficacy of CA in protecting against pulmonary fibrosis. CA (14 mg/kg) and SB216763 (20 mg/kg) were administrated to bleomycin-induced pulmonary fibrosis mice for 3 weeks. The results concluded that CA alleviated the inflammation and collagen deposition in pulmonary fibrosis. In addition, CA reduced MDA level, enhanced SOD and TAC activities, and increased the activity of the Nrf2/HO-1 pathway. CA also regulated the expressions of apoptosis-related proteins. Moreover, CA enhanced autophagy via upregulating LC3, beclin1, PINK1, and reducing p62. CA also increased expression of LAMP1 and TFEB, and inhibited the release of lysosome enzymes from ruptured lysosomes. These results provide new evidence that CA protects against pulmonary fibrosis through inhibiting oxidative stress and apoptosis. In addition, autophagy abnormality and lysosome dysfunction are restored by CA.

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“…NA1-115-7 is the latest type of selective Mcl-1 inhibitor that specifically induces apoptosis in Mcl-1-dependent tumor cells, and two hours of treatment is sufficient to trigger cell death [ 9 ]. Natural products with high bioactivity and low toxicity have been widely used in tumor therapy research [ 47 ]. Both Allyl isothiocyanate [ 48 ] and Pyrethrum extract [ 49 ] weere found to have a role in regulating Mcl-1 levels, but the exact mechanism remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Targeting Mcl-1 Degradation by Bergenin Inhibits Tumorigenesis of Colorectal Cancer Cells

Gan

Han

et al. 2023

Pharmaceuticals

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Myeloid leukemia 1 (Mcl-1) is frequently overexpressed in human malignancies and emerged as a promising drug target. In this study, we verified the inhibitory effect of bergenin on colorectal cancer cells both in vivo and in vitro. In an in vitro setting, bergenin significantly reduced the viability and colony formation and promoted apoptosis of CRC cells dose-dependently. Bergenin decreased the activity of Akt/GSK3β signaling and enhanced the interaction between FBW7 and Mcl-1, which eventually induced Mcl-1 ubiquitination and degradation. Using the HA-Ub K48R mutant, we demonstrated that bergenin promotes Mcl-1 K48-linked polyubiquitination and degradation. In vivo studies showed that bergenin significantly reduced tumor size and weight without toxicity to vital organs in mice. Overall, our results support the role of bergenin in inhibiting CRC cells via inducing Mcl-1 destruction, suggesting that targeting Mcl-1 ubiquitination could be an alternative strategy for antitumor therapy.

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p62-Nrf2 Regulatory Loop Mediates the Anti-Pulmonary Fibrosis Effect of Bergenin

Cited by 16 publications

References 56 publications

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

Calycosin Ameliorates Bleomycin-Induced Pulmonary Fibrosis via Suppressing Oxidative Stress, Apoptosis, and Enhancing Autophagy

Targeting Mcl-1 Degradation by Bergenin Inhibits Tumorigenesis of Colorectal Cancer Cells

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